Research In The News (May)

This blog posting covers a couple of different topics, but starting with a piece of bad news:

Perle Biosciences Ends A Phase-II Trial of a Combination Cure

In November 2015 I blogged on a clinical trial by Perle Biosciences testing a combination of Cyclosporine and Omeprazole.  You can read the details here:
http://cureresearch4type1diabetes.blogspot.com/2015/11/perle-biosciences-starts-phase-ii-trial.html
Unfortunately,  that trial was listed as "Prematurely Ended", but I'm not sure exactly when.  There hasn't been an official press release on the trial, but JDCA quoted Perle Biosciences's president as saying the trial was stopped because "Enrollment was disappointing in Europe and we are planning to move all studies to the U.S."

Of course, I'm hopeful that they do start a trial in the US, and soon.  They are working with a combination of drugs: one of which stops the autoimmune attack and the other regrows beta cells. Both are already approved in the US (one is over the counter).  So you can see why this is an exciting treatment.

Unfortunately, this is not the first time Perle has had problems starting a study.  Prior to starting this European study, Perle filed paperwork to start two studies in the US.  This paperwork languished for over two years and the American studies never did start.   A parallel effort in Europe did led to this study, which has now been ended.

JDCA Coverage: http://thejdca.org/practical-cure-project-update-perle-bioscience-drug-combination-human-trial-ends-prematurely

Not In Human Trials: Stem Cells From Self

Researchers were able to create beta cells from stem cells, the stem cells having been created from skin cells of people with type-1 diabetes.  This might be important for a couple of reasons.  First, these cells could be used to test new drugs.  Many people have noticed (especially in the world of type-1 diabetes) that treatments which work on mice often don't work on people.  This is a way to test treatments on beta cells similar to a type-1 diabetic's actual beta cells.  Second, these cells could be used in transplants.  But remember, that only solves half the transplant problem.  Transplanted beta cells have two problems: the body's good immune system is trying to kill them because they are foreign and the body's bad immune system is trying to kill them because they are beta cells.  Since these cells are from the patient's own body, they will not have the first problem, but might still have the second problem.

To the best of my memory, previous reports of making beta cells from stem cells always involved the use of 3rd party stem cells (ie. the stem cells did not originate from the person who would eventually get the beta cells).  So this is a step forward in that regard.

This is animal research only right now, but could get into human trials in 3-5 years, which would then take an additional 10-15 years to become generally available.  That is, assuming it is successful.

Press Release: https://www.sciencedaily.com/releases/2016/05/160510132809.htm
Paper: http://www.nature.com/ncomms/2016/160510/ncomms11463/full/ncomms11463.html


Stepping Back from Artificial Pancreas Coverage

I've decided to scale back my coverage of artificial pancreas research.  This is for two reasons:

1. Because limited functionality Artificial Pancreas devices are already available from Medtronic now in Europe (the 640G) and in the United States (the 530G), and because an all-but-meal Artificial Pancreas device (the 670G) is planned for release in both places in the next few years, there is a lot of "regular" news coverage on Artificial Pancreas developments.  I do not think I'm adding a lot of value to Artificial Pancreas research reporting.  To be blunt: DiabetesMine, diaTribe, ASweetLife, and similar web sites are doing such a good job publicising AP progress, I don't feel like I'm needed in that area.
2. Because there is so much progress being made, on so many different Artificial Pancreas fronts, the avalanche of information is overwhelming me.  I just can't keep up.

Obviously, these are both good reasons to stop coverage.  I'm absolutely confident that a full Artificial Pancreas will be available in the United States in a few years, and I'd rather spend my time following research that is less certain, and harder to interpret.

If you are desperately in need of an AP update, read these:

• http://www.healthline.com/diabetesmine/artificial-pancreas-what-you-should-know which includes one paragraph on each of 11 (!) different commercial companies working on APs.
• http://insulinnation.com/treatment/bigfoots-artificial-pancreas-could-hit-the-market-by-2018/ for an update on Bigfoot, specifically.
• http://www.wsj.com/articles/tech-savvy-families-use-home-built-diabetes-device-1462728637 "do it yourself" AP in the news.
• http://www.healio.com/endocrinology/pediatric-endocrinology/news/online/%7Bdca7dc70-73a6-471c-be8a-2d394d288308%7D/artificial-pancreas-more-effective-than-sensor-augmented-pump-in-young-children reports on AP vs. CGM+Pump trial for kids at summer camp.  AP wins.

My Internet World

I use Blogger, LinkedIn, Facebook, and Twitter, but I divide up my internet world like this: The blog is very specifically focused on clinical trials aimed at curing type-1 diabetes. If that is what you care about, then either follow the blog or sign up for mail notifications when a new entry is posted. (There is a field in the upper right hand corner of the blog for that.)  My twitter covers type-1 diabetes more broadly and also some non-diabetes issues which are important to me.  It is more than half type-1 and less than half other issues.   I try to keep LinkedIn very strictly for work related stuff, and Facebook for family and friends.  So if you are linked with me either on LinkedIn or Facebook, but only care about diabetes news, then you'd probably do better to either sign up for emails from my blog or link with me on Twitter.

Joshua Levy
http://cureresearch4type1diabetes.blogspot.com
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

Summary of EASD 2015

EASD is the European Association for the Study of Diabetes.  Their conference is the largest diabetes research gathering in Europe.  I did not attend, but reviewed all the abstracts, posters, and 100s of tweets sent with the EASD2015 hashtag.  This posting is my summary.

Unfortunately, as with ADA 2015 earlier this year, there was not much research aimed at a cure which had reached human trials.  I've divided this posting into four areas: news on human trials aimed at a cure, artificial pancreas research, high buzz research, and other research I found interesting.  But there was only one abstract dealing with a cure in human trials.  Disappointing.

Research In Human Trials Aimed At A Cure

Proinsulin peptide immunotherapy in type 1 diabetes: safety data of a first in new-onset type 1 diabetes phase 1b trial || Abstract #503
http://www.easdvirtualmeeting.org/resources/proinsulin-peptide-immunotherapy-in-type-1-diabetes-safety-data-of-a-first-in-new-onset-type-1-diabetes-phase-1b-trial--2
These researchers are testing a type-1 diabetes vaccine made from part of an insulin molecule.  They are testing it for safety in newly diagnosed type-1 diabetics.
The poster is not on line, but you can see the abstract.  It appears that the study was strictly safety-only, and there were no safety issues, but no data on effectiveness, either.

Artificial Pancreas Research

There was a lot of AP research.

This was a presentation by the Cambridge group:
http://www.easdvirtualmeeting.org/resources/twelve-week-unsupervised-day-and-night-closed-loop-insulin-delivery-during-free-daily-living-in-adults-with-type-1-diabetes-a-multicentre-randomised-cross-over-study--3
33 adults used an AP for 12 weeks "free range".  Trial was open label, cross-over design.  (Meaning that all patients were both treatment group and control group at different times.)  AP did not handle meals.  AP did better than non-AP in terms of average BG, and no worse for lows.  AP also did better on A1c.  This research was published in the New England Journal of Medicine:
http://www.nejm.org/doi/full/10.1056/NEJMoa1509351
and is also discussed here:
http://www.clinicalendocrinologynews.com/specialty-focus/diabetes/single-article-page/artificial-beta-cell-insulin-systems-post-more-positive-data/8e1e8f69192b2d3f1dc40f418cffb9a6.html
and here:
http://www.medpagetoday.com/MeetingCoverage/EASD/53621

This was a presentation by groups in France and Italy using the University of Virgina AP:
http://www.easdvirtualmeeting.org/resources/hba1c-improvement-with-less-hypoglycaemia-in-patients-with-type-1-diabetes-wearing-an-artificial-pancreas-for-two-months-from-dinner-to-breakfast
35 adults used an AP overnight for two months. Trial was cross-over design.  AP did better than non-AP in terms of time in target, with less time in both high and low BG.
One patient dropped out of this study because he was not able to trust the device enough to participate in the study.  This patient was a professor of mathematics.  (This got a laugh during the presentation.)
These researchers are now testing 24 hour use of the device.

This presentation was by Steven Russell on the Bionic AP (same project as Dr. Damiano works on):
http://www.easdvirtualmeeting.org/resources/the-bionic-pancreas-when-will-the-dream-come-true
This presentation included previous data from adults and camp kids, but also new (to me) data from younger children (6-11 years old).  This was also at camp, and was 5 days on, 5 days off (cross-over design).  The BG improvements seen in these younger kids was better than seen in adults or in camp kids.  In my opinion, the improvements seen in these kids were striking.

He then presented data from a "free range" trial of 40 adults for 11 days on, and 11 days off (cross-over) study.  This data was also very good.  The whole presentation was well done, and well worth viewing, but if you just want some quick data: fast forward to slide 25 (usual care) and then compare it to 26 (AP); this is for one selected patient, but you can see the huge improvement.

He then presented data from a comparison of glucagon vs. no glucagon study.

Finally he presented their target (hoped for) timeline:

• Transitional Studies: 2013 - 2016
• Production of a fully integrated device (prototype already made via private donations).
• Bridging Studies: starting in 2016
• Pivotal Studies: 2017 - 2018
• Review by FDA: 2018
• Commercial availability: late 2018 or early 2019

Dr. Russell said that the FDA had indicated that this device and long term glucagon use, could be approved based on a single pivotal trial of 450 patients for 6 months, with a 6 month extension for 100 of the patients.  (And this length and size is due to the needs of the glucagon approval.)

Also, Tidepool is collaborating with this research team in creating the user interface for their AP.

High Buzz Research

The research which generated the most buzz, by far, was the results of the EMPA-REG study.
However, this was a huge study of a SGLT2 drug in type-2 diabetes, so I won't comment.

There were also a lot of "Insulin vs. Insulin" and "New Insulin" papers and posters.  These are studies which show that one type of insulin is better than another, or that a new type of insulin is safe and effective.  I didn't count, but suspect there were over 20 of them, but this kind of research does not excite me.  There was some early work on a weekly shot basal insulin, and that is interesting to me. The research was on people, too.  But it is still years off, I think.

Glucagon nasal powder: an effective alternative to intramuscular glucagon in youth with type 1 diabetes (Abstract #42) generated some buzz:
http://www.easdvirtualmeeting.org/resources/glucagon-nasal-powder-an-effective-alternative-to-intramuscular-glucagon-in-youth-with-type-1-diabetes--2
You can watch the 15 minute presentation or read the abstract, at this web page.
Slide #5 shows clearly that glucagon nasal powder is similar to glucagon injection.
This tweet contains a one chart summary: https://twitter.com/jgryan0/status/643779712385478656
Patients in this study were between 4 and 17 years old; a previous study had focused on adults.
The nasal formulation was much easier to use, and (of course) no needle was needed.  Also the same nasal dose can be used for youth of all ages, so no more "half shots" for younger/smaller kids.
One patient sneezed immediately after getting the nasal glucagon, and this patient's BG levels did not rise, but the researcher wasn't worried because glucagon is usually given to unconscious people, who don't sneeze.  The company involved (Locemia Solutions) is "in discussions with regulatory agencies".

There was a phone app (I think called "gocarb") where you took a picture of a plate of food, and it estimated carbs.  Here are some of the tweets for that:
https://twitter.com/sugartweaks/status/643400361588465664?ref_src=twsrc%5Etfw
I'm a little dubious about this whole idea, but it did generate a lot of positive tweets.

Dexcom's G5 will soon be available in Europe:
https://twitter.com/danielvegh/status/643770125095706624

The Google/Dexcom tiny BG sensor also generated some buzz:
https://twitter.com/diaTribeNews/status/643339894522142720?utm_source=fb&utm_medium=fb&utm_campaign=sciencehorse&utm_content=643759843656884224


Other Research I Found Interesting

The talk by Andrew Hattersly:
http://www.easdvirtualmeeting.org/resources/insights-into-the-beta-cell-from-patients-with-monogenic-diabetes
This is a one hour talk given by Dr. Hattersly, who basically discovered monogenic diabetes (often called MODY).  I really enjoyed it, even if I did not understand all of the science.  The talk is good because it shows how different scientific work comes together to make important discoveries, and how science is a team effort, and patients are involved.  Monogenic diabetes  is caused by a single genetic mutation.  There are several different types of monogenic diabetes , each involves the mutation of a different single gene.  This is quite different than classic type-1 diabetes, where there are many genetic features, some of which make type-1 more likely, some less likely, plus environment triggers, all of which come together to cause type-1 diabetes.  Monogenetic is binary: you have the gene, you get the disease.

The key points from this talk are two fold:

1. Anyone diagnosed with type-1 diabetes when they are under six months of age, actually has neonatal diabetes (one form of monogenic diabetes ).  Neonatal diabetes can be treated with insulin, but can also be treated with a much cheaper pill (no shots!)  If you, or someone  you know, was diagnosed when less than six months old, and uses insulin, you (or they) may want to talk to your doctor about trying to switch to the pill.  More information: http://www.diabetesgenes.org/content/neonatal-diabetes
2. Dr. Hattersly estimates that between 1% and 3% of the people diagnosed with type-1 diabetes actually have some form of monogenitic diabetes. Except for neonatals, these people generally must be treated with insulin, just like type-1s, but it's still valuable knowledge.  He has an experimental web page to calculate a person's chance of having monogenic type-1 diabetes: http://www.diabetesgenes.org/content/mody-probability-calculator

Autoimmune diseases in children and adults with type 1 diabetes from the type 1 diabetes exchange clinic registry || Abstract #499
http://www.easdvirtualmeeting.org/resources/autoimmune-diseases-in-children-and-adults-with-type-1-diabetes-from-the-type-1-diabetes-exchange-clinic-registry--2
This link has an abstract, the poster, and a 5 minute discussion by the author.
The Type 1 Diabetes Exchange is a huge project, funded by the Helmsly trust, to gather all kinds of data on over 25k people who have type-1 diabetes.    Some findings:
The #1 additional autoimmune disease found in type-1s is thyroid disease at 19%.
Celiac's is #2 at 6%.


Sustained glycemic control and less nocturnal hypoglycemia with new insulin glargine 300 U/ml versus glargine 100 U/ml over 1 year in Japanese people with type 1 diabetes mellitus (EDITION JP 1) || Abstract #4http://www.easdvirtualmeeting.org/resources/sustained-glycaemic-control-and-less-nocturnal-hypoglycaemia-with-new-insulin-glargine-300-u-ml-versus-glargine-100-u-ml-over-1-year-in-japanese-people-with-type-1-diabetes-mellitus-edition-jp-1--2
ADA 2015 had at least one paper (which I found interesting) suggesting that higher density insulins were better for type-2 diabetics.  Some extremely obese type-1 diabetics need to refill their pump every day with standard u100 insulin, but only every other day with u300 insulin.  This is a money and convenience issue.  But additionally, there was evidence that higher density insulins were more effective; that fewer units were needed for the same carb or basal situations.  This study found that type-1s used more insulin, but had lower nocturnal numbers and at the same time, fewer lows.  That's still a good outcome.

I found the comparison to u100 to higher density insulins interesting, especially if we get sets that can last longer than 3 days, the pressure for high density will become stronger.

Joshua Levy
http://cureresearch4type1diabetes.blogspot.com public
joshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

Artificial Pancreas Updates From ADA (July 2015)

In my opinion, artificial pancreas (AP) technology was the single most important technology of the American Diabetes Association Scientific Sessions this year.  There were many papers, posters, and presentations on artificial pancreases and related technologies (such as continuous glucose monitoring, stable glucagon, etc.)  Nothing generated more Twitter buzz.

This blog posting attempts to summarize a little of the research presented.  There was way too much for me to cover it all, and so this posting gives light coverage to the most important news.

My overall summary is that we are no longer talking about if there will be an AP.  The question is: when there will be an AP, and how many APs, and how many different types of technology they will use.  I continue to be heartened by:
(a) the progress made by AP research projects over the last few months (and years)
(b) the large number of new companies entering the field
(c) the product roadmap announced by Medtronic as they move their existing partial AP to a full AP.

The AP world is more and more driven by commercial considerations, rather than research considerations, and that is a strong signal that we are close to general availability.  (Close meaning years, but not too many of them.)

This tweet summarizes my thoughts, as well:

“Closing the loop is no longer a mystery; it’s not a puzzle. We just have to do it.” 

https://twitter.com/eliotmbrenner/status/607536971192377344

Second Bi-Hormonal Artificial Pancreas In Development

I recently found out about a second bihormonal AP  (in addition to Dr.  Ed Damiano's).  These researchers are in The Netherlands, and you can read more about it here:

http://www.inredadiabetic.nl/diabetes-product-ontwikkeling/
http://www.inredadiabetic.nl/us/history/
http://www.inredadiabetic.nl/news/

It's a little hard for me to figure out exactly where they are, and I have not found any articles in scientific journals.  However, it appears that earlier this year they ran a two day test on one person, and got quite good results.  The average BG was 125.  Based on that they are hoping to run two clinical trials (called APPEL 4 and APPEL 5) later this year.  They hope those trials will used as the basis for European "CE" approval.

Maybe a Third?

They haven't started recruiting yet, but this looks like a phase-II trial for yet a third bi-hormonal artificial pancreas.  I'll blog more fully if they start recruiting:

https://clinicaltrials.gov/ct2/show/NCT02379299

Back To Ed Damiano's Bi-Hormonal Artificial Pancreas

Not from ADA, but from another conference, comes this summary of Ed Damino's current status:
http://www.medpagetoday.com/MeetingCoverage/AACE/51551?xid=nl_mpt_DHE_2015-05-16&eun=g118127d0r

But if you want a summary in 140 characters, here it is, from
https://twitter.com/DiabetesMine/status/607298177952321537:
Damiano says #BionicPancreas showing ave BGs of 135-142, which would equate to 6.5% A1C.
[What's not to like!]

Plus there was this good news tweet:
From https://twitter.com/InsulinNation/status/607300794875002882:
Ed Damiano says there is room temperature stable glucagon that stays good for up to a year. Needs FDA approval.

Medtronic's 670G

The Medtronic 670G, as announced, will be an "all but meals" style, single hormone artificial pancreas, available in the United States in April 2017.  As far as I know it is the most powerful AP with a clear commercial delivery date.  For comparison, the 640G is already available in Europe, but does not prevent "highs," only "lows".

diaTribe interviewed a patient who has used the 670G as part of a clinical trial:
http://diatribe.org/medtronic-minimed-670g-hybrid-closed-loop-exclusive-interview-17-year-old-trial-participant

This is Medtronic's press release summary of results from a 640G study, a 670G study, and some other research they presented at ADA:
http://finance.yahoo.com/news/medtronic-accelerates-path-artificial-pancreas-140201655.html
The current plan is for the 640G to be available next year, and the 670G the year after.

This news resulted in the following tweets (and many more, of course):
https://twitter.com/DiabetesMine/status/607197166193508353
https://twitter.com/DiabetesMine/status/607198339600392192

More General AP News

The following, more cautionary tweets report on other aspects of AP research:

From https://twitter.com/InsulinNation/status/607284169622880256:
During artificial pancreas study, the AP couldn't be used 1 in 3 nights because of tech issues (sensors) or family/health issues.[But I don't know which AP this tweet is about!]

From https://twitter.com/DiabetesMine/status/607284048931770368:
CDE Laurel Messer: Still enough tech issues exist with CGM sensors to impact hoe [sic, should be "how"] closed loop is used in kids and young adults.
From https://twitter.com/InsulinNation/status/607278840193400832:
Predictive pump technology significantly reduced nighttime lows in kids in almost 1000 night study. [But again: I don't know what AP this refers to!]

The following link goes to a summary of one of the ADA sessions:
http://www.saluteh24.com/il_weblog_di_antonio/2015/06/artificial-pancreas-moving-toward-pediatric-use-2015ada-meeting-in-boston.html

Personal testimonial (with graph) of how well an AP works, but I don't know which one!  Anyone recognize the screen?
https://twitter.com/DiabeticSisters/status/607709090278699008

Bigfoot Explodes Big  (In a Good Way!)

Bigfoot is a one year old company.   They had a very successful ADA and generated a lot of "buzz", which this tweet tries to summarize.
From https://twitter.com/diaTribeNews/status/604309757093011456:
@BigfootBiomed acquires Asante pumps! Goal to enter pivotal trial of full #artificialpancreas system late 2016

A "pivotal" trial is industry-speak for a phase-III clinical trial.  What they are saying is that they hope to start phase-III trials of an AP next year.  That would put them shoulder to shoulder with Medtronic and front running bihormonal research projects.  Even if they are overly optimistic, and they actually start those tests in 2017, they are still not that far away from a commercial AP.

But even more promising (to me) is that Bigfoot feels like a tech start up, not a medical device company. It feels like Silicon Valley rather than Washington D.C.  I can't tell if that's a marketing strategy or the truth, but if you look at the founders, look at the tactics (reuse the failed carcass of another project), and the strategy: it really does look like the way things happen "out here".

When a company like that can successfully create an AP, it means that APs are technology gizmos, and not medical devices, and technology products can improve much more quickly than medical products.  I'm sure the FDA will have something to say about it, but even if Bigfoot is just a 20% step in the direction of Silicon Valley, that's going to "light a fire underneath" some medical device companies.

The following link goes to one diaTribe story, but that story has links to other stories, and you can get the whole saga of how big they've grown, how quickly, and how important that might be:
http://diatribe.org/bigfoot-biomedical-acquires-asante-snap-pump-technology

TypeZero: Yet Another New Company Focused On A Single Hormone AP 

And if that were not enough, TypeZero Technologies is yet another new company trying to create a single hormone AP "from scratch".  DiabetesMine has a summary article:
http://www.healthline.com/diabetesmine/typezero-tech-closed-loop-commercialization

This is based on AP research done at the University of Virginia which I have reported on before.

Comparison

There was some debate at ADA about which was better: single hormone artificial pancreases, or bihormonal artificial pancreases.  My first reaction to this debate was this: who cares?  Either one is so much better than what we have now, let the people who like insulin only APs develop those, and let the people who like insulin and glucagon APs develop those, and let the market decide, or maybe let the market decide that there is room for more than one AP technology.  I mean some people have cable while others have satellite, why not the same with APs?  Have we learned nothing from the death of communism?  Let the market decide, as fed by the strongest proponents of each system.

My second reaction to this debate was that it can never be resolved by research. The data we have now is pretty clear: single hormone APs result in average BG numbers about 10 points higher than dual hormone APs  (for example mid 130s vs mid 140s).  However, dual hormone APs are more complex to manufacture, more complex to operate, and involve the tiny risk of long term, very low dose glucagon (and that risk is unknown, and will remain unknown for years).  So some people are going to say dual hormone is 10 points better than single hormone, end of story.  But others will say, mucking about with refilling two reservoirs is just not worth 10 points.  And neither of these opinions is right or wrong, they are just different.  And always will be.

However, even if research cannot answer a question, it can still inform the discussion, and there have been some papers directly comparing the two systems. The following tweet is one summary, but the links to the abstracts below contain more data.

From https://twitter.com/sarhoward/status/608301471529107457:
Haidar: Both single and dual hormone artificial pancreases better than pump for BG control at night, dual better for reducing hypos

http://www.thelancet.com/journals/landia/article/PIIS2213-8587(15)00141-2/abstract
http://www.thelancet.com/journals/landia/article/PIIS2213-8587(14)70226-8/abstract


Joshua Levy
http://cureresearch4type1diabetes.blogspot.com
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

Artificial Pancreas Update (May 2015)

I have decided, for 2015 at least, to do quarterly updates for Artificial Pancreas research. The area is moving forward so quickly that I think that quarterly updates are warranted.

The term "artificial pancreas" refers to using a continuous glucose monitor (CGM) to feed data to a computer, which controls an insulin pump, and in some models, a glucagon pump as well. Artificial pancreas refers to using existing technology in all these areas, but connecting them together so that a person does not need to worry about counting carbs or blood glucose levels. It is all done automatically. Most people do not consider this a cure, but I follow AP research because some people do consider it a cure.  There is no doubt that such technology would be a huge step forward in treatment, and would largely prevent "dead in bed" due to low blood glucose events.

An earlier version of this blog had the wrong dates for future Medtronic product releases.  I'm sorry about that.  This posting has the correct dates.  Thanks to Tamar Sofer-Geri for finding the mistake.

Artificial Pancreas Update for April 2015

The JDRF uses a 6 step model to describe milestones on the way to the fully featured artificial pancreas that we all want.  You can read about those milestones here: http://jdrf.org/research/treat/artificial-pancreas-project/.
So when I refer to "step 1" and "step 4" and so on in this blog, I'm referring to the steps described by JDRF.

Corporate News from Medtronic

Back in January, Medtronic made the following product announcements:

• The 640G (predictive low glucose suspend) will ship in Europe in April 2015.
• The 640G will ship in the United States in April 2016.
• The 670G will ship in the United States in April 2017.
• The 670G will ship in Europe in April 2018.

News (from Close Concerns / diaTribe): https://www.closeconcerns.com/knowledgebase/r/ce9abf26

There are three pieces of good news included in those predictions.

First, the 640G is a step 2 Artificial Pancreas, so it will predict and avoid low blood glucose events.

Second, the 670G (depending on exactly how it turns out) could be a step 3 or 4 device.  That means it will predict and avoid both low BGs and high BGs, but not cover meals automatically.

Third, it means that Medtronics believes that the FDA's previous approval delays will stop:

• There was a 2.5 year delay (from European approval to US approval) for the 530G.
• Medtronics expects a 1 year delay for the 640G.
• Medtronics expects a 1 year advantage (US before Europe) for the 670G.

I hope they are right about this!  FDA's delays in earlier AP approvals are one of the major reasons AP development has been slow, and European availability is ahead of us. If the FDA is able to fix this problem over the next few years, that is a huge piece of good news for all AP companies and ultimately, all AP users.

MD-Logic Goes Commercial

MD-Logic is one of the artificial pancreas projects which has been in phase-II clinical trials.  I previously blogged on it in Nov-2014: http://cureresearch4type1diabetes.blogspot.com/2014/11/artificial-pancreas-update.html

In the past, it has been a research project, but a company called DreaMed Diabetes was founded to commercialize it, and they recently signed an agreement with Medtronic.  According to diaTribe:
http://diatribe.org/medtronic-signs-exclusive-agreement-use-glucositter-artificial-pancreas-software-future-insulin
Medtronic plans to use this technology in their artificial pancreases after the 670G.  The 670G will be a step 4 AP (automatic except for meals), while the MD-Logic based follow on will be a step 5 AP (automatic including meals).

Also, MD-Logic's blood glucose control algorithm got a "CE" mark in Europe (which is their "approval to sell" symbol).  You can read about it here:
http://www.diabetesincontrol.com/articles/diabetes-news/17774-artificial-pancreas-software-algorithm-receives-approval-in-europe-
However, I'm not sure what that means from a practical point of view.  You cannot use an algorithm by itself.  It has to be part of a piece of software or hardware, and right now no one is selling any product which uses the algorithm.  Maybe this CE mark will speed Medtronic's approval in Europe when the time comes?

Artificial Pancreas News From Tandem (makers of t:slim)

I slogged through a Tandem analyst's call in Feburary, which you can read here:
http://seekingalpha.com/article/2946926-tandems-tndm-ceo-kim-blickenstaff-on-q4-2014-results-earnings-call-transcript?part=single

There are only a few paragraphs on AP research, and my rough translation of them is this:

Tandem is currently experimenting internally, and not on people, with both predictive low glucose suspend (step 2 AP) and predictive high glucose dosing (step 3 AP).  In the second half of 2015 they will start the paperwork to run a clinical trial testing predictive low glucose suspend.  Based on discussions with the FDA at that time, they will have  better idea of how many clinical trials will be required for approval (and therefore how long it will take).  Also they will have a better idea about testing both the predictive low suspend and high dosing at the same time, or release one and then the other.

Bihormonal AP Update from CarbDM's Diabetes Summit

I attended CarbDM's "Diabetes Summit" in Silicon Valley last month.  It was wonderful, even though I could not stay to the end.  Listening to the morning speakers was very informative, but in this blog I'm going to limit myself to discussing  Dr. Ed Damiano's talk.

Dr. Damiano is working on a bihormonal (insulin and glucagon) AP, called the "Bionic Pancreas". The key piece of information from his talk was that they will finish the current round of phase-II trials on April 27th (that's the last day of data collection).   Another round of studies is planned for the second half of 2015.  For next year, the plan is to create a device that can be sold and spend the rest of 2016 and 2017 testing it.

Dr Damiano reported on results from several clinical trials (adults and children who use the AP under different circumstances).  For all these studies, the numbers were great (in my opinion).  They averaged in the low 140s or high 130s in different trials.

There were some other interesting tidbits: the daily dose of glucagon used by people on this bihormonal AP was between 1% and 3% of the dose used in a single "rescue" injection, so a relatively small amount.   Also, the amount of insulin used by people on the AP was about the same as people in the control group.  So it's clear that the bihormonal AP is using insulin more efficiently, not just using more insulin.

CarbDM's: http://carbdm.org/
The Diabetes Summit: http://carbdm.org/summit/

International Conference on Advanced Technologies & Treatments for Diabetes (ATTD 2015) 

This was a conference held in Feburary in Europe that had dozens of papers, many of which covered artificial pancreas research, continuous glucose monitoring techniques, and related areas.

You can see all of their posters here:
http://dasterminal.com/posters/attd2015/
Abstracts for a huge number of papers are here:
http://online.liebertpub.com/doi/full/10.1089/dia.2015.1525

Joshua Levy 
http://cureresearch4type1diabetes.blogspot.com 
publicjoshualevy at gmail dot com 
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

Artificial Pancreas Update (Jan 2015)

Sound track for this blog is "Living After Midnight" by Judas Priest, but performed by The Donnas:
http://grooveshark.com/#!/s/Living+After+Midnight+Judas+Priest/3ASqUY

Research into the Artificial Pancreas (AP) continues to move forward.  The term "artificial pancreas" refers to using a continuous glucose monitor (CGM) to feed data to a computer, which controls an insulin pump, and in some models, a glucagon pump as well.  Artificial pancreas refers to using existing technology in all these areas, but connecting them together so that a person does not need to worry about counting carbs or blood glucose levels.  It is all done automatically.

Metronic Starts Selling a "Step 2" Artificial Pancreas in Australia

The JDRF uses a 6 step model to get to the fully featured artificial pancreas that we wall want.  You can read about that model here:  http://jdrf.org/research/treat/artificial-pancreas-project/

Right now, Medtronic makes the only commercially available "step 1" artificial pancreas.  However, just recently they started publicising a "step 2" artificial pancreas in Australia.  The difference is that "step 1" APs cut off insulin if you are already too low, while "step 2" cuts you off before you get too low.    This is an important improvement in functionality, but it is also an important regulatory hurdle. The model number is 640G.  I can't find any press releases, or any notice on their web site, but karri on CWD posted this link to a promotional video:
https://www.youtube.com/watch?v=wl6WDkxXjBc
There are also several "Ambassador Reviews" on the Medtronic Diabetes ANZ youtube site.
It looks like they are taking orders for the device now.  However, I can't see anything on the web site related to the 640G.  Maybe they know I'm from the USA, and can't get it?

Of course, the next issue for us Americans is FDA approval.  Medtronic's "step 1" device took 31 months after European approval, before the FDA approved it!  It will be interesting to see if the FDA repeats that fiasco or not.  There has been a lot of progress, several meetings between the FDA and patient advocates (such as DOC, diaTribe, JDRF, etc.) and now we will see if any of that matters. But the clock is ticking now, and we will know a lot more when we see how long the FDA delay of approval is.


A Direct Single Hormone vs. Dual Hormone Comparison

In the past, I've tried to compare Single Hormone AP results to Dual Hormone AP results, by comparing similar results from different studies.  However, it's much better to compare the same result in the same study, rathern than combining data from different studies.  A group of researchers at Institut de Recherches Cliniques de Montreal, Montreal, QC, Canada (and elsewhere) recently did exactly this comparison.  They directly compared a regular pump plus CGM, to an insulin only AP, to a insulin and glucagon AP.  Patients (12 years or older) were treated for 3 24 hour periods.  The trial was not blinded. Funding was from the Canadian Diabetes Association, JDRF, and Medtronic (see above for involvement). They reported the following data:

Measure	Pump + CGM	Insulin AP	Dual Hormone AP
Time spent in target range	51%	62%	63%
Hypoglycaemic events	52	13	9
Symptomatic hypoglycaemic events	12	5	0
Nocturnal hypoglycaemic events	13	0	0

Opinions

I think the clear result of this trial is that the dual hormone AP is very slightly better than the Insulin AP, and they are both noticeably better than the current standard pump and CGM.  This result is similar to previous studies.

Abstract: http://www.thelancet.com/journals/landia/article/PIIS2213-8587(14)70226-8/fulltext
Clinical Trial Registry: http://clinicaltrials.gov/ct2/show/NCT01754337

Many Articles in the January Journal of Diabetes Science and Technology

The Journal of Diabetes Science and Technology had a special issue on glucagon therapy.  There were a couple of articles on stable glucagon, which is required for a bihormonal artificial pancreas (such as Dr. Damiano is working on):

From this abstract http://dst.sagepub.com/content/9/1/8?etoc:

Data are presented that demonstrate long-term physical and chemical stability (~2 years) at 5°C, short-term stability (up to 1 month) under accelerated 37°C testing conditions, pump compatibility for up to 9 days, and adequate glucose responses in dogs and diabetic swine. These stable glucagon formulations show utility and promise for further development in artificial pancreas systems.

From this abstract http://dst.sagepub.com/content/9/1/24?etoc:

Data are presented that demonstrate physical and chemical stability under presumed storage conditions ([over] 2 years at room temperature) as well as “in use” stability and compatibility in an Insulet’s OmniPod® infusion pump. Also presented are results of a skin irritation study in a rabbit model and pharmacokinetics/pharmacodynamics data following pump administration of glucagon in a diabetic swine model.

Here is a diagram of their results.  Note that they are comparing their glucagon to standard glucagon, so their trial is successful if the same colored lines are close to each other, and they are:

Although both of these are animal trials, for this kind of test, I think results in animals are likely to mirror results in people.  They are really measuring the stability of the glucagon, and the test subject species doesn't have a big impact on that.  So my normal worries about "works in mice, fails in people" are pretty small for this kind of research.

Adding Physical Activity Measurements to Aritifical Pancreas Calculations

Also in The Journal of Diabetes Science and Technology, there is this paper:
http://dst.sagepub.com/content/9/1/80?etoc
(People in the San Francisco bay area will notice that the authors are mostly local: Drs. Stenerson, two Paynes, Ly, Wilson, and Buckingham.)

This paper attempted to use data on physical activity to improve an artificial pancreas's BG numbers. The idea is simple enough: we all know that physical activity lowers BG numbers.  If an artificial pancreas knew how active you were, could it do a better job of controlling BG numbers?   The kids in the study (average age 13), did a soccer workout ("football workout", in the rest of the world) on two separate occasions.  In one case, data from an accelerometer was used to help calculate real time insulin dosing, and in the other case, this data was not used.  BG and hypoglycemic events were measured both during the soccer, but also after it, until the next morning.  There were 18 kids in the study.

Overall BG numbers were similar in each group.  Hypoglycemia events were higher when not using the accelerometer, but the difference between groups was not statistically significant. (This is the scientific way of saying "close, but not quite".)

Discussion

From my point of view, there are a couple of ways to interpret this result:

1. One could say that the study was just too early and too small to interpret the results, and it's really more of a proof of concept of how accelerometers could be tested in the future.  The most that can be said is that more research should be done. 
2. Or, one could say that accelerometer data is not needed for an artificial pancreas, because it had no statistically significant effect here.  And this is a good thing, because it means we will not have to burden type-1 diabetics with accelerometers (in addition to pump(s) and a CGM), because the extra information they provide is not needed.
3. Or, one could say that existing algorithms and accelerometers are not good enough, and we need to develop better ones in order to take advantages of this information.
4. Or, one could sort of split the difference, and say that most people don't need accelerometer data (as also supported by the good BG numbers reported by other AP tests which don't use them). However, for serious athletes who do need this extra data, we need to develop better algorithms (or accelerometers), if we are going to successfully use this data. 
5. Or, we can view this research as answering the question "how much physical exertion is needed before an AP needs exertion data to work well?"  The idea is that, of course at some level of vigorous exercise, accelerometer data will be needed.  This trial just shows that the soccer exercises wasn't enough, and we need to do something even more vigorous until it does matter.

No matter which interpretation appeals to you, we are still very early in the testing of accelerator enhanced APs.  I'm sure there will be more clinical trials before there is any consensus on the proper way to integrate accelerator data into APs.  

Interview with Dexcom

Here is a two part interview with the CEO of Dexcom, a big CGM maker.  He talks about future development, both in terms of CGMs for APs and CGMs as a replacement for finger sticks.  I found part 2 more interesting than part 1, but here are links to both:
http://www.meddeviceonline.com/doc/how-dexcom-plans-to-eliminate-the-finger-stick-and-bring-cgm-to-the-masses-part-one-0001
http://www.meddeviceonline.com/doc/how-dexcom-plans-to-eliminate-the-finger-stick-and-bring-cgm-to-the-masses-part-two-0001

Another Summary

Here is another writer's summary of artificial pancreas progress for 2014.
http://www.medpagetoday.com/Endocrinology/GeneralEndocrinology/49342

Homebrew Artificial Pancreas

As Dave Berry used to say: I'm not making this up!

This project is being called "Hacking an Artificial Pancreas" or "DIY Artificial Pancreas", but in the tradition of Silicon Valley, I would called it "Homebrew Artificial Pancreas".  It looks like we have reached the point where people can cobble together a functional AP in their garage.

You can see pictures here (two quite different paths):
https://scottleibrand.wordpress.com/2014/12/15/how-does-a-closed-loop-artificial-pancreas-work-when-you-diy-or-diyps-closed-loop-is-working/
http://circles-of-blue.winchcombe.org/index.php/2015/01/11/wearenotwaiting-thanks-to-dexdrip-introduction/
https://twitter.com/stephenistaken

If you speak twitter: #DIYPS #WeAreNotWaiting #dexdrip

Less than $100 in parts. A little soldering (sometimes).  What could possibly go wrong?

When Steve Jobs and Steve Wozniak made the Apple I they were basically making something that they could not buy, and that's what these guys are doing.  Of course the Steves were not replacing  an organ of the body.

I want to thank Dominik for sending me this. I will never look at a Raspberry Pi the same way, again.

Joshua Levy 
http://cureresearch4type1diabetes.blogspot.com 
publicjoshualevy at gmail dot com 
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

Artificial Pancreas Update (Nov 2014)

This is a quick update on several artificial pancreas (AP) projects.  The term "artificial pancreas" refers to using a continuous glucose monitor (CGM) to feed data to a computer, which controls an insulin pump, and in some models, a glucagon pump as well.  Artificial pancreas refers to using existing technology in all these areas, but connecting them together so that a person does not need to worry about counting carbs or blood glucose levels.  It is all done automatically.

Medtronic Starts Two Phase-III Trials 

Medtronic is currently the leader in commercial development of an artificial pancreas.  They have already released CGM/pump combination that automatically shuts down insulin injection if blood glucose levels go too low for too long.  This existing technology is very likely to prevent "dead in bed", and it is the first small step towards an artificial pancreas.

The next step will be what's called "predictive shutoff".  While the existing system will only stop insulin when blood glucose levels have already gone too low for too long, the new system will use knowledge of insulin on board and blood glucose trends to cut off insulin before blood glucose levels drop below acceptable levels.  This is a big step forward in terms of keeping people in healthy blood glucose ranges, and it is also a big regulatory step forward.  It means that software will be making changes based on the expected (future) situation, not the known (past) situation.

Medtronic is starting two studies of this feature.  An American study will use 84 people at several different sites, while an international study will have 100.  The American study specifically says it is phase-III, and I suspect the other one is as well, but it doesn't say that specifically.  This would be great news, because a new device needs two phase-III trials before it can be approved for marketing in the United States, and both of these studies hope to finish by December 2014.  I view these studies as an attempt to get to market with a "step 2" artificial pancreas device as described in the diagram below.

The American study has one contact person:
Julie Sekella (818) 5765171 julie.sekella@medtronic.com

For all these locations (not all of which have started recruiting, yet):

• AMCR Institute, Inc.  Escondido California
• Stanford University Department of Pediatric Endocrinology, Palo Alto California (Bruce Buckingham)
• Barbara Davis Center of Childhood Diabetes, Denver Colorado (Satish Garg)
• Yale University Diabetes Research Program, New Haven Connecticut
• Atlanta Diabetes Associates, Atlanta Georgia (Bruce Bode)
• University of Virgina, Charlottesville Virginia (Stacey Anderson)
• Rainier Clinical Research, Renton Washington (Ronald Brazg)

The international study has these two locations:

• Schneider Children's Medical Center of Israel, Contact: Moshe Phillip, PhD + 972 3 9253747 mosheph@post.tau.ac.il
• University of Ljubljana, Faculty of Medicine, Contact: Tadej Battelino, PhD +386 1 5229235 tadej.battelino@mf.uni-lj.si

Clinical Trial Records:
http://clinicaltrials.gov/ct2/show/NCT02130284
http://clinicaltrials.gov/ct2/show/NCT02179281
News: http://www.marketwatch.com/story/medtronic-begins-pivotal-study-of-first-predictive-low-glucose-management-technology-for-people-with-diabetes-2014-10-14?reflink=MW_news_stmp

There is a third clinical trial, which is described here: http://clinicaltrials.gov/ct2/show/NCT02160184 and which is expected to enroll 12 people and finish Feb 2015.  It's not clear to me if it is testing the same predictive shutoff feature as the other two.  It is being run in Spain.  Contact: Mercedes Rigla, MD, PhD +34-93-745-8412 mrigla@tauli.cat

Two of the three studies described here refer to a commercial model number: 640G.  

MD-Logic Update

MD-Logic refers to another group of researchers working on a different artificial pancreas.  This AP is in Step 3 or 4 in the diagram below.  They recently published new data.  People used their artificial pancreas for 6 weeks (night only) in their regular lives.  So they were "out and about".  This was a cross over trial, meaning each person spent 6 weeks using the closed loop and six weeks not.  Half the group used the closed loop first, and half of them used closed loop second.  The results were all very good:

• Reduced time spent in hypoglycemia 
• Increased the percentage of time spent in the target range of 70–140 mg/dL 
• Time spent in substantial hyperglycemia above 240 mg/dL was reduced by a median of 52.2% 
• Overnight total insulin doses were lower in the closed-loop nights
• The average daytime glucose levels after closed-loop operation were reduced by a median of 10 mg/dL

Clinical Trial: http://care.diabetesjournals.org/content/37/11/3025?etoc

Interview with JDRF's Dr. Kowalski

This interview has a lot of interesting information about how JDRF and AP research interact:
https://myglu.org/articles/a-pathway-to-an-artificial-pancreas-an-interview-with-jdrf-s-aaron-kowalski

It includes the JDRF "AP Step/Generations" diagram, which is how they think an AP will be developed over time.  You can read more about these steps here:
http://jdrf.org/research/treat/artificial-pancreas-project/

New Artificial Pancreas Project

Another new artificial pancreas project is getting underway at Rensselaer Polytechnic Institute, which you can read about here:
http://news.rpi.edu/content/2014/10/21/1-million-nih-grant-enables-clinical-trials-artificial-pancreas
http://www.meddeviceonline.com/doc/artificial-pancreas-to-begin-clinical-trials-0001
they have not started human trials yet, but it sounds like they will, soon.

Are They Working Together?

One question I get asked about different groups doing similar research is: are they working together?  And usually, I don't know.  However, in the case of Artificial Pancreas research, I know that the different groups are working together, because in some cases, there is overlap among the researchers.  To give you just two examples:

• Bruce Buckingham is working on the Medtronic clinical trial, the University of Virginia clinical trials, and the planned Rensselaer clinical trial.  Plus algorithms that he worked on were used in the Cambridge AP work.
• Moshe Phillip is working on both the Medtronic and the MD-Logic clinical trials.

It's clear that the AP groups are not working "in a vacuum".  They are all aware of each others work.

Direct Comparison (Updated)

The chart below is a comparison of all AP projects which I know about that are either in clinical trials, or about to start them.  Some of these projects are not included in this blog posting, but are described in previous postings: http://cureresearch4type1diabetes.blogspot.com/search/label/Artificial%20Pancreas

Group	FDA Phase	JDRF Step	Average BG Estimated A1c	Size	Adolescents?	Duration	AP Use
Boston University	II	6	138 6.4	53	Yes	5 days	24 Hours/Day
Cambridge	II	3	146 6.7	17	No	8 days	24 Hours/Day
MD-Logic	II	3		24	Yes	90 days	Night Only
Virginia	II	3	135?	13	No	2 days	24 Hours/Day
Medtronic	III	2	Just Started	184	Yes	2 days	24 Hours/Day
Rensselaer			Not Started

Joshua Levy 
http://cureresearch4type1diabetes.blogspot.com 
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

ADA 2014: Type-1 Diabetes Cure Research, Artificial Pancreas

At the 2014 ADA Scientific Sessions, there were several reports on progress on artificial pancreas (sometimes called "closed loop").  Unfortunately, all of them were reported on a day that I was not at the convention, so the information below is mostly from the printed materials at the convention, news reports, and convention "buzz".

The "Bionic" Pancreas:
Bihormonal, Closed Loop, Artificial Pancreas Progress

This was clearly the big news of the scientific meeting.  Here is my previous coverage on this (and it includes links to DiaTribe's more complete coverage):

http://cureresearch4type1diabetes.blogspot.com/2014/04/the-bihormonal-artificial-pancreas.html

Bihormal refers to supplying both insulin and glucagon (so it can raise or lower a person's blood glucose).  Closed loop artificial pancreas refers to automatic dosing as needed with data from a CGM to a pump without human intervention.  Bionic is a marketing name used by Dr. Damiano's group at Boston University.

There were two big publications on the Bionic AP.  The first was in a scientific journal, published the month before the show, and the second was a presentation at the show.

First, I'l discuss the study published just before the show.  The basic set up was that people wore the devices for one day of calibration, and then two days of data collection.   Data was collected for four groups: adults and adolescents, and people who signaled when they were going to eat a meal, and those that didn't.  No one counted carbs or dosed in response to meals.  The signaling group just told the AP that they were about to eat a breakfast, lunch or dinner; nothing about the content.

Group	Average BG	Estimated A1c	% in range   (70-180)
Adults Before Treatment		7.3
Adults who signaled meals	132	6.2	80
Adults without meal signaling	142	6.7	70
Adolescents Before Treatment		7.9
Adolescents who signaled meals	162	7.3	68
Adolescents without meal signaling	175	7.7	60

What this means, is that for adults who did not signal when they were going to eat, they had an average BG level of 142, a likely A1c level of 6.7 (if they had done this for 3 months), and their BG levels were in range 70% of the time!  Now, that looks pretty good, but the news gets better.

Here are the results from the follow up study, done by the same researchers, and given as a scientific talk.  This study was "free range" adults who were free to roam over 3 square miles of Boston, staying in a hotel, working out at a gym, and eating mostly at restaurants, while the adolescents were attending camp.  For this study, no one signaled meals.  It included 20 adults and 32 adolescents, which makes it phase-II sized by my reckoning.

This study has only two data points that matter:

Average BG Number   (for both adults and adolescents)	Estimated A1c
138	6.4

There was slight complexity in the data.  That 138 number was the average over all five days of the test.  The researchers expected that the first day would be worse than the other four, because the unit was calibrating itself to the patient the most during that first day.  For adults, this worked out, the next four days average BG was 133 suggesting that long term use would result in an even lower number, and might even drop a few more points (over time, as the AP better learned how the person reacted to insulin, glucagon, and food).  But for adolescents, that's not what happened.  They averaged 147 over days 2-5.  Even if 147 (A1c of 6.7) is the long term number, that is still a complete success.   It is lower than the ADA standard of 7.5 for adolescents.  But it is a mystery to me why those days should average higher than the first day.

Summary of NEJM data: http://www.nejm.org/action/showImage?doi=10.1056%2FNEJMoa1314474&iid=t02

Note: information for this section came from an ADA abstract, a JCEM paper, and a NEJM abstract.   You can read the whole NEJM article here:
http://www.nejm.org/doi/full/10.1056/NEJMoa1314474#t=articleTop
JCEM abstract here:
http://www.ncbi.nlm.nih.gov/pubmed/24483160

Single Hormone vs Bihormonal Artificial Pancreas
A group from Canada gave a talk where they directly compared injected insulin, an insulin AP, and an insulin and glucagon AP.  For average BG numbers, they found that both types of APs were similar to each other (the dual pumps were only very slightly better), and that they were both significantly better than injections.  However, when they looked at low BG events, then the dual hormone APs had significantly fewer such events than single hormone APs.  This makes sense, since the dual hormone pumps can directly prevent lows by dosing glucagon.

So this Canadian trial suggests that a bihormonal AP might do a little better than a "classic" AP, but it should not do vastly better, if measured by average BG.  When I first saw that poster, I was a little dubious.  Two hormones seemed like much better technology than one.  But then I saw the results below.  One of the complexities, is how does one measure an AP?  Using average BG is easy and straightforward, but should we also measure low BG events and/or high BG events?  If you do (especially low BG events), then the dual hormone APs might look better in comparison.

The Cambridge Artificial Pancreas

With all the excitement about the bihormonal AP, it is important to remember that there are also several "classic" AP projects out there.  For example, the results from the Cambridge AP, a "classic" insulin-only AP, were almost as good as the bihormonal results.  There were something like 7 presentations on various aspects of this project, so it was very well represented.

The "24 hours a day" trial included 17 people, and ran for 16 days (8 days with AP and 8 days with regular treatment).  They also reported on a nighttime only trial, which ran for 90 days!  Again, half with AP and half with regular treatment.

It's big results that matter, from the 24 hour and day trial, are:

Average BG Number   (for both adults and adolescents)	Estimated A1c
146	6.7

MD-Logic Artificial Pancreas Project

What's better than two closed loop, artificial pancreas projects?  Three!  The MD-Logic project uses a "fuzzy logic theory algorithm" to predict insulin dosing.  The research group presented a poster, which showed that using the MD-Logic AP at night, improved BG numbers the next day.  This clinical trial included 24 people and lasted for 3 months (6 weeks using the AP, 6 weeks not, for comparison).

People who used the AP woke up about 15 points lower (on average) than people who did not use it. Looking at all the BG numbers the next day, people who used the AP the night before had an improvement of about 11 points on average.  People who did not use the AP were in range about 66% of the time, while those not using the AP were in range about 62% of the time.  (Range was 70-180).

Source is poster 949-P.

The Virginia Artificial Pancreas

This is another ongoing research project into a "classic" artificial pancreas.  In the trial reported on at ADA 2014, 13 people were tested for 42 hours: 14 hours "open loop" treatment, and 28 hours of "closed loop" treatment.  People in the trial could move about a hotel.  This same research group is planning a 2 month trial of the same AP.

Source is poster 954-P and 104-LB.

Direct Comparison

Group	Average BG Estimated A1c	Size	Adolescents?	Duration	AP Use
Boston University	138 6.4	53	Yes	5 days	24 Hours/Day
Cambridge	146 6.7	17	No	8 days	24 Hours/Day
MD-Logic		24	Yes	90 days	Night Only
Virginia	135?	13	No	2 days	24 Hours/Day

When you look at that, you might say the two hormones are better than one.  But I would not read too much into that difference.  It's not huge (8 BG points and 0.3 A1c), and remember that the single hormone solution is simpler all the way around: only one hormone to buy and load into the pump, less moving parts on the device, and so on.  (Not to mention the fact that Glucagon hasn't yet been approved for this application, although that is expected.)  Of course, the comparison is based on average BG, so might miss extra low BG events in the single hormone APs.

None of this competition bothers me in the least.  I love the idea of having four closed loop systems getting to market at about the same time with slightly different feature sets.  Having a bihormonal AP with slightly better control competing against a single hormone AP which is slightly simpler, sounds like just the sort of competitive situation that feeds progress in a capitalist economy.

Other Bits and Pieces

Poster 75-LB compared CGM data from actual BG data (measured using laboratory grade equipment) from blood pulled directly from a vein. They found that CGM data was very similar to the actual BG data, and that even when different, the differences were small. The researchers conclude that existing CGM technology is not the "weakest link" of AP technology.

Poster 747-P asked people who were testing a closed loop AP, what they thought of it. They liked it. They liked it because it provided better BG control, reassured them that nothing bad would happen while they slept, and improved BG control the next day.  Poster 110-LB contained similar information, but focused on the remote monitoring of an AP in a family situation (ie. parents remotely monitoring children).  A major conclusion of this research was that families wanted the AP/remote monitoring combo being tested; it did not need any improvements at all, it just needed to be made available.

Poster 948-P tested a closed loop system using diluted insulin compared to regular insulin, for small children (aged 4-7).  They found that diluted insulin worked a little better.  Average BG levels were the same, but time spent in range was 8% higher when diluted insulin was used.

Poster 951-P tested a closed loop system which (in addition to BG data) also used energy expenditure and galvanic skin response data.  These are two measures of energy use.  The hope was that by using energy expenditure data, they could make a better AP.  However, the data showed very little difference between using this data and not, and even this little difference was only when BG was above 250.

Summary

My summary of closed loop, artificial pancreas research is this:  We are seeing cure level control in phase-II clinical trials and for several different AP systems.  This is great news, for several reasons. First, it means they "only" need to get through phase-III trials (and marketing approval) for these APs to be sold in the US. They don't need to do better than the results they already have, just produce the same results in larger trials. Second, it means that if one falls apart, there are others which can still get marketed. Third, it means that the technology is ready. When one AP is successful, that team might just be ahead of the rest, but if four groups can do it, that means the technology is here for all.

Joshua Levy 
http://cureresearch4type1diabetes.blogspot.com 
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF, JDCA, or Tidepool news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.

Research In The News (May)

This post is a collection of interesting items that have not yet made it into clinical trials, or which were unsuccessful in previous clinical trials, but are still being worked on.  These are not aimed at a cure.

Comparing Three Continuous Glucose Monitors

This is the summary of a study aimed at comparing CGMs:

The Navigator and G4 Platinum had the best overall accuracy, with an aggregate mean absolute relative difference (MARD) of all paired points of 12.3 ± 12.1% and 10.8 ± 9.9%, respectively. Both had lower MARDs of all paired points than Enlite (17.9 ± 15.8%). Very large errors (MARD > 50%) were less common with the G4 (0.5%) than with the Enlite (4.3%) while the number of very large errors with the Navigator (1.4%) was intermediate between the G4 and Enlite.

Full Study: http://dst.sagepub.com/content/early/2014/04/21/1932296814532203.full.pdf+html%20


New Treatment Option for Type-1s?

LX4211 is an experimental drug designed to cause people to pee out more sugar than normal.  It is designed to cause people to need less insulin at meals, because they can get rid of more sugar by urinating it out.

Quote from the news:

Lexicon said the drug, codenamed LX4211, reduced the total dose of insulin taken by patients at meal times by 32 percent, compared with a 6 percent reduction in patients given a placebo.

News: http://www.reuters.com/article/2014/04/14/us-lexicon-pharm-diabetesdrug-idUSBREA3D0KB20140414

Discussion
When I first heard of this I thought it was a "cheap trick" and not particularly important.  But using 32% less insulin at mealtimes (which is probably about 16% less in total), is a pretty big effect, so it is at least interesting.  I would be even more interested if it improved A1c or BG numbers, since those are directly correlated with better health.  Also, the people in the study had "poorly controlled" type-1 diabetes, but the exact level of control was not stated in the clinical trial record. So it is important to see what happens with people whose control is normal or average.

This drug has been (or is being) tested in a total of 12 clinical trials; one of which is on type-1 diabetics specifically.  The type-1 test was on 36 people.  The study says that people in it must be "willing to refrain from using carbohydrate counting to adjust insulin during the study".  I'm not sure what is going on with that, but if they require people to change their insulin dosing regime as part of the study (and especially to not count carbs), that is certainly something where details matter.

There is a diagram describing how this drug works on the company's web page (but the rest of the page is mostly about type-2):
http://www.lexgen.com/pipeline/lx4211.html


Enzyme Based Artificial Pancreas

This is another way of making an artificial pancreas that uses chemistry rather than electronics. Unfortunately, it looks to me like they are many years away from even starting human tests, and once those start, they are still many more years away from availability.  Still, it is a good idea, and the more different paths to a cure that are being worked on, the better.

News: http://phys.org/news/2014-04-mechanobiology-enzyme-micropump-autonomously-insulin.html

Bi or Tri Hormonal Artificial Pancreas
The link below is to a company trying to develop a tubeless bi or even tri hormonal artificial pancreas.  Sounds interesting, but I can't tell when the website was last updated.  One of the items is a job listing, and it contains the following two quotes:

The CoreMD and "wedges" electronic hardware designs have already been completed. You will work closely with hardware and software engineering senior management in fine-tuning and prototyping (SLA) its pumping mechanism design, making re-design suggestions to save power/space, and capturing that design in SoliWorks. You will then test the SLA and re-design it if needed.  [Which sounds pretty good.]

We are looking for volunteers willing to work "pro bono" (free of charge) [Which does not sound good at all.]

http://pancreum.com/index.html

Serova

Below is an update on Serova's Cell Pouch.  It looks like they had good results on the very early testing, and expect to spend the rest of 2014 getting more, similar data.  They are still testing with immunosuppressive drugs, and obviously, this gets a lot more interesting when they stop using those.

http://online.wsj.com/article/PR-CO-20140422-903834.html

New Delivery Mechanism

The link below reports on another "cured in mice" experiment. This was done by combining GAD-65 IL-10, and an anti-CD3.  (I'm not holding my breath on that getting into human trials; not with the problems GAD65 and anti-CD3s have already had.)  However, I was interested in the dosing method.  They modified (possibly via genetic engineering) a safe bacteria, which is commonly found in the gut, to generate two of the drugs they gave.  This sounds like a very interesting and broadly useful technique, if they can control the dosing sufficiently.

http://diabetes.diabetesjournals.org/content/early/2014/03/25/db13-1236.abstract?papetoc

INGAP Continues

INGAP is a beta cell growth hormone.  It was tested on type-1 diabetics and did not have positive results.  The news article below, which reports on a high school science project, reminds me of two things:

First, some researchers never give up.  Some of them are so committed to their discoveries, that they will continue to work on them even after there have been significant failures in clinical trials. This probably is a good thing; we want researchers who are "all in" and willing to push things as far as they can possibly go, even in the face of failure.  Those are the kind of researchers who will get the eventual cure into our hands.  However, it is important to remember just how committed they can be, when evaluating what they say.

Second, it is always shocking to me just how far technology has gone, in terms of letting younger people do more serious research.  Lab equipment has gotten easy enough to use, and cheap enough to use, so that high school students can do more serious research than they ever could before, and that has to be a good thing.

http://www.montrealgazette.com/news/Montreal+teen+awarded+diabetes+research/9757443/story.html

Joshua Levy
http://cureresearch4type1diabetes.blogspot.com 
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF, JDCA, or Tidepool news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.