Phase-II Results from Rebooting The Immune System To Cure Type-1

First, a discussion about naming.  In the past, I've referred to this treatment as the "Burt" treatment, because that was the senior (last listed) author of the first paper I saw on it, and because I didn't have a better name for it.  I haven't seen Dr. Burt's name on clinical trial for this treatment in many years, so it's no longer an appropriate name.  But I don't have a better name.  In any case, you can read my previous blogging about this treatment under the label "Burt" on my blog:
http://cureresearch4type1diabetes.blogspot.com/search/label/Burt

Second, a little background. The original clinical trial of this treatment, in Brazil, was one of the very few clinical trials which actually cured people of type-1 diabetes. I know that is a provocative statement, so let me be clear: Some of the people treated in this trial did not need to use external insulin (yet still had reasonable A1C numbers while eating normal diets) for as long as the study ran. Some of these people were followed for years. This was not just a "couple of weeks" or even a "couple of months" event.

Third, some important safety issues. Basically, the treatment is to "reboot" the immune system, hobbling the immune system, and then treating it so that when it comes back, it does not attack the body's own beta cells. There are two serious safety issues here: first, during the time the immune system is down, the patient must stay in an isolation ward in a hospital, and is subject to opportunistic infections, which can cause death. Second, the act of shutting down the immune system is a big deal, and might cause problems "down the road". Cancerous tumors are a particular worry. Neither of these risks is completely unknown. Very similar immune system "reboots" are used today to treat cancer, and some other autoimmune diseases and their safety is understood. Never the less, the level of risk is higher than other possible cures for type-1 diabetes.

The Studies

This paper is not reporting on the results of one study.  Rather, it was reporting on a pool of patients enrolled at three different sites, one in Poland and two in China.  There were a total of 65 people included (24 in Poland, and 13 and 28 in China).  All studies enrolled people as young as 12, while the Polish study limited recruitment to the first 6 weeks after diagnosis, the Chinese studies accepted people for a year after diagnosis, but these are all honeymoon diabetics.  There were a few other differences in experimental procedures, as well.

The Results

The following points are all quotes from the abstract:

• A total of 59% of individuals with T1D achieved insulin independence within the first 6 months
• 32% remained insulin independent at the last time point of their follow-up
• All treated subjects showed a decrease in HbA1c levels and an increase in C-peptide levels compared with pretreatment.

The authors' summary of their own results (also quoted from the abstract) is:

1. That remission of T1D is possible by combining [bone marrow stem cells] transplantation and immunosuppression; 
2. That [their procedure] represents an effective treatment for selected individuals with T1D; and,
3. That safer ... therapeutic options [based on bone marrow stem cells] are required.

And I think that's an excellent summary.

Here are some other points that I'd like to make:

• Of the 65 people reported on, one died of sepsis; obviously, this is the worst adverse effect possible.
• 34 people experienced adverse effects (65 events in total).  There was no published data on severity of these events.   As an example, the most common adverse event was fever, but there are no notes on how serious or threatening the fever was.  Alopecia was the second most common adverse effect.
• The earlier in the honeymoon period that a person was treated, the more successful the treatment.

Discussion

There are lots of interesting discussion points in here, and I don't have time or space to go into all of them, but here are a couple:

The researchers believe that a specific type of immune cell, called a CD34+, is critical to success of this technique. Remember that the immune system has many different types of cells, which are often named based on proteins on their outside coating which have these "CD" numbers.  CD34+ is not a cell I have seen specifically "called out" in previous research done in people.  However CD34+ cells are found in umbilical cord blood, which has been used in human research, as well as in bone marrow (as in this trial).

The researchers did measure the long term health of the immune system after treatment, and their summary was "Immune system recovery was rapid and complete".  So they found no evidence of long term weakness in the immune system after this treatment.

What is the future direction of this work?  The researchers discuss two paths for future development of a safer cure based on this work.  The first path is to improve the treatment, by using less immunosuppression at the start, and stronger drugs to prevent infections during treatment.  There are many different immunosuppressive drugs in use, and it may be that a safer drug (or drug combination) can be used in the future.  Similarly, there are many drugs designed to prevent infection by bacteria, viruses, etc.  and it may be that there is a better combination of these drugs available. The second path, is to make the treatment more effective, possibly by increasing the number of CD34+ cells infused back into the patient.

Is this treatment a cure?  That depends on your view of safety.  With a death rate of 1 in 65, I think few people would consider this a cure.  However, if you assume that someone with type-1 diabetes lives (on average) 5 years less than someone without, then in an actuarial (purely mathematical) sense, this treatment does extend average life. This is comparing shaving a few years off of many people's lives vs. cutting a few lives very short.  While this might be a mathematically viable comparison, I don't think it's how most people really think, and certainly not in making decisions about their children.  But of course, research is fueled by hope for the future: what it will grow into, not limited to what it is right now.

Previous Blogging: http://cureresearch4type1diabetes.blogspot.com/search/label/Burt

Abstract: http://diabetes.diabetesjournals.org/content/63/9/3041?etoc

I want to thank the authors of the paper, who provided me with a copy so that I could blog on it.
Normally, this paper is behind a pay wall.

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.

Will That Clinic Cure You (Or Your Kid)?

One thing that I am thankful for, is the relative lack of quacks and charlatans in the world of type-1 diabetes.  Sure, we have a few researchers who say "cured in 5 years", and a plague of reporters and bloggers always looking forward to amplify whatever fool thing they say.  But that is very different from the outright fraudsters who are attracted to some other diseases.  We get fewer of those.  This posting describes how to look at doctors and clinics which claim to cure/treat type-1 diabetes and decide for yourself if they are worth your money, time and energy. Although it is targeted specifically at far away clinics (especially stem cell clinics). Most of what I write here will apply very well to other treatments "too good to be true".

Far Away Clinic X Says They Can Cure Type-1 Diabetes! 
Have You Heard Of Them?

Every now and then I get a question about some clinic or doctor who claims to be able to cure type-1 diabetes.  When I get these emails, if I have time, I look into the clinic or doctor.  They are mostly the same, they take stem cells from a person's bone marrow, and then reinject them back into the person.  Although some of them inject other stuff.

The rest of this blog contains four different ways to evaluate a clinic or doctor who claims to cure type-1 diabetes:

1. Five questions to ask.
2. Common excuses for not having data.
3. Danger signs.
4. How much evidence of safety and effectiveness do they have, and how much do you need?

Five Questions To Ask

Actually, before asking any questions, search the web.  What do the patients say about the clinic? Especially, what do the people who were cured of type-1 diabetes say about the clinic?  Obviously, any clinic that can cure type-1 diabetes is going to have scores of happy customers posting to every internet forum you can imagine.  (Not just one or two, but swarms of them.)  So start by reading posting on the various type-1 forums.  How many of their customers have posted happy results on www.childrenwithdiabetes.com?  How about tudiabetes.org?

I don't know about you, but if my daughter was cured, you couldn't stop me from posting everywhere about it!  I would go out of my way to help by talking to reporters, potential patients, venture capitalists, anyone…..  Nothing would make me happier than to make the discoverer of a cure for type-1 diabetes rich.

Clearly, it is easy to post fake reviews and postings in the web, so happy customer testimonials need to be researched.  (Do they reply to email?  Did they post somewhere besides the clinics' own web page?  Did they post on type-1 forums prior to their cure?)  But if you find nothing, then they obviously haven't cured anyone, or very few people.  

After that, here are the five questions that I would ask of any person or any clinic who says they can cure type-1 diabetes:

1. Where is your data?  I'll describe how to use this data in the next section.  But if you ask this question, and get excuses rather than data, then it's clear they have nothing.  Remember, everyone who does not have data, will certainly have excuses.   Whatever the excuses, ignore them, but do look at the data they provide.  
2. Who have you cured?  This is pretty obvious, but in the cases I've seen, the person or clinic has claimed to be able to cure people for a long time, yet doesn't have a bunch of cured people available.  In one case, the guy claimed to have cured over 10,000 people in the last 20 years, yet not one of them had ever posted to a forum or spoken to a reporter.  In another case, a clinic claimed to have used their cure for 15 years, yet again: no forum posts, no interviews with the media, no discussions with potential new patients, no one available. 
3. What insurance do you take? / What country's medical plans send their type-1 patients to you to be cured?  This might strike you as silly questions, since none of these guys are ever covered by insurance.  But think about it: your insurance company spends thousands of dollars every year treating your type-1 diabetes.  They are going to continue to spend that money for years, maybe decades.  If someone could cure type-1 diabetes, even for $20,000, your insurance company would be overjoyed to pay for it.  Indeed, they would likely force you to go get cured, so they could avoid paying out all the money they do now.  So this is a serious question. Taking it a step further, there are many European countries which have "single payer", or have some form of public health insurance.  In those countries, the minute someone is diagnosed with type-1, the  public health insurance knows they are going to have to pay over $100,000 over that person's life.  In those countries, they would save vast amounts of money by chartering a jet, and shipping all their type-1 patients to this clinic to be cured.  Even if the country were in Scandinavia, and the clinic in Mexico.  So why don't they?
4. How many type-1 diabetics work for you?  They're all cured, right?  Many people with type-1 diabetes end up working in clinics for people with type-1 diabetes.  So an obvious question is, do you employ any type-1 diabetics, and have you cured them?  After all, type-1 diabetics would flock to employment at a clinic that really could cure type-1 diabetes, both to cure themselves and to cure others. 
5. What did you do before?  In a certain sense, I don't care what someone did before they cured type-1 diabetes.  If their previous job was sitting under a bridge and eating goats, that's fine with me, as long as they have peer-reviewed data showing that they cured type-1 diabetes. However, in cases where they don't have data, or it is not peer reviewed, then I think it is worthwhile to look into what they have done before.  For example, what if a guy's previous job was "the founder of the 'Essene Order of Light', an offshoot of a New Age religion based upon modern interpretations of the Essenes, an ancient Jewish sect?" (This quote comes from the man's self bio.)  Does that make you nervous? Should it?  And don't laugh about this example, it is a real guy, Dr. Gabriel Cousens, who really claims to be able to cure type-1 diabetes.  

Common Excuses For Not Having Data

Remember, when you ask for data, and the clinic gives you excuses for not having data, my advice is not to consider if the excuses are good or not, because it just doesn't matter.  If they don't have the data, then they don't have the data.  Having an excuse is never a replacement for missing information. But with that in mind, the following excuses are common:

Privacy is a common excuse which you should ignore, for two separate reasons: first of all, you don't want to know people's names, you want to know how they did, so you are not asking for personally identifying information; second, if this clinic has cured people, those people should be overjoyed and excited about others being told about their successes.  Think about it: if a clinic cured your child, and the clinic asked if they could write up your experience as a case study, and even have you talk to future patients, you would say "yes" in a heartbeat, right?  You would want to tell others about this cure.

Another excuse, is that "no one will publish my results showing a cure".  If you get that, say, "No problem!  I'll take a look at your manuscript, I don't care if it is published or not!"  And see what happens.  Obviously, a peer reviewed article would be better, but if they don't have a manuscript, they never even tried to get it published.

A third excuse is "no one will pay for a study to show my treatment works!".  Tell them, that's fine, but you'd still like a summary of how many of their patients were cured, and for how long. No complex study, just the basic data.  And if they don't keep that, what does that say about their follow up with their existing customers?

Danger Signs

In general, I focus on peer-reviewed evidence of effectiveness and safety; the kind that comes from clinical studies.  However, when looking at treatments for my daughter, I don't ignore danger signs associated with fraud.

No matter how much or how little data a clinic has to support their cure, these signs can provide a separate warning that you are getting into trouble.  None of these prove that the clinic or doctor in question is a quack, but I've found that they are suggestive that the treatment is shaky:

1. Do they use the same treatment to treat different diseases?  Many of these clinics (especially the stem cell clinics) treat all diseases the same.  In some cases the treatment is absolutely identical, treating lung cancer, the exact same way as heart attacks, as type-1 diabetes, as eye problems, etc.  In other cases, the treatment is identical, except that the injection is in a different place. Ask yourself: does that make sense?  Cancers are a large group of related diseases, and they are treated very differently.  So does it make sense for these guys not only to treat all cancers the same, but heart attacks and autoimmune diseases, as well?  For me, it does not.
2. Any clinic run by, or associated with, any doctor who has lost his license somewhere else.  (If they can cure type-1 diabetes, there is no reason for them to associate with anyone even slightly "shady".) 
3. Associating their treatment with other, different treatments that are in the news. 
4. Associating their research with reputable organizations (often Universities), which are actually doing different research.  

For points 3 and 4: Some of the more sophisticated clinics have links on their web pages to studies that supposedly support their ability to cure people. When I have tracked down these studies, I often find that they share only a buzzword or two with whatever the clinic is doing.  So if their marketing literature uses the term "stem cells" then they will have a link to some academic research, which also uses the same term, but otherwise is completely different from what they are doing.

How much evidence of safety and effectiveness do they have, and how much do you need?

The critical question, that you need to answer before you think about a specific clinic or treatment, is how much evidence do you need?  Not just for that one clinic or that one treatment, but for all of them.  For example, the FDA generally requires four clinical trials before they will approve a new treatment.  But that's them, and you are free to choose a different level of evidence, if you want. Maybe you are OK with only two clinical trials?  Or three?  Maybe you want four clinical trials, and two years worth of real world experience, before you will use a new treatment.  These are all reasonable answers to the question.  There is no one universal answer.

Once you have your answer, and you've considered it calmly, and grown comfortable with it.  Then, you need to apply it to these clinics.  In my experience, they have almost no strong evidence that their treatments work.  So even if you have quite low standards (just two peer reviewed papers showing results, for example), they usually can not even make that low bar.  Even if your requirement is "they don't need any published papers at all, I just want to talk to five people who they have cured, one of who I find myself", my guess is that you will not be able to find them.

My experience has been that these clinics are very strong in providing reasons why they have never published papers, why they don't even have the (unpublished) data you want.  Very strong in describing why the FDA, the AMA, the ADA, and everyone else is against them.  But they are very weak in terms of data to support you giving them thousands (sometimes tens of thousands) of dollars. At the end of the day, these kinds of excuses don't even start to suggest that they are actually curing anything.

Finally, I would be very careful about clinics that claim to cure type-1 diabetes, but only provide evidence that they are "helping" type-1 diabetes.  Often these clinics will provide personal testimony from people who say things like "my son's type-1 got much better after the treatment" or "he stopped having lows (or highs or big spikes after meals) after the treatment".  If this is the kind of improvement they advertise, then personal testimonials are the absolute worst way to document it. This is the kind of results where you need to see average BG numbers, or A1c improvements or other hard data that things are getting better.  One of the good things about type-1 as a disease, is that a cure is obvious.  No one can scam a cure.  But "improvements" are easy to scam, so that is what is claimed, then data points are even more important.  (And in reality, if they claim the treatment results in better control, how can they possibly claim that if they don't have specific data showing it?)

In Conclusion

Quack doctors and clinics will always have a good story. They tell you what you most want to hear, and so can be the siren song of hope. Selling cures to people with incurable diseases is a lucrative market for them. So I hope that when you see such cures available, you will ask the questions I discuss here, and think about the data you get in response.

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.

Extra Reading

JDCA "State of the Cure" Update

Each year the JDCA (Juvenile Diabetes Cure Alliance) puts together a summary of cure research.  As a JDCA fellow I contributed information to this effort, although I did not help write the report.  In my opinion, it's a excellent document, well worth reading.  It's only about 15 pages long.  In addition to scientific information on a cure, it also includes information on money: how it's raised, who spends how much, etc.

http://www.thejdca.org/wp-content/uploads/2014/11/SOTC-2014-Final.pdf

JDRF Slide Show On Prevention

This is a great slide show put together by Jessica Dunne who is the Director of Discovery Research for the Juvenile Diabetes Research Foundation.  It is 12 slides.  In addition to material on possible viral and microbiome ("gut") triggers of type-1, it also includes data on growth in type-1 diagnosis, genetics, and so on.

http://www.tudiabetes.org/forum/attachment/download?id=583967%3AUploadedFile%3A3546968


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.

Beta-O2 Starts a Phase-I Trial (and an update on encapsulated beta cells generally)

Introduction to Encapsulated Beta Cells

Encapsulated beta cells are implanted devices.  The encapsulation coating allows blood sugar in, and insulin out, but does not allow the body's immune system to attack the beta cells. It also allows nutrients in and waste products out. This allows the beta cells to naturally grow and to react to the body's sugar by generating insulin which goes into the body's blood system. Meanwhile, the body's autoimmune attack cannot target these beta cells, and you don't need to take any immunosuppressive drugs (as you would for a normal beta cell transplantation).  The cells inside the coating are human beta cells, and different companies get their beta cells from different sources.

Beta-O2 Starts a Phase-I Clinical Trial

Beta-O2 is starting a phase-I clinical trial of their "ßAir Bio-Artificial Pancreas" (encapsulated beta cell) device as a possible cure for type-1 diabetes.  The devices itself is similar to other encapsulated beta cell devices (ie. Diabcell by LCT, Encaptra by ViaCyte, etc.) with one important difference: the device is injected with oxygen once a day.  This is a manual step performed by the patient.  The company claims it will take about 2 minutes, and provides pictures of the device used, which looks like a needle attached to tubing.  You can read about the device here: http://beta-o2.com/living-with-sair/

The clinical trial is pretty standard for a phase-I trial: 8 people will use the device for 6 months, and be followed for an additional 6 months.  They will test for safety and effectiveness (C-peptides, Insulin usage, and A1c numbers), and hope to finish in March 2016.

The clinical trial is being run by the Uppsala University Hospital.  Contact information is: Per-Ola Carlsson, MD, PhD  Phone number:  +46 18 4714425  Email:  Per-Ola.Carlsson@mcb.uu.se.  This trial is for adults with long established (5 years or more) type-1 diabetes.  One unusual requirement for this trial is that patients must start out using 1 unit of insulin per day per kilo of weight (or less).

The clinical trial is expected to cost about US$ 1 million, with JDRF paying for half.

Press release: http://www.fiercemedicaldevices.com/press-releases/first-patient-successfully-implanted-safetyefficacy-study-beta-o2s-air-bio
Clinical Trial Record: http://clinicaltrials.gov/ct2/show/NCT02064309

Other Encapsulated Beta Cells Research Underway

Interest in encapsulated beta cells seems to be cyclical.  When my daughter was first diagnosed, about 10 years ago, encapsulated beta cell devices were a strong area of research.  But one by one, most of the devices failed.  We then went through several years with only one company (LCT) in human trials.  Now, however, interest appears to be picking up with a new generation of human trials underway.  Here is a quick summary of the encapsulated beta cell devices that I know of:

Beta-O2: Just started a phase-I clinical trial.
Viacyte: Just started a phase-I clinical trial.
LCT: Has been doing phase-II trials for several years, but has not made any forward progress (in terms of better results), in years.
Hospital St. Luc research project: Completed (?) a phase-I trial, but not sure about any progress recently.
AZ-VUB: In phase-I, but I don't know any details.
DRI Biohub: Started clinical trials for infrastructure for such a device, but still using immunosuppression.
Sernova: Started clinical trials for infrastructure for such a device, but still using immunosuppression.
Islet Sheet Project: In animal testing.
Harvard Project: In animal testing (?).
Chicago Diabetes Project: Still using immunosuppression.
Nuvilex: Starting animal testing soon.

In my opinion, these are a lot of different research groups, all focused on the same type of cure.  For me, that's good news, because it suggests that many people believe this technology is ready to lead to a cure.  And that makes me optimistic.  Unfortunately, previous "waves" of encapsulated beta cell devices did not lead to a cure, so that makes me nervous.

Background Information

http://en.wikipedia.org/wiki/Cell_encapsulation
https://www.landesbioscience.com/pdf/HunkelerPDF.pdf

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.

Type-1 and Obstructive Sleep Apnea

A reader of this blog asked me what I knew about the relationship between Obstructive Sleep Apnea (OSA) and Type-1 Diabetes.  I didn't know anything, but over the last few weeks, I've been looking through the research.  There is not a lot, but what there is, I've summarized here.

The sound track for this posting is Bon Jovi's I'll Sleep When I'm Dead:
http://grooveshark.com/#!/s/I+ll+Sleep+When+I+m+Dead/wu1oT

This is an area where it is important not to mix up type-2 and type-1 diabetes, and to remember that people who say "diabetes" almost always mean "type-2 diabetes".  One of the more common causes of OSA is being overweight, and this is also one of the more common causes of type-2 diabetes (although in neither case is it the only cause).  The result is that OSA is highly correlated with type-2 diabetes.

However, there has been a little research on type-1 diabetes and Obstructive Sleep Apnea (OSA), and that is what I'm focusing on here.

But first, a little background on OSA:
http://en.wikipedia.org/wiki/Obstructive_sleep_apnea
http://www.webmd.com/sleep-disorders/guide/understanding-obstructive-sleep-apnea-syndrome

Question 1: How common is OSA?

Simple Answer: about 5% of the general population, and about twice that in people with T1D.

Detailed Answer: The overall rate is about 4% [r2] or 5.7% [r4] of the population, but the rate for people who have T1D is about 10% [r3] or 12.7% [r4].  One study [r6] found that sleep apneas were much more common in type-1 diabetics, than in type-2 diabetics.  Study [r8] found high levels of sleep apneas in people with type-1 diabetes, but had no comparison group.

Question 2: Is OSA a danger sign for people who have T1D?

The [r4] study found no connection between sleep issues and HbA1c numbers.  But [r5] found that patients' poor glycemic control and worse apneas were correlated (but no way to tell which caused the other, or if they were both caused by something else entirely). The "Sleep and Glucose Regulation in Youth With Type 1 Diabetes Mellitus" study [r7] is clearly based on the idea that bad sleep results in worse BG control.  Their data shows a clear correlation, but again,I don't see a causal direction.  Although it seems reasonable to me to think that if you BG was out of range, that would cause sleeping problems, rather than the other way around.

Question 3: Is OSA an early warning signal of T1D?

While there is no question that OSA can be an early warning sign of type-2 diabetes, I was not able to find any studies suggesting that it was an early warning sign for type-1.

Question 4: Does OSA cause T1D?
Question 5: Does T1D cause OSA?

I could not find any research on these questions.

Ongoing Studies

There is only one related clinical trial currently running.  They are comparing people who have type-1 diabetes to those without, and are investigating relative rates of OSA, type-1 issues which might cause OSA, and OSA impacts on complications of type-1.  The study includes 145 people, and is expected to be completed in Sept. 2016.  They are recruiting in Paris, France.
Clinical Trial Record: http://clinicaltrials.gov/ct2/show/NCT01935765

There is another small study at the University of Arizona, where students with type-1 will be asked to extend their sleeping hours.
Clinical Trial Record: http://clinicaltrials.gov/ct2/show/NCT01739712

My Summary

My basic conclusion from all this, is that there is very little research in this area.  Based on what we have, it looks like OSA is much more common in people who have type-1 diabetes than in others, and maybe even more common in people with type-1 than type-2 diabetes.   This is a major change in perspective, since OSA is traditionally associated (in people's minds) with type-2 diabetes. Unfortunately, almost nothing else is known about the causality or effects of OSA in people who have type-1 diabetes.

References

[r1] http://en.wikipedia.org/wiki/Obstructive_sleep_apnea
[r2] http://www.webmd.com/sleep-disorders/guide/understanding-obstructive-sleep-apnea-syndrome
[r3] http://www.ncbi.nlm.nih.gov/pubmed/21679352
[r4] http://www.ncbi.nlm.nih.gov/pubmed/21573904
[r5] http://www.ncbi.nlm.nih.gov/pubmed/10907113 (this study uses the term "insulin dependant diabetes", but they are clearly studying children, so I'm assuming they are type-1)
[r6] http://www.ncbi.nlm.nih.gov/pubmed/4004160
[r7] http://www.ncbi.nlm.nih.gov/pubmed/22215921  mass media report here:
http://www.medpagetoday.com/Endocrinology/Diabetes/30460 and clinical trial record here:
http://clinicaltrials.gov/ct2/show/NCT00848822
[r8] http://www.endocrinology.dk/index.php/spor-24-blandet-endokrinologi/488-96-prevalence-of-sleep-apnea-in-danish-type-1-diabetes-patients



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.

Three Unsuccessful Trials

This blog posting summarizes several clinical trials aimed at curing type-1 diabetes which have failed.  These are never fun, happy blog postings, but they are important.  One of the big problems with trying to understand research based on mass media reporting is that failures are rarely covered at all.  The soundtrack for this posting is "Down" by Melissa Lambert:
http://grooveshark.com/#!/s/Down/4BHhwn

Sitagliptin and Lansoprazole Unsuccessful in Phase-II Trial

This was a combination therapy.  The researchers were attempting to combine a drug to stop the autoimmune attack and another drug to trigger beta cell growth.  Both drugs were approved for other purposes, and commonly used.  Unfortunately, it didn't work.  Summary from abstract:

At 12 months, the mean change in C-peptide area under curve was −229 pmol/L for the treatment group and −253 pmol/L for the placebo group; this difference was not significant (p=0·77).

Abstract: http://www.sciencedirect.com/science/article/pii/S2213858714701159
Blog at start of trial: http://cureresearch4type1diabetes.blogspot.com/2010/08/possible-cures-for-type-1-in-news-mid.html

Pioglitazone Unsuccessful in Phase-I Trial

Pioglitazone has been approved for use in type-2 diabetes for over 10 years. It is part of a larger drug family called thiazolidinediones which have been shown to preserve beta cells in animals with type-1 diabetes, and to reduce death of beta cells in petri dishes.  It was being tested as a honeymoon cure, but did not pan out:

Conclusion: In this pilot study, pioglitazone did not preserve β cell function when compared to placebo.

Article: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3890222/
Previous blogging: http://cureresearch4type1diabetes.blogspot.com/search/label/Pioglitazone

Stop Covering Lisofylline

As far as I can tell, no one has done human trials of this treatment for over two years, so I'm going to stop considering it as a possible cure, unless something new comes to light.  Lisofylline is an anti-inflammatory.

Previous coverage (one blog posting) is here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Lisofylline


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.

VC-01 by ViaCyte Starts a Phase-I Clinical Trial

Some people are horrified at the idea of curing diseases by using embryonic stem cells.  If you are one of those people, stop reading now!  This posting is all about curing type-1 diabetes using human embryonic stem cells.  In the future, you should skip over all my blog postings with the tag VC-01 or ViaCyte.

ViaCyte (previously known as Novocell) has started a phase-I clinical trial for their encapsulated beta cell product, which is called VC-01.  This device is designed to cure type-1 diabetes.  The encapsulation coating allows blood sugar in, and insulin out, but does not allow the body's immune system to attack the beta cells. It also allows nutrients in and waste products out. This allows the beta cells to naturally grow and to react to the body's sugar by generating insulin which goes into the body's blood system. Meanwhile, the body's autoimmune attack can not target these beta cells, and you don't need to take any immunosuppressive drugs (as you would for a normal beta cell transplantation).  The cells inside the coating are human beta cells, grown from human embryonic stem cells.   Here is the company's official diagram:

This Trial

This trial will enroll 40 adults who have had type-1 diabetes for over 3 years.  There is no control group, but some people will get two implants while others will get 4 or 6 implants.  C-peptide will be measured after 6 months, and safety issues will be tracked for 2 years.  They hope to finish in August 2017.

Patients are being recruited now in San Diego, California, USA, and they plan to add more locations in the future.

Clinical Trial Record: http://clinicaltrials.gov/ct2/show/NCT02239354
ViaCyte Page: http://viacyte.com/products/vc-01-diabetes-therapy/
Twitter Traffic: https://twitter.com/hashtag/viacyte

Discussion and Opinions

Encapsulated beta cells seem like a straight forward cure for type-1 diabetes, but companies have been working on them since the 1990s, without creating a cure.  There appear to be several difficult problems to solve, especially getting oxygen to the new cells.   Bottom line is this: while encapsulated beta cells sound like a "just needs engineering" cure for type-1 diabetes, decades of work has not led to a cure yet, so it is obviously harder than it looks.

Finally, ViaCyte is very well funded.  In the last few months, they have gotten over $16 million from CIRM, $20 million from Johnson and Johnson, $5 million in venture capital, and half a million from JDRF.

Similar Work

LCT's Diabcell is similar to ViaCyte's VC-01, in that they are both encapsulated beta cell devices. They do use different encapsulation coatings, and Diabcell uses pig beta cells, while VC-01 uses beta cells grown from human embryonic stem cells.  LCT has been tested in people for over 6 years, and is currently in phase-II trials.  (At one time it had approval to be sold in Russia, but it never was sold there.) There is also a device being tested at the University Clinical Hospital Saint-Luc in Belgium, which uses human beta cells (from cadavers) and a different encapsulation coating. 

Several organizations are doing animal tests on various encapsulated beta cell devices.  These include Cerco Medical, Beta-O2, DRI, and several more.

Finally, several organizations are doing human tests on beta cell devices which are not (yet) encapsulated, but they hope to encapsulate in the future.  DRI is doing work like this, as is Serova.  If beta cells are not encapsulated, then you must take immunosuppressives for the rest of your life, so I don't consider those a cure, yet. However, if they then progress to the point where immunosuppressives are not needed, then they would be a cure.

Terminology Note

Some of the news coverage refers to VC-01 as an "artificial pancreas", however I only use that term for electro-mechanical devices.  I use the term "encapsulated beta cells" for devices like VC-01.  You might also hear people refer to it as a "bioartificial pancreas".

If you care about the stem cell production method, here is the company's diagram:

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.

JDRF Funding for a Cure 2014

In the US, we are in the "Walking Season" when JDRF asks us to walk to raise money for a cure. So I'd like to do my part, by reminding you all of how important JDRF is to the human trials of potential cures for type-1 diabetes, which I track.

Let me give you the punch line up front: 70% of the treatments currently in human trials have been funded by JDRF. (And the number is 71% for the later phase trials) This is a strong impact; one that any non-profit should be proud of.  This summary does not include Artificial Pancreas research or stem cell growth trials, because there are so many of those that it would be hard to include them all. For a recent summary of some (not not all) AP research, please read this blog posting: http://cureresearch4type1diabetes.blogspot.com/2014/07/ada-2014-type-1-diabetes-cure-research.html

Below is a list of all the potential cures, grouped by phase of trial that they are currently in, and separated into potential cures that JDRF has funded, and potential cures that JDRF has never funded.

This list is a list of treatments, and many of these are being tested in more than one clinical trial.  For example, the "ATG and autotransplant" treatment is actually running three trials, but since they are all testing the same treatment, it is only one item in the list.  The list below uses the following marks to show the nature of the treatments:
    (Established) One or more trials are open to people who have had type-1 diabetes for over a year.
    (Prevention) This treatment is aimed at preventing type-1 diabetes, not curing it.

Also remember that I give an organization credit for funding a treatment if they funded it at any point in development; I don't limit it to the current trial.  For example, JDRF is not funding the current trials for AAT, but they did fund earlier research into it, which helped it grow into human trials.  I include indirect funding of various kinds.  For example, the JDRF funds nPOD and helps to fund ITN and several other organizations, so I include research done by these other groups as well, as being indirectly JDRF funded.

Cures in Phase-III Human Trials
Summary: currently there are no treatments aimed at curing type-1 diabetes which are in phase-III trials (under the definition of cure that I use).  This is the second year in a row there have been no phase-III trials underway, and it's not a good thing.  Even worse, I don't see a phase-III study starting even next year.  However, phase-III trials grow out of phase-II trials, and there was big growth in the number of phase-II trials this year.  I'm very hopeful that in a few years, these will naturally result in a number of phase-III trials.

Cures in Phase-II Human Trials
Summary: there are 21 trials in phsae-II, and 15 of them have been funded by JDRF, while 6 have not. Here are the treatments that have been funded by JDRF:

• AAT (Alpha-1 Antitrypsin) by Grifols Therapeutics and also Kamada 
• Abatacept by Orban at Joslin Diabetes Center
• Abatacept by Skyler at University of Miami (Prevention)
• Aldesleukin (Proleukin) at Addenbrooke’s Hospital, Cambridge, UK
• Diabecell by Living Cell Technologies  (Established)
• Diamyd, Ibuprofen ("Advil") and Vitamin D by Ludvigsson at Linköping University
• Gleevec by Gitelman at UCSF
• Oral Insulin (Preventative)  
• Rituximab by Pescovitz at Indiana
• Stem Cell Educator by Zhao (Established)
• Teplizumab (AbATE study team)
• Teplizumab by Herold/Skyler/Rafkin (Preventative)
• Umbilical Cord Blood Infusion by Haller at University of Florida
• Ustekinumab by University of British Columbia
• Xoma 52 by Xoma Corp  (Established)

Not funded by JDRF:

• ATG and autotransplant by Burt, and also Snarski, and also Li
• Atorvastatin (Lipitor) by Willi at Children's Hospital of Philadelphia
• BCG by Faustman at MGH  (Established)
• Brod at University of Texas-Health Science Center
• Secukinumab by Novartis Pharmaceuticals
• Vitamin D by Stephens at Nationwide Children's Hospital  (Prevention)

Cures in Phase-I Human Trials
Summary: there are 19 trials in phase-I, and 13 of them are funded by JDRF, while 6 are not. Here is the list funded by JDRF:

• Alefacept by TrialNet
• ATG and GCSF by Haller at University of Florida  (Established)
• ßAir bio-artificial pancreas by Beta-O2's at Uppsala University Hospital in Sweden (Established)
• TOL-3021 by Bayhill Theraputics   (Established)
• CGSF by Haller at University of Florida
• Trucco at Children’s Hospital of Pitt / Dendritic Cells (DV-0100) by DiaVacs   (Established)
• IBC-VS01 by Orban at Joslin Diabetes Center
• Leptin by Garg at University of Texas
• Lisofylline by DiaKine
• Nasal insulin by Harrison at Melbourne Health  (Prevention)
• Polyclonal Tregs by both Trzonkowski and Gitelman 
• Pro insulin peptide by Dayan at Cardiff University
• VC-01 by Viacyte (Established)

Not funded by JDRF:

• CGSF and autotransplant by Esmatjes at Hospital Clinic of Barcelona  (Established)
• Encapsulated Islets at University clinical Hospital Saint-Luc   (Established)
• Etanercept (ENBREL) by Quattrin at University at Buffalo School of Medicine
• Monolayer Cellular Device  (Established)
• Rilonacept by White at University of Texas
• The Sydney Project, Encapsulated Stem Cells  (Established) 

Summary of all Trials
40 in total
28 funded by JDRF
So 70% of the human trials currently underway are funded (either directly or indirectly) by JDRF. Everyone who donates to JDRF should be proud of this huge impact; and everyone who works for JDRF or volunteers for it, should be doubly proud.

Just Looking at Trials on Established Type-1 Diabetics
13 of these treatments (33%) are being tested on established type-1 diabetics.
Of these, 8 are funded by JDRF
So 62% of the trials recruiting established type-1 diabetics are funded by JDRF.

Compared to Last Year
In 2013 there were 37 treatments in clinical trials, in 2014 there are 40 (growth of 8%)
In 2013 there were no treatments in Phase-III trials, in 2014 there are none (no change).
In 2013 there were 15 treatments in Phase-II trials, in 2014 there are 21 (growth of 40%).
In 2013 there were 22 treatments in Phase-I trials, in 2014 there are 19 (drop of 14%).

How I Count Trials for This Comparison

• I give an organization credit for funding a cure if it funded that cure at any point in it's development cycle.
• I mark the start of a research trial when the researchers start recruiting patients (and if there is any uncertainty, when the first patient is dosed).  Some researchers talk about starting a trial when they submit the paper work, which is usually months earlier.
• If there are different clinical trials aimed at proving effectiveness as a cure and as a preventative, or effectiveness in honeymooners and established diabetics, then those are counted separately.
• For trials which use combinations of two or more different treatments, I give funding credit, if the organization in the past funded any component of a combination treatment, or if they are funding the current combined treatment. Also, I list experiments separately if they use at least one different drug.
• The ITN (Immune Tolerance Network) has JDRF as a major funder, so I count ITN as indirect JDRF funding.
• I have made no attempt to find out how much funding different organizations gave to different research. This would be next to impossible for long research programs, anyway.
• Funding of research is not my primary interest, so I don't spend a lot of time tracking down details in this area. I might be wrong on details.
• I use the term "US Gov" for all the different branches and organizations within the United States of America's federal government (so includes NIDDK, NIAID, NICHD, etc.)
• I don't work for the US Gov, JDRF, or any of the other organizations discussed here.  I have a more complete non-conflict of interest statement on my web site.

Some Specific Notes:

• The FDA's clinical trials web site lists two studies being done on Cyclosporine and Lansoprazole ("Prevacid") as a combination treatment.  These trials were listed over 18 months ago but not started recruiting patients.  I have not included them in my list of clinical trials. 
• LX4211: This drug is a SLGT2, and I don't think it is likely to be a cure.  It might turn into a treatment that can be paired with insulin for better results, but not a cure.
• Serova's Cell Pouch and DRI's BioHub: These two clinical trials are both testing one piece of infrastructure which might be used later in a cure.  They are testing a part of a potential cure.  However, in both cases, the clinical trials being run now require immunosuppression for the rest of the patient's life, so I'm not counting them as testing a cure.
• INGAP: This treatment was in human trials twice, but long in the past.  The current testing is being done by a high school student, and I'm not counting it as cure research until I see better results than were seen before (and which previously led nowhere).
• GABA

This is an update and extension to blog postings that I've made for the previous five years:
http://cureresearch4type1diabetes.blogspot.com/2013/10/jdrf-funding-for-cure-2013.html
http://cureresearch4type1diabetes.blogspot.com/2012/09/jdrf-funding-for-cure-2012.html
http://cureresearch4type1diabetes.blogspot.com/2011/10/jdrf-funding-research-for-cure-2011.html
http://cureresearch4type1diabetes.blogspot.com/2010/09/jdrf-funding-research-for-cure-2010.html
http://cureresearch4type1diabetes.blogspot.com/2009/09/jdrf-funding-research-for-cure.html
http://cureresearch4type1diabetes.blogspot.com/2008/10/jdrf-funding-of-cure-research-phases-ii.html

Finally, please remember that my blog (and therefore this posting) covers research aimed at curing or preventing type-1 diabetes that is currently being tested in humans.  There is a lot more research going on, not covered here.

Please think of this posting as being my personal  "thank you" note to all the JDRF staff, volunteers, and everyone who donates money to research a cure for type-1 diabetes:

Thank You!

Finally, if you see any mistakes or oversights in this posting, please tell me!  There is a lot of information packed into this small posting, and I've made mistakes in the past.

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.

DiaPep277 Development Canceled Due To Alleged Misconduct

This is the first paragraph from yesterday's press release from Hyperion:

Hyperion Therapeutics, Inc. (HPTX) today announced it is terminating development of DiaPep277 for newly diagnosed Type 1 diabetes. The company has uncovered evidence that certain employees of Andromeda Biotech, Ltd., which Hyperion acquired in June 2014, engaged in serious misconduct, including collusion with a third-party biostatistics firm in Israel to improperly receive un-blinded DIA-AID 1 trial data and to use such data in order to manipulate the analyses to obtain a favorable result. Additional evidence indicates that the biostatistics firm and certain Andromeda employees continued the improper practice of sharing and examining un-blinded data from the ongoing DIA-AID 2 trial. All of these acts were concealed from Hyperion and others. The Company has suspended the Andromeda employees known to be involved, is notifying relevant regulatory authorities, and continues to investigate in order to explore its legal options. Hyperion employees were not involved in any of the improper conduct.

A note on terminology:  Hyperion did not use the term "fraud" in describing what happened, although Globe News did, and another news service said "falsified data".  Instead, in their conference call and press release, Hyperion used terms like "serious misconduct and deceit", "collusion", "extensive measures to conceal their wrong doing", "actively and consistently lied", "dishonesty and deceit", "deception was extraordinarily serious", and so on.  Based on all that, I do think that "fraud" is the right term, but it is important to remember that I mean this word in the English dictionary meaning [d1], not the legal meaning.  No one has been convicted of any crime, not even charged, and I doubt anyone ever will be.

The sound track for this posting is here:
http://grooveshark.com/#!/s/Saturday+Night+s+Alright+for+Fighting/2UTbqy
(Note this is The Who's version, because I can hear the words better in it than in Elton John's.)

As usual [d] notes are at the bottom of the posting, and provide more details.

Background on DiaPep277

DiaPep277 is a peptide (a part of a protein).  It is a small part of a naturally occurring protein called "heat shock protein 60".  The hope was that it would cause the immune system to stop attacking beta cells.  Development was done by Andromeda (either as a separate company or a division within another company), and no other company is doing work in this area.  It is one of the potential cures for type-1 diabetes that I have followed from the very beginning of my research.  It had already finished phase-II trials when my daughter was diagnosed in 2003.  I have made more postings on DiaPep277 than any other potential cure, except for Diamyd.  You can read them here:
http://cureresearch4type1diabetes.blogspot.com/search/label/DiaPep%20277

In 2008 I published a blog based on DiaPep277's earliest data from a phase-III trial and I felt the results were so small it was unlikely to be successful.  You can read that here:
http://cureresearch4type1diabetes.blogspot.com/2008/08/disappointing-news-on-diapep-227.html
However, in 2011 I published this slightly more upbeat blog:
http://cureresearch4type1diabetes.blogspot.com/2011/11/andromedas-diapep277-succeeds-in-phase.html
I continued to follow it until 2013 when I "threw in the towel" stating that the results seen so far were so small that they could not lead to a cure (although I still held out hope they could lead to a new treatment).
http://cureresearch4type1diabetes.blogspot.com/2013/06/possible-cures-for-type-1-in-news-june.html

What Happened?

As you read my description of what happened, it is important to remember that all my information comes from Hyperion (except for a tiny bit from Evotech), and none of it comes from Andromeda, or any of the specific employees who are alleged to have participated in the dishonesty.  If Andromeda or the people involved publicize their side of the story, I will likely need to update this, based on that new information.

It is normal practice to run two large clinical trials to get the data required by the FDA and the EMEA, and Andromeda had started two: DIA-AID-1 and DIA-AID-2.  They were designed to be twin studies and have 450 people each [d2].  Just last June, DiaPep277 was sold to Hyperion.  This sale included all rights to the new drug, and the transfer of some Andromeda employees who were working on it.  At that point DIA-AID-1 was complete and had been published, but DIA-AID-2 was not quite finished.  The completion date is early 2015.  So the Hyperion statistics team were evaluating the entire DIA-AID-1 data set, as a sort of practice run to get ready to analyse the DIA-AID-2 data, when it was ready.

You can read the DIA-AID-1 results in this paper:
http://care.diabetesjournals.org/content/37/5/1392.full.pdf+html
Thanks very much to Diabetes Care, published by the ADA, for making the whole paper available on line.

When the Hyperion statisticians looked at the full data set for DIA-AID-1, they noticed something very odd.  If they analyzed the entire data set, then DiaPep277 did not have a statistically significant good effect in the primary outcome measurement.  The clinical trial had failed.  However, Andromeda had excluded 30+ patients from the analysis because they had violated the rules about who should be signed up [d3].  With those exclusions, the data showed a statistically significant good effect in the primary outcome [d4].  The study had succeeded. That's unusual, because the exclusions are supposed to be made "blind" (not knowing if the drug worked for those people, or even if they got the drug), and excluding people randomly from a trial, should not change the outcome.  These exclusions were done by an outside company which was involved in the clinical trial, and that company was not supposed to know who got the drug and who got the placebo.

Except Hyperion's investigation found (according to Hyperion) that some of the Andromeda employees passed data to the outside company, and people at that company used that data to selectively remove patients from the study to bias the results.  Also, Andromeda employees changed the primary end point of the study [d5], so that it would be successful. In both cases, the decision was made "unblinded" (i.e. knowing who received DiaPep277, and who received placebo), when the decision should have been made "blind". This completely undercuts the results of the clinical trial.  Hyperion said that this did happen in the DIA-AID-1 trials results, and was also in process of happening in the DIA-AID-2 trial [d6]

Although Hyperion was careful not to name the company that did the statistical analysis for Andromeda (they always referred to it as an Israeli Biostatistics company), nor did they name any of the people involved.   However, on page 1399 of the DIA-AID-1 paper, there is discussion of what companies did statistical analysis as well as describing what each author did in running the study and writing the paper.  (In the future, I'll be checking to see if this company or these researchers are involved in any research I report on.)

Impact

Hyperion has said that there is no way to move forward with regulatory approval for DiaPep277, and they will not attempt it.  So DiaPep277 is dead.  That's the short term impact.  I suppose they could try to sell it to someone else, but who would want to buy it now?

The medium-term impact has three questions:

1. Will the paper describing the results from the DIA-AID-1 trial be retracted?  It was published in Diabetes Care (a journal of the American Diabetes Association), so it will be interesting if the authors retract it, or if the editors/publishers retract it [d7].

2. Will there be a civil lawsuit?  Will anyone face a criminal charge?  Remember that Hyperion paid tens of millions of dollars for DiaPep277 based largely on results which were invalid.  Andromeda and the nameless Biostatistics company are Israeli, while Hyperion is American, and I'm sure that will complicate both civil and criminal legal matters.

3. In addition to the results paper, Andromeda employees also published a research paper comparing the primary end points (new and old) of their study.  If Hyperion's can show that this data was manipulated, then this study should be retracted as well.

The abstract of the paper is here:
http://www.ncbi.nlm.nih.gov/pubmed/24408401
and says specifically that the findings were "unexpected", which Hyperion claims is untrue.

The long term impact is less predictable, but could be much wider.  How many other studies used the same biostatistics company?  Some of the researchers involved in this study are very big names, and have published many other papers, and worked with other companies, including some companies doing clinical trials.

Some Personal Notes

I gave up on DiaPep277 long ago, so in that sense, it was dead to me even before this came up.  But it is still deeply shocking.  (A statistician that looked at this situation described it as "staggering".)  At the end of the day, new drug safety and effectiveness are supposed to be shown via scientific testing. There is a lot of good statistics used to show that results are meaningful, and not due to chance, accident or mistake.  But all those statistics assume that the people running the study are not liars or cheats.  Detecting people who are willing to commit serious misconduct in their scientific studies is not easy.  Implementing the procedures necessary to detect active deceit in all scientific studies would be horribly expensive.  Currently, the FDA uses statistical methods, to find "honest" mistakes, rather than do the sort of investigations and surveillance required to find premeditated fraud.  That's part of the reason why I think it's important to the scientific process to see what consequences the people and corporations face in this case.   Because if other people and other corporations see that they don't face huge consequences, then they will be more willing to risk the same kind of misconduct that is alleged here.

In general, this blog does not report on financial transactions.   That is specifically because of Andromeda and DiaPep277.  Whenever a company buys a new drug, there are always very positive press releases, and early on I thought about reporting those in the blog.  But I noticed that DiaPep277, in particular, was getting passed around to a lot of different companies, and for no good reason that I could see.  I don't remember now all the moves (this was years ago), but I'm pretty sure that Andromeda sold it, got it back, sold it to someone else, and got it back again.  All the companies were Israeli, and as I remember it, some of them were partial owners of each other [d8].  I did not understand it.  That's a lot of moving around in a small market.  It convinced me not to report on company-to-company movement in my blog; that it didn't mean anything, or at least I didn't know the meaning.  But now, in retrospect, I wonder if it was a sign of trouble.  

Finally, I want to personally urge Hyperion to make public the researchers involved, and the evidence about each one's involvement in this alleged misconduct.  There are 21 named authors of the DIA-AID-1 study, and 6 named authors of the change-of-primary-endpoint paper (with much overlap).   Right now, all of these researchers are "under a cloud"  but it is likely that many of them did nothing wrong.  Maybe none of them did anything wrong, and the misconduct was done by others, or never happened at all.  But in any case, the whole type-1 world deserves to know who did what, and the supporting evidence.

Extra Discussion

[d1] For example (from dictionary.com): "deceit, trickery, sharp practice, or breach of confidence, perpetrated for profit or to gain some unfair or dishonest advantage."

[d2] This is a quirk of the American approval process.  It is law that there must be two studies to confirm the results.  Therefore, you can not run one 600 person study, you must run two 300 people studies, even if they are otherwise identical.

[d3] It is common for some patients enrolled in a clinical trial to be excluded from the results for a variety of reasons.  The most common is that someone drops out, and complete data for that person is not available.  However, people are sometimes enrolled by mistake in violation of the study's rules. For example, a trial might require first treatment within 100 days of diagnosis, but a review of paperwork, after the study completes might determine that the patient signed the paperwork within 100 days, but didn't actually get the drug until later.  Data for that patient would be (properly) dropped from the study results.

[d4] If you look at the patient flow diagram on page 1394 of the paper, you can see that a total of 34 patients were excluded from analysis.  It is the two boxes just below the "allocated" boxes, and these changes impacted both the "mITT" data and the "PP" data.  The claim Hyperion made was that these exclusions were made "unblinded" and were specifically tailored to bias the results.

[d5] The primary end point is the most important result of a clinical trial.  Usually, there is one primary end point, and several (less important) secondary end points.  If the primary end point shows a statistically significant good effect, then the trial is successful.  If this is not seen, then the trial is unsuccessful.  The FDA generally determines effectiveness of new drugs based on primary end points.  So therefore, changing the primary end point of a study, in the middle of the study is very unusual, and if it was done "unblinded" (ie. with knowledge that the current primary end point is failing, or the new one succeeding) that is scientific fraud (in my opinion).  Its the moral equivalent of moving the goal posts to the ball's location, rather than putting the ball through the (stationary) goal posts.

In the case of DIA-AID-1, both the original primary end point, and the new primary end point involved measuring C-peptide, but the two end points measured it in different ways.  The details are described in the comparison paper.  Abstract is here: http://www.ncbi.nlm.nih.gov/pubmed/24408401

Remember that although Hyperion has said that this happened in the DIA-AID-1 study, I have not seen their supporting evidence, and so have no way of knowing if this is correct or not.

[d6] As part of this research the DIA-AID-2 data collected to date was unblinded, and Hyperion said that there is almost no chance that it would end up showing a good effect in the primary end point.  (Remember that most of the DIA-AID-2 data has already been collected, even as they are still waiting for the last few patients to get the last few data points.)

[d7] To be blunt, the paper contains the following two quotes (pages 1393 and 1394), which Hyperion now claims are untrue:  "Participants, investigator site staff, persons performing the assessments, and data analysts were blinded to patient allocation from the time of randomization until database lock" and "The study protocol was amended, and the statistical analysis plan was planned and finalized before the study was unblinded, with the GST clearly defined as the primary end point."

[d8] Even now, I don't have a complete list, but here is a partial list of companies involved in DiaPep277 development: Andromeda, Clal Biotechnologies, Teva, Peptor, DeveloGen, and Evotek.

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.

ADA 2014: Other Topics, Pediatric Approval and Big Data

This blog posting covers two topics which I found interesting at ADA's Scientific Sessions 2014.  It contains much more of my personal opinions than a regular post.

Barriers to Pediatric Treatment Approval

This was an ADA session on getting drugs/treatments/devices approved for pediatric use.  It focused on one topic: why is it so hard to get pediatric approval for diabetes treatments (both in type-2 and type-1)?  The entire discussion panel took the position that getting pediatric approval for new treatments was too long/slow/difficult, and so there was no discussion of safety trade offs, or the that the extra work of pediatric approval led to commensurate increased safety.  Everyone just assumed that it didn't.

The answer to the question of why pediatric approvals were so hard was basically this: The FDA requires testing on adults before testing on children (part of the Helsinki protocol on medical testing).   So treatments get approved on adults.  But the FDA requires separate testing on children.  So approval for children comes years after approval for adults.  You don't want to start your pediatric testing before you know that the treatment is going to be approved for adults, so there will always be a gap of many years.  However, doctors can prescribe a treatment for anyone, once it is approved.  So if the treatment looks safe for kids, doctors will prescribe it, once it is approved for adults.  Many parents will encourage this, by clamoring for the newest treatments available.   Now the drug companies think to themselves, why bother testing on kids?  We're already getting profits from kid's prescriptions, and that's only going to increase.  So there is little motivation for them to do pediatric testing.  Of course insurance companies try to say "we won't pay for it for kids, because it hasn't been approved for kids", and sometimes they succeed and sometimes not.  At the end of the day, that just limits the treatment to more wealthy families, which creates another problem; newer pediatric treatments are limited to the wealthy, even for people who have insurance.

All of this leads to the worst possible outcome, from a patient's point of view: drug companies don't test in children, and doctors routinely prescribe for children.  We have use without testing.   Officially, the FDA can wag it's finger at both industry (for not testing) and doctors (for prescribing), but the bottom line is that it's the FDA's policies that promote this sad state of affairs.  (And the FDA can blame the Helsinki protocols for the problem, when the problem might really be their simple minded implementation of those protocols.)

In Europe, they have shifted towards requiring a plan for pediatric testing as part of the adult approval process, and the FDA is considering a similar change.  The idea, is that since some doctors will prescribe a treatment for children once it is approved for adults, the regulator agency should require some testing (or at least planning for testing) on children even as part of adult approval.

Another idea, promoted by researchers and industry, is to share control groups.  Right now, if you want to test a treatment, you need a treated group and a control group.  That often means you must recruit twice as many people than actually get the drug.  For example 150 people get the drug, and another 150 go through the study, but never get the drug.  To test a second drug you need to recruit another 300 people, and so on.  The idea here is to test several drugs at once, all sharing the same control group, so maybe recruiting 600 people to test 3 new drugs, instead of the 900 people it would take now.

Discussion (My Opinions)

I don't have a easy solution to this problem, but I think there are a few obvious things to consider:

1. Although children are not identical to adults, we are all the same species (well, maybe not teenagers, but everyone else :-) and the current FDA policies that require testing on adults and then testing on children need to be relaxed to take into account both the similarities between adults and children, and the differences.
2. Many devices are likely to work very similarly in children as in adults, and such devices should have extremely simplified child testing requirements.  In some cases having combined phase-III trials and approval.  (How can anyone claim that a BG meter is going to be different for children than for adults.  Even for a pump or CGM, the differences are likely to be tiny or nothing because the physiology that they are based on in the same.)
3. On the other hand, drugs which impact growth or hormones are likely to have a different effect on children, and at the very least should follow the same adults first policy we have now.
4. In between, there are lots of drugs which are likely to work very similarly for adults and children, and these could undergo overlapping (but not completely combined) testing, where some testing was done on adults first, but abbreviated testing can be done on children.
5. In general, I think the EU's solution (more work up front) is not a good one, because it slows down approval by creating more hoops to jump through.  Also, if there was child-only problem with the drug, it might still block adult approval, and I don't think that is a good thing.
6. Also, I think allowing doctors to prescribe "off label", but having many insurance companies not pay for "off label" use creates some bad effects as well.  But the question of insurance is much too big a "can of worms" to discuss here.

Two side-discussions on childhood type-2 diabetes:
1. In general, ADA 2014 sessions labeled "pediatric" were about half type-1 diabetes, and about half type-2 diabetes.  In itself, this shows how fast childhood type-2 diabetes is growing, since even 15 years ago, pediatric diabetes was almost a synonym for type-1 diabetes.
2.  I was really shocked by how bad the outcomes were for people diagnosed with type-2 diabetes in childhood.  In type-1 we are used to serious side effects that happen decades down the line, and can be minimized with good control during all that time.   But that's not the reality of type-2 diabetes in childhood.   Very serious side effects can happen during childhood.  They are hit with bad complications much earlier and much more commonly than people with type-1 diabetes.

Big Data

The term "big data" refers to using huge amounts of data to answer questions that were not even considered when the data was collected.  A "classic" data base task might be to record all the books a person buys, so that you can see what authors they like.  A "big data" task might be to record every book a person views while shopping, and every book they discuss on-line, and how quickly they read each page of each book they own, in order to answer questions about what they like, why they like it, and what they do based on their likes, etc.

There was an entire session on "Big Data" at ADA 2014. Although I don't work in Big Data specifically, I am a software engineer, and I do understand the topic.  It was interesting to hear how medical researchers view big data, and also interesting that none of the papers in this session would be considered "big data" by software engineers.

Monitoring Data from Doctor Office Visits

Two of the talks focused on what I would call "more data" (but no where near "big data").  These guys were talking about integrating more medical data from more sources.  But the amounts of data they were talking about was so small that they would not qualify as "big data" for anyone in the industry. (Indeed, the data was so small, it would easily fit "in memory" for a mid-sized virtual machine at my work site.)

One talk focused on scraping information from medical records and aggregating it.  Basically, they installed a server at a 100 or so doctors' offices ("medical practices") that used electronic medical records.  Every night, the server software would look at the newly updated records, and pull useful information and send it to a central server for analysis.  No identifying information was sent, so all data was anonymous and there were no privacy issues.

This data could be used to get an early warning of a flu outbreak or a rare side effect in an approved drug or an unusual drug interaction.  I very much hope that this can be used as a "safety blanket" to encourage more streamlined drug approvals, followed by more rigorous real use surveillance.  I think this combination can lead to the win-win of faster approvals and safer drugs.

In a real world (although small) application on this idea, the researchers looked at all problems reported by type-2 diabetics.  They noticed that many people who took two specific drugs at the same time had complaints about high BG numbers.  Now each of these drugs were supposed to lower BG numbers. Both had been extensively tested and found safe and effective in lowering BG numbers.  But by looking through 1000s of medical records, they found over 100 people who happened to take both, and they often had complaints (also in the their medical records) of high BG numbers.  The two drugs had never been systematically tested together.  The researchers gave both drugs to mice, and saw the mice BG numbers go up.   So the statistical discovery was confirmed in animals.  (Since it was a bad side effect, confirmation in animals was enough, you don't need to test something like that in people.)

A factoid from another talk at ADA 2014: In the US, 76% of people over 60 are taking more than one prescription drug.  And I'm sure the number is much higher for people diagnosed with a chronic disease like diabetes.  Yet drugs are often not tested together; indeed, people taking other drugs (especially for the same disease) are often specifically excluded from clinical trials to avoid uncertainty as to which drug is having what effect.

Recruiting and Running Clinical Trials on a Social Network

Another talk focused on using members of type-1 diabetes on-line groups as recruitment pools for studies, and making study participation much more like social networking.  I would view this as "crowd sourcing" clinical trials.  Therefore, it would be more natural to people who grew up updating Facebook status and sharing pictures.  Presumably such people are comfortable sharing their A1c, which drugs they take, and complications they experience.  These researchers have published some studies based on data from members of the TuDiabetes on-line community.

The researchers were generally worried about such things as "informed consent" to participate in a research study (and ethics in general), and also the quality of the data (especially self selection of the participants).   They did notice that early adopters tended to have better A1c numbers than expected, which suggested to me that they were "skimming" the people with good control, rather than a representative sample.

Discussion  (My Opinions)

Personally, for the "trials via social networks" idea, I'm more worried about deliberate manipulation, and I asked the speaker about this issue.  Not in type-1 diabetes, but in some other diseases, there are organized patient groups that have very strong points of view about their disease, and have actively tried to manipulate scientific research to agree with their views. (See discussion below.)  The researcher I questioned hoped that by using reputable groups (in this case TuDiabetes) they could minimize manipulation, and that statistical analytics might detect or prevent it.

I think that is wishful thinking because people can organize on one forum and then move to another to implement their manipulation, and also because the kinds of statistics usually used are not designed to detect or prevent deliberate, organized manipulation.  At the very least, we would need new kinds of statistics and new kinds of surveillance to protect these studies.

Details about Manipulation

For example, already in vaccine, abortion, and chronic fatigue syndrome (CFS) research, I have seen organized attempts to bias research by selectively submitting reports of side effects, boycotting research that might show something they don't believe, influencing participants in the research, etc.

Currently, the most common form of manipulation is creating spurious VAERS reports.  VAERS is a reporting system for vaccine side effects.  However, any medical professional can submit anything they want into the system.  So anti-vaccine groups run organized campaigns to ask doctors and nurses they work with to submit "side effects" that they claim are caused by vaccines.  Anti-abortion groups do the same for those vaccines which were developed using cell lines from aborted tissue.  Conservative religious groups do it for vaccines targeting sexually transmitted diseases.

More advanced forms of manipulation are also already in use.  Some chronic fatigue syndrome patients have started campaigns to actively discourage fellow patients from signing up for studies that might disprove their pet theories, boycott all studies by researchers who have previously published results they don't like, and even sabotage studies by getting patients to drop out of studies they have already started if those studies might come to a conclusion they don't agree with.  Both CFS groups and anti-abortion groups have organized mass ethics complaints against researchers whose work they disapprove of.

Research done via social networks would be even more open to similar organized attacks.

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.