February 18-21, 2015; Paris, France - Full Report – Draft

Executive Highlights

In this report, we bring you our full coverage of the 8th International Conference on Advanced Technologies & Treatments for Diabetes (ATTD 2015) held in Paris, France from February 18-21. The profile of this conference has risen in a big way in recent years and 2015 was no exception – the meeting grew a robust 25% from ~2,000 attendees in 2014, welcoming 2,542 attendees from 90 countries to the City of Lights. It’s pretty amazing to recall how much this conference has grown (in significance and size) since the ~400 attendees at the inaugural meeting in 2008. We are already looking forward to next year – February 3-6 in Milan, Italy – when we hear and see so much more on what’s happening in technology.

This year’s ATTD had a clear focus on the artificial pancreas, with a slew of at-home studies reporting data and perspective on overnight vs. 24-hour use. Unexpectedly, Dr. Moshe Phillip (Schneider Children's Medical Center, Petah Tikvah, Israel) shared that the DREAM Consortium received a CE Mark for its overnight MD-Logic closed-loop algorithm (recently licensed by Medtronic), the first to receive regulatory approval in the world. We also heard updates on ambitious home studies taking place at Cambridge and the transatlantic DiAs consortium. More broadly speaking, it was exciting to see the dialogue shifting from the research setting (e.g., efficacy and safety concerns) to the real-world challenges of closing the loop – an entire workshop was even devoted to the psychosocial aspects of the artificial pancreas, providing a strong reminder of the importance of human factors design as the field moves toward this new paradigm in treatment.

In new devices, Medtronic headlined the conference with new clinical and user evaluation data on the recently launched MiniMed 640G/Enlite Enhanced system with SmartGuard (predictive low glucose suspend). We also got a glimpse into the future with early data from a camp study of the MiniMed 670G/Enlite 3 hybrid closed loop system (patients still bolus for meals) and a seven-day study of the next-gen Harmony CGM. Meanwhile, Abbott’s standing-room-only corporate symposium on FreeStyle Libre was also a highlight – European clinicians shared lots of real-world enthusiasm on the 14-day, factory-calibrated sensor replacement for fingersticks. First-time, encouraging data on BD’s new infusion set was also a major highlight, and we look forward to an expected FDA clearance this summer and launch this year.  

On the drug front, a phase 3 study (n=75 adults) suggested Locemia’s exciting intranasal, needle-free glucagon powder for severe hypoglycemia was non-inferior to standard intramuscular glucagon injection. Phase 2a pump data on Xeris’ G-Pump glucagon found similarity, though not exact therapeutic equivalence to Novo Nordisk’s GlucaGen. In new insulins, we heard a positive perspective on Afrezza’s clinical profile from Drs. Eric Zijlstra and Tim Heise (Profil, Neuss, Germany), while a CGM study on Sanofi’s Toujeo (insulin glargine U300) highlighted the formulation’s PK stability vs. Lantus.

Below, please find our full coverage of ATTD 2015, opening with our themes and followed by five categories of reporting: (i) Artificial Pancreas; (ii) Glucose Monitoring; (iii) Insulin Delivery; (iv) Additional Topics; and (v) Exhibit Hall.

Themes

New Devices

• ATTD 2015 brought fresh perspective on newly commercialized devices from Abbott (FreeStyle Libre) and Medtronic (MiniMed 640G). We heard plenty of real-world perspective and tremendous enthusiasm for Abbott’s new 14-day factory calibrated sensor, which had been on the European market for just five months (as of February). Meanwhile, Medtronic’s MiniMed 640G (launched in January) had its coming-out party at ATTD, including new clinical data and our first test drive of the system’s user interface.
  
  • The corporate symposium on Abbott’s FreeStyle Libre was so packed with several hundred people that organizers had to leave the auditorium doors open to handle the overflow. There was a lot of enthusiasm in Q&A about how this is being used in the real world, and how much demand there is. Said Dr. Iain Cranston, “Half my patients have not done a fingerstick in two months. They come to rely on Libre.” Indeed, there is still capacity constraint on the manufacturing front, which is probably only adding to the enthusiasm – in February, all current customers were being served, but were only being sent two sensors (one month’s worth) at one time. [See the most recent update from Abbott’s 1Q15 call.] The corporate symposium also shared new encouraging hypoglycemia and YSI accuracy data from the product’s CE Mark trial – the 14-day factory calibration is the real deal, with an impressive overall MARD of 11.8% vs. YSI and an MAD of 9.5 mg/dl vs. YSI in hypoglycemia (51-80 mg/dl). Combined with the form factor and initial strong reception, FreeStyle Libre could be transformational for many clinicians and patients; therapy changes can be much easier with Libre, as can being a successful doctor.
  • Medtronic’s MiniMed 640G – newly launched in Europe and Australia – had a major presence in several corporate symposiums and the ATTD exhibit hall. Dr. Tadej Battelino presented strong clinical data on the new pump platform with predictive low glucose management (“SmartGuard”) – use of the new feature in the 100-patient, two-week SportGuard RCT resulted in a 41% reduction in hypoglycemia events <65 mg/dl (p=0.02). Notably, a six-month study (n=150) is ongoing in Australia (Dr. Tim Jones) and a six-week study (n=30) is starting in Germany (Dr. Thomas Danne). Meanwhile, Dr. Pratik Choudhary (King’s College London, UK) led a standing-room only workshop on the new system, including a hands-on demo and data from a 40-patient user evaluation study. The hypoglycemia prevention data was similarly strong, and the Enlite Enhanced sensor (Enlite 2) came in with an improved MARD of 9.8% vs. fingersticks. Some of the patient quotes were quite illuminating: “Fantastic piece of technology – life changing”; “Felt confident exercising [for the] first time in a long time”; “Remarkably user friendly”; and “...worked well at preventing low. Silent mode was great – it does its thing in the background.” Our first-time demo of the pump in the workshop and exhibit hall left us equally impressed with the new design, menus, and highly customizable SmartGuard preferences. As a reminder, the pivotal study of the MiniMed 640G is ongoing in the US, and Medtronic expects to submit the PMA to the FDA “later this calendar year” (ambitiously, a US launch is slated by April 2016, per JPM 2015).
• ATTD is increasingly becoming a key venue for new data, and we heard notable orals on Locemia’s intranasal glucagon, BD’s new infusion set, and Medtronic’s MiniMed 670G (hybrid closed loop) and Harmony CGM sensor.
  
  • Locemia: A phase 3 study (n=75 adults) suggested Locemia’s exciting intranasal, needle-free glucagon powder for severe hypoglycemia was non-inferior to standard intramuscular glucagon injection. This oral also provided a first look at the dramatically improved, single-button push delivery of the Locemia rescue device (see a picture on Twitter here). The team is doing other studies, including a usability study (n=200), and we assume a launch could happen as early as late 2016 or early 2017 (if regulatory goes well).
  • BD: A pilot study compared BD’s new infusion set to Medtronic’s Quick-set in 25 healthy participants. The BD set reduced flow interruptions by 77%-82% and occlusion events (which included occlusion alarms) by 77-79% vs. the Quick-set. The set has been submitted to the FDA, and BD is hoping for clearance by this summer. Dr. Larry Hirsch said that the new set will be compatible with Medtronic Paradigm and Luer lock reservoirs (i.e., Animas, Roche, Tandem), a huge win for patients. Additional studies with HCP insertion and patient self-insertion are underway/have been submitted for presentation.
  • Medtronic (MiniMed 670G): A camp study compared the MiniMed 670G/Enlite 3 hybrid closed loop system (patients still bolus for meals) to threshold suspend with the MiniMed 530G. Surprisingly, there were no statistically significant differences in any of the glycemic parameters between the groups, in part due to remarkably excellent control in the 530G group (likely reflective of camp care) and a conservatively tuned 670G algorithm. The overnight control with the 670G was “excellent.” We saw the integrated system for the first time, which looks very seamless and low burden. The 670G algorithm is understandably a work in progress at this point, but Medtronic is clearly moving quickly – per JPM 2015, the hope is to launch this device by April 2017 in the US. Dr. Fran Kaufman shared that a three-month study to evaluate the 670G’s safety might support approval in the US.
  • Medtronic (Harmony CGM sensor): A seven-day study evaluated the company’s fifth-generation Harmony sensor in 15 adult type 1s. Overall MARD was 9% vs. YSI during meal tests and 10% vs. the study meter for the entire duration of the trial (~3,000 evaluation points). The redundant electrochemical sensor weights the signals from two sensors differently in case one is determined to be off-target.

Closing the Loop

• Entering ATTD 2015, one of the biggest questions in diabetes technology was how academic closed-loop systems would translate into commercial products – that question remained top of mind following Dr. Moshe Phillip's (Schneider Children's Medical Center, Petah Tikvah, Israel) announcement that the DREAM consortium had received a CE Mark for its overnight MD-Logic closed-loop algorithm. The group established a new company, DreaMed Diabetes, for the purpose of commercialization; Medtronic subsequently licensed the algorithm following the conference. We believe licensing is an attractive option for academic groups across the board, as it puts technology in the hands of industry members (pump and sensor companies) with the business and regulatory experience and financial resources to deliver products at scale. We also learned about UVa’s regulatory and commercialization plans for DiAs from Dr. Boris Kovatchev (UVA, Charlottesville, VA). The team met with the FDA on February 5 and received notably positive feedback on two fronts: (i) a closed-loop control algorithm does not need to reside on an insulin pump – it can reside on an outboard device, such as a smartphone or even a smartwatch; and (ii) academic trials can be counted for product approval. As we understand it, the UVA team does not intend to commercialize the DiAs system alone; the researchers will invite industry partners (i.e., pump and sensor companies) to bring it to market. The goal is to build a near-commercial system for one more large trial to support regulatory approval, hopefully through the NIH’s $20 million call for outpatient artificial pancreas studies. The bigger question for UVA – and other academic groups pursuing partnerships – will be getting the right deal terms and incentives aligned so that multiple companies can work together to get a closed-loop system approved (e.g., Dexcom CGM + another company’s pump).
• In contrast to last year’s focus on overnight systems, full 24-hour closed-loop was the focus of multiple talks at ATTD 2015. Speakers widely acknowledged that overnight systems face fewer challenges (such as meals, exercise, and stress) – however, the overwhelming message was that day+night control not only stands to reduce the effort and burden of managing diabetes, but can also be safe and effective in a hybrid closed loop format. We saw new data from the DREAM Consortium comparing fully closed-loop control over four days+nights compared to sensor-augmented pump therapy. Average glucose in the closed-loop arm was 144 mg/dl, with 68% of the time spent in range (70-180 mg/dl), while in the SAP arm, average glucose was 159 mg/dl, with 58% of time spent in range. Dr. Boris Kovatchev (UVA, Charlottesville, VA) summarized similar success for UVA’s DiAs system in fully closed-loop mode; he presented a meta-analysis of 62,173 hours of DiAs use from 18 completed and ongoing studies (n=302). During 24-hour closed-loop control, average blood glucose dropped slightly (148 vs. 154 mg/dl on open loop time), while time in range (70-180 mg/dl) improved to 73% vs. 66% on open loop. Ultimately, we feel that the jury is still out on the relative benefits/drawbacks of fully closed-loop (lower burden, daytime hypo/hyperglycemia minimization, more challenges, higher patient expectations) vs. overnight closed-loop alone (less risk, outstanding control, regulatory questions, lower patient expectations). In any case, it is positive to see how far closed-loop work has progressed – as opposed to ATTD 2014, day+night studies are not the exception, but have become the norm in the field. This is exciting to be sure!
  
  • Another big question on the 24-hour closed-loop front concerns the benefit (incremental vs. significant?) of these systems vs. nighttime control alone. We heard compelling perspective from Dr. Roman Hovorka (University of Cambridge, UK), who summarized his team’s seven-day 24-hour home studies by emphasizing that most of the improvement came during the night – “The night is the place where closed-loop can do best.” We would agree that improvement is likely for most people at night, that nighttime is likely responsible for better days, and that there is likely to be less perceived hassle and lower patient expectations (i.e., it’s hard for a patient to say, “I could do better than this!” in the overnight period). However, there is some nuance to the debate as well. For instance, interpreting the findings of day+night closed-loop vs. usual care can be tricky, as pilot study control groups often achieve control that is not representative of the general population. This point was echoed by JDRF’s Dr. Aaron Kowalski, who reminded us that control groups do much better than their baseline A1cs would suggest. We hope this translates to better closed-loop performance in real-world settings, and a larger delta between open- and closed-loop in the overnight vs. 24-hour periods. The debate also begs an even bigger question: are the patients currently in closed-loop trials (diligent, motivated, fairly well-controlled) those who stand to benefit the most from early 24-hour hybrid closed loop systems?
• The real-world challenges of closing the loop, especially on the psychosocial side, emerged as another theme at ATTD 2015. Multiple speakers spoke to the importance of considering the design elements that will maximize benefit, assure safety, and manage sky-high patient expectations. These ideas have historically been understudied, and we were intrigued by the suggestion that behavioral endpoints should have a place in future clinical trials. Dr. Katharine Barnard (University of Southampton, Southampton, UK) advocated for psychosocial measures as the primary endpoints in some studies, suggesting that payers acceptance of A1c alone is hurting the field – after all, patients have to use a technology for it to be effective. Dr. Lutz Heinemann (Science & Co., Düsseldorf, Germany) also spoke on this point, reminding us that not all patients will be excited to use the artificial pancreas when it arrives on the market. He pointed to CGM as an example of a technology that was initially heralded as a “must-have,” but which is still not used by close to a majority of diabetes patients. With closed-loop in particular, the expectations are high, and we hope that the minor burdens in Gen 1 devices (e.g., announcement of meals and exercise, connectivity, higher device burden, early user interfaces) will be communicated and managed upfront. As Dr. Kowalski explained, “Insulin does not work fast enough yet to have a fully automated system. If we set the wrong expectations, we’re doomed to failure.” [We note that the bionic pancreas team has shown roughly similar glucose control between meal announcement and no-meal announcement, suggesting a fully automated system may be possible with glucagon.]
  
  • Unquestionably, setting patient expectations will be key for the field moving forward. While closed-loop will be a welcome prospect for many, the notion of taking diabetes management out of patient hands entirely may be anxiety-inducing for others. Speakers noted that we cannot expect to hand a patient an artificial pancreas and expect them to trust the system; confidence has to be built over time (a view emphasized in Dr. Pratik Choudhary’s presentation of MiniMed 640G user evaluation data). In addition, we would point out that even when the field gets to fully closed-loop, these systems may not work for everyone. Identifying patients that are optimal for certain systems (overnight vs. fully closed-loop) poses yet another opportunity and challenge that will need to be addressed.

Insulin Delivery

• This year’s ATTD featured a bigger focus on type 2 diabetes, especially the results of Medtronic’s OpT2mise trial (pumps vs. MDI in type 2). A key take-home message was that pump therapy likely does not require the same level of complexity in type 2 diabetes as it does in type 1. Dr. Ohad Cohen (Sheba Medical Center, Tel Hashomer, Israel) drove this point home during a Medtronic workshop, stressing that while it may be counterintuitive for clinicians, a single basal rate and fixed bolus doses will suffice for most obese, insulin resistant patients with type 2 diabetes. In a similar vein, we saw positive results (A1c reductions of 1.8% from a baseline of 8.9%) from a pilot study of CeQur’s PaQ insulin delivery device in type 2 diabetes, suggesting that simpler devices without dose adjustment capability may be sufficient (and more approachable) for those with type 2. While the OpT2mise results lend more clinical credibility to pump therapy as an option for type 2 diabetes, we heard many remaining unanswered questions. Cost and hassle factor (for patients and providers) look to be two of the biggest hurdles to overcome. It remains unclear what level of cost-effectiveness payers would expect and how it would be measured, though Mr. Ole Henriksen’s (Last Mile P/S, Copenhagen, Denmark) promising analysis predicted that cost-effectiveness can potentially be achieved at under 10 euros per day (at least in the type of population enrolled in OpT2mise). In addition, speakers including Dr. Irl Hirsch (University of Washington, Seattle, WA) raised questions about the feasibility of implementing pump therapy for type 2 diabetes on a large scale, particularly for primary care providers.
  
  • The emphasis on improved insulin therapy for patients with poorly controlled type 2 diabetes stands in contrast to speakers at other conferences, who suggest moving away from insulin. For example, at Obesity Week 2014, speakers including Dr. Timothy Garvey (University of Alabama, Birmingham, AL) suggested that addressing obesity needs to be a greater priority with these patients and that adding more diabetes medications (particularly those that lead to weight gain) is unlikely to be effective. At ACC as well, the implicit assumption for most speakers seemed to be that avoiding insulin in this population should be a priority, and the majority of diabetes-related talks focused almost entirely on non-insulin therapies. Food for thought (and a potentially interesting debate topic at a future conference!). As with most topics in diabetes, this is likely not an either/or question, and we are glad to see pump therapy emerging as another tool in the toolbox for type 2 diabetes.

Additional Topics

• Commentary and data on new insulins and glucagon formulations at ATTD was overall quite positive. Locemia’s phase 3 study for its intranasal needle-free glucagon powder achieved non-inferiority vs. intramuscular reconstituted and injected glucagon. It is hard to understate the importance of simplifying glucagon kits for both patients and their families/friends/caretakers, and Locemia’s intranasal pump (similar to a spray for a cold) should be able to do just that – see the device comparison here. Phase 2 data on Xeris’ G-Pump liquid-stable glucagon formulation for pumps also demonstrated sufficient comparability to reconstituted glucagon; the primary relevance for this Xeris project is for the closed loop (MGH/BU Bionic Pancreas). Meanwhile, we heard a vote of confidence in Sanofi and MannKind’s inhaled insulin Afrezza from Dr. Eric Zijlstra (Profil, Neuss, Germany), who really believes in Afrezza’s hypoglycemia benefit and sees potential relevance for the artificial pancreas from Afrezza’s strikingly fast onset of action. Turning to basal insulin, in a phase 2 study on Sanofi’s recently-launched Toujeo (insulin glargine U300), CGM was able to demonstrate more of Toujeo’s benefits vs. Lantus (insulin glargine U100) by showing improvements in glycemic variability, which A1c alone simply cannot show. There is great potential for greater use of CGM in the clinical development of new drugs, especially given increasingly marginal incremental A1c improvements in areas like insulin. As a counterpoint to the general drug-related optimism at ATTD, Dr. Tim Heise offered a few words of caution on oral insulin. He characterized clinical data on oral insulin so far as fairly lackluster, with low bioavailability and inter-patient variability serving as major challenges (although as with better glucagon, the convenience here would be amazing from a patient perspective).
• A thematic backdrop during the entire meeting was the challenge for diabetes technology from a regulatory and reimbursement perspective. Medicare and Germany’s IQWiG have not smiled upon CGM, but Dr. Thomas Danne (Diabetes Center for Children and Adolescents, Hannover, Germany) noted in a presentation that patient advocacy represents a powerful force against stubborn government agencies. Specifically, he cited a German protest to preserve access to rapid-acting insulin analogs for children and argued that patients should be allowed a role in making decision on reimbursement. Part of the onus is on the research field, as the evidence base for CGM’s cost effectiveness and positive impact on psychosocial factors is not yet as strong and persuasive as it could be. Many remarks from a speaker from the German Federal Joint Committee (G-BA), which issues final rulings on cost effectiveness and reimbursement, were hair-raisingly conservative. However we were glad to hear him share that some German sickness funds are developing pilot schemes for covering flash glucose monitoring in standard benefits packages.
  
  • In addition to reimbursement hurdles, regulatory red tape came up in the conference conversation. Dr. Danne argued that the “18-month half life” to get new technology into European patients’ hands (say nothing of the US) has been frustrating for providers and patients (we’re sure industry is not always thrilled either). In keeping with his theme of patient empowerment from the reimbursement part of his presentation, he listed Nightscout as an example of grassroots patient-led reaction to the slower pace of the regulatory process.

Artificial Pancreas

Workshop: Psychosocial Aspects Relating to the Use of the Artificial Pancreas

Introductory Presentations

Lori Laffel, MD, MPH (Joslin Diabetes Center, Boston, MA), Korey Hood, PhD (Stanford University, Stanford, California), Jill Weissberg-Benchell, PhD, CDE (Northwestern University, Chicago, IL), Lutz Heinemann, PhD (Science & Co., Düsseldorf, Germany), and Katharine Barnard, CPsychol (University of Southampton, Southampton, UK)

The packed panel began the workshop by introducing their shared goal: the creation of a dedicated working group focused on the psychosocial aspects of diabetes technology, with a focus on the artificial pancreas. The group is looking to pick up steam, and already has a funder in the Helmsley Charitable Trust – many thanks as always to HCT for doing so much good work in type 1 diabetes. The second half of the allotted time was dedicated to a lengthy panel discussion and audience comment session, but first the panelists rose to give brief presentations, summaries of which can be found below.

• Dr. Lutz Heinemann warned the audience not to assume that all patients will be excited to use the artificial pancreas when it arrives on the market. We think this is incredibly important and we were so glad to hear this emphasized. We believe this is especially true in the daytime. We think improvements are pretty likely for most people at night, that they will cause better days, and that there is likely to be less – perhaps much less – perceived hassle likely at night. He pointed to CGM as an example of a technology that was initially heralded as a must-have but which is still not used by close to a majority of diabetes patients (of course, some of this is perceived or real patient or provider hassle, some is cost, etc.). Dr. Heinemann lamented the dearth of data on the psychosocial aspects of diabetes technology but noted that alarm fatigue, feedback from patients’ families, and other patient-reported outcomes have a clear impact on a technology’s success. He expressed disappointment that the German IQWiG agency refused to consider patient-reported outcomes data in its cost-effectiveness assessment for CGM – we wonder how advocacy could help impact this.
• Dr. Korey Hood brought a psychologist’s perspective to the panel, noting that patient attitudes, wishes, emotions, and beliefs are often understudied (or never studied, we might add). Describing the working group, he noted that the Helmsley Charitable Trust has agreed to fund the project – how wonderful it was to hear this! The goal is to develop and validate a set of measures to assess the psychosocial and psychological impact of the artificial pancreas. These measures will be self-administered, which should allow data to be collected efficiently from a broader range of patients. Some of the variables to be evaluated include ease of use, human factors, impact on daily function, trust in a device, and perceived impact on diabetes control.
• Dr. Jill Weissberg-Benchell shared feedback from patients in recent and ongoing studies for the Bionic Pancreas. The results, a few of which we summarize below, were largely in line with what one would expect and laid an excellent foundation for the subsequent discussion. She cited trust in the device as a factor that impacted both adults and children. We were so happy to hear her impressions; Dr. Weissberg-Benchell and other leaders of this session are truly brilliant and incredibly insightful.

Table: Selected feedback from adult and pediatric type 1 diabetes patients in Bionic Pancreas studies

	Adults (n=20)	Children (n=19, age 8-12)
Positive	- Greater peace of mind - More freedom with food choices - More freedom to live their lives - Prevention of lows - Less worry	- Faith the device could handle their highs and lows - Ability to do more things that they liked - Easier to do what they wanted to do - Allowed them to be more relaxed and less worried
Negative	- Changing glucagon daily - Burden of carrying equipment - Uncomfortable to wear all necessary equipment	- None

• Dr. Lori Laffel discussed an instrument she helped develop to assess CGM self-efficacy (CGM-SE), or confidence. Validation studies, which were just published in Diabetes Technology & Therapeutics, found that pediatric type 1 diabetes patients with higher CGM-SE scores used CGM significantly more three and six months after initiation and also had significantly lower A1c levels than those with lower CGM-SE scores (delta A1c of ~0.8% at three months and ~0.5% at six months between the higher and lower scoring subgroups).
• Dr. Katharine Barnard spoke about psychosocial factors in diabetes management earlier in the day during a Sanofi-sponsored symposium on Challenges in Diabetes. She strongly advocated for the inclusion of psychosocial measures as endpoints in clinical trials, and ideally as the primary endpoint in some studies – in her view, the fact that funders will only accept trials with a primary outcome related to A1c is a fundamental problem. She believes closed-loop devices represent a completely new paradigm because they would be the first to completely take diabetes management out of the patient’s hands – a welcome prospect for some but potentially anxiety-inducing for others.

Panel Discussion – Selected Highlights

Dr. Jordan Pinsker (Sansum Diabetes Center, Santa Barbara, CA): I run the artificial pancreas clinical trials at Sansum and I believe I share a common experience when patients come in for evaluation who say they wear CGM, but when I ask to see it they don’t have it with them. It turns out they don’t actually use it often, not because of cost or a lack of interest in glycemic control, but because they don’t see the benefits as outweighing the costs. I have grave concerns that when we tell patients that they will still need to bolus with an artificial pancreas or will need to tell the system when they eat, patients will perceive that the benefits may not outweigh the costs. We recently published an article on this with Dr. Barnard. What will artificial pancreas users expect of the system?

Dr. Aaron Kowalski (JDRF, New York, NY): I find it interesting and – well I wouldn’t want to say disappointing – to hear presenters throw around the term “artificial pancreas” without a proper definition of what an artificial pancreas is. I would argue that there isn’t just an artificial pancreas. There are a series of systems that will become more automated over time. We have seen here the 640G system that will reduce some hypoglycemia. There will be treat-to-range systems. Jill mentioned the anecdote from the boy in the Bionic Pancreas study who said that the tool stopped him from thinking about a plate of food as a math problem. That comment made me sad, because no artificial pancreas will fix that problem now or in the near future. Insulin does not work fast enough yet to have a fully automated system. If we set the wrong expectations, we’re doomed to failure. If you set the expectation that a closed loop system will reduce some hypoglycemia and will provide some degree of help, you’ll set the balance properly. Starting with defining what the artificial pancreas is will be very important. There is not going to be a fully automated system until we have faster-acting insulin.

Audience Comment: We should be designing different systems at different levels, to follow up on Aaron’s point. Even if we can get to a fully automated system, it may not work for everyone. There should be different levels of automation. Perhaps these systems should be designed for specific age groups. What works for an adult may not work for a teenager. I love Ed Damiano’s Bionic Pancreas, but while it may work for his son, it won’t work in everyone in my practice from age three to age 40. Also, I would like to see the gradual introduction of these types of systems. If you gave me a fully self-driving car today, I wouldn’t use it. It would take me many months before I could build the confidence. We can’t just give patients the artificial pancreas and tell them to go out and start using it right away. I would want to see some process for introducing it – maybe having monthly visits where different features were activated step-wise.

Audience Comment: I have had type 1 diabetes for 46 years and I have no idea how I’m going to be able to completely switch off from managing my diabetes. I would like to build on Aaron’s point: yes we have been talking about the artificial pancreas as a finished product, but it is a system that has multiple components. We’ve been hearing about overnight trials for years. I’ll have that now, please. As a patient, I’ve been working hard for 46 years and I’d really fancy a day off. It would be nice to be on call rather than on duty. I have an insulin pump and I’m always using either CGM or Flash Glucose Monitoring. When I calibrate and see that the sensor is tracking closely, I gladly bolus and correct based on its readings. I trust the technology I’m using. I’ll take whatever you can give me – better is better.

Audience Comment: Many of the current psychosocial studies are conducted as part of pilot studies, meaning that they happen in very self-selected subjects who are motivated and love technology. That group may not be representative of the general population.

Audience Comment: As a community we would benefit if we did not use terms like adherence and compliance. [Audience applause] If we make a lousy product then it is our problem and not the patient’s problem. When we use those terms, we assume that we are right and the patient is wrong. This applies even for CGM. Yes, CGM is helpful. But from another vantage point, it’s like a GPS: it will tell you where you are, but not what to do. Or put another way, it is like sitting in a room full of mirrors when you don’t like the way you look.

Dr. Bruce Buckingham (Stanford University, Palo Alto, CA): At the first ATTD, everything was in silico. Now, we’re talking about human factors. This is so critical, thinking about family members and significant others and notifications. We’re now looking not at what the artificial pancreas can do over a couple of days, but over years. We’ve made tremendous progress to get to the point where we can now really deal with human factors. We’ve moved from the engineering to the human relationships.

Plenary: Closing the Loop – Home Studies

Opening Remarks

Dr. Moshe Phillip (Schneider Children's Medical Center, Petah Tikvah, Israel)

Dr. Moshe Phillip announced that the DREAM consortium has received a CE Mark for its overnight MD-Logic closed-loop algorithm, marking the software as the first closed-loop algorithm to receive regulatory approval. The approval is a notable milestone for the closed-loop field as whole, and now the question is when and how patients can get it – and when the first system will receive approval! The “academic” group established a new company, DreaMed Diabetes, to commercialize the algorithm; following the meeting, Medtronic licensed the algorithm for incorporation into future-generation pumps.

Hybrid Closed-Loop Control Using The Medtronic 670G And Enlite 3 System In Type 1 Diabetes At Diabetes Camp

Trang Ly, MD (Stanford University, Stanford, CA)

Dr. Trang Ly presented the first study we’ve seen on the MiniMed 670G hybrid closed loop system using the Enlite 3 sensor. The seven-day camp study randomized 20 patients to either hybrid closed loop (MiniMed 670G – patient still bolus for meals) or threshold suspend (MiniMed 530G). Disappointingly, there were no statistically significant differences in any of the glycemic parameters between the groups. This was in part due to remarkably excellent control in the 530G group (73% time in 70-180 mg/dl vs. 70% on the 670G), perhaps reflective of camp care. Overnight control with the 670G was “excellent,” with patients on hybrid closed loop spending 80% of the night in range (70-180 mg/dl) vs. 68% in the 530G group. The daytime issue seems to be the aggressiveness of the algorithm, which is being improved for future studies. The Enlite 3 sensor came in with a MARD of 12.6% vs. fingersticks and a median ARD of 9.7% (n=742). The integrated system seems very seamless and low burden (algorithm built into the pump + Enlite 3 CGM; picture here) – participants were in closed-loop for 93% of the time, and sensor values were obtained 99% of the time. Connectivity has been a major Achilles heel in artificial pancreas research, so it’s great to see Medtronic making improvements on this front. The algorithm sounds like a work in progress at this point, and slated improvements include additional adaptability, allowing patients to enter their own carb:insulin ratio, and more. In a later presentation, we learned that there is a 12-day study of the MiniMed 670G. As a reminder, Medtronic hopes to launch this device by April 2017 in the US.

• The MiniMed 670G includes a hybrid closed loop algorithm fully integrated into the pump. It uses Medtronic’s fourth-generation sensor (which we have been calling the Enlite 3 though we note the nomenclature seems to vary globally). The pump can operate as a standalone pump with pre-programmed parameters. If CGM information is available, it can also run predictive low glucose suspend (a la the MiniMed 640G). Last, it can run hybrid closed loop, where patients bolus for meals and the pump takes care of things in the background.
• Medtronic is using a PID-based control algorithm with insulin feedback. It targets a set point of 120 mg/dl. The 670G algorithm doses every five minutes and cannot deliver more than a patient-specific maximum insulin limit (e.g., 2.3 units per hour). The algorithm has some adaptability –the major component is in the max insulin limit. There is some adaptability with carb:insulin ratio and ISF as the median total daily dose changes from the preceding six days; however, the effect of that overall on the algorithm is minimal. The carb:insulin ratio is algorithm derived. The system performs automatic corrections when a meter glucose value is above 200 mg/dl.

Update on Home Closed Loop Studies and Factors Affecting Outcomes

Roman Hovorka, PhD (University of Cambridge, Cambridge, UK)

Dr. Roman Hovorka summarized 860 nights of unsupervised closed-loop at home from three published studies, reprised his comparison to the Bionic Pancreas’ Beacon Hill study from DTM 2014, and mentioned Cambridge’s four ongoing unsupervised home studies. The latter include two three-month trials and two 1-4 week trials – as of March, the team has an impressive 12 years of data on unsupervised home closed loop! Speaking more generally, Dr. Hovorka stressed the need for adaptive systems that can cope with variable insulin needs (his graph showing the variability in nightly insulin delivery – from 50% to 200% of the pre-programmed basal – “shows why we need closed-loop”); highlighted the need for intention to treat analyses in closed loop studies; and asked for more properly designed studies to compare the benefits of various approaches. We couldn’t agree more. In Q&A, Dr. Peter Chase wondered whether the first commercial systems should only target the night, since the outcomes are so much better. Dr. Hovorka agreed, though said the regulatory bodies are struggling with how to define “nights”; as a result, many believe commercial products will likely need to show they work during the day too. [We believe the patient expectations would be easier to meet with a night-only system first though we understand the rationale if the FDA has asked organizations to go with 24/7. Certainly, this seems to be the approach Medtronic is taking with the MiniMed 670G: a hybrid closed loop system that will work 24/7, but has the biggest bang for the buck at night. Indeed, Medtronic’s slide earlier in the meeting called it “overnight and hybrid closed-loop.” We think this is all about giving patients choice – those who don’t need/want the daytime closed-loop can turn it off; we imagine most everyone would like and benefit from the nighttime control. That said – we doubt many will turn off the daytime though they will be more critical of it (stemming from “disturbances” like food and exercise and stress!) – that’s why we would rather the night alone be first, so that patients can see the power of it without the “interruptions” and variability of real life. We also think patients may actually eat less responsibly, etc., if they have a closed loop, which will not be helpful in generating good early data.]

• Dr. Hovorka pooled data from Cambridge’s two recently published, four-week, overnight home studies of unsupervised closed-loop (Hovorka et al., Diabetes Care 2014; Thabit et al., Lancet Diabetes Endocrinol 2014). The randomized, crossover trials included 24 adults and 16 adolescents and compared CGM alone for 28 days to closed-loop for 28 days – a total of 860 nights of closed-loop were obtain. In the intention to treat analysis (“I really stress that”) mean time in target (70-144 mg/dl) increased from 41% to 59% (p<0.001), and time <70 mg/dl decreased from 2.9% to 1.9% (p=0.014). He noted that 2.9% on control nights translates to just 10 minutes of hypoglycemia, a “very low” number compared to other studies. Mean glucose improved from 157 mg/dl to 142 mg/dl. 
• In summarizing the team’s seven-day day+night home studies (Leelaranthna et al., Diabetes Care 2014), Dr. Hovorka emphasized that most of the improvement came during the night. “The night is the place where closed loop can do best.” There was some improvement during the day, but it was not as pronounced. On the Cambridge system, patients bolus for meals during the day. As is now the norm with home studies, mean glucose improved (158 to 146 mg/dl), time in 70-180 mg/dl improved (64% to 73%), and patients spent less time below 70 mg/dl (4.3% to 3.1%). This came with 14% less insulin.
• As he did at DTM 2014, Dr. Hovorka directly compared the Beacon Hill Bionic Pancreas trial (Russell et al., NEJM 2014) and his group’s recently published day-night study (Leelarathna et al., Diabetes Care 2014). He expressed concern that the Boston researchers are not only overly aggressive in their use of glucagon, but that insulin-only approaches can provide just as good control as using both hormones. We thought his analysis was thought-provoking, though somewhat difficult to unpack, given that the trials were different.
  
  • In directly comparing Beacon Hill with his team’s work, Dr. Hovorka suggested that insulin-only systems may provide similar control to insulin+glucagon systems. He did acknowledge that the Bionic Pancreas achieved greater reductions in mean blood glucose from the same baseline of 159 mg/dl (133 vs. 146 mg/dl) and greater time in range of 70-180 mg/dl (80 vs. 73%) than those seen in the Cambridge study; however, he stressed that patients on the Bionic Pancreas also spent slightly more time in hypoglycemia than those on insulin-only closed-loop (4.1% vs. 3.1%).
  • Dr. Hovorka also asserted that the comparison to the control group in the Cambridge study was more challenging than in Beacon Hill. First, the Cambridge team used an intention-to-treat analysis (whether closed-loop was functioning or not), while Beacon Hill only considered time when closed loop was operational. Second, the control group in the Cambridge study had real-time CGM always available, while only ~50% of patients in Beacon Hill were on real-time CGM (i.e., patients who did not normally wear a real-time CGM to manage their diabetes were not given one during the usual care arm).
  • Dr. Hovorka noted that in Beacon Hill, participants had a 32% increase in their daily insulin dose during closed-loop. He implied that the increase results from a “stop-and-go” approach to hormone administration that, in his eyes, aggressively doses insulin and depends on glucagon to counteract that “excessive” administration. Dr. Hovorka also pointed to glucagon administration in these patients that exceeded physiological levels (0.8 mg per day, almost a rescue dose).
  • The Bionic Pancreas (BP) did not deliver more insulin than usual care (UC) in three of the team’s four completed outpatient studies (when there was perfect parity between the control arm and experimental group): 2013 summer camp study [0.79 units/kg/day UC vs. 0.82 units/kg/day BP]; 2014 summer camp study [0.68 units/kg/day UC vs. 0.66 units/kg/day BP]; and multicenter study preliminary data in 20 patients [0.69 units/kg/day UC vs. 0.70 units/kg/day BP]. The one exception to this trend was the Beacon Hill study, where the Bionic Pancreas delivered more insulin than in the Usual Care arm. The greater insulin use came in the 11 participants whose mean glucose was >154 mg/dl during usual care, not for the nine participants whose mean glucose was < 154 mg/dl during usual care).
  • In a follow-up conversation at DTM 2014, Dr. Damiano shared two reasons why the bionic pancreas may have delivered more insulin in Beacon Hill: (i) the 11 participants that used more insulin on the bionic pancreas than in usual care may have been underinsulinized under usual care, since all 11 of those subjects had glucose levels >154 mg/dl under their own care; and (ii) different participant behavior on the bionic pancreas (e.g., eating out at restaurants every day vs. usual care eating at home). Indeed, the team has anecdotal evidence that Beacon Hill participants took significant liberties with regard to carbohydrate consumption on the Bionic Pancreas relative to what they did on their own care at home – the participants had been urged to “stress the system,” which is different from everyday care. Even still, insulin utilization in the comparator arm for those subjects who achieved mean glucose levels below 154 mg/dl on their own care were not statistically significantly different from the amount of insulin they received on the bionic pancreas.
• While Dr. Hovorka’s perspectives were thought-provoking, the studies are difficult to compare. Specifics can vary drastically from study-to-study, which makes it challenging to put the stats up side by side and draw conclusions. However, it was another reminder that the value of glucagon continues to be a controversy in artificial pancreas development.

Questions and Answers

Dr. Yogish Kudva (Mayo Clinic, Rochester, MN): In your four studies, are you using adaptive closed-loop, and is that only during basal? How are you handling meals?

A: For meals, we use the standard bolus wizard for meal delivery. We haven’t changed that. We do use more adaptive behavior, as people’s insulin needs change week to week. People who go on skiing holiday, insulin delivery reduced, especially in Austria. One needs to be really responsive to these changes.

Dr. Eda Cengiz (Yale University, New Haven, CT): You showed slide with the percentage of insulin delivery compared to the pre-programmed basal. Did you see associations with glycemic variability, age, C-peptide, or gender?

A: We didn’t look at C-peptide. We tried to look at age and anything else to explain the variability between people. It’s something that we would like to predict – higher variability in insulin needs.

Dr. Peter Chase (Barbara Davis Center, Denver, CO): This may be heresy, but in the old days two years ago, we talked about closed loop in stages, with the night first. With night working so much better, as we go commercial, would we be better to start with nights first?

A: I think we do better on the nights. I think the issue with the regulatory bodies is how to define nights. For commercial products that are night only, it sounds like the FDA still wants you to show how it works in the day. My feeling is that people like it during the day, but it just doesn’t provide as much benefit.

Q: The system purely controls basal? It doesn’t take un-announcement of meals or physical activity into account?

A: The system has the ability to indicate exercise, and the system will take into account. There is a feature in the algorithm that reduces insulin delivery. With the bolus calculator, the system also learns and gets information from the pump to adjust insulin delivery high or low. We are currently doing sub-optimally controlled subjects, and not everyone boluses for meals. We have standard behavior. The system needs to cope with this. People have a life to live.

Integration of The MD-Logic System into Daily Management of Diabetes

Revital Nimri, MD (Schneider Children's Medical Center, Petah Tikvah, Israel)

Dr. Nimri presented a host of never-before-seen data, including the latest interim results from the consortium’s three-month overnight study and recent findings from a four-day fully closed-loop study.

• Interim results from DREAM’s randomized three-month overnight study look promising. The trial is evaluating the safety and efficacy of long-term overnight home use of MD-Logic vs. sensor-augment pump (SAP) therapy. The study has reported data from 12/36 patients (six on closed-loop; six on SAP). Patients on MD-Logic have spent 63% time-in-range, with only 1.3% of the time in hypoglycemia (< 60 mg/dl); patients in the control arm have spent only 43% time-in-range despite using more insulin (10.3 units vs. 7.9 units), with 3.4% of the time in hypoglycemia. So far, the data looks largely consistent with previous overnight findings, something the full results from other centers will confirm.
• It is also outstanding to see that the consortium has completed its first day-night closed-loop study. This “over-the-weekend,” four-day trial was new to us and investigated fully closed-loop control for 60 hours compared to SAP at three centers across Europe. The crossover design consisted of a three-week run-in period on SAP before randomizing patients to 60 hours of closed-loop or SAP therapy.
• Average glucose in the closed-loop arm was 144 mg/dl, with 68% of the time spent in range (70-180 mg/dl). In the SAP arm, average glucose was a bit higher at 159 mg/dl, with 58% of time spent in range. Patients in neither arm experienced much hypoglycemia (0.9% CL vs. 0.8% SAP). We would highlight that these are motivated patients in excellent control to begin with, and MD-Logic was able to bring them safely into even tighter control. On the insulin front, patients on closed-loop used significantly less total basal insulin (54 units CL vs. 62 units SAP) and significantly more bolus insulin (64 units CL vs. 47 units SAP) than those on SAP, though it was notable to see that total daily dose was not significantly different between the two arms.

Parallel Session: Twelve Years of Collaborative Transatlantic Research on Artificial Pancreas

DiAs Update and Key Study Learnings

This impressive session provided a whirlwind update on all things happening with the DiAs system around the world. Below, we enclose some of our top learnings from this session: (i) Dr. Boris Kovatchev (UVA) shared major studies planned for 2015 and presented a meta-analysis of 62,173 hours of DiAs use from 18 completed and ongoing studies; (ii) Dr. Aaron Kowalski (JDRF) expressed concern in Q&A over the feasibility of an overnight-only system (vs. 24-hour/day); (iii) Dr. Hans De Vries (Academic Medical Center) presented positive new data from a 36-patient, two-month, at-home hybrid closed-loop study in Europe; (iv) Dr. Stacey Anderson (UVA) shared that the ongoing DiAs study testing three-weeks of overnight and three-weeks of 24/7 closed-loop at home has secured a five-month extension; (v) Stanford’s experience closing the loop at camp reminded us that control groups are doing much better than their baseline A1c’s would suggest; and (vi) Dr. Claudio Cobelli suggested that some of the newer, faster insulins could “really mak[e] a difference” in closed-loop control, based on some early modeling work he has done.

• UVa’s Dr. Boris Kovatchev highlighted DiAs’ history (introduced in 2011) and future, including major studies planned for 2015:
  
  • UVA’s “Project Nightlight,” an 11-month study testing alternating treatment modalities, will start sometime after March 1 (NIH-4). The approach is discussed in more detail below, but patients will cycle through sensor-augmented pump therapy, nighttime, 24-hour, and nighttime (a second time) closed-loop control. In addition to what approach works best, the idea is to see what patients prefer. 
  • Reducing hypoglycemia and reversing hypoglycemia unawareness with one month around the clock closed-loop control at home (NIH 3: UVA, Stanford). It’s tremendous to see a study in hypoglycemia unawareness, a population that stands to benefit significantly from automated insulin delivery. We wonder how large the study will be and if it will be possible to show a benefit on severe hypoglycemia.
  • A four-center trial will test UCSB’s Adaptive Zone Model Predictive Control (NIH 5: UCSB, UVA, Mayo, Padova). Dr. Kovatchev did not share more details on the length, design, or start date of this study.
• Dr. Kovatchev also presented a meta-analysis of 62,173 hours of DiAs use from 18 completed and ongoing studies (n=302). Results shown below are weighted by study, which have occurred in the US, France, Italy, Holland, and Israel and tested three different control algorithms (USS Virginia, Pavia’s RCM, and UCSB’s Zone MPC) – as a reminder, the DiAs framework allows investigators to swap algorithms in and out.
  
  • DiAs has performed tremendously during overnight studies: time spent <70 mg/dl has been reduced by two-thirds (1% vs. 3%), average glucose has improved to 139 mg/dl (vs. 153 during open-loop), and overall time-in-range (70-180 mg/dl) has risen to 78% from 64% during open loop. 
  • During 24-hour closed-loop control, time spent <70 mg/dl has been more than halved on closed loop (1.8% vs. 3.8% on open loop), while time in range (70-180 mg/dl) has marginally improved to 73% on closed loop vs. 66% on open loop. Average blood glucose has dropped slightly during closed loop: 148 vs. 154 mg/dl on open loop.
• JDRF’s Dr. Aaron Kowalski expressed concern in Q&A over the feasibility of an overnight-only system: “A theme here is overnight vs. 24 hour. I look down at Dr. Hovorka, as we have debated this. I worry a little bit that as we display data from these pilot studies, folks not as familiar with the field will not see a big difference between daytime closed-loop vs. open loop. But as Dr. Buckingham showed, these pilot studies are so controlled. The control group is testing frequently and there is often staff nearby. So you see a compression of glucose control that is not representative of the general population. [see below] A key issue is, ‘What is overnight?’ I don’t think there is ever going to be an overnight-only system. Are there scenarios when a closed loop would underperform in a broader sense or lead to bad scenarios during the day?” [Note: This remark reiterated Dr. Kowalski’s back-and-forth with Dr. Roman Hovorka at last year’s EASD Diabetes Technology Meeting.]
• Stanford’s experience closing the loop at camp reminded us that control groups are doing much better than their baseline A1c’s would suggest. Note in the table below – control groups are coming in with a baseline A1c of 8.2-8.4%, though while at camp, averaging glucose values equivalent to A1c’s of 7.1-7.3%! This was an encouraging reminder that automated insulin delivery should ideally do much better in a real-world setting, as the delta between open- and closed-loop should be wider. Of course, this is to say nothing of the types of patients that go to camp or enroll in closed-loop studies – those who are diligent, motivated, and in-touch with their clinical care teams. In addition, many of the patients that would most benefit from closed-loop systems are often not include in these trials (e.g., those with A1c’s of >10%, those with hypoglycemia unawareness, very young patients, etc.). 

	Pre-Camp A1c	Pre-Camp estimated average glucose (mg/dl)	Average Glucose at Camp (mg/dl)	Estimated A1c from Camp Mean Glucose
Sensor-augmented Pump (control)	8.4%	194	156	7.1%
Control to range	8.0%	182	143	6.6%
Damiano Camp Control	8.2%	189	162	7.3%
Damiano Camp Bionic Pancreas	8.2%	189	141	6.5%

• Dr. Hans De Vries (Academic Medical Center, Amsterdam, Netherlands) presented the first data from a 36-patient, two-month, at-home hybrid closed-loop study (one of two final AP@home studies). The crossover trial has randomized patients to begin with either two months of sensor-augmented pump therapy or two months of closed-loop at home (from 8 pm – 8am, dinner included). Dr. DeVries presented preliminary graphs from the first half of the crossover trial. The system uses the DiAs, a Roche pump, the Dexcom G4 (+ the Mazlish box for Bluetooth relay).
  
  • Though he did not share specific numbers, time spent in hypoglycemia appeared to decline by ~50% (p<0.05), and time spent above range declined from ~36% to ~30% (p<0.05). Mean blood glucose was not significantly different between open and closed-loop. This was an intent-to-treat analysis from all patients who completed more than six weeks of the study.
  • Dr. DeVries commented that such a dinner-to-morning closed-loop system might be possible to design into a commercial product– it  could simply be made available on the device (via GPS or Wi-Fi) when patients get home, and disappear when they leave home. We thought this was a novel approach to the question – “What is overnight?” – as it flips the challenge of defining a specific time period to defining a set location (home, where patients spend most nights and risks are lower than during daytime meals, exercise, etc.).
  • This AP@Home study has two one-month extensions planned: four weeks of 24/7 closed-loop (uncontrolled) and four weeks of 24/7 closed loop with an individually adaptive algorithm (uncontrolled).
• UVa’s Dr. Stacey Anderson shared that the ongoing DiAs study testing three-weeks overnight and three-weeks 24/7 closed-loop at home has secured a five-month extension! The trial is taking place at UVA, UCSB, Stanford, Padova, Montpellier, Israel. Changes requested prior to prolonged are use in progress. The team hopes to add a temporary basal feature and has already switched to the recently approved Dexcom Share receiver (previously, they were using the Mazlish box to send the Dexcom G4 data to the DiAs algorithm running on an Android phone).
  
  • US patients in the study have spent half the time in hypoglycemia during combined closed-loop day + nighttime use (2% vs. 4%), and significantly their improved time-in-target (74-76% vs. 66%). Results are even more impressive overnight, with 0% of the time spent in hypoglycemia (vs. 2% on open loop) and 78-81% time in 70-180 mg/dl (vs. 67% on open loop).
• Based on modeling studies, Dr. Claudio Cobelli suggested that some of the newer, faster insulins are “promising” and “really making a difference” in closed-loop control. He did not specify which, though we wonder if he was referring to data on Novo Nordisk’s FiAsp (ultra-fast aspart), which suggest it’s particularly faster than Novolog in the first hour. In our view, the speed of insulin – which directly affects a system’s ability to deal with meals and exercise – is really the biggest unsolved problem in closing loop.

Parallel Session: AP Data Club

Closed Loop Control Modalities in Type 1 Diabetes: Efficacy and System Acceptance

Boris Kovatchev, PhD (UVA, Charlottesville, VA)

Dr. Boris Kovatchev shared his view on why the artificial pancreas is not a “single-function device”, but a platform for technology deployment. He emphasized that closed loop control is one of many possible apps running on a scalable mobile medical network (e.g., sensor-only mode, pump-only mode, safety mode, closed-loop) – patient preferences and signal availability determine the active treatment modality. Dr. Kovatchev shared the design of an 11-month study (starting sometime after March 1) to compare sensor-augmented pump, overnight-only, and 24-hour closed-loop control. This sounds fascinating and we look forward to seeing how patients do, as well as what they prefer. In a notable conversation with us outside the session, Dr. Kovatchev shared much more about the UVA team’s approach to regulatory and commercialization. The researchers met with the FDA on February 5 and received notably positive feedback on two fronts: (i) a closed-loop control algorithm does not need to reside on an insulin pump – it can reside on an outboard device, such as a smartphone or even a smartwatch; and (ii) academic trials can be counted for product approval. As we understand it, the UVA team does not intend to commercialize the DiAs system alone; the researchers will invite industry partners (i.e., pump and sensor companies) to bring it to market. The goal is to build a near-commercial system for one more large trial to support regulatory approval, hopefully through the NIH’s $20 million outstanding call for outpatient artificial pancreas studies.

• “Memo: The artificial pancreas is not a single function device – it is a platform for technology deployment.” Dr. Kovatchev highlighted that various treatment modalities will (and should) be possible with these systems, and closed loop control is just one of many treatment options that can be run on a scalable mobile medical network. Patient preference and glycemic targets at a particular time determine the particular treatment modality, as does signal availability (e.g., if the CGM is not operating). In his view, long-term artificial pancreas use will inevitably require activation of different treatment modalities at different times. What’s more, systems are bound to fail, and as such, they must default to a known state of operation.

Treatment Modality	Available Devices	Services
1. Sensor Algorithm Support (“Sensor Mode”)   The default mode of operation in case of pump failure.	- CGM - MDI/insulin pen – information is manually fed into the system.	Trends, alerts, advice, cloud applications
2. Pump algorithm support (“Pump mode”) The default mode when CGM is not available.	- SMBG - Pump	Safety: hypoglycemia prevention, cloud applications
3. Safety supervision e.g., modulating basal rate and avoiding hypoglycemia	- CGM - Pump	Trends, alerts, advice Safety: hypoglycemia prevention, cloud applications
4. Closed-loop control e.g., modulating basal rate, correcting highs, and avoiding hypoglycemia	- CGM - Pump - Others (SMBG, heart rate?)	Trends, alerts, advice Safety: hypoglycemia prevention, closed-loop control, cloud applications

• An 11-month, NIH-supported, at-home closed-loop study will test different treatment modalities using the DiAs system (starting sometime after March 1). The study will use the DiAs platform (Android phone running control algorithm/user interface and connecting to a Dexcom CGM and Roche pump). Group A will proceed through the following treatment modalities (10 weeks each) using the DiAs system: sensor-augmented pump, overnight closed loop, day+night closed loop, and overnight closed loop. Group B will do the same four segments, but in a different order: overnight closed loop, day+night closed loop, overnight closed loop, and sensor-augmented pump. In addition to what approach works best, the idea is to see what patients prefer. This should offer interesting perspective on the question of overnight-only vs. 24-hour closed-loop. (We would note that during the overnight-only phase, the system only allows closed-loop control between preset times (e.g., 11pm - 7am) – patients cannot simply run it during the day).
• Dr. Kovatchev contrasted the configuration of the DiAs system to the “very limited” approach taken in the traditional artificial pancreas system configuration. In the latter, the closed-loop user interface, algorithm, and communication functions are built into the pump. Dr. Kovatchev called this approach “very limited” – it’s difficult to get a cloud connection (e.g., remote monitoring, trend recognition, analytics, remote diagnostics), the user interface is limited by the pump’s real estate, and upgrading the system is a challenge. The UVA team prefers an “alternative artificial pancreas system configuration” – a CGM, a pump, an artificial pancreas hub (smartphone), and cloud services. The phone takes the function of closing the loop. This helps overcome the key aforementioned down sides of building the algorithm into the pump. Of course, the phone brings new challenges in (e.g., more devices to carry, more vulnerable to glitches, battery life, durability), so time will tell which approach emerges as quicker and better for patients. 
  
  • As we understand it, the UVA team met with the FDA on February 5 to answer questions about the DiAs system configuration and the possibility of academic trials counted for product approval. FDA gave the UVA team positive answers on both counts! Most notably, the Agency told UVA that a closed-loop control algorithm does not need to reside on an insulin pump; it can reside on an outboard device, such as a smartphone or even a smartwatch (with the appropriate software solutions for safety and security). The major positive is that closed-loop approaches will not need to build new hardware with the control algorithm/interface integrated into a pump. This means any sensor-augmented pump could close the loop with an external device (provided there is rigorous system and software validation). Dr. Kovatchev cautioned that patients will not be able to swap components in and out – the entire system (phone running control algorithm, pump, CGM) will still be reviewed as a Class III medical device. We assume such an approved system would have a stripped down smartphone with very limited functionality.
  • As we understand it, the UVA team does not intend to commercialize the DiAs system alone; the researchers will invite industry partners (i.e., pump and sensor companies) to bring it to market. The goal is to build a near-commercial system for one more large trial. This would take advantage of the outstanding $20 million NIH call to fund large outpatient artificial pancreas projects. UVA intends to apply with a consortium of nine centers (three Europe, six in the US). The application date is April 15.

Questions and Answers

Dr. Bruce Buckingham (Stanford University, Stanford, CA): How about using DiAs in MDIs – those not using pump? Could they use it for safety supervision, without wearing equipment?

A: We have not done the trials, but have plans to do it with Dr. Marc Breton. It is entirely possible to feed MDI information into the system, to consider the profile of long-acting insulin, and still make some recommendations – short of closing the loop.

Corporate Symposium: Advanced Hypoglycemia Protection in Action (Sponsored by Medtronic)

Advanced Hypoglycemia Protection in Action

Pratik Choudhary, MD (King’s College London, UK)

Dr. Pratik Choudhary led a standing-room only workshop (n=50ish) on the new MiniMed 640G/Enlite Enhanced system with SmartGuard (predictive low glucose suspend), including a hands-on demo and new data from a 40-patient user evaluation study. Most notable was the glycemic data from the user evaluation study, in which SmartGuard performed beautifully – over 2,322 suspend-before-low events, the mean lowest sensor glucose value was 3.9 mmol/l (70 mg/dl), and only 3% of suspend-before-low events (n=74) went to the low limit (3.2 mmol/l, 58 mg/dl). This was impressive hypoglycemia prevention in our view. Notably, the Enlite Enhanced sensor had an average MARD of 9.8% in this user evaluation study, suggesting significantly improved accuracy over the original Enlite (vs. fingersticks). Dr. Choudhary also shared a number of quotes from patients in the study – it was terrific to hear the positive impact this system has had on participants. We also enjoyed a demo of the pump in the workshop and exhibit hall – we were impressed with the new pump design, menus, and highly customizable SmartGuard setup. More details below!

MiniMed 640G User Evaluation Data

• Dr. Choudhary gave a sneak peek at results from the 40-patient EU user evaluation study of the MiniMed 640G. Children and adult patients in Copenhagen, London, and Barcelona wore the system for four weeks and evaluated its new features and training.
• Over four weeks, participants (n=38 on the slide) had an average of 2.3 suspend before low events per day – this translated to 2,313 events, a surprisingly high number and a reminder of how many moderate lows patients with type 1 diabetes face every day. Mean duration of suspends was only ~57 minutes.
• SmartGuard performed very well – the mean lowest sensor glucose value was 3.9 mmol/l (70 mg/dl), and only 3% of suspend-before-low events (n=74) went to the low limit. Suspend thresholds were set at 3.2 mmol/l (58 mg/dl) – this was impressive performance in preventing lows in our view. Time spent <70 mg/dl was just 3%, and patients spent 75% of the time in the target of 70-180 mg/dl. The study was not powered for glucose outcomes, and there was no control group, so it’s hard to draw significant conclusions from the data. [See Dr. Tadej Battelino’s presentation elsewhere in this report for the 640G RCT.]
• Compared to baseline, both mean glucose and standard deviation were slightly improved on the MiniMed 640G in adults and children (~9 mg/dl or ~0.5 mmol/l). The study was not powered for glucose outcomes, and the slide did not contain p-values. The data were directionally interesting, though did not enable any conclusions about the system, other than it is not dramatically changing mean glucose or glycemic variability.
• Notably, the Enlite Enhanced sensor had a mean MARD of 9.8% in this user evaluation study, suggesting significantly improved accuracy over the original Enlite (MARD of 13-14%). Dr. Choudhary said this in passing and did not discuss whether it was vs. YSI or fingersticks (we later learned that it was, indeed, vs. fingersticks), or how many calibrations per day were needed. He did emphasize that the improved accuracy in part stems from a new algorithm that now sits on the transmitter (as opposed to the pump in prior Medtronic devices).
• Notably, the Veo’s issue of repeated alarms at night has now been rectified – as noted below, patients can choose whether they want any alarms with SmartGuard, and the specific periods of time where they do or don’t want them.
• Dr. Choudhary emphasized that patients took some time to adjust to the system. Given years of treating lows on their own, it took many patients 2-3 weeks to feel comfortable that SmartGuard could mitigate hypoglycemia.

Patients’ Views on the MiniMed 640G [grammatical errors were included on the slides]

“In day took some carbs and manually restarted. Could rely on this feature to go to bed with glucose at lower levels than usual.” “Stopped me going low so I didn’t have to deal with the after effects of hypo.” “Very positive – worked well at preventing low. Silent mode was great – it does its thing in the background.” “Loved all the info on the home screen. If I treated the hypoglycemia ended up high – should have left it alone.” “Fantastic piece of technology – life changing. I don’t find the low suspend as useful – I’m already low when it suspends; suspend before low is more...” [rest of quote was cutoff] “Felt confident exercising first time in a long time – I could exercise without drinking two bottles of Lucozade! Amazing to avoid the horrible scary feeling completely – took me a while to have confidence in it but by my second sensor I was there. “In day usually took carbs and restarted basal; at night didn’t wake and pump sorted low out. Surprised how it alerted me in the day before I got low. At first not sure how much glucose to take – but found needed much less hypoglycemia treatment now.” “Remarkably user friendly. Avoided over treatment hypos. Gave me confidence – user override important if I doubted it. Training important – changing hardwired behaviors is tough.”

• Dr. Choudhary’s last slide succinctly summed up the user evaluation experience: “Patients loved the 640G. Clear, effective, unobtrusive. It makes them feel safe. Would you drive a car without ABS?” We look forward to hearing more on-the-ground patient experiences, since corporate symposia can’t offer the full picture of a device’s pros and cons.

Hands-On Workshop – Setting up SmartGuard

• In a short hands-on workshop, attendees had the opportunity to setup SmartGuard, which is found in the “sensor options” – “low alerts” menu. Medtronic has done an excellent job of making the setup as easy as possible, and we got the hang of it with only a few glances at the two-page quick-start guide. SmartGuard requires setting up four different parameters: (i) time segment; (ii) low limit; (iii) suspend by sensor options; and (iv) alert options. The approach is somewhat reminiscent of the Tandem t:slim’s insulin profiles (i.e., where a slew of options is bucketed under one heading – in the case of the 640G, the low limit, suspend, and alert options are bucketed under the time segment).

I. Time Segment	II. Low Limit	III. Suspend By Sensor Options	IV. Alert Options
Patients can select up to eight time segments to define a different profile of low settings. This is a major win, as it would allow patients to set different day vs. night profiles (for example), when hypoglycemia risks and alarm preferences are much different. As a patient said above, “It does its thing in the background.”	The low glucose limit for the time segment. This limit is the lowest sensor glucose value that a patient would like to avoid reaching. All suspend and alert options are based on the low limit identified for the time segment. It can be set from 2.8-5 mmol/l (50-90 mg/dl). We like the universality of a single low limit, as well as the very understandable language around what this limit means (“value that you would like to avoid reaching”).	1. Suspend before low (i.e., predictive low glucose suspend) 2. Suspend on low (i.e., threshold suspend) 3. OFF If 1 or 2 is selected, insulin delivery will automatically resume if sensor glucose is above the low limit and trending upwards or if the maximum two-hour suspend time has been reached.	For each time segment, patients can choose whether they want to be alerted: 1. Before low 2. On low 3. Resume basal alert Notably, patients can turn all these alarms off during a time segment (e.g., at night), meaning the pump will suspend and resume insulin in the background.

• “Everything in this pump is pretty much customizable,” said the rep in our visit to the Medtronic booth. The ability to shut off all alarms and let the pump do the work in the background is one of the major promises of automated insulin delivery – taking the burden off the patient and putting it in the hands of technology. While the MiniMed 530G badgered patients with loads of alarms and messages, it’s great to see that these can be turned off at night with the 640G.

Hands-On Workshop – Observations on Pump Design

The workshop also allowed us to browse the 640G’s menus and hold it for the first time.

• The 640G’s color, light-adjusting screen lived up to the hype. It’s not quite an iPhone-quality screen, but it’s a massive improvement over the grayscale screens of previous Medtronic pumps. The black background with white writing is very sharp and high contrast – this change should be especially significant at night, where there is now no need to turn on a backlight.
  
  • The screen is also much larger than on previous pumps, an advantage most readily apparent in the bolus wizard. Four lines of text fit on the screen (blood glucose correction, IOB, carbs, and the bolus amount), in addition to the top bar containing status icons. Instead of scrolling, an ok button takes the pump into the next screen, where a normal, dual, or square wave bolus can be selected. The screen seems roughly on par in surface areas to the OmniPod PDM’s screen.
  • The color screen has also allowed Medtronic to do more with color-coding and indicators. For instance, toggling certain options changes them from gray (OFF) to lit up with a green indicator (ON). In another case, the reservoir icon is lit up green, orange, or red to indicate how much insulin remains. These are small but meaningful changes, and perhaps taken for granted in the smartphone era.
• The 640G pump body is slightly curved and feels a bit larger in volume than the Paradigm line of pumps, but not overtly so. In some ways, it looks smaller because it is oriented vertically instead of horizontally. The pump can be used with one hand, unlike previous Medtronic pumps that had to be held horizontally and used with two thumbs (i.e., it’s now like holding a smartphone instead of a video game controller).
• The pump is much easier to navigate through using a four-way arrow key, a back button, and a select button – as a reminder, older Medtronic pumps had up/down arrows, a back button (ESC), a select button, and a bolus wizard button. The 640G also has a menu button to return to the main menu at any time; we rarely needed to use this in navigating through the pump, but it is helpful. The interface is not quite as easy as the touchscreen on Tandem’s t:slim, but it is a marked improvement over previous Medtronic pumps.
  
  • Home screen: It’s fantastic to see insulin-on-board on the home screen, side-by-side with the CGM data. We loved that feature of the Animas Vibe (see the diaTribe test drive) and are glad to see it now incorporated in the 640G. The home screen also has many status icons like battery, reservoir, alarms, etc.
  • From the home screen, two menus can be immediately accessed: bolus and basal. The bolus menu allows viewing active insulin (we’re not sure what this screen shows differently from the home screen), the bolus wizard, a manual bolus, and a preset bolus. The basal menu allows access to a temp basal, preset temp basal, and basal patterns. It was great to see these very common pump functions quickly accessible.
  • The pump’s main menu (i.e., pressing the menu button) has nine screens: suspend delivery (i.e., manually suspend the pump), audio options, history, reservoir and tubing, insulin settings, sensor settings, event markers, reminders, and utilities.
• Like the Tandem t:slim and Insulet OmniPod, Medtronic also has more confirmation screens in the 640G. Messages such as “Changes not saved – exit without saving changes?” and bolus confirmation popups are now built into the pump. This is the way all pumps are going for human factors sake, and though it does add some patient hassle, some will appreciate it for a drug as dangerous as insulin.
• The Enlite Enhanced (Enlite 2) is reportedly more accurate, though Medtronic has not shared any new clinical data. As a result, the MiniMed 640G manual still cites the same MARD as the Enlite. However, Enlite 2 is 80% smaller, and uses a new algorithm built right into the transmitter. As noted above, Dr. Pratik Choudhary said the MARD was 9.8% in the user evaluations vs. fingersticks. The transmitter also uses a new frequency and can store up to 10 hours of data and backfill the information into the pump.
• Other new features we learned about: patients can stop bolus delivery while a bolus is in progress; louder and more customizable alarms than on previous Medtronic pumps; the ability to make preset boluses (e.g., “Dinner – 2.5 units”); and the ability to copy basal patterns.
• See our initial report on the Australian launch for more discussion of the pump’s features.

Questions and Answers

Q: How do you judge how to treat hypoglycemia?

A: There are a couple factors that go into it. If the pump suspends on its own, and there is no active insulin, you don’t need to treat it. That’s the thing people picked up. If it suspended and there was active insulin on board, we didn’t quite get enough hypos to get a clear algorithm. What I came to was this: if active insulin is about the basal rate, you don’t need to do anything. If it was over a unit, you probably need that level of carb based on your insulin:carb ratio. The key thing is that active insulin is on the home screen.

Q: How often did patients have problems with calibration of the sensor?

A: On the whole, we haven’t looked at it specifically. MARD was 9% - the accuracy was much better. It was out of range much less often.

Q: It’s important to note that you’re also avoiding the low levels, where the sensor is less accurate.

A: Yes. The sensor is cutting out insulin at a level of 80-120, and it is more accurate in that range.

Q: So during the night, you don’t use the alarm and don’t correct the low by eating. During the day, you look at active insulin. But I’m inclined to say don’t look at anything.

A: At night, you’re less likely to have active insulin. In the day, it comes from the tail end of boluses, so active insulin plays a slightly bigger part. It took people a bit of time to trust the system. Of course, if you just took six units, and you’re already at four units on board, stopping 0.6 units of basal isn’t going to make a difference.

Q: Can you think about two pump settings, one with a working sensor and one with a non-working sensor? With the working sensor, can you crank up insulin? And if the sensor isn’t working, it goes back to safe mode?

A: That’s a tricky one. You need to have a very switched on patient so that they know what’s happening there. You do run the risk if the sensor misses hypoglycemia, of driving low. But the question is, ‘Would this system tempt you to use a higher basal than normal?’ I tend to go for 50/50. In pediatrics some go for 70/30. I would struggle to say that it’s the right thing to do to run a higher basal.

Adam Brown (Close Concerns, San Francisco, CA): What was your biggest surprise as you did the user evaluations? And what is the one thing you would like to see improved as Medtronic looks to the next generation?

A: The biggest surprise – when people took the system off, we asked them two questions. First, we know that reimbursement for CGM is patchy. Most don’t have it. So the first question was, “Would you use this over the Veo if you didn’t have sensors?” In other words, is the pump on its own any better than the Veo? They all said yes. The menus are clearer. The alarms are more adaptable. There is a quick and easy bolus. That was a surprise. There was an extra button press to validate every bolus, and that annoyed some patients.

The second surprise was how much subliminal discomfort and fear of nocturnal hypoglycemia there is. People are scared of hypos. I was surprised by how much people came back with reassurance. The pump would switch off before patients were in hypoglycemia. Once they had a few nights, they would say, “It suspended twice last night! I didn’t even realize.” I was surprised by the impact of that factor on the patients. It’s the same thing we see with closed loop. Even when people are sleeping calmly, there is a subliminal level of anxiety at night.

Adam: And how about the one improvement?

A: We’d want to see the other half of that algorithm – the closed-loop piece. And then some people didn’t like the extra bolus confirmation screen.

Corporate Symposium: Introducing the New Frontiers in Artificial Pancreas System (Sponsored by Medtronic)

Introducing The MiniMed 640G

Tadej Battelino, MD (University Children's Hospital, Ljubljana, Slovenia)

A completely packed auditorium listened intently as Dr. Tadej Battelino presented clinical data on the MiniMed 640G from the 100-patient, two-week SportGuard randomized trial (SmartGuard ON vs. OFF). In the primary outcome, use of SmartGuard led to a 41% reduction in the median number of hypoglycemia events/week <65 mg/dl (p=0.02) and a 56% reduction in events <60 mg/dl (p=0.007). Median hypoglycemia AUC and time spent in hypoglycemia <65 mg/dl were also reduced by 56% and 41%, respectively, when SmartGuard was turned on. Time spent in hyperglycemia >140 mg/dl was significantly greater, though the significant difference disappeared for time spent >180 mg/dl. This is perhaps to be expected, given the suspension of basal insulin and depending on where patients are setting their low threshold. Notably, Dr. Tim Jones has an ongoing six-month RCT evaluating the MiniMed 640G with SmartGuard, which should give valuable longer-term data (including A1c) on the device – we even wonder if a significant finding could emerge on severe hypoglycemia. Medtronic is putting admirable effort on the clinical data front with this system, and we look forward to what comes out of these studies.

• SportGuard was an investigator initiated, 100-patient RCT of the MiniMed 640G. Patients were randomized to use the 640G with or without SmartGuard for two weeks with a three-day run-in. The primary outcome was the number of hypoglycemia events, defined as sensor glucose <65 mg/dl (<3.6 mmol/l). Of the 100 subjects enrolled, 98 completed the study at two sites (Slovenia and Israel). The mean age was 13 years, the mean A1c was 7.7%, and the mean duration of type 1 diabetes was 6.5 years. The study wrapped up on February 4, 2015, and the data analysis is ongoing. Dr. Battelino showed preliminary results.
• In the primary outcome, use of SmartGuard led to a 41% reduction in the median number of hypoglycemia events/week <65 mg/dl and a 56% reduction in events <60 mg/dl (2.9 vs. 1.7 events, p=0.02; 1.6 vs. 0.7 events, p=0.007). There were a median of zero events <50 mg/dl in both groups. We felt this was strong data on avoiding hypoglycemia for such a short RCT.
• Median hypoglycemia AUC and time spent in hypoglycemia <65 mg/dl were reduced by 56% and 41%, respectively, when SmartGuard was turned on (1721 vs. 749 mg/dl*min, p=0.009; 206 vs. 121 minutes, p=0.01). As would be expected, patients also had a much shorter magnitude and duration in hypoglycemia with the PLGM algorithm.
• Time spent in hyperglycemia >140 mg/dl was significantly greater with SmartGuard turned on: 6,002 minutes vs. 6,576 minutes (p=0.01). However, the difference largely disappeared for time spent >180 mg/dl: 3,846 minutes vs. 3,981 minutes (NS).
• Dr. Tim Jones has an ongoing six-month RCT evaluating the MiniMed 640G with SmartGuard. The objective is to compare the % time in hypoglycemia (<63 mg/dl) during six months of therapy with SmartGuard turned ON vs. OFF. The five-center, prospective study will randomize participants to SmartGuard ON or OFF.  Over 50 participants have been enrolled to date, and the goal is to enroll a total of 176 patients. This study should offer better perspective, certainly for A1c and potentially for severe hypoglycemia.
• Dr. Thomas Danne has a six-week, prospective, single-arm (before/after comparison) of the MiniMed 640G starting up in Europe. The primary outcome is area under the curve in hypoglycemia with and without SmartGuard. Twenty-four participants will be enrolled at three sites in Germany.

The Evolution of the Closed Loop System

Fran Kaufman, MD (Chief Medical Officer, Medtronic Diabetes, Northridge, CA)

Ending the session, Dr. Fran Kaufman took the podium and shared updates on the MiniMed 640G in the US and provided new details on the MiniMed 670G hybrid closed loop system.

• Dr. Kaufman said that the US regulatory trial of the MiniMed 640G is “poised to begin very shortly” in the “coming days/weeks.” As we understand it, this is the same in-clinic pivotal trial that started last October, though it was paused to allow time to tweak the algorithm. The expected completion date is July 2015, and as we mentioned in Medtronic’s earnings report in February, the company expects to submit the PMA to the FDA “later this calendar year” (launch by April 2016, per JPM 2015).
• Dr. Kaufman shared several slides with never-before-seen details on the MiniMed 670G/Enlite 3 hybrid closed loop systems.
  
  • US IDE – “Potential regulatory pathway.” The study will be entitled “Safety evaluation of the hybrid closed loop (HCL) System in type 1 diabetes”. The objective is to show that hybrid closed loop algorithm is safe and performs as indicated. The study will be three months in length with “intensive evaluation” in either month 1, 2, or 3. A multi-day hotel study is included in the protocol of visits. Patients will have a nighttime companion for the duration of the study. It was not clear what the comparator is in this study, but we assume it is open-loop sensor-augmented pump therapy. Devices will include the Enlite 3 sensor, MiniMed 670G insulin pump, Bayer Contour Next Link BGM, and CareLink (though CareLink will be set up quite differently for closed loop). As soon as Medtronic starts the study (patients ages 14-75 years), a pediatric study in children will also move forward. Kudos to Medtronic for including over 65 – we hope they recruit aggressively for this. Same goes for starting the study in children simultaneously.
  • Hybrid closed-loop algorithm and settings: Low and high alerts will be set at 70 and 300 mg/dl, respectively. The target glucose for the hybrid closed loop algorithm will be set at 120 mg/dl. An exercise feature may be used that raises the target to 150 mg/dl during activity – pretty smart! Several alarms are fixed into the system: sensor glucose <50 mg/dl, sensor glucose >300 mg/dl for one hour; and sensor glucose >250 mg/dl for three hours. The slide did not say, but it sounds like patients will bolus for meals as normal, and the system will take care basal insulin in the background.
• Medtronic now describes automating insulin delivery in four steps: low glucose suspend (MiniMed 530G/Veo), predictive low glucose suspend (MiniMed 640G), “overnight and hybrid closed loop” (we assume this is the MiniMed 670G, though the slide did not say), and “closed loop.” We assume the last step would be fully automated and not require any manual bolus dosing for meals. 

Glucose Monitoring

Oral Presentations

A Feasibility Study Of A Novel Redundant Electrochemical Sensor For Continuous Glucose Monitoring In Patients With Type 1 Diabetes (T1d)

Amin Sharifi, MD (St. Vincent’s Hospital, Melbourne, Australia)

We got a closer look at Medtronic’s fifth-generation “Harmony” sensor, a redundant approach incorporating signals from two sensors. Harmony involves two parallel planar electrochemical sensors; as we understand it, this is the fifth generation sensor in Medtronic’s pipeline (following Sof-sensor, Enlite 1, 2, and 3). A seven-day study evaluated the sensor in 15 adult type 1s (each wore two identical Harmony sensors) – on two days accuracy was assessed with a standardized meal test and YSI, and throughout the trial comparisons were made vs. a study blood glucose meter. The sensor achieved a MARD of 9% vs. YSI during the meal tests and a MARD of 10% vs. the study meter for the entire duration of the trial (~3,000 evaluation points), one or two percentage points better than the MARDs (vs. BGM) of the individual sensors. Presenter Dr. Amin Sharifi (St. Vincent’s Hospital, Melbourne, Australia) argued that sensor redundancy also extended the lifetime of the sensor, though the benefits (less than half an additional day of use and ~3% longer display time) were pretty marginal. What was more impressive to us was how seemingly intelligent the Harmony system was – in one case in which one sensor veered off course, the system terminated its signal and preserved accurate readings. JDRF and Helmsley were listed as supporters of the study; the two foundations announced a partnership with Medtronic in 2012 focused on an orthogonally redundant sensor that will combine electrochemical and optical sensing mechanisms in one sensor. That has not moved forward quickly at all, and we wonder if Medtronic has now focused effort on solely electrochemical redundancy (per this study). A key question with redundancy is manufacturing cost, and for Medtronic, when this sensor would come to market – a 9.0% MARD is what Dexcom’s G4AP algorithm has now, and Gen 6 should be roughly similar with potentially fewer calibrations and a potentially longer wear time.

Parallel Session: Clinical Practice in Treatment of Diabetes in the Pediatric Age Group

Approaches to Behavioral Interventions to Encourage CGM use in Pediatric Patients

Lori Laffel, MD (Joslin Diabetes Center, Boston, MA)

Dr. Lori Laffel shared preliminary results from the CGMi trial that is evaluating barriers to greater CGM use in pediatric patients. The 24-month randomized controlled trial is comparing the effectiveness of a “family-focused behavioral teamwork intervention” vs. standard education and support in the initiation of CGM in youth age 8-17 with type 1 diabetes. The primary endpoint is change in A1c at 12 months. The trial is ongoing with an estimated completion date of April 2015, but Dr. Laffel presented preliminary data on CGM use during the first year. Notably, 72% of patients found to be eligible during screening declined to participate in the trial, and half of them cited reluctance to use CGM as their specific reason for declining – quite a sobering indication of the barriers to greater uptake. On a slightly brighter note, out of the 130 patients who did enroll, 70% were still using CGM after 12 months. In an attempt to identify the factors underlying the high rates of CGM discontinuation (or “dis-continuous glucose monitoring,” as Dr. Laffel put it) among youth, the investigators asked the families of all enrolled patients to identify the key challenges they had experienced with the device. The three factors cited much more frequently by the group that discontinued CGM were difficulty managing glucose alarms, wearing the sensor, and carrying the receiver – in other words, fundamental aspects of the device (perhaps THE most fundamental!) rather than technical glitches.

• Dr. Thomas Danne (Diabetes Center for Children and Adolescents, Hannover, Germany) echoed similar themes during a subsequent panel discussion, saying “the biggest problem with CGM devices is they’re not useful.” He noted that the enormous early success of Abbott’s FreeStyle Libre supports the theory that hassles like false alarms and calibration are potentially the main barrier to greater use of CGM. He positioned future closed loop systems as the best solution to these problems, urging the audience to “work on FDA to get big studies in the American market so we finally bring less burden to patients.” We agree that Libre’s incredibly positive reception (read more about it here) has been an excellent illustration of the value of reduced hassle factor. The big question is if closed-loop devices will be the killer app for CGM and pumps; some key barriers include price and a perceived loss of control over diabetes.

Parallel Session: Glucose Control in the ICU

Glucose Control in the ICU using Continuous Glucose Monitoring: What Level of Measurement Error is Acceptable?

Malgorzata Wilinska, PhD (University of Cambridge, UK)

Dr. Malgorzata Wilinska presented simulation data suggesting that CGM with a MARD of up to 10% can be just as effective and even reduce severe hypoglycemia risk, compared to intermittent blood glucose measurements in the ICU. This study utilized a virtual population of 56 critically ill patients over a 48-hour ICU stay and tested three different ICU protocols (Yale, University of Washington, and NICE-SUGAR). The findings showed that mean glucose values and glycemic variability were similar for blood glucose measurements and for CGM with a measurement error of up to 15%. Notably, measurement errors of up to 10% for CGM use could lead to similar or favorable results in frequency and duration of hypoglycemia in this patient population. Interestingly, the type of protocol made a greater difference on glucose control than the different levels of CGM measurement error did – an indication of how essential it is to design an appropriate protocol. As Dr. Wilinska commented, CGM use in the ICU can significantly reduce workload compared to blood glucose methods as the devices can easily provide more frequent measures, trending information, and also improve safety with its alarms. CGM in the hospital has always struck us as a no-brainer from a clinical and cost perspective, which is why it’s been perplexing to see the challenges of Edwards, Echo Therapeutics, and very slow movement from others.

Corporate Symposium: Clinical Utilization of the FreeStyle Libre System (Sponsored by Abbott)

FreeStyle Libre System Accuracy Study

Timothy Bailey, MD (UCSD, San Diego, CA)

Dr. Tim Bailey shared never-before-seen data from Abbott’s 72-patient, 14-day pivotal CE Mark trial of its factory calibrated FreeStyle Libre system, which demonstrated a solid overall MARD of 11.8% vs. YSI (the study had 1,238 paired sensor-YSI points). We first saw top line results from this study at EASD 2014, where Libre demonstrated an overall MARD of 11.4% vs. FreeStyle Precision BGM (13,195 paired points). One criticism of the data shared at EASD was the use of BGM as the reference device, as most CGM studies have in-clinic days with YSI – it was good to see that the 14-day, factory calibration holds up against that standard as well. New subgroup analyses also showed that the sensor remains accurate near the hypoglycemic range, where MAD was 9.5 mg/dl vs. YSI for glucose values in the 51-80 mg/dl range – this is the first time Abbott has shared this data (see below). As a reminder, the product label recommends a confirmatory fingerstick when hypoglycemic, though commentary during Q&A suggested that patients are routinely skipping these steps, a testament to its real-world accuracy. Similarly, the sensor maintained its accuracy even when glucose values were rapidly changing as Dr. Bailey shared a comparison of data excluding vs. including all points <80 mg/dl or changing at >2 mg/dl/min. Reported MARD were not statistically different for the two subgroups: 10.4% (exclusive) vs. 11.4% (inclusive).

• As a reminder, the pivotal study was conducted in four centers across the US in type 1 and type 2 patients on insulin therapy. Patients wore two sensors on the back of their arm for 14 days and were asked to: (i) perform eight capillary blood glucose tests daily; (ii) scan the sensor following each test; and (iii) attend three in-clinic eight-hour YSI sessions. Notably, Dr. Bailey shared that 24% of patients had a baseline A1c > 8.5% and that 22% of patients had a baseline A1c < 7.0% - a nice mix of well-controlled and out-of-control patients.
  
  • We saw topline results from this study at EASD 2014 where Abbott’s factory calibrated FreeStyle Libre system demonstrated an overall MARD of 11.4% vs. FreeStyle Precision capillary fingersticks (87% of points were in Zone A of the Consensus Error Grid, 13% in Zone B). MARD was lowest on day one (15.7%), improved to 11.9% on day two, and hovered between 10.3% and 11.8% on days 3-14. The study had 13,195 paired FreeStyle Libre-BGM data points (range: 23-498 mg/dl).
• FreeStyle Libre demonstrated excellent accuracy in the hypoglycemic range vs. both YSI and fingersticks. MAD was just 9.5 mg/dl vs. YSI (n=53) and just 10.0 mg/dl vs. fingersticks (n=901). A bigger testament to Libre’s hypoglycemic accuracy came from Dr. Bailey’s colleague, Dr. Iain Cranston who noted, “Half my patients have not done a fingerstick in two months. They come to rely on Libre.” The data below is cut at 50 mg/dl and 80 mg/dl, so it is tough to know what the accuracy is for <70 mg/dl vs. > 70 mg/dl (i.e., did most of the 50-80 mg/dl points fall in the 70-80 mg/dl bucket?). Even still, based on our experience wearing the device, it is very accurate in hypoglycemia, so the point is more semantics than anything.

Table 1: FreeStyle Libre vs. YSI in Hypoglycemia

Glucose Level (mg/dl)	MAD (mg/dl)	N
< 50	26.0	2
51-80	9.5	53

Table 2: FreeStyle Libre vs. BG Capillary for Low Blood Glucose

Glucose Level (mg/dl)	MAD (mg/dl)	N
< 50	12.6	145
51-80	10.0	901

• Libre demonstrated impressive results even when glucose values were rapidly changing. Dr. Bailey shared subgroup analysis for results excluding vs. including all points < 80 mg/dl or changing at > 2 mg/dl/min. Impressively, the reported MARD were not statistically different: 10.4% (exclusive) vs. 11.4% (inclusive). We thought this was a clever and smart way to summarize the data.

Table 3: Sensor Results During Times of Rapidly Changing/Low Blood Glucose

Glucose level	Measurement vs. capillary BG	All Data		Excluding results < 80 mg/dl or changing at >2 mg/dl/min
		Results	N	Result	N
< 100 mg/dl	MAD	11.3 mg/dl	2,153	10.3 mg/dl	905
> 100 mg/dl	MARD	10.7%	11,042	10.2%	9,341
All	MARD	11.4%	13,195	10.4%	10,246

• Dr. Bailey shared positive data from user experience studies of FreeStyle Libre in the pivotal study. There was no background on how these questions were asked – we assume Yes/No. Still, the data pointed to why patient uptake has been so strong in these early days, especially in those that have avoided current CGM due to comfort/wearability:
  
  • 100% agreed that the sensor was easy to apply.
  • 88% agreed that applying the sensor was less painful than a routine fingerstick (more to the point, we’d add that it’s only required every 14 days).
  • 86% agreed that the sensor did not get in the way of daily activities.
  • 96% agreed that Libre is comfortable to wear.
  • 96% agreed that scanning the sensor is less painful than pricking my finger (We’re not quite sure how these 4% of patients were scanning or what magical lancing device they were using – Adam and Kelly have both used it and say the scanning is completely painless.).
• Very few adverse events were reported among patients in the study. Only 26 subjects reported any sort of discomfort around the sensor insertion site and all reports were consistent with what would be expected following insertion of a sensor into the skin:
  
  • Moderate to severe erythema – 4% of the time
  • Other moderate symptoms – 1% of the time
  • Mild symptoms – less than 9% of the time (Moderate vs. mild symptoms were not defined.)
• Although Libre is only approved for upper arm wear, commentary during Q&A suggested that most patients are taking liberties with sensor placement, and the re-location does not appear to be affecting accuracy. Said Dr. Iain Cranston (Portsmouth Hospitals NHS Trust, Portsmouth, England) during Q&A: “Most people using Libre have purchased the devices themselves, so will put it where they damn well like. The upper quadrant of the buttocks is a popular place, and it stays on for two weeks. On the abdomen is another popular place, but more likely to fall off. It’s incredibly anecdotal reporting thus far though.” The upper arm can be a tough sell for patients (less body fat for some; more visible), so we are not surprised to see patients taking initiative, as they have with traditional CGM as well. The company has said it is exploring approval for some of these other sites for wear, though that would simply allow for different marketing and training more than greater uptake.

Questions and Answers

Q: You mentioned Libre’s great precision – why would you want to cross check with fingersticks?

Dr. Bailey: It turns out that the precision of this can replace fingersticks. There are still some caveats with rapid changes or with hypo but a replacement is here and that’s pretty exciting for patients.

Dr. Cranston: Half of my patients have not done a fingerstick in two months. Patients have come to rely on Libre.

Q: D you have to wear the sensor on your arm? Could you wear it anywhere else? What would be the differences?

Dr. Bailey: At my site, you had to wear it on your arm. In reality, you can’t even imagine all the places patients actually put the devices, but I don’t know the data.

Dr. Cranston: Most people using Libre have purchased the devices themselves, so will put where they damn will like. The upper quadrant of the buttocks is a popular place, and it stays on for two weeks. On the abdomen is another popular place, but more likely to fall off. It’s incredibly anecdotal reporting thus far though.

Q: Is there any data on interfering substances?

Dr. Cranston: I have not seen study data relating to it, though I believe it is there. It is not something I recommend people need to avoid. I think the clinical sheet that comes with it tested against 20 substances, and although they can measure differences in the value from that, they are not clinically different.

Q: Could you tell us more about the first hour of insertion after the new sensor?

Dr. Bailey: The first hour is the calibration. In our study, 100% of the sensors came online. The only sensors that did not perform had to do with problems with insertion. Once they were inserted, they all reported accurate data.

Dr. Riveline: In my experience, patients noted that accuracy was not as good in the first day.

Dr. Cranston: I tend to advise people to not act according to what they see on the sensor in the first 12 to 14 hours. In an anecdotal way, it does appear that the sensor will tend to read a little bit lower on day one. It’s totally anecdotal and someone from the company will probably shoot me for saying that but that’s what I’ve heard.

Dr. Bailey: This is the first presentation of the YSI data; there will be more data pretty soon.

Q: Any allergic reactions to adhesives? Are there any case reports on that? Maybe on social media?

Dr. Cranston: Yes, on social media there are absolutely reports of that. There were photos of that – like people can be allergic to any adhesive. What I’ve found absolutely stunning and what I’ve seen is that they leave them on! It shows how much they like Libre. Normally when you have something that itches, you take it off. Some patients have had quite a nasty reaction because they want to leave the sensor on.

Q: What about the sensor in a hairy area? Or the abdomen? Do people need to be careful about knocking it off?

Dr. Cranston: It’s only a five-millimeter sensor. So if it’s really hairy area, then you might have problems with getting the sensor inserted. On the back of the arm, I have never shaved an arm to put it on. As for knocking a sensor off, of course you can. People tend to put it on the front part of the arm and it gets knocked off. But on the back, it is better.

Q: Can you talk about Libre vs. BGM?

Dr. Cranston: This should pass as a glucose meter. It meets all the criteria.

Q: Would you recommend patients to do more or less fingerstick measurements in the first 24 hours after putting the sensor on?

Dr. Riveline: I would recommend the same number of SMBGs as usual due to the lower accuracy.

Dr. Cranston: I would say it depends on why they have it. But what I tell patients is not to react to what’s happening actually. I tell them to try not to react too much in the first week. Once you have an idea of what your profiles look like, then in the second week, you can react.

Q: What happens to the needle used to insert the sensor?

Dr. Clifford Bailey (Moderator): It’s in and out before you can see it.

Q: Do insurance companies pay in the US, UK, and France?

Dr. Bailey: It’s not clear in the US. Reimbursement is critical for patients to have access. It would be wonderful if this were covered. It’s not covered in the US or France.

Dr. Cranston: In the UK, it has not been looked at by NICE. I’m not aware of any immediate plans to do that. There is the question of whether an individual can get it funded, but that’s a conversation between the patient and insurance companies and I’m not sure that anyone’s managed it.

Dr. Riveline: I think we have to fight to obtain reimbursement but it hasn’t happened yet.

Dr. Clifford Bailey: If you look at the costs incurred by fingersticks compared with this, then this is very competitively priced. I think that that’s going to be a very big factor in actually deciding the mass use of this new device.

Dr. Cranston: Yes, about ten tests a day is the same price.

Q: How do you think about Libre plus a pump?

Dr. Riveline: I think it’s a good thing for a lot of patients but there is no combination with a pump. It depends on the patient. There are patients who don’t want to have alarms. For some patients with a pump, that’s a good thing.

Dr. Cranston: It’s important to say what it’s not. The Libre plus a pump cannot be an artificial pancreas since data is not continuously collected but instead is episodically collected. That said, many Libre users don’t have pumps. They are treating with insulin injections as they normally would. Is it accurate? In my eyes, yes it is. Do they do it? Yes, they do. Some patients have used a wizard with this and nobody’s factored in an arrow-based wizard, but they visually adjust.

Q: In a situation of rapidly changing glucose, there is a lag time. How does this work out for Libre?

Dr. Bailey: The overall lag time is 4.5 minutes. We don’t have data on rapid change. This is when you want to confirm with fingersticks. Particularly when it’s trending down, check with fingersticks.

Dr. Cranston: When they see a vertical arrow, it is easy to flash again in five minutes. I say, don’t work on a single value. The first flash tells you that you need another again. It’s not that hard to get a second look.

Q: How is it possible to have this MARD without calibration?

Dr. Bailey: Everyone is working on this technology. This is the first released product. Every product out there has its advantages. That’s the one thing about this product.

Dr. Cranston: Let’s make it clear that it’s not that this isn’t calibrated. It is. It’s just not calibrated against fingersticks. It’s calibrated in the lot.

Dr. Bailey: It also has to do with drift. Other sensors would drift and you would have to recalibrate. This one doesn’t drift. Standard meters aren’t that accurate too. So factory calibration is great because it gets rid of using inaccurate meters in calibration.

Q: Can I walk across the street to the nearest pharmacy and buy one?

Dr. Riveline: In France, it was possible to have the device directly bought from the company. But it’s no longer available because a lot of type 1 patients asked for the device. So we have to wait for more devices to be built. The cost is 120 euros for the device and 60 euros for each sensor.

Q: Could you comment on the clinical relevance of using Libre?

Dr. Cranston: I don’t think that there is anybody who has come to me with a profile or that I have put a sensor on where we haven’t gotten clinical value from the profile. There is always something we can clinically get out of the profile.

Q: Is there enough data yet to make diabetes diagnoses in previously undiagnosed patients?

Dr. Cranston: I think it’s a really good question. We’re trying to collect some data about that. Traditionally, diagnosis is based on complications. So we’d have to do it indirectly. I have to say, when you see a normal glucose profile on one of these devices, there’s nothing else that looks like a normal glucose profile. Low variability and a completely flat profile is what normal looks like. We’re looking at Libre in post-transplant profiles to see how it changes.

Corporate Symposium: Dexcom Continuous Glucose Monitoring – Superior Technology Leading to Quality of Life Improvement and Innovation with the Artificial Pancreas (Sponsored by Dexcom)

Dexcom Continuous Glucose Monitoring in Technology – Leading the Way in Accuracy, Performance and Innovation

Jake Leach (Senior VP of R&D, Dexcom, San Diego, CA)

Mr. Jake Leach headlined the Dexcom symposium with new pediatric data on the G4AP algorithm (MARD 10% vs. YSI, consistent with adults), news that the new Bluetooth-enabled Share receiver is available for AP research, at least 10 slides on Gen 5 (submission expected “within the next couple of months,” on pace with the goal for March), multiple slides on the Apple watch integration, the first screenshot of the Android Share app, and more.

• The new Dexcom G4AP algorithm (Software 505) demonstrated a MARD of 10% vs. YSI in a 79-patient pediatric study (2-17 years old). This was impressively similar to the 9% MARD originally collected in adults. Notably, 91% of points were within 20%/ 20 mg/dl, consistent with the 93% observed in adults. Sensors were inserted in the upper abdomen or upper buttocks and calibrated every 12 hours with SMBG. The seven day study included one in clinic session vs. YSI in 6-17 year-olds (they spared the 2-5 year olds!) on day one, four, or seven. Dexcom collected 2,262 paired CGM-YSI points in a wide data range of 40-40 mg/dl. The study was presented as a poster at this ATTD (Laffel et al.).
  
  • This data should allow Dexcom to secure pediatric approval for the new algorithm, which was initially approved and launched in November for patients 18 and over. Mr. Leach noted that patients should especially see more responsiveness with the new algorithm when glucose is changing.
• The new Bluetooth-enabled Share receiver (approved in January) “really enables remote monitoring 24 hours per day.” With the original Share system + docking cradle, remote monitoring was really limited to nighttime or when an outlet was nearby. The portability benefits are significant. We also couldn’t help but think of this as an indirect reference to Nightscout. As we noted in our Share receiver approval report, Nightscout is not going away, though the convenience of the Share receiver seems quite high, and once an Android version is out, the reasons to choose Nightscout may be less compelling.
  
  • In line with the new Share receiver, Dexcom is making available an orange Share AP receiver for investigational use (“a new tool for artificial pancreas research”). The receiver includes the new G4AP (Software 505) algorithm. This device will allow investigators to wirelessly send results from the Dexcom receiver to an artificial pancreas controller via Bluetooth – an especially big benefit for home studies. In the past, researchers have had to hardwire the artificial pancreas controller to the Dexcom receiver (e.g., the Bionic Pancreas brick), or use other solutions like the Mazlish box. Dexcom has an FDA master file and an investigator brochure; Mr. Leach asked attendees to contact Dexcom through its website. [We’d note that the 24-hour closed-loop at-home study of DiAs was recently extended for five months and will use the Dexcom Share receiver.]
• The Gen 5 mobile platform is “on track” for an FDA filing “within the next couple of months.” As a reminder, the goal as of Dexcom 3Q14 and JPM 2015 was a filing in calendar 1Q15 (by March), which means things seem to be going according to plan. Mr. Leach showed several screens of the interface, which we previously saw at JPM 2015. However, he did point out that the app enables “in-app help screens” to answer common questions and help troubleshoot problems. As we’ve reported in the past, G5 will also build in the Share capabilities and offer the Share receiver to communicate directly with the Bluetooth enabled transmitter (backup for the phone or if someone doesn’t want to use a phone) – the transmitter has the flexibility to communicate with two devices. See a picture on Twitter here. [Following ATTD, the device was submitted to the FDA; management is cautiously optimistic for approval by the end of 2015.]
• Mr. Leach had multiple dedicated slides on the Apple Watch integration with Dexcom apps, starting with the Follow app – as we reported just prior to ATTD, the plan is for this app to be ready once Apple releases the watch in April. See a picture on twitter here. Said Mr. Leach, “We intend to link up most of our apps with the Apple Watch once it’s released.”
• We got a first glimpse at the Android Follow app, which looked identical to the Apple version – see a picture on Twitter here. Though the Android app is trailing the Apple Follow app quite a bit (the Apple version was launched in October), Dexcom hopes to develop these in parallel going forward. This is great news for patients, since “Where is the Android version?” is one of the most common questions we hear. Dexcom is also working on an Android version of Gen 5.
• Mr. Leach devoted a full slide to the renewed Dexcom and Insulet collaboration – see a picture on Twitter here. Insulet was the only pump company to have a dedicated slide. Indeed, Asante was not listed on any slide, though Mr. Leach mentioned them verbally. Tandem and Animas were not mentioned at all. The gating factor on this partnership will be Insulet’s new PDM, which is slated to be shown at ADA 2015 and submitted to the FDA by the end of the year.
• In line with Dexcom’s JPM 2015 presentation, Mr. Leach showed the new sensor applicator, which permits sensor application with one hand. The single push button device hides the needle and deploys the sensor in 50 milliseconds. See a picture on Twitter here.
• Also from JPM, Dexcom showed its new 30% smaller transmitter vs. the current G4 Platinum slim transmitter. Notably, the new transmitter is also lower cost to manufacture!
• Mr. Leach showed encouraging topline data on the Gen 6 sensor from a 40-patient study (more than we recall seeing at JPM) – a single calibration at startup (two BGM values) resulted in an 11.7% MARD vs. fingersticks (days 1-7) and similar 12.1% MARD vs. fingersticks (days 1-10). The pilot study didn’t use YSI and values were blinded to patients, something Dexcom plans to change in studies going forward. Mr. Leach said the team is “very excited about the performance.” As we noted at JPM, this is slightly worse accuracy than G4AP (MARD: 9.0% with two calibrations per day), but the tradeoff of only calibrating at startup and a longer approved wear time is likely worth it. Gen 6 will block interfering substances with a new membrane, as well as employ new algorithms to detect more outliers.

Corporate Symposium: The Link Between Performance and Clinical Value of CGM (Sponsored by Roche)

Update on the Clinical Evidence of CGM – What Does It Mean For Reimbursement?

Thomas Danne, MD (Diabetes Center for Children and Adolescents, Hannover, Germany)

Dr. Thomas Danne discussed reimbursement and regulatory challenges for CGM; more upliftingly, he also shared some ways in which patients are taking a stand. The “18-month half life” it takes to get new technology into patients’ hands in Europe (say nothing of the US), in his view, has been frustrating for providers and patients, not to mention industry. We were pleased to hear Dr. Danne specifically highlight Nightscout as an example of a grassroots patient-led reaction to the extensive regulatory red tape. Of course, the FDA’s recent approval of the Dexcom Share receiver and loosening of the review for apps and devices tied to CGM should help the entire field on this front. Turning to his home turf, he noted with concern that the notorious German authorities will soon rule on reimbursement for CGM (2015 or 2016, per what we heard last week at EASD Diabetes Technology). For background the IQWiG and G-BA authorities have already wreaked havoc in the type 2 diabetes drug landscape. Here too, however, patients have asserted themselves – Dr. Danne displayed a picture of a patient protest to preserve access to rapid-acting insulin analogs for children, and we imagine a similar wave of advocacy could improve the outcome of the government’s upcoming decision on CGM. Despite these bright spots, Dr. Danne acknowledged that the evidence base for CGM’s cost effectiveness is not yet as strong as it needs to be, partially because existing meta-analyses that do not examine CGM in sufficiently targeted patient populations. Ultimately, he suggested that patients should take a greater role in making decisions on reimbursement, and wondered aloud whether it should be patients or scientists (and in what balance) who lead decisions on reimbursement policy. 

The Clinical Relevance of CGM Accuracy

Jessica Castle, MD (OHSU, Portland, OR)

As part of Roche’s session on “The Link Between Performance and Clinical Value of CGM,” Dr. Jessica Castle provided a most valuable clinical perspective on the key areas of improvement for CGM, especially in preparation for the closed loop. Her list, which was refreshingly patient-oriented, included: (i) optimizing first-day sensor performance, which generally suffers with current designs due to the wound response; (ii) assessing telemetry in the real world to ensure that cell phones and other possibly interfering wireless signals do not lead to dropped sensor data (particularly important once sensors are Bluetooth-enabled); (iii) identifying and eliminating “egregious” sensor errors while reducing batch-to-batch sensor variability; and (iv) eliminating the acetaminophen effect and other interference issues that could lead to falsely high readings and insulin over-dosing. The list served as an excellent reminder that despite the positives we hear about CGM, the massive improvements over the past few years, and the work on automated insulin delivery, there is still important progress to be made. We salute Dexcom and Medtronic and Abbott for working and improving on all these fronts – we see all of Dr. Castle’s wishes as addressable and in these companies’ pipelines.

Insulin Delivery

Oral Presentations

Continuous Subcutaneous Insulin Infusion (CSII) Sets - Reduced Flow Interruptions With A Novel Investigational Catheter Infusion Set

Larry Hirsch, MD (BD Diabetes Care, Franklin Lakes, NJ)

Dr. Larry Hirsch presented encouraging data from a pilot study comparing BD’s new infusion set to Medtronic’s Quick-set in 25 healthy participants. Each participant wore two of each set, one inserted manually and one with an inserter; diluent was used and pressure was tracked for basal and bolus infusion. The results were impressive and highly statistically significant using either an inserter or manual insertion – the BD set reduced flow interruptions by 77%-82% and occlusion events (which included occlusion alarms) by 77-79% vs. the Quick-set. Time spent with flow interruptions was extremely low with the BD set vs. the Quick-set (p=0.018 for insertions with the inserter, and p=0.006 for manual insertions). Leakage and kinking was infrequent and not significantly different, though we noticed the BD set did have a notably higher frequency of kinked cannulas upon removal (5 vs. 1 – NS) – Dr. Hirsch noted that all of these events occurred in the first 1-2 days of the study.  Dr. Hirsch did not share any product design details, but revealed in Q&A that the set has been submitted to the FDA, and BD is hoping for clearance by this summer. He also said that it will be compatible with Medtronic Paradigm and Luer lock reservoirs (i.e., Animas, Roche, Tandem), a huge win for patients. Additional studies of the BD set with HCP insertion and patient self-insertion are underway/have been submitted for presentation. The company hopes to provide “a great deal more information” at ADA in June, AADE in August, and EASD in September.

• There are numerous reports of CSII insulin delivery irregularities. Patients find elevated blood glucose that may/may not respond to a correction bolus – so called “unexplained hyperglycemia.” According to Van Bon et al., DT&T 2011, ~60% of subjects reported at least one of these “unexplained hyperglycemia” events over a 13 week period, and ~30% of subjects had at least one occlusion set alarm. Added together, that means ~2/3 of patients had at least one of these events. When unexplained hyperglycemia occurs without an occlusion alarm, it is often termed “Silent occlusion.” Patel et al. (DT&T 2014) found a ~15% failure rate of initial insertions (hyperglycemia that was not reduced with a correction bolus, within about 8 hours) with a polymer set.
• BD has developed an investigational set with a different design, intended to improve flow reliability – no details were shared on how the set improves flow, but we do know it is a plastic cannula. In preclinical swine studies, the new BD set reduced pressure rises and time with flow interruption by ~75% vs. sets from Medtronic, Roche, and Animas (Poster 221 at this ATTD).
• This trial was a single site, open label comparison between the BD set and the Medtronic Quick-set. It enrolled 25 participants without diabetes. Each participant had four basal/bolus diluent infusions in the abdomen through two of each set – one was manually inserted and one was inserted with Medtronic’s Quick-serter. All insertions were done by study HCPs. After set removal, the infusion site was assessed for leakage, swabbed, and measured; no leakage meant <0.5 units. In-line pressure data was collected throughout the study through use of a transducer.
• Four insulin pumps were connected by line extension tubing to the transducer. On the other side, tubing went to the infusion sets of interest. Device placement took five minutes, followed by one minute of catheter priming. Basal infusion then took place at a rate of one unit per hour, followed by bolus infusion of 10 units for 10 minutes. Then, basal infusion of one unit per hour resumed for 30-60 minutes. A forced occlusion tubing clamp ended the study and served as a positive control.

OpT2mise study: The Impact of Insulin Pump Therapy on treatment Satisfaction and Resource Utilization in Patients with Type 2 Diabetes

Ronnie Aronson, MD (LMC Diabetes & Endocrinology, Calgary, Canada)

While the headline results from the Medtronic-sponsored OpT2mise trial were a net positive for pumps, the trial provided evidence of pumps’ costs as well. This presentation of secondary results regarding treatment satisfaction and resource utilization by co-investigator and co-author Dr. Ronnie Aronson (LMC Diabetes & Endocrinology, Calgary, Canada) provided evidence for both sides of the equation. Although Dr. Aronson highlighted the across-the-board 10-20% improvements in a treatment satisfaction seen with pumps in OpT2mise, he also shared that there were nearly triple the number of unscheduled physician’s office visits in the pump group (0.76 visits/patient) than in the MDI group (0.28 visits/patient). The difference persisted when only study-related unscheduled visits were counted (0.66 visits/patient with pumps vs. 0.20 visits/patient with MDI), and there was a non-significant trend towards more hospitalizations in the pump group (15 vs. 9) although based on relatively few events. Dr. Aronson attributed the imbalance in office visits to the learning curve with pumps. Indeed, providing a peek at numbers from the second six months of the trial, he showed a roughly threefold drop in the incidence of unscheduled visits compared to the first six months in patients in the pump arm. Even so, we can see from data like this why providers perceive a possible hassle factor (and cost!) in getting patients started on pumps, despite the clinical benefits and improvement in overall patient satisfaction.

D-Nav: A Real–World Evaluation Of A Novel Assistive Technology (D-Nav) To Optimise Glycemic Control In Those With Type 2 Diabetes Requiring Insulin Therapy

Roy Harper, MD (South Eastern Health and Social Care Trust, Dundonald, UK)

Dr. Roy Harper (South Eastern Health and Social Care Trust, Dundonald, UK) presented results from a pilot evaluation of Hygieia’s d-Nav device, an insulin titration device with built-in blood glucose meter capability. The single-center study in Northern Ireland enrolled 126 patients with diabetes (122 with type 2) treated with insulin for at least a year – 51% on basal/bolus, 42% on premixed insulin, and 7% on basal insulin only. Patients were instructed to use the device to test their glucose before every insulin injection and when they suspected hypoglycemia; the device would then recommend an insulin dose (if needed) as well as providing weekly insulin dosage updates based on blood glucose patterns with the aim of achieving a “balance” between reducing glucose and avoiding hypoglycemia (we hope to hear more specific details about how the algorithm works in the future). Among the 96 active participants, average A1c dropped significantly from 9.2% at baseline to 7.8% at the first follow-up visit (3-5 months) and 7.5% at the second (6-12 months); there was also a significant increase in the percentage of patients with an A1c ≤7.5% (12.6% at baseline; 45.1% at the first follow-up; 60.2% at the second follow-up). In many cases, the glycemic improvements likely resulted from increased insulin dosage; the average total daily insulin dose increased from 84 units at baseline to 153 units after 26 weeks. On the negative side, participants experienced an average 3.5-kg weight gain, and 40% reported an increase in mild hypoglycemia; there was no significant increase in severe hypoglycemia.

• Dr. Harper portrayed d-Nav as a service that can help patients manage the frequent dose adjustments necessary for successful insulin therapy without extensive support from clinicians – something that is sorely needed given the limited time most providers have with patients. The group is currently conducting a larger evaluation (n=260) in an attempt to “regionalize” the product throughout Northern Ireland; Dr. Richard Bergenstal is also initiating an NIH-funded study that could support uptake in the US. Dr. Harper said that the reception among patients has been very positive thus far, suggesting that weight gain and hypoglycemia have not been major barriers in most cases. Given the framing of d-Nav as a pseudo physician replacement, we are curious to see how amenable HCPs are to the device if it becomes more widely used – we imagine that some would embrace it as a useful tool to support greater self-management, while others might perceive it as infringing on their control over patients’ treatment regimens.

Insulin Glargine 300 U/mL vs 100 U/mL: Glucose Profiles of Morning Vs Evening Injections in Adults With T1DM Measured with Continuous Glucose Monitoring (CGM)

Timothy Bailey, MD (UCSD, San Diego, CA)

This multicenter phase 2 CGM study enrolled 59 type 1 diabetes patients who were randomized to Toujeo or Lantus and crossed over between morning and evening injections, wearing CGM for the entire duration of the study (this designed really enabled others to assess the value in a way that A1c alone just doesn’t allow). During the final two weeks of each crossover period (when the insulin dose was fixed) there was no significant difference between time-in-range (80-140 mg/dl) between the Toujeo and Lantus groups, although there did appear to be a small trend in Toujeo’s favor. However, an analysis of the last four hours pre-injection showed less than half the change in glucose with Toujeo vs. Lantus. CGM traces included in the slides really showed the difference in intra-day PK stability with Toujeo vs. Lantus, especially with morning dosing. Toujeo also showed a 5%-15% improvement in various standard deviation-based measurements of glycemic variability over Lantus. The CGM data definitely showed some benefit with Toujeo over Lantus, particularly in the early weeks where there is more stability –  this is important since that is a common week for patients to otherwise decide to drop therapy (this was the time there appeared to be less nighttime hypoglycemia). Big picture, we were encouraged to see CGM used in an insulin trial and hope more manufacturers do such studies in the future as it makes it easier to assess results. We look forward to seeing more qualitative data as we believe this also has a major impact on adherence. 

Sustained Glycemic Control and Less Hypoglycemia with New Insulin Glargine 300 U/mL vs. 100 U/mL: 1-Year Results in T2DM with Basal+Mealtime Insulin (EDITION 1)

Geremia Bolli, MD (University of Perugia, Perugia, Italy)

We also saw full one-year data from the phase 3 EDITION I trial – these results were presented as posters at ADA and EASD last year but this was the first time we were seeing them on the big screen. The six-month primary results found equal A1c reductions of 0.83% from baseline (8.2%) with both formulations and a reduction in hypoglycemia at some time points with Toujeo. We were intrigued to see that in the second six months, Lantus’ efficacy began to wane very slightly while Toujeo’s held firm, leading to a modest but statistically significant 0.17% difference between the arms (p=0.007); mean fasting plasma glucose levels and weight gain at the end of the trial were not significantly different between groups. There was either a significant decrease or a non-significant beneficial trend in hypoglycemia, depending on how hypoglycemia was defined – it would’ve been terrific to see CGM in the full trial so time in hypoglycemia could be assessed.

Plenary Session: Opening Ceremony

CSII In Type 2 Diabetes: Evolution or Revolution?

Yves Reznik, MD (Centre Hospitalier Universitaire de Caen, Caen, France)

In the opening keynote, OpT2mise lead investigator Dr. Yves Reznik covered key results from the Medtronic-sponsored trial and summarized the predictors of success with pumps. This fits in with a broader theme of more focus on pumps in type 2 diabetes, and we were glad that Dr. Reznik touched upon other randomized and observational studies as well given that this was the day’s one non-sponsored session. For background, in the main analysis of OpT2mise (published last summer in the Lancet and shown as a late-breaking poster at ADA 2014), A1c declined by 1.1% in those on an insulin pump compared to 0.4% in the MDI group (p<0.001) after 27 weeks in the context of a roughly 20% lower daily insulin dose and less hypoglycemia. The most important predictors of success with pumps were higher baseline A1c, more advanced education, and frequency of daily boluses – some of these secondary analyses were presented as a poster at EASD. Factors that did not impact success with pumps included diabetes duration, older age, the degree of overweight at baseline or weight gain during the trial, compliance (as determined by SMBG frequency), and mild cognitive dysfunction – it was encouraging to see that these factors were not deal-breakers for pump usage, which is typically positioned for younger, tech-savvy patients. Notably, Dr. Reznik confirmed that 12-month OpT2mise results should be presented at this year’s ADA. He also called out the recent ADA/EASD 2015 Position Statement Update for only mentioning insulin pumps once, in the context of LADA. He suggested that pumps could be included in the insulin intensification diagram as an option if patients do not reach goal on MDI. A point well taken, though the cost must come down for sure.

Plenary Session: Technology and Type 2 Diabetes

Treatment of Type 2 Diabetes: What Are The Best Options?

Richard Bergenstal, MD (International Diabetes Center at Park Nicollet, Minneapolis, MN)

In a talk on insulin pumps in type 2 diabetes, Dr. Richard Bergenstal questioned how serious the field is about reaching A1c targets, emphasizing that earlier introduction of therapies might produce better results. Filling in for Dr. Bruce Bode (Emory University, Atlanta, GA), Dr. Bergenstal opened his presentation by asking whether using treatments like insulin pumps as “rescue therapies” is the best approach, noting that 80% of patients with type 2 diabetes on insulin are not at goal. He returned to this theme during Q&A, pointing out that despite stated A1c targets of 7-7.5%, most providers do not take action until a patient’s A1c reaches 8.5-9%. This is incredibly disheartening to hear from a patient (and system) perspective. With regard to insulin pumps specifically, Dr. Bergenstal believes the available evidence suggests that pump therapy (including patch pumps) can produce substantial glycemic improvements with lower insulin doses compared to MDI and potentially improve patients’ quality of life. He called for future randomized trials comparing the effectiveness of pumps (including patch pumps) vs. other type 2 diabetes therapies, particularly basal insulin/GLP-1 agonist combination therapy. We agree that an evaluation of the cost/benefit profile of insulin pumps compared to newer pharmaceutical options for type 2 diabetes (e.g., SGLT-2 inhibitors, once-weekly GLP-1 agonists, new combination drugs) would be a very interesting subject for future trials. Dr. Irl Hirsch (University of Washington, Seattle, WA) put forward during Q&A that the playing field has changed even since the OpT2mise trial began in 2012, and it remains to be seen whether implementing pump therapy for type 2 diabetes on a large scale is worth the cost and hassle factor, particularly for primary care providers. We continue to wonder the impact of “time in zone” on long-term complications and hope that moving forward, analysis of big data may help answer some of these questions.

Parallel Session: ARIA –Nothing New under the Sun?

Inhaled Insulin Reloaded: Impact of Afrezza and Oral Insulin: What Is Going On?

Eric Zijlstra, PhD (Profil, Neuss, Germany) and Tim Heise, MD (Profil, Neuss, Germany)

An afternoon tag team from two Profil scientists featured a positive perspective on Afrezza and recognition of the challenges in developing oral insulins. Dr. Eric Zijlstra began by comparing Pfizer’s previous inhaled insulin Exubera to a mayfly – an insect that undergoes a long developmental phase but lives for just one day (this got some laughs). Although we heard doubt at the 2014 FDA AdComm whether Afrezza could obtain a hypoglycemia claim, Dr. Zijlstra argued in favor of a hypoglycemia benefit given that the reduction in hypoglycemia was seen in both well-controlled and poorly controlled patients. [As noted in our report on the FDA approval, the label only includes the type 2 diabetes hypoglycemia and weight data, ignoring the benefits in type 1.] Dr. Zijlstra characterized the Sanofi partnership as a win-win, and expressed enthusiasm about the potential to use Afrezza as part of an artificial pancreas system to provide initial postprandial control – something that is badly needed until faster-acting insulins are developed. The UCSB team has presented encouraging data on this front in the past, and we hope to see more discussion of this. Al Mann has commented that the ideal combination for might be a basal insulin patch pump with Afrezza.

• Dr. Tim Heise’s presentation provided a balanced view of the benefits and challenges associated with oral insulin. Oral delivery provides a more physiologic route that should lower hypoglycemia risk and reduce weight gain. The harsh pH of the stomach and presence of proteases pose formidable challenges; recent phase 2 data on Novo Nordisk’s oral GLP-1 agonist OG217SC showed almost 300x lower bioavailability with oral delivery (though very positive effects on A1c). Lilly’s peglispro (which is liver-selective) was recently delayed due to liver safety questions, and we wonder if oral delivery (which also involves first-pass liver processing) may have the same risks. Dr. Heise characterized clinical data on oral insulin from Emisphere, Biocon/BMS, and Oramed as slightly lackluster, with weaker efficacy and/or inter-patient variability. Dr. Heise continues to believe that there is lots of potential in oral insulin (especially oral basal insulin), but there remains much room for headache and frustration as well.

Corporate Symposium: Pump Therapy for Type 2 DM Patients – A New Therapeutic Paradigm (Sponsored by Medtronic)

OpT2mise

Ohad Cohen, MD (Sheba Medical Center, Tel Hashomer, Israel)

At a Medtronic workshop focused specifically on the OpT2mise trial, Dr. Ohad Cohen stressed that pump therapy for type 2 diabetes does not require complex dosing calculations. He acknowledged that this is counterintuitive for many clinicians who are used to treating patients with type 1 diabetes, admitting that even he couldn’t resist the urge to make small dosing adjustments during the trial. However, for the patient population studied in OpT2mise (i.e., poorly controlled, obese, insulin-resistant, long duration of diabetes), he recommended simply using a single basal rate and fixed bolus doses, arguing that small adjustments are unlikely to be meaningful in the context of large insulin doses (“four units per hour!”) and limited glycemic variability (i.e., since there is usually some residual beta cell function). Overall, Dr. Cohen characterized pump therapy as one of the most appealing options for patients not at goal at the “end” of the type 2 diabetes treatment algorithm. We agree that the potential for greater A1c improvements (1.1% with pumps vs. 0.4% with MDI in OpT2mise) with less insulin and no increased risk of hypoglycemia or weight gain compared to MDI is an exciting prospect.

• On the other hand, we have also heard speakers (including Dr. Timothy Garvey at Obesity Week) suggest that addressing obesity should be a greater priority with these patients, and adding more diabetes medications (particularly those that lead to weight gain) is much less likely to be effective. Food for thought... From that perspective, doubling down on insulin therapy – especially Dr. Cohen’s recommendation to increase the insulin dose if patients are still not reaching target – would not be ideal. However, he did also encourage providers to reevaluate patients’ oral medication regimens, eliminate those likely to cause weight gain, and try a GLP-1 agonist. Certainly, there is no single right way to treat type 2 diabetes, and we’re glad to see pump therapy (hopefully) becoming more accepted as another option in the toolbox, particularly globally.
• At the end of the session, a Medtronic rep asked attendees to take part in European market research for a “dedicated pump” for type 2 diabetes. While the Medtronic/Sanofi type 2 diabetes partnership has been dissolved (see our Medtronic earnings report from February), the company clearly remains committed to the area, as evidenced by the recent hiring of the highly respected Dr. Bob Vigersky as top medical lead for the type 2 program. We will be watching closely for more details on the proposed device and hope to see what emerges that is clinically effective, designed to fit the needs of type 2 patients, cost-effective, and simple enough to compete with once-weekly GLP-1 agonists (a tall order!).

Corporate Symposium: Simple Insulin Infusion for People with Type 2 Diabetes (Sponsored by CeQur)

Demonstration of Glycemic Control in PaQ Feasibility Study

Julia Mader, MD (CeQur, Marlborough, MA)

Dr. Julia Mader presented encouraging preliminary data from CeQur’s pilot study of its PaQ insulin delivery device in patients with type 2 diabetes (n=8). The trial consisted of three study periods: baseline MDI (one week), transition from MDI to PaQ (1-2 weeks – to ensure that patients were on an appropriate basal rate), and PaQ treatment (12 weeks). Preliminary results indicated that PaQ treatment reduced A1c a strong 1.8% from a baseline of 8.9% (n=6; one patient has yet to report and one patient dropped out of the study). Looking at individual data, it was great to see that every patient who transitioned to PaQ experienced an A1c reduction (i.e., 100% of patients saw some glycemic benefit). Considering the short duration of the study, Dr. Mader emphasized that the “1.8% A1c reduction is pretty impressive by itself.” We would agree! Based on these positive results, the company is hoping to transition into a larger clinical trial (n=25) later this year. This study will pave the way toward a hoped-for 2016 launch of PaQ in both the EU and US (details on this new timeline below).

• During Q&A, CeQur management shared new updates on the PaQ launch timeline. The company is now planning an EU launch in 2016, a slight delay relative to previous guidance that put a launch in 2015 (CE Mark approval came in November 2012). CeQur is planning a soft launch in Germany – and potentially Sweden – before expanding.
  
  • In the US, CeQur plans to submit an FDA 510(k) application this year and is cautiously optimistic for a 2016 US commercial launch. This is the first time we can recall the company providing US timing, a great signal of internal confidence. As a reminder, the company appointed Mr. Douglas Lawrence as Chief Executive Officer in April 2014, and we are hopeful that his background at BD will help CeQur navigate the complex US regulatory landscape.
  • CeQur will continue to do clinical studies throughout 2015. Dr. Mader described the next trial in the pipeline, a larger version (n=25) of the pilot study that will use blinded CGM. This is great to hear, and we will be eager to see data on time in zone and hypoglycemia.
• Returning to the pilot study, we would point out that secondary outcomes were positive as well. Total daily dose of insulin and body weight were not statistically different from baseline. On the insulin dose front, 75% of patients successfully transitioned to PaQ with the first basal dose, which is hopefully a good sign that the device should be easy for HCPs to transition patients onto. No severe hypoglycemic events, serious adverse events, or catheter site infections were reported.
  
  • Hopefully, future studies will include data on the bolus adherence front (e.g., average number of daily boluses on MDI vs. PaQ). We see the ease of bolusing on PaQ vs. MDI as a major advantage to this device and suspect that a larger study would likely bear out the expected improvement in adherence, particularly in patients sub-optimally controlled and/or forgetful.

Simple Insulin Infusion is Cost-Effective

Ole Henriksen (Last Mile P/S, Copenhagen, Denmark)

Mr. Ole Henriksen presented a health economic analysis of the cost-effectiveness of insulin pump therapy in type 2 patients in Germany. The modeling study was designed to answer one question in particular: Given that pumps were shown to be superior to MDI in poorly controlled patients (per Medtronic’s OpT2mise study), at what cost level is CSII a good value for money? The researchers utilized the “UKPDS Outcome Model” to predict life-years saved, running the analysis based on the cost of insulin therapy in Germany and patient outcomes collected from the OpT2mise trial. Results indicated that pump therapy would be “highly cost-effective” at a daily cost of 5.3 euros and would be “cost-effective” up to a daily cost of 9.2 euros. (Cost-effectiveness was defined according to thresholds establish by the World Health Organization). During Q&A, Mr. Henriksen noted that the cost-utility does not derive entirely from projected reduction in complications associated with pump use (~19,000 euros over a lifetime) as one might expect. Rather, he emphasized that the addition of life years projected by the model for patients on pumps plays a major role as well.

• It was notable to hear the prediction that cost-effectiveness with pumps in type 2 patients can be achieved at under 10 euros per day – however, the findings seem to raise as many questions as they provide answers: (i) How was the cost of MDI in Germany estimated? (ii) Will the average type 2 patients be motivated to use pump therapy as conscientiously as those in OpT2mise were? (iii) What does this mean for cost-effectiveness for the “average” type 2 patient since OpT2mise was conducted in patients in poor control?
• It is great to see the effort at modeling what has become a big topic of controversy for type 2 patients. However, we would note that the goal is to get payers to appreciate this value. We wonder how they would respond to the modeling data and whether they would demand more “real-world” findings to support these claims. It’s hard for us to know exactly what data payers want to see to cover simple CSII.

Panel Discussion

Q: When talking about the improvement in glucose control with continuous infusion, what contributes more to the improvement we see? Better adherence or the flatter profile of the resulting insulin levels?

Dr. Juan Pablo Frias: Probably both. But, better adherence is probably the bigger factor. I think certainly having the device attached to you and not missing the multiple doses is the factor that helps patients. The better bioavailability certainly plays a role as well in terms of more physiological delivery.

Q: How does the device stick on the body?

Dr. Peter Gravensen: The device is built with adhesive tape, so it is taped onto the body.

Dr. Leslie Lilly: We have done a number of adhesive studies to assess for dermal irritation and for comfort. So we have identified the type of dermal tape that meets those criteria.

Q: I would worry that the PaQ insulin-containing balloon would suddenly burst and dump insulin faster than desired into my patient? Can you explain why this can’t happen?

Dr. Gravensen: When we have pressurized insulin, we have to ensure that the insulin cannot get into the user any more quickly than we intend. Any pathway from the product into the user consists of checks and balances. There is redundancy built in, just like it is for aircrafts or space shuttles.

Q: Can I buy the pump today?

Dr. Lilly: We do have a CE Mark for the product. We are planning a limited launch in Germany by the end of this year. And then, we’ll expand. [Correction: Management shared after the symposium that the EU launch is actually planned for 2016.]

Q: Mr. Henriksen, in your model, where is the cost-utility coming from? I assume it is coming from the fewer complications?

Mr. Ole Henriksen: Actually, the cost of insulin plays a big role. The reduction in complications is not the biggest factor, but the addition of life years in the model is a major factor as well. That’s the two parts of it.

Q: Can you comment on clinical trial results and the significance of the A1c drop?

Dr. Julia Mader: Our first two-week study showed an improvement in A1c even though you would not expect it in such a short period of time. We just completed our first three-month study. Now, we’re looking forward to another three-month study. However, the 1.8% A1c reduction we saw here is pretty impressive by itself. That is a substantial improvement in and of itself. That too, anecdotally, we’ve heard that some of the patients in our trials that have gone back on MDI have seen their A1c increase again. They want to come back to our trial.

Additional Topics

Oral Presentations

Intranasal Glucagon For Treatment Of Insulin-Induced Hypoglycemia In Adults With Type 1 Diabetes: A Randomized, Cross-Over Non-Inferiority Study

Michael Rickels, MD (University of Pennsylvania, Philadelphia, PA)

Dr. Michael Rickels presented a phase 3 study (n=75 adults) comparing Locemia’s exciting intranasal needle-free glucagon powder for severe hypoglycemia to standard intramuscular glucagon injection. The randomized, crossover trial at eight T1D Exchange clinics administered IV insulin until blood glucose <60 mg/dl. Five minutes after stopping insulin (mean nadir was ~46 mg/dl), glucagon was given – a 3 mg intranasal dose at one visit and a 1 mg intramuscular dose at the other visit. Notably, Locemia’s intranasal glucagon was non-inferior to intramuscular injection: all subjects responded with an increase in blood glucose, although 1% of the Locemia arm and 0% of the intramuscular arm failed to achieve the primary outcome (an increase in blood glucose to >70 mg/dl OR an increase >20 mg/dl from nadir within 30 minutes post-administration – this seemed like an unconventional endpoint, but it was agreed upon with the FDA). Median time to achieve the primary outcome was 10 minutes for intramuscular injection vs. 15 minutes for intranasal delivery. The five minute delay in pharmacodynamics for intranasal delivery was fairly inconsequential in our view, given the time it takes to prepare a traditional glucagon kit vs. the needle-free, single-button push delivery of the Locemia device (see a picture on Twitter here). Nausea and vomiting occurred at a similar frequency, though transient head/facial discomfort were more common with intranasal glucagon (25% vs. 9%) – not a major issue given the circumstances under which this would be given. The Locemia team is doing other studies, including a usability study (n=200) and pediatric study.

• This presentation represented the first public display we’ve seen of Locemia’s needle-free, intranasal delivery device for severe hypoglycemia – it looks like a dramatic improvement over existing glucagon kits. The plastic device fits in the palm of the hand and contains a dry powder formulation. To administer the glucagon intranasally requires one step (to be performed by a caregiver in treating an episode of severe hypoglycemia): depress the plunger into the device chamber. That single step compresses the air in the device and dispenses the powder into the nose (similar to nasal spray for a cold). The device contains a 3 mg dose of glucagon, higher than the 1 mg dose in a rescue kit. 
• Locemia is furthest along on the improved glucagon rescue delivery front – both Xeris (auto-injector) and Biodel (auto-reconstitution pen) have yet to begin their phase 3 studies. We assume Locemia could use the 505(b)(2) regulatory pathway, which means the company could potentially come to market as early as late 2016 or early 2017. We do wonder about partnerships and what commercialization will look like.

Hi-Touch/Hi-Tech: Diabetes Management Manual, A Type 1 Diabetes Guide to the Universe, with Embedded Videos, Interactive Elements & Unlimited Updates

Joe Solowiejczyk (President and Founder, A Mile in My Shoes)

Diabetes educator and therapist Mr. Joe Solowiejczyk (President and Founder, A Mile in My Shoes) provided an inside look into his interactive e-book, “A Type 1 Diabetes Guide to the Universe.” The e-book, available in the Apple App Store, integrates the psychological and family aspects of diabetes to help youth and their families learn to manage the disease as independently as possible. Mr. Solowiejczyk noted that the purpose is to “make it feel very similar to going to the doctor’s office,” which is accomplished through various embedded videos (which can be viewed offline) of both Mr. Solowiejczyk as well as of families and children from the US, Canada, and Australia. The e-book also includes a comprehensive range of chapters on diabetes management (e.g., insulin doses, meal planning, and exercise). Mr. Solowiejczyk highlighted that the response to this educational tool has been “tremendous” with its blend of high-touch and high-tech components. In addition, he called for any investors or collaborators who are interested in helping expand “A Type 1 Diabetes Guide to the Universe,” as the e-book is currently only available in English. Looking forward, Mr. Solowiejczyk plans to write similar books on the relationship of diabetes to celiac disease, sports and extreme sports, as well as ADHD/Asperger’s syndrome, with his ultimate long-term goal being an artificial intelligence version of himself that can have virtual conversations with patients. Recognizing the need for better education tools for both patients and their caregivers especially, we applaud Mr. Solowiejczyk for authoring this e-book and taking a unique and more engaging approach to education. As the field continues to suffer from a shortage of providers, we believe that tools like these are critical to help patients manage their own care more and more independently.

Factors Associated with Severe Hypoglycemia in Older Adults with Type 1 Diabetes

Stephanie DuBose, MPH (Jaeb Center for Health Research, Tampa, FL)

Ms. Stephanie DuBose presented data suggesting that hypoglycemia unawareness and glycemic variability are the main factors underlying the high rates of severe hypoglycemia in older adults with type 1 diabetes. The case-control study evaluated 201 patients in the T1D Exchange Registry aged 60 years or older with a duration of type 1 diabetes ≥20 years, none of whom used CGM. The investigators categorized patients based on whether they had experienced severe hypoglycemia in the past 12 months and used lab tests (e.g., A1c, C-peptide levels), psychosocial assessments, and blinded CGM to identify the key factors that differed between the two groups. Results showed that the cases (the group that had experienced severe hypoglycemia) had significantly higher rates of hypoglycemia unawareness (58% vs. 25%; p<0.001) and high glycemic variability (38% vs. 12% in at least the 75^th percentile; p<0.001) compared to the controls. The percentage of patients with both hypoglycemia unawareness and high glucose variability was also significantly higher among cases than controls (24% vs. 5%; p=0.003). Notably, there was no significant difference in average A1c (7.8% vs. 7.7%; p=0.06) or the percentage of patients with an A1c <7% (26% vs. 28%; p=0.44) between the two groups, suggesting that at least in this population, tight glycemic control was not associated with a greater risk of severe hypoglycemia. Excitingly, Ms. DuBose noted that she and her colleagues are planning a study investigating whether CGM could reduce the risk of severe hypoglycemia in these patients, explaining that this is “what the FDA would want to look at to get Medicare to approve these devices in this population.” We are thrilled to see more research being done in this area, as we strongly believe that greater access to CGM would allow many older patients with longstanding diabetes to minimize the risk of severe hypoglycemia without sacrificing glycemic control.   

• Other factors that differed significantly between cases and controls included: fear of hypoglycemia (scores of 38.5 and 31.6, respectively, on the Hypoglycemia Fear Survey; p<0.001), frequency of blood glucose monitoring (six times/day vs. five times/day; p=0.02 – not clinically meaningful), and use of beta blockers (40% vs. 21%; p=0.006), though there was no correlation between beta blocker use and hypoglycemia unawareness. A significantly higher percentage of cases also had reduced cognitive capacity as measured by the Montreal Cognitive Assessment (MoCA), but Ms. DuBose noted that this may have been a result of severe hypoglycemia rather than a contributing factor.
• There was no significant difference between the groups for factors including: mean glucose (175 mg/dl for both; p=0.58), time with blood glucose between 70 and 180 mg/dl (51% vs. 52%; p=0.28), daily function, rates of depression, diabetes numeracy, and C-peptide levels. There was a trend toward more overall hypoglycemia in cases vs. controls (65 vs. 43 minutes/day with blood glucose <60 mg/dl), but it was not statistically significant (p=0.12).
• These results open an interesting discussion relative to Dr. Irl Hirsch’s (University of Washington, Seattle, WA) ATTD presentation advocating for higher A1c targets in patients with longstanding type 1 diabetes. Dr. Hirsch argued that given the unacceptably high rates of severe hypoglycemia in this population (~20% risk per year with a duration of diabetes >20 years) and the mixed evidence regarding the benefits of strict control, less stringent targets are likely appropriate for many patients. While we certainly agree that the dangers of hypoglycemia should not be overlooked, these data suggest that tighter control (as measured by A1c) may not be driving severe hypoglycemia. CGM may help, but the lack of evidence from clinical trials confirming that hypothesis has been one of several barriers to Medicare coverage of CGM; our fingers are crossed that the upcoming study Ms. DuBose alluded to can help remedy that.

Questions and Answers

Dr. Robert Vigersky (Walter Reed National Military Medical Center, Bethesda, MD): Did you analyze the results with respect to A1c? In type 2 diabetes, there’s a U-shaped curve that describes the frequency of hypoglycemia related to A1c. Did you look at that?

A: Not yet, but we have a manuscript planned that will include that.

Q: With the variability data, in terms of generalizability, if you define high variability as higher than 75% of the population, that’s less generalizable. Many of these subjects would fit the criteria for starting the 530G. There is a clinical remedy for this. What further studies would we need?

A: We’ve formed a working group for the next study. We want to look at the CGM study and go from there and look at what the FDA would want to get Medicare to approve these devices in this population. It is less generalizable; we defined high variability as a measure to look at the combination of those two factors [glycemic variability and hypoglycemic unawareness], and it was specific to this group.

Dr. Irl Hirsch (University of Washington, Seattle, WA): We’ve published in pediatric and adult patients the relationship between A1c and severe hypoglycemia. In both groups – it’s more striking in pediatrics but not specific to the older population – there’s a U-shaped curve between severe hypoglycemia and A1c. I don’t know this for a fact, but I think the highest A1cs have more hypoglycemia because of decreased frequency of testing. That would be different from type 2 and from the conclusions of the DCCT.

Parallel Session: Diabetes Technology Research

NIDDK/NIH Initiatives for Diabetes Technology Research

Guillermo Arreaza-Rubin, MD (NIH/NIDDK, Bethesda, MD)

Program Director Dr. Guillermo Arreaza-Rubin (NIH/NIDDK, Bethesda, MD) provided a list of the NIDDK’s program priorities in diabetes technology, which included artificial pancreas, human islets, bio-artificial/encapsulation strategies, and the imaging of beta cells. Dr. Arreaza-Rubin highlighted that the NIDDK is focusing on technologies to support the newly established Human Islets Research Network (HIRN) in order to develop strategies to protect and replace functional beta cell mass. In addition, the program is researching new technologies for the advancement of cell replacement research such as bio-artificial and encapsulation, of which Dr. Arreaza-Rubin noted NIDDK is working to complement HCT and JDRF’s work in this area. He also highlighted that significant progress has been made in the imaging work of beta-cells in better understanding the cells’ natural history, inflammation, and engraftment. Other priorities included developing new technologies for complications and assessment of risk (for earlier diagnosis and prognosis of type 1 diabetes) as well as research into automated-mechanical hormone replacement therapies such as artificial pancreas systems. Notably, NIDDK has been collaborating with the FDA, specifically in discussing recently published guidance (for low glucose suspend and artificial pancreas systems) as well as in participating in collective workshops.

• Dr. Arreaza-Rubin mentioned that there will likely be a collaborative JDRF/FDA/NIH artificial pancreas workshop in the spring of 2016. Due to the presentations by the JDRF and Helmsley Charitable Trust (see below), Dr. Arreaza-Rubin did not focus as much on the NIH’s artificial pancreas efforts, but highlighted that the coordination efforts among the NIH, Helmsley Charitable Trust, and JDRF are ensuring that the research is not overlapping. He discussed the main conclusions from 2013’s artificial pancreas workshop on what is needed, which included better metrics to assess sensor reliability, the need of calibration-free CGMs, the need for improved infusion sets and methods, and more. Dr. Arreaza-Rubin pointed out that these concerns continue to remain valid today and suggested that there may be another workshop next spring.
• The NIDDK is currently supporting academic centers and industry to fund research on more stable and rapid-acting insulin and glucagon formulations, improved glucose sensing, and more. Other funded research areas include: (i) devices that combine sensing and hormone delivery; (ii) biocompatibility strategies to extend the life of implantable miniaturized glucose sensors; (iii) clinical testing of dual ambulatory hormone replacement automated systems; (iv) testing the use of other hormones to optimize physiological glucose control; (v) overnight and daytime testing of novel closed-loop algorithms; (vi) physiological and behavioral inputs to improve control of closed-loop systems; (vii) glucose-responsive insulin biomaterials platforms; and (viii) centralized and control artificial pancreas hubs with plug and play capability.
• Dr. Arreaza-Rubin also highlighted during Q&A that he has been in conversations with Mr. Dana Ball (Executive Director, T1D Exchange & CEO, Unitio) to design studies that can better convince payers for reimbursement. In discussing the challenges with the CMS on various devices, Dr. Arreaza-Rubin pointed out the importance of garnering solid evidence appropriate for the Agency. He emphasized that this is essential in geriatric populations, as CGMs lose coverage in Medicare.

JDRF and Helmsley Charitable Trust Initiatives for Diabetes Technology Research

Aaron Kowalski, PhD (JDRF, New York, NY) and David Panzirer (Helmsley Charitable Trust, New York, NY)

In a discussion on priorities in technology, Dr. Aaron Kowalski (JDRF, New York, NY) and Mr. David Panzirer (Helmsley Charitable Trust, New York, NY) emphasized the importance of increasing patient access and including the patient’s voice early on. Dr. Kowalski highlighted that the ultimate success of the artificial pancreas is making sure people with diabetes achieve better outcomes, which is accomplished through expanding patient access. He emphasized that moving forward, JDRF’s funding will focus on “breaking barriers” with regulatory bodies, payers, and clinicians so that the artificial pancreas can become a less costly system available to more people. This is of course also a sign that artificial pancreas technology has adequately progressed to shift major focus to issues of reimbursement and access. Following Dr. Kowalski, Mr. Panzirer noted that the Helmsley Charitable Trust (HCT) shares JDRF’s vision and that “the single most important thing that needs to be worked on is including the voice of the patient from day one,” citing the relatively low penetration of insulin pumps and CGMs. In addition, he emphasized that primary care providers must be better educated to treat type 1 diabetes, as the majority of people with diabetes do not have access to an endocrinologist. Notably, Mr. Panzirer also emphasized that a significant barrier to innovation is the lack of end users, as companies lack the competitive incentives to move forward on pumps and CGMs with so few people on devices. It was valuable to hear both Dr. Kowalski and Mr. Panzirer on the same page, as the HCT and JDRF represent two of the most influential funders and voices in type 1 diabetes.

• During Q&A, Dr. Kowalski introduced his idea of the diabetes “scorecard” as a method to incorporate patient, provider, and payer voices when assessing different therapies. He commented that the field focuses too much on A1c, while burden and cost are often disregarded early on in the development of a therapy. Therefore, his scorecard evaluates therapies based on three factors – glycemic control, burden, and cost – which would be assessed by patients, providers, and payers. This scorecard’s potential to help consider different stakeholder’s views, according to Dr. Kowalski, could help provide guidance in driving the field forward. Certainly, it sounds quite aligned with what the Bigfoot Biomedical team is working on, and we look forward to a more formal document summarizing the scorecard.

Parallel Session: Safety of Medical Devices for Diabetes

A Pediatrician’s View from Across the Pond – Pumps and Sensors

Desmond Schatz, MD (University of Florida, Gainesville, FL)

Dr. Desmond Schatz provided a comprehensive overview of “where we are” with pump and CGM use in the US pediatric population. Dr. Schatz prefaced his talk by putting the disappointing status of glycemic control in this population in context by sharing updated numbers from the T1D Exchange. As of January 2015, fewer than one in five US children is meeting ADA guidelines for glycemic control (A1c <7.5%) despite an average annual income of ~$80,000/year in this population. Given the technology available, Dr. Schatz stressed that the numbers are in part a reflection of the underutilization of pumps and CGM in this population. Indeed, he associated pump use directly to better glycemic control by sharing recent data from the T1D Exchange. As we saw at ATTD 2011, the average A1c of pump users in the database is ~0.6% lower than that of injection users. On the CGM front, penetration is still just 5% in T1D Exchange participants <26 years vs. 22% for those >26 years. Indeed, he emphasized that the ADA’s statement on CGM use (“a useful tool” for adults > 25 years) is a conservative approach that “needs to be extended” to younger children.

• Dr. Schatz shared updated data from a subset of the T1D Exchange (n=16,791) on the proportion of US type 1 patients not at goal. The trend was incredibly depressing given how much better the tools have gotten. As a reminder, the target A1c for patients <18 years is 7.5%; the target A1c for those >18 years is 7.0%. Young adults continue to represent that most challenging population to manage with fewer than one in five patients ages 13-25 in goal.

Table 1: Proportion of US Type 1s at A1c Goal

Ages (years)
	<6	6-12	13-17	18-25	26-49	>50
% Meeting A1c Goal	22%	22%	17%	14%	31%	29%

• On a more positive note, Dr. Schatz shared T1D Exchange data showing that US pump penetration has been on an encouraging trajectory since 2010. Though certainly not representative of the whole US type 1 population, the data reveal the gradually increasing penetration of insulin pumps in the type 1 population over the last few years. Use of pumps in pediatric patients <13 years old has increased quite substantially over time, rising from 43% to 62% in those <6 years and 54% to 65% in those 6-12 years. This was pretty marked movement in just four years and we wonder how this breaks down by company – Insulet has historically been very strong in pediatrics, and we wonder how the company has fared vs. Medtronic, Animas, Roche, and Tandem. 

Table 2: Insulin Pump Use by Age in the T1D Exchange

	<6	6-12	13-17	18-25	26-49	>50	Overall
2010	43%	54%	53%	53%	61%	59%	53%
2014	60%	62%	65%	58%	55%	63%	60%

• The presentation also featured updated numbers on the penetration of CGM in the US type 1 population as of the past three months. It is disappointing to see the limited uptake of CGM (5%) in the young adult population (ages <26), a number that has not increased since the T1D Exchange first enrolled patients (per numbers provided by Dr. Irl Hirsch at AADE 2014). We believe this is due to several factors: younger patients have less on-body real-estate and awareness to manage their own diabetes; devices have not gotten accurate enough until recently; remote monitoring and connectivity has only recently gotten convenient, with efforts like Nightscout and the Dexcom Share receiver.

Table 3: CGM Use by Age in the T1D Exchange

	<13	13-26	>26
CGM Use	5 %	5%	22%

• Though the utility of CGM is already well established, Dr. Schatz reaffirmed this conclusion using DKA data in CGM users vs. non-users. Data came from the past three months in the T1D Exchange. In <13 and >26 year olds, CGM users have approximately half the rate of DKA vs. non-users.

Table 4: Prevalence of DKA – CGM vs. Non-CGM Users in the T1D Exchange

Ages (years)
	<13	13-26	>26
Non-CGM Users	6.9%	9.0%	3.1%
CGM Users	3.2%	7.0%	1.8%

• Dr. Schatz also shared T1D Exchange data on the relationship between mean A1c and insulin pump use. This data has remained remarkably consistent since Dr. Irl Hirsch’s presentation at ATTD 2011. The real-world data seems to roughly corroborate what Medtronic and others have found in RCTs of pumps.

Table 5: Mean A1c – Insulin Pump Therapy vs. Injection in the T1D Exchange

	Pump Users	Injection Users	Overall
A1c	7.9%	8.5%	8.2%

• Dr. Schatz acknowledged that pre- and post-market surveillance methods for pumps in the US are woefully inadequate. As we have heard in the past, he called out the lack of regulatory scrutiny on insulin infusion sets (“almost none”), expressing “surprise” that such a key feature of the technology’s safety would be overlooked. Similarly, he called for a more systematic and transparent approach to collecting adverse event data, acknowledging that the current MAUDE database is inadequate. That said, Dr. Schatz highlighted the recent online publication of the ADA/EASD Position Statement on Insulin Pumps as a step in the right direction.
• Dr. Schatz stressed that there are a number of factors that need to improve with CGM as well: (i) improved accuracy and reliability; (ii) redundancy beyond glucose oxidase; and (iii) calibration-free devices. We’d add much smaller and better connected devices to that list. We’re not sure if redundancy beyond glucose oxidase is really a key needed improvement – many artificial pancreas experts have said that a MARD <10% is accurate enough to run closed loop, and Dexcom’s G4AP algorithm is already there.

Questions and Answers

Dr. Tadej Battelino: Although it is strict, the FDA seems to understand that providing good technology is part of the deal. Is that fair to say?

A: You’re right. We have seen a change in the FDA. They really want to work with us. They recently down-classified secondary display of CGM data. That was a surprise to me. I think with all of this that there’s a change in FDA attitudes and approaches.

Q: You showed that people have better becomes with CGMs and pumps when used. How do we encourage more use?

A: I think it’s education. I think that very often we talk about technology and its wonder and don’t spend enough time explaining all the features of the pump and benefits and what could go wrong. I think that patients are often surprised when things go wrong. We don’t usually explain that well enough, and I think that if we were to spend more time going through these things, more people would be using these devices and less quick to abandon them.

The Need for Postmarket Surveillance of Cleared Blood Glucose Monitors

David Klonoff, MD (Mills-Peninsula Health Services, San Mateo, CA)

Dr. David Klonoff pointed out the need for programs to improve the safety of inaccurate blood glucose monitors and of wirelessly connected diabetes devices. He opened with a summary of the current state of post-market surveillance of blood glucose monitors, highlighting that cleared devices do not always function as well as they did to become cleared. He stressed that inaccurate meters are risky for making treatment decisions and particularly for calibrating CGMs. On this front, Dr. Klonoff provided an update on the Diabetes Technology Society’s (DTS) Surveillance Program for Cleared Blood Glucose Meters. As we understand it, the program has not yet received the requisite funding to begin testing meters, which was slated for mid-2015 (per his comment’s at the September update). He shared a new model for the program in which members of industry would volunteer to have their meters tested. Dr. Klonoff also highlighted the cybersecurity of connected medical devices (e.g., insulin pumps) as another safety issue and announced the launch of a new DTS program to develop a cybersecurity standard for such technologies. The program comes out of conversations with the FDA, stemming both from concerns regarding intentional (i.e., grassroots efforts to access data) and malicious efforts to hack devices. On the latter front, we would agree that as wirelessly controlled medical device become the standard in our field, the risks associated with confidentiality and integrity of data have grown exponentially. DTS will begin by forming a steering committee to discuss what such a cybersecurity standard would look like. A timeline was not provided though we assume we will hear more on this front later this year.

• Dr. Klonoff laid out an ambitious slew of milestones for DTS’s Surveillance Program for Cleared Blood Glucose Meters, including: (i) the completion of the BGMs testing protocol this winter; (ii) the certification the document; and (iii) raising money for testing.
• Dr. Klonoff also described a new model for the program in which members of industry would volunteer to have their meters tested. For example, Company A would provide funds to have Company A’s meters tested, and Company B would provide funds for Company B’s meters to be tested. In return, companies would receive the DTS’s “seal of approval” that Dr. Klonoff hopes would become a kind of de-facto approval status. We do wonder how feasible this model is considering that: (i) there are no clear consequences for company’s that do not pass DTS’ program; (ii) there is no indication that payer’s would remove cheaper devices from formularies given that those devices have been FDA approved; and (iii) the BGM environment is already strapped for cash. The need for improved post-market testing is undeniable, and we applaud Dr. Klonoff for persevering on this front despite the fact that industry has not fully bought into the concept.
• Dr. Klonoff raised some concerns over recent grassroots efforts to hack connected medical devices (e.g., NightScout, #DIYPS) – the commentary is in line with other remarks we have heard on his front as some doctors have expressed genuine concern about the reliability of improvised technologies that have not gone through standard regulatory review.  Some – not necessarily Dr. Klonoff – may be upset that laymen can devise these high-tech gadgets on their own, usurping the role of the experts to develop, promote, and explain the latest breakthroughs. From our view, parents will always do what they think is best for their children, particularly given the danger of insulin.  That said, Dr. Klonoff was speaking from the perspective of safety and we are not surprised he did not get into the politics.

Parallel Session: Impact of New Technologies on the Healthcare System

Market Access of Antidiabetics in Germany: Assessment of Antidiabetics by the Federal Joint Committee (G-BA)

Marco Petschulies, PhD (Federal Joint Committee, Berlin, Germany)

The German Federal Joint Committee (G-BA) has stirred up controversy in the diabetes drug field in recent years by slashing reimbursement based on its cost effectiveness assessments. For this reason, we were looking forward to seeing the G-BA’s own Dr. Marco Petschulies on the podium to get the agency’s perspective on its actions. Perhaps unsurprisingly, the thoughts we heard from him were very far on the conservative side in terms of regulation and reimbursement. Dr. Petschulies highlighted past IQWiG/G-BA analyses that found no additional benefit with rapid-acting insulin analogs vs. human insulin, no benefit of SGLT-2 inhibitors vs. sulfonylureas, and no additional benefit with CGM. Part of the issue is that the G-BA only considers benefits in terms of mortality, morbidity (cardiovascular, cerebrovascular, or long-term complications), health-related quality of life, and undesirable effects like hypoglycemia; the G-BA has very strict guidelines for assessing these criteria in terms of study design and the assessment of outcomes. The G-BA does not factor benefits such as weight loss and blood pressure reductions into its assessment of diabetes drugs’ effectiveness. In the G-BA’s defense, Dr. Petschulies noted that very few diabetes drug classes have disappeared from the market entirely due to the G-BA’s reimbursement actions, although choice within classes has diminished significantly. For this reason (according to him), the German public has not raised much issue with the majority of G-BA actions in diabetes. While that could be true in the short term, one could argue that Germany is no longer paying for its fair share of drug innovation in diabetes – we do not see the G-BA’s policy as sustainable in the long term.

• One area for optimism: Dr. Petschulies noted that some German sickness funds (public nonprofit payers) are enacting pilot programs to add Flash Glucose Monitoring to their standard benefit packages. This approach of experimenting with new technologies and therapies stands in contrast to the characteristic German federal approach of only paying for therapies that have a wealth of long-term data backing them up.
• Looking ahead, Dr. Petschulies noted that the G-BA may re-assess DPP-4 inhibitors in mid-2016 when more long-term data is available. It is unclear whether the potential upside or downside is greater given that the trials so far have been neutral from a cardiovascular safety perspective. SGLT-2 inhibitors, for the time being, will not be reimbursed at much of a premium over generics.

Parallel Session: Challenges in Diabetes

Immune Interventions in Type 1 Diabetes 2015

Jay Skyler, MD (University of Miami, Miami, FL)

Dr. Jay Skyler (University of Miami, Miami, FL) outlined a proposed combination approach to type 1 diabetes immunotherapy that he plans to investigate in an upcoming clinical trial. After a rapid-fire overview of the many (mostly failed) studies of immune therapies to prevent or delay the progression of type 1 diabetes, Dr. Skyler argued that an effective immune intervention may require a combination of as many as four or five agents given the resilience of the human immune system. He outlined a general approach, consistent with his presentation on the subject at EASD, that would involve (i) an anti-inflammatory agent (anti-IL1B or anti-TNF); (ii) an immunomodulator (anti-CD3, anti-CD20, co-stimulation blockade, or ATG); (iii) stimulation of regulatory T-cell activity (IL2, GCSF, or a Treg infusion); (iv) a diabetes-related antigen (oral insulin or GAD vaccine); and (v) an agent that preserves beta cell health (GLP-1 agonist). His specific protocol includes ATG, GCSF (which have shown promise in combination in clinical trials), an anti-inflammatory agent, and a GLP-1 agonist. Acceptance of such an aggressive approach would clearly require a shift in mindset for many in the field – to illustrate this, Dr. Skyler contrasted the reaction to his proposed therapy from pediatric endocrinologists (“I would never do that to my patient”) with that of transplant surgeons, who argue that even more immunosuppression is likely necessary.

Parallel Session: Diabetes and Mobile Apps

Technology-Enabled Interventions: The Future is Now

Neal Kaufman, MD (DPS Health, Los Angeles, CA)

Dr. Neal Kaufman (DPS Health, Los Angeles, CA) stressed that randomized controlled trials are a poor way to examine digital telehealth interventions in diabetes. He pointed out that such studies are so time-intensive that the technology is often obsolete by the time results are reported. He did acknowledge that RCTs have value – particularly in understanding what drives patients to technology – but emphasized that “technology itself moves too fast.” He suggested that paradigms of investigation need to change, such that the field accepts short-term economic analyses showing cost-savings in self-selected populations enrolled in telehealth programs as opposed to waiting for longer-term A1c and complications outcomes. In fact, Dr. Kaufman noted that studying reduced hospitalization rates over just a 12-month period has shown significant cost benefit (up to $364 per patient) in those involved in such programs. Ultimately, we believe his vision for the future of telehealth provides valuable food for thought, especially because many innovative healthcare startups are not experienced in the vagaries of funding, conducting, and publishing RCTs. We believe that digital interventions have great potential to reduce the financial burden on the healthcare system and improve patient self-management, particularly by facilitating more convenient follow-up, just-in-time education, real-time feedback, and increased attention.

Parallel Session: Clinical Practice in Treating Adult Patients with Diabetes

Individualizing Treatment Targets for Adult Patients with Type 1 Diabetes

Irl Hirsch, MD (University of Washington, Seattle, WA)

Dr. Irl Hirsch (University of Washington, Seattle, WA) advocated for higher A1c targets in patients with longstanding type 1 diabetes and a high risk of hypoglycemia. He explained that while there is certainly data suggesting benefits from intensive glycemic control, the evidence is somewhat mixed – the relationship between tight control and reduced mortality is not as clear as many had predicted, and the falling rates of microvascular complications in recent decades may be a result of more effective insulin regimens (i.e., routine use of mealtime insulin and CGM) as well as lower A1c targets. He also discussed the limitations of A1c as the sole indication of glycemic health, noting that ~14% of patients in his practice have misleading A1c values due to various confounding conditions.

• Given these limitations, Dr. Hirsch argued that there is scant evidence to support extremely strict control for patients with a duration of diabetes >20 years and that the risk of hypoglycemia should not be ignored; for example, he cited data showing a ~20% risk of severe hypoglycemia (defined as seizure or coma) per year for patients with a duration of diabetes >20 years. Dr. Hirsch noted that he spends more time persuading older patients with hypoglycemia unawareness and low A1cs to set higher glycemic targets than he does trying to implement more intensive control. We certainly agree that the risks of hypoglycemia should not be underestimated and that less stringent targets may be appropriate for some patients. However, we do wonder whether greater access to and use of CGM in this population could allow more patients to achieve tighter targets without undue risk of hypoglycemia – come on CMS! We also think patient choice should be part of this – while DCCT didn’t enroll many people over 65, we also haven’t seen data showing no correlation between tight A1cs and complications. Due to the young age at which many get type 1, there are heaps of patients with duration of diabetes over 20 years and we suspect many would not necessarily want to just take a higher target for the same reason – there isn’t data showing that a higher target will serve them well (and as noted, there are other ways to avoid severe hypoglycemia if a person has access). We do acknowledge if cost is a problem, and if using more low-cost glucose strips and testing more often isn’t possible, a higher target sounds reasonable (even though some patients may not want them). Dr. Robert Gabbay noted in the same session that risk of hypoglycemia (rather than history of hypoglycemia) should influence A1c targets, and use of CGM (which can significantly reduce that risk) is not incorporated into most guidelines on setting individualized goals, which is a shame from our perspective.

Parallel Session: EU and Diabetes

GOCarb

Peter Diem, MD (Bern University Hospital, Switzerland)

Dr. Peter Diem (Bern University Hospital, Switzerland) presented a valuable update on GoCarb, a mobile platform that supports individuals with type 1 diabetes by automatically estimating the grams of carbohydrate in a meal (in near real-time) based on a single photograph. Such a carbohydrate counting system is certainly a patient’s dream, and while the work is still early stage, this system seems very encouraging. Indeed, the app moved into the outpatient setting last year and has seen promising results. Dr. Diem shared those findings, which were collected over a nine-day period in patients with type 1 diabetes (n=19) at Bern University Hospital. Patients were given six meals per day and asked to estimate the carbs in each meal on their own before using GoCarb. Results indicated that the mobile platform was significant better than individuals at predicting carbohydrate content (absolute error: 13 grams vs. 28 grams), and 80% of the time, GoCarb error came in at under 20 grams (clinically accurate, according to Dr. Diem). A key question is whether the system will be able to scale to a variety of foods and mixed meals, as we cannot imagine that the selection at the hospital restaurant was particularly diverse. The team’s second clinical trial is scheduled for August 2015. It is great to see movement on this front, since carb counting is incredibly challenging – even for experts – and an effective mobile app would be a huge win.

Plenary: Neuroimaging in Insulin Resistance

Neuroimaging in Insulin Resistance

Stephanie Amiel, MD (King’s College London, London, UK)

Dr. Stephanie Amiel (King’s College London, London, UK) gave a well received talk on a potential neural link between insulin resistance and altered food-related behavior. Dr. Amiel – an expert on hypoglycemia – was intrigued to research this topic after discovering that circulating insulin levels impact a substantial portion (~20%) of glucose metabolism in the brain. While it is increasingly clear that obesity and metabolic dysfunction are associated with changes in neural circuits involved in appetite regulation, she said that the direction of the relationship has not been demonstrated – “we don’t know what drives what.” Dr. Amiel and her colleagues conducted a series of studies examining brain activation in insulin sensitive vs. insulin resistant subjects with comparable BMIs of ~25 kg/m². fMRI and other neural imaging techniques showed that these non-obese, insulin resistant individuals displayed abnormal activation patterns in brain regions associated with reward and with responses to anticipating and eating food. Importantly, when the insulin resistant group underwent an insulin-sensitizing treatment regimen with lifestyle interventions and metformin, many of these patterns became comparable to the control group.

• Dr. Amiel also presented results from a neuroimaging study comparing obese patients who had undergone bariatric surgery with BMI-matched controls who had not. As expected, the post-surgical patients were less insulin resistant and displayed greater activation of brain regions associated with appetite inhibition. Interestingly, they also had abnormally increased activity in brain regions associated with reward salience; applying similar findings from studies of hypoglycemia unawareness, Dr. Amiel hypothesized that a lack of emotional salience around the rewarding aspects of food might be a component of the altered appetite/satiety signaling seen in obesity, suggesting that the sort of behavioral interventions used to increase awareness of hypoglycemia might be helpful in this area as well. While far more research must be done to understand the neural mechanisms underlying metabolic dysfunction, we wonder if these intriguing findings could hold potential for new approaches that address altered neural pathways at much earlier stages.

International Technology Fair

Xeris – Clinical Development Overview of XeriSol Glucagon

Brett Newswanger (Xeris Pharmaceuticals, Austin, TX)

Mr. Brett Newswanger, Xeris’ Director of Glucagon Products, provided an overview of the company’s glucagon portfolio. It was valuable to get an up-to-date look at the status of Xeris’ pipeline and a window into what to expect later this year (see table below). In addition to a peek at data from one patient in a phase 2a mini-dose trial (covered above), we also saw phase 2a results from a pump study (G-Pump) vs. Novo Nordisk’s GlucaGen delivered via OmniPod (abstract #0196). Though the pharmacokinetic profile was comparable in terms of area under the curve in the first 150 minutes, the G-Pump reached an 11% higher maximum concentration and took 10% longer to reach that point than GlucaGen. To us it makes sense that it would take longer to reach a higher peak concentration. Despite the slight nuanced differences, it appears that the results are enough to support G-Pump’s continued development, especially given its great potential for bi-hormonal closed loop. That said, we’ve heard that bioequivalence is a major factor on the regulatory side of glucagon, so we’ll have to see how the data plays out.

Table: Xeris’ glucagon pipeline

	Current Status	Plans for 2015
G-Pen	FDA end-of-phase-2 meeting complete	Multicenter pivotal trial
G-Pen Mini	Phase 2a study complete	Phase 2 studies: outpatient study, exercise study, alcohol study
G-Pump	Phase 2a study complete (ATTD abstract 0196)	Closed loop bihormonal pump study

Corporate Symposium: Achieving Therapy Targets with Innovative Solutions for Personalized Diabetes Management

Personalized Diabetes Management – where are we today?

Matthias Axel Schweitzer, MD (Roche, Mannheim, Germany)

Dr. Matthias Axel Schweitzer delivered a wide-ranging talk on the current status of personalized diabetes management. The highlight of the presentation came in Q&A when Dr. Schweitzer shared that Roche does not intend (in the short-term) to create open APIs that allow patients to access their own data. Dr. Schweitzer acknowledged that this needs to happen in the future, but that both a regulated market and concerns over patient liability handicap these efforts. Indeed, he noted that Roche is instead focused on delivering “safe and proven” solutions and, in redirecting Brandon Arbiter’s (Tidepool) question, he painted a less optimistic picture for fans of data liberation, connectivity, and open-source solutions, commenting that open formats are “a long, long ways off.” We will be interested to see where this goes; there has certainly been significant value that has come from putting data in patient hands and allowing patients to solve real-world problems as seen in the success of NightScout – that said, now that NightScout is more “official” we also don’t know where service, liability, etc. will land. Horizontal systems allow for clinically relevant innovation and scaling that is hard to achieve in the current, closed proprietary medical-device-manufacturer-as-software-developer model. Overall, we are optimistic about all the work happening on interoperability, though it would be great to see Roche and Medtronic jump more fully on board and partner with a company like Tidepool.

Corporate Symposium: Supporting Patients Across the Spectrum of Care (Sponsored by Sanofi)

Customized Support for Youth with T1DM

Thomas Danne, MD (Diabetes Center for Children and Adolescents, Hannover, Germany)

In a discussion on customized support for youth with type 1 diabetes, Dr. Thomas Danne (Diabetes Center for Children and Adolescents, Hannover, Germany) noted that digital technologies “might be the next big step in diabetes education.” He emphasized that the field is hugely worthwhile to explore right now considering:  (i) the number of youth familiar with smartphones, apps, and websites; (ii) that over 70% of type 1 youth have not met glycemic targets; and (iii) that more than 1,000 digital support tools are publically available. As we have seen over the past 12 months, digital health has a lot of momentum, though it is rare to hear a clinician sharing such positive sentiments. He also pointed out the positive role that social integration and peer engagement can have in translating these digital interventions into relevant outcomes. Indeed, we believe that the potential of diabetes online community is often understated, and it was great to hear him call attention to the benefits of sharing the burden of the disease with others.

Exhibit Hall

Abbott

Abbott’s distinctive yellow booth greeted attendees at the front right of the exhibit hall. FreeStyle Libre was the focus, and a slew of representatives offered demos of the new technology. The device launched last fall, and is still clearly generating a lot of excitement judging from the “oohs and aahs” we overheard from attendees seeing the technology for the first time. Representatives noted that reimbursement remains a primary goal moving forward, though emphasized that the fast uptake – which has exceeded manufacturing capacity – is a terrific sign that patients are already appreciating the value proposition.

Bayer

Bayer representatives hinted at a next-generation Bluetooth-connected BGM in the company’s pipeline – this is the first we have heard on this front. Representatives provided a rough timeline, suggesting a launch is “one to two years away.” We have heard very little from Bayer on the pipeline front over the past 12 months, so it is positive to see that the company is still actively investing in R&D despite the fact that the challenging market conditions do not lend themselves to innovation. Reps also highlighted the company’s Next Link 2.4 meter that recently launched with Medtronic’s MiniMed 640G system in Australia. The meter is now available for purchase throughout the EU. As a reminder, the device’s key innovation relative to the first-gen Next Link is the remote bolus feature, a huge convenience win for patients that we think will be well received.

Cellnovo

Cellnovo had a one-manned booth at the edge of the exhibit hall, where we learned that its pump system has launched in both the UK and France. We learned that the uptake in Europe has been solid with the France launch two months in and the UK launch having begun its launch at the end of 2013. There were no updates on progress in the US, although we last heard of a potential FDA filing in 2014. As a reminder, the Cellnovo system consists of three components – a pump/rechargeable battery unit and disposable insulin cartridge, a color touchscreen handset with an integrated meter (LifeScan Vita strips), and a web-based data management system. For more background on Cellnovo, please see our last coverage of the company.

CeQur

The enthusiastic CeQur team provided us a demo of the company’s PaQ insulin delivery device and an updated timeline on both EU and US commercialization efforts. As noted above, the company is now hoping for a EU launch in 2016 (CE Mark approval came in November 2012), a slight delay relative previous guidance that put a launch in 2015. In the US, CeQur hopes to submit an FDA filing this year and is optimistic for a launch in 2016. As a reminder, the company appointed Mr. Douglas Lawrence as Chief Executive Officer in April 2014, and we are hopeful that his background at BD will help CeQur navigate the complex US regulatory and commercial landscape.

J&J

J&J’s modest booth was devoted exclusively to the Animas Vibe. Reps spoke broadly about the Vibe’s success, touching briefly on its recent FDA approval. When asked to comment on the future of Animas’ pipeline, reps did not divulge any details though noted, “As it is for everyone, the artificial pancreas is the future.” We hope this is true, as J&J has not indicated significant progress on this front besides a couple small inpatient feasibility studies presented at ADA 2013 and ADA 2014.

Medtronic

Medtronic’s large booth showcased the brand new MiniMed 640G, allowing attendees to walk up and play with the pumps. An Australian rep was highly enthusiastic, noting that patients are “delighted” to get the pump, which has a cool factor that sets it apart from “just another medical device.” More details can be found in the presentations above from Drs. Tadej Battelino and Pratik Choudhary, including our perspective after handling the new device. 

Roche

Roche’s booth gave attendees the opportunity to play around with the Accu-Chek Connect (standalone meter + smartphone app + web portal) and Accu-Chek Insight (next gen insulin pump with BGM remote) systems. The demo of the former featured a look at the sleek new Connect app for iOS that is set to launch in April 2015. (As a reminder, the Connect app is currently only compatible with Android OS). Representatives were silent when asked about progress on the CGM front, though as we understand it, the company’s novel CGM remains at least 12 months away from commercialization.

-- by Melissa An, Adam Brown, Varun Iyengar, Emily Regier, Manu Venkat, and Kelly Close