Hydroxychloroquine (Plaquenil) Starts a Phase-II? Trial To Prevent Type-1 In Presymptomatics

This study is testing a medication, called hydroxychloroquine (HCQ) to assess safety and effectiveness to prevent individuals at risk of type 1 diabetes from progressing to type 1 diabetes.

HCQ is approved by the U.S. Food and Drug Administration as a treatment (not a cure) for malaria, lupus, and rheumatoid arthritis.  It operates through several pathways, including as an anti-inflammatory.  HCQ has been used for over 60 years, but has not previously been studied as a treatment to prevent T1D.

This Study

These researchers are recruiting 200 people who are at least 3 years old and test positive for 2 or more autoantibodies as part of TrialNet.  2/3s will get the drug and 1/3 will get a placebo and will be a control group.   The study involves 5 visits in the first 6 months, then 1 visit every 6 months for the remainder of the study (about six years).

The primary end point is the number of people who progress to having abnormal blood glucose numbers or to being diagnosed with type-1 diabetes.  (The hope is that few people getting the treatment will make this progression, as compared to the placebo group.)  The study started in Aug-2018 and they hope to finish in 2024.  Prevention studies take a long time, because the onset of type-1 takes a long time, so the researchers need to wait a long time to see if fewer people get the disease.

This trial is part of TrialNet and is being funded by JDRF.

The study's web page is here: https://www.trialnet.org/our-research/prevention-studies/hydroxychloroquine-hcq
This study is recruiting at several sites all over the US:

Barbara Davis Center: Aurora, Colorado, United States, 80045
Contact: Betsy Burke    303-724-6766    Betsy.Burke@ucdenver.edu 
Principal Investigator: Andrea Steck, MD
       
University of Florida: Gainesville, Florida, United States, 32610
Contact: Jennifer Hosford    352-294-5759    jennifer.hosford@medicine.ufl.edu 
Contact: Paula Towe    352-294-5761    pdtowe@peds.ufl.edu 
Principal Investigator: Desmond Schatz, MD   
  
University of Miami: Miami, Florida, United States, 33136
Contact: Della Matheson    305-243-3781    dmatheso@med.miami.edu 
Contact: Natalia Sanders-Branca    305-243-6616    n.sanders1@med.miami.edu 
Principal Investigator: David Baidal, MD 
    
University of Pittsburgh: Pittsburgh, Pennsylvania, United States, 15224
Contact: David Groscost    412-692-7241    david.groscost@chp.edu 
Contact: Kelli Delallo    412-692-5210    kelli.delallo@chp.edu 
Principal Investigator: Dorothy Becker, MD       

Vanderbilt Eskind Diabetes Clinic: Nashville, Tennessee, United States, 37232
Contact: Brenna Dixon    615-337-9597    brenna.dixon@vanderbilt.edu 
Contact: Faith Brendle    615-936-8638    faith.brendle@vanderbilt.edu 
Principal Investigator: William Russell, MD       

University of Texas Southwestern Recruiting
Dallas, Texas, United States, 75390
Contact: Lauren Boyles    241-648-4717    lauren.boyles@utsouthwestern.edu 
Principal Investigator: Philip Raskin, MD       

Benaroya Research Institute: Seattle, Washington, United States, 98101
Contact: Mary Ramey    206-342-6945    mramey@benaroyaresearch.org 
Contact: Marli McCulloch-Olson    206-515-5239    Marli@benaroyaresearch.org 
Principal Investigator: Carla Greenbaum, MD       

Wikipedia on HCQ: https://en.wikipedia.org/wiki/Hydroxychloroquine
Clinical Trial Registry:  https://clinicaltrials.gov/ct2/show/NCT03428945

Case studies:
* https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4206615/
* https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3029247
Use in Type-2:
* https://www.researchgate.net/publication/270282245_Ipca_gets_first_approval_for_HCQ_in_diabetes

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.

Vitamin D and Omega-3s (EPA/DHA "Fish Oil") Start a Patient Driven Study

This study is interesting for two reasons.  First, because of what is it testing as a possible prevention of type-1 diabetes.  Second, because of how it is doing the testing.  There are lots of important discussion areas in how this study is being run: it's quite unlike anything done before.  I discuss several of these issues at the end.  This is a long posting.

I've used d-footnotes, such as [d1] for extra discussion, and r-footnotes, such as [r1] for references.  Both of these refer to extra information at the  bottom of the post.

The Basics
This study is testing Vitamin D and Omega-3s oils, specifically Docosahexaenoic Acid (DHA) and Eicosapentaenoic Acid (EPA), as a prevention of type-1 diabetes in people who have tested positive for at least one auto antibody.  Both of these treatments have been areas of interest as possible cures, prevention, or treatments of type-1 diabetes for many years and I've blogged on them many times before [d1].

A quick summary of existing research would be: there is enough to be hopeful, but no clear evidence of success.  There are a couple of case studies, and a population study or two suggesting that Vitamin D or Omega-3 might be effective.  But there are also studies which suggest that these treatments don't help.  This uncertainty is why there are currently seven studies running that look at this question from different points of view [d2].

This study is being driven by the parents of people with type-1 diabetes and the GrassrootsHealth organization [r1].  Funding is provided by the Children With Diabetes Research Foundation [r2].  The methodology is to recruit people who want to use Vitamin D and Omega-3 oils, to try to prevent the onset of type-1 diabetes.  Every few months, they will do blood tests, fill out a questionnaire, and report if they are diagnosed with type-1 (or other diseases).  The hope is that their rate of diagnosis can be compared to the published rates from TrialNet (and similar studies) to see if the treatment prevents or delays the symptoms of type-1 diabetes.

I usually cover intervention trials, and this is not an intervention trial.  The organizers describe it as a "field study", but I would describe it as between a population study and a registry.  All of these terms (field, intervention, population, and registry) are described in [d3].  Intervention trials are the highest quality, and the only type of trial accepted by the FDA in an approval process.  But all types of trials add to our knowledge and can spur more research.

The Vitamin D / Omega-3 T1D Action Project (PreventT1D)

The idea behind this project is pretty simple: TrialNet participants who test positive for at least one autoantibody volunteer to take Vitamin D and Omega-3s and report if they are diagnosed with type-1 diabetes.  Participants will be counseled to try to get their Vitamin D level up to 40-60 ng/mL and their AA/EPA ratio (a measure of Omega-3s) below 3:1, but the final decision about supplements and dosing will be up to the patient.  The goal is to compare results with other TrialNet participants.  Over many years of operation, TrialNet has published good data on how long it takes (on average) to see type-1 diabetes symptoms, depending on how many autoantibodies you have.  You can see my blog on this here:
https://cureresearch4type1diabetes.blogspot.com/2013/10/time-to-diabetes-by-number-of-antibodies.html

So, if they do their analysis right and enough people are involved, it should be pretty obvious if the treatment prevents or delays type-1 diabetes.

But it is important to realize, that this is not an intervention trial, and not even an old-school population based study.  This is "Web 2.0" / "We Are Not Waiting" philosophy applied to scientific research, which means that they are purposefully doing things very differently than a classic intervention study.  A lot of people's opinions of this research is going to boil down to attitudes about how important standardization is, how successful current research procedures are, and how much benefit is found in trying non-standard research techniques.   

The plan is to run the study for 5 years, with a possible extension if people want to participate for longer.  The end point of interest to the type-1 community is "incidence and progression of diseases listed on the questionnaire (with tracking of specific lab markers for study sub-set(s)) as they relate to any of the nutrients studied and their corresponding lab test results".  Each family will choose their own supplements, and control their own dosages (although there are recommended brands and dosages).  There is no control group, and no discussion of blinding the data analysis [d4].  Also, they will enroll as many people as possible, and don't have a set duration, so I don't know when we can expect the first published results.

I have been told that they will be measuring A1c, C-reactive protein (a measure of inflammation, not to be mixed up with C-peptide), D3 levels, and AA/EPA ratios, every three months, but I have not found a published source for that.

The PreventT1D study is a T1D focused part of the much larger D*action project.  The D*action project is a 15,000+ person study looking at Vitamin D supplementation in general and is run by the GrassrootsHealth organization.  Their goal is to increase awareness of the health benefits of Vitamin D and encourage people to take Vitamin D supplements.  (Their phrase is "moving public health messages regarding vitamin D from research into practice".)  The entire Vitamin D saga/controversy is far too large and complex to cover here, but I've included some discussion in [d5].

Recruiting
This study has already started recruiting.  You can join using the web here:
https://daction.grassrootshealth.net/
Since this trial is being run over the Internet, and all you need to do is take over the counter supplements and mail in your samples for testing, you can participate from anywhere and you don't ever meet with a doctor.

The primary investigator for the type-1 diabetes part of the study is Dr. Michael Clare-Salzler from the University of Florida.  The overall investigator is Cedric F. Garland.  The information sheet for patients is here: https://daction.grassrootshealth.net/research-subject-information-sheet/

More information is available at these web sites:
http://preventt1d.org
https://www.facebook.com/groups/preventautoimmunedisorders

(Note that the three web pages listed in this section are my primary sources for information about this study.  When they conflicted, I generally used them in the order presented here (first the D*action web page, then the PreventT1D web page, and finally, the Facebook group.)

Worrisome Issues
There are several aspects of this study which I find worrisome:

No Standardized Treatment 
This is a big issue:  Patients in this trial are not all taking the same treatment.  Although Vitamin D and Omega-3s get most of the press, the "cocktail" listed on the web page actually lists five treatments (DHA, low dose aspirin, mulitvitamin with antioxidants, green tea extract, and Vitamin D).  However, no doses or suppliers are listed, which means that everyone is going to end up taking something different.  (And most of those treatments are unregulated, so the difference between brands could be huge.)  Obviously, in standard intervention trials, this would be completely unacceptable.  Even in this population trial, it may make it hard or impossible to interpret the results, since there really isn't one population being studied.

Pay To Play
This trial requires participants to pay GrassrootsHealth (the official organizer) for Vitamin D and Omega-3 tests.  See more details in [d6].  I've never seen a serious medical trial done on type-1 diabetes in the US where the participants need to pay the organizers to participate.  Obviously, this skews the people who participate (only those who can pay), but it is not illegal or against FDA regulations [r3].  It does bring up some ethical issues (which I will not discuss here).  The cost of testing will be about $600 for Vitamin D only and $1000 for both Vitamin D and Omega-3s, and more if you choose to participate for longer than 5 years.  Participants will also pay for the supplements they use.  The Children With Diabetes Research Foundation has a program to assist with funding for families who have a child with T1D but cannot afford the cost of the testing.  See their web site for details.

No trial registration / No Set Size or Patient Groups
This trial is not registered with the FDA's clinical trial registry, nor with any of the international trial registries.  Registration is only required for intervention studies for FDA approvals, but many population trials and registry trials do voluntarily registration, but this group has not.

Trial registration typically includes how many people will be enrolled, and if there are different groups within the study, how those groups will be defined.  This information makes it clear how long the trial will last, and gives some understanding of how the data will be analysed.  Since this study is not registered and that information is not publicly available for T1D participants, it is hard to know what results will be published.

Vague Endpoints
Some trials publish very specific end points.  These often include (a) the importance of the end point in terms of being primary, secondary, or other, (b) what is being measured, (c) how it is being measured, and (d) when it is being measured.  But some trials publish only vague end points.  For example, they might omit the exact method used.  However, this study is the most vague that I've ever blogged on.  End points are not listed as primary, secondary or other.  No time frames are given.  And even what is reported is listed just as "lab tests" and "incidence and progression of diseases listed".  This is a previously unseen level of vagueness, and leaves open the possibility of "cherry picking" and "results switching" [d7] of data.

Other weaknesses of this study are discussed briefly in [r4], which more broadly discusses hype and hope in type-1 diabetes research.

The Three Big Questions

At the end of the day, I think each of us needs to come to our own decisions on the value of this kind of research.  But I do think we should frame our thinking in terms of the following three questions:

Will We Benefit From This Study?
This is not as easy a question to answer as you might think.  Some people will say that any research helps, and therefore (of course) this research helps.  But others are not so sure.  It's not clear to me if this research could ever be published in a scientific journal, and if not, does it really contribute?  If you look at the "Worrisome Issues" listed above, there are several good reasons why this study may not be taken seriously, and if people don't trust the results, then what is the point of doing the study?

Studies involve direct costs, indirect costs, and opportunity costs.  Prevention studies (such as this one) typically need to enroll lots of people and follow them for many years, so all these costs are high.  Therefore the question of "at the end of the day, will anyone trust the results" is huge.

Will This Study Interfere with Intervention Studies?
There is no question that intervention studies are much more powerful than population studies (or field studies or registries, whatever this study is called).  So another point to consider is: will this study make doing intervention studies harder by siphoning off potential participants.  There is real controversy about this.  The people interested in this study often say things like "I tested positive for two autoantibodies and was told there was nothing I could do.  I don't want to do nothing."  On the other hand, I've heard researchers say things like "TrialNet is running several prevention studies that are recruiting right now, and they'll fly people to centers to participate, etc."  So there is a real difference of perception about whether this study is the only one available or whether it is recruiting in competition with more scientifically powerful intervention studies. [d8]

I will add one data point to the controversy: I live in Silicon Valley (near San Francisco) and we have lots of studies going on here.  At the last JDRF OneWalk there was a joint flyer given out which listed 23 studies recruiting near me right now.  Exactly 1 of these studies (Abatacept, NCT01773707) is aimed at the same group as this PreventT1D study is aimed, requiring two autoantibodies and an age of 6 or higher.  So there is no question that people with one autoantibody or under 5 years old could enroll in the PreventT1D trial, but not in any other local trial.  However, people who are older and have two autoantibodies do have a choice.  But in that case, enrolling in one in might prevent enrolling in the the other.  Even if one person is allowed to enroll in both, it may not be known if the results are due to one or the other treatment, which could make analyzing results tough.

Is This Study A Pathfinder?
Another important question is "Even if imperfect, this study might be a trailblazer to a new way to do clinical trails, and if it is, is that worth supporting even if there are some problems in this specific study?"  When doing something new, the first example often has some problems. Yet, if we abandoned new things at the very first problem, then we would never find the new directions that make the big improvements possible.

On a similar note, what if this study is on the right track to a new kind of study, but has pushed things a little too far?  This is also a common mistake in people experimenting with new ways of doing things. Again, as an experiment in research methodology, it might be worth supporting so that the next project learns from this project, and gets the benefit of crowd sourcing research subjects without the problems caused by pushing the technique quite as far as this team has chosen to push it.

A related idea is that this project might benefit future research if it pushes more conventional researchers to use the web more in the future.  If it encourages researchers to use the web more effectively, to integrate the web into every aspect of running an intervention clinical trail, then it might be worthwhile to support, even if the specific data coming out is less useful [d8].

My Opinions On This Study

1. This is a question that is important to people in TrialNet (and their parents), and so I'm happy to see research focused on this question.  This is a case where there is real scientific controversy, and more studies are needed.

2. I think the idea of harnessing the Internet (and its large, connected population of interested people) is a great idea.  I hope it gets reused and refined in future research, and that conventional researchers incorporate more "Web 2.0" in their methodologies.

3.  I think the combination of pay to play, vague endpoints, different supplements/dosing for different people, and no set size or groups, make this particular study in between a scientific study and a marketing campaign for the company doing the testing.  And I'm profoundly nervous about that.

4. I'm looking forward to the publication of results from this study.  How these results are published and what information is included in the publication(s) will help me to understand if this is a marketing ploy to manipulate science or a new way to leverage the Internet to do large scale science in a way not seen before.  When the results are published, some of the things that I'll be looking at carefully are:

• Is the publication peer reviewed?  Is it treated as a scientific result or as raw material for marketing literature.
• Are the results published in a way which makes them easy to compare with existing results from TrialNet (and elsewhere).
• Who was included in the study and who was excluded, how were trial drop outs reported?  This can be an issue with any registry based trial, but is especially an issue with this study.  The big question will be: if you loose contact with a participant, how does that impact your results.  [d9].
• More generally, how were the various worrisome issues (discussed above) dealt with?  Were they ignored?  Was the data analysed specifically to address them?  Was a larger study size effectively used to lower the risk of spurious results?

5. At the end of the day, I'm unsure if this is a worthwhile trial or not, but because I'm unsure, I'm looking forward to seeing how it turns out.  I may change my mind when I see the methodology behind their published results.  And if the only output of this is a bunch of self-serving press releases, then I will certainly change my mind.  However, I think it is important to give new ideas the benefit of the doubt at least until we see the results.  I do think that this group is trying to push the envelope of what is a scientific study (which is why some researchers don't consider it a "real" study).  Since I'm a "Silicon Valley Boy" I totally support trying new things and seeing what happens.  If we don't try something because we don't know what will happen, then we will never try anything new.   And with this trial, safety is not an issue.

Extra Discussion

[d1] You can read a summary of Vitamin D research aimed at prevention here, but it is 6 years old:
https://cureresearch4type1diabetes.blogspot.com/2012/12/vitamin-d-for-prevention.html
You can read all my blogging on Vitamin D here:
https://cureresearch4type1diabetes.blogspot.com/search/label/Vitamin%20D

For Omega-3s, I've only blogged on one study (on DHA) which has completed, and it was unsuccessful:
https://cureresearch4type1diabetes.blogspot.com/2016/07/research-in-news-july.html
but there might be a few more out there that I missed.

[d2] Right now, there are at least 7 intervention trials testing Vitamin D and/or Omega-3s:
* One tests Vitamin D only on honeymooners aged 10-21.   (NCT03046927)
* One tests Vitamin D and Omega-3s on honeymooners and established, children and adults (for a total of four groups.  Within each group, half get just Vitamin D and the other half D and Omega-3s  (NCT03406897).  This is the POSEIDON trial.
* Four studies using Viatmin D and Diamyd in combination with various other treatments, on various populations.  (NCT02352974, NCT02464033, NCT02387164, NCT03345004)
* One study of Vitamin D and Saxagliptin (a type-2 medicine) on people with adult onset type-1 diabetes.  (NCT02407899)

The NCT numbers above are the FDA's clinical trials registry number for each study.
The list above only includes trials registered in the USA, so I would expect there to be several population or registry studies not included.  Foreign intervention studies are usually included, but there could be one or two which are listed elsewhere.

[d3] Types of studies:
Clinical Trials: A group of similar people are divided up: some get a treatment (an intervention) and some don't.  These are the best form of clinical trials, and the only form accepted as evidence by the FDA when applying to get a new drug approved.
Population Study: A group of people naturally doing one thing, are compared against a group of people who naturally do not do that same thing.
Field Study: (Usually used in ethnography and social sciences, not medicine.)  A study where researchers measure what is happening in the world, without trying to change it, or comparing one group to another.
Registry Study: The researchers register a (hopefully large) list of people who are all similar in some way (for example, by treating a specific disease with a specific drug), and then gather information about those people.  These studies are often exploratory, looking for differences between people in the registry and "average" people.

[d4] This study will use TrailNet data as a comparison group, but this is not a control group.  In particular, some TrialNet participants may be taking Vitamin D or Omega-3s, and that would hurt the comparison.  Also, using a comparison group from a different study creates problems that would not occur if they had their own control group.  Even though there is no control group, blinding might still help in the analysis based on the treatment (comparing those who took just Vitamin D to those who also took Omega-3 oils), or how many autoantibodies the people started with, or previous use of Vitamin D or Omega-3s

[d5] Traditionally, the FDA has considered a blood level of 20 ng/ml, or higher, to be a healthy level of Vitamin D.   Levels above 80 ng/ml can cause direct health problems (toxicity).  Recently there has been a push by some doctors that levels should be 30 ng/ml or higher for best health.  This is controversial, and the New York Times recently had a good (in my opinion) article on the controversy:
https://www.nytimes.com/2018/08/18/business/vitamin-d-michael-holick.html
The doctors affiliated with Grassroots health, go farther even than this, however, and recommend 40 ng/ml to 60 ng/ml as a normal level of Vitamin D, and recommend testing to ensure you have that level, and supplements if you don't.

[d6] The GrassrootsHealth web site says that they will do the testing and lists the costs I've included.  However the WIRB document on the Facebook page says that any lab can do the tests (and does not list specific prices).   Also, there are scholarships available to people who want to participate, but can not afford to, but these are not described, although I have been told that The Children With Diabetes Research Foundation will assist those who need assistance, through GrassRootsHealth.

[d7] "Cherry Picking" is a bad science technique where data is only gathered from people (or in situations) which support the researcher's goals.  "Results switching" is a bad science technique where the researchers expect to report on one end point, but that end point does not show what they want, so they look around for some data closer to what they want, and publish that instead.

[d8] On a more personal level, the whole point of TrialNet (which is a large, multi-year, multi-million dollar project) is to screen people for autoantibodies, both to help those people and their parents, but also to recruit them into prevention studies.  TrialNet is a shared foundation for many prevention studies.  This PreventT1D trial can be viewed as a sort of crowd sourced, web 2.0, #WeAreNotWaiting competitor to TrialNet; a clear message (from some patients) that TrialNet is too slow, too exclusive, too official, too bureaucratic, too limited, and so on.

[d9]  It is clear to me that this study will be large enough, so that by excluding certain people, you can come up with any results you want.  So it will be important that the published results document exactly how people are included, excluded, and how drop outs are handled.

References

[r1] https://grassrootshealth.net/?post_projects=about-us
"GrassrootsHealth is a nonprofit public health research organization dedicated to moving public health messages regarding vitamin D from research into practice."

[r2] http://cwdfoundation.org/

[r3] From http://stm.sciencemag.org/content/7/298/298ps16
"There do not appear to be any clear legal or regulatory prohibitions on charging for participation in a research study."

[r4] Dr. Skyler gave a talk at EASD 2018 where he really "burned"  (said bad things about) this study.  Slides 50-53 cover preventt1d specifically:
https://www.easd.org/virtualmeeting/home.html#!resources/hope-and-hype-where-are-we-with-type-1-diabetes
The talk was based on a paper which you can read here:
https://www.diabetesresearch.org/file/research-publications/2018_Hope-vs-hype---where-are-we-in-type-1-diabetes---Diabetologia-on-line-12-26-17.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, JDCA, or Bigfoot Biomedical news, views, policies or opinions. In my day job, I work in software for Bigfoot Biomedical. 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.

Golimumab Update

Golimumab (sold as Simponi) is an immune system modulator, which has been approved in the United States and many other countries for treatment of several autoimmune diseases, so testing it on type-1 diabetes makes a lot of sense.  Simponi has already been approved to treat rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, and ankylosing spondylitis.

Golimumab is a monoclonal antibody, which is an artificially created antibody which targets one very specific molecule in the body.   If a disease is caused by that molecule (or a cell marked by that molecule), then using a monoclonal antibody to target it is promising.  Golimumab targets tumor necrosis factor alpha (TNF-α) which causes inflammation, and is well known to be involved with type-1 diabetes. 

There are three on-going clinical trials of Golimumab (Simponi):

T1GER: SIMPONI® to Arrest Beta-cell Loss in Type 1 Diabetes
Who: 84 people aged 6-21 with honeymoon type-1 (first 100 days)
What: 52 weeks of treatment
When: Started Aug-2016 and expects to finish May-2020 (fully enrolled in Aug-2018)
Where: 33 sites in the USA (but they are no longer recruiting)
Run by: Janssen Research & Development

SIMPONI (Golimumab) Therapy in Children, Adolescents and Young Adults With Pre-Symptomatic T1D
Who: 30 people aged 6-21 with two or more autoantibodies, but no "classical" symptoms of T1D
What: 26 weekly injections
When: Started Oct-2017 and hopes to finish July-2021
Where: Colorado, Finland, Sweden  (they are still recruiting new people)
Run by: Janssen Research & Development

Targeting Beta Cell Dysfunction With Liraglutide or Golimumab in Longstanding T1D
Who: 30 people aged 18-50 who have had type-1 for more than 3 years
What: 8 weeks of treatment
When: Started Aug-2018 and hopes to finish June-2020
Where: Idaho and Washington  (they are still recruiting new people)
Run by: Benaroya Research Institute

Summary
I like this as a complete program.  These three studies cover Golimumab from many different points of view: people before they are diagnosed, honeymooners, and people with longstanding type-1. Two of the studies are for children 6-21 years old, and one for adults 18-50.  All are reasonable size.

The downside, is that we have to wait until 2020 to see results.  The good news is that by 2021, we'll have results from three different studies to look at.

Discussion
Curing type-1 diabetes in people with established type-1 is generally thought  to require two successes.  First the autoimmune attack must be stopped, and second beta cells must be regrown.  Golimumab targets the autoimmune attack, but is not known to regrow beta cells.  By itself, such a treatment might cure presymptomatic or homeymoon type-1 (because those people still have some beta cells), but is unlikely to cure established type-1.

Clinical Trial References:
  * https://clinicaltrials.gov/ct2/show/NCT03298542
  * https://clinicaltrials.gov/ct2/show/NCT02846545
  * https://clinicaltrials.gov/ct2/show/NCT03632759

Drug Web Page: http://www.simponi.com/
Drug Wikipedia Page: https://en.wikipedia.org/wiki/Golimumab
TNF  Wikipedia Page: https://en.wikipedia.org/wiki/Tumor_necrosis_factor_alpha

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 Bigfoot Biomedical news, views, policies or opinions. In my day job, I work in software for Bigfoot Biomedical. 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 2018

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: 69% of the treatments currently in human trials have been funded by JDRF. (And the number is 86% for the later phase trials.) This is a strong impact; one that any non-profit should be proud of.  Below is a list of all the treatments, grouped by phase, and separated into groups that JDRF has funded, and those JDRF has never funded.

Many of these treatments are being tested in more than one clinical trial.  For example, the "Polyclonal Tregs" treatment is running at least two trials, but since they are both 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.
    Presymptomatics: One or more trials are open to people who have 2 or more autoantibodies, but have not yet started showing symptoms of type-1 diabetes.
    Prevention: This treatment is aimed at preventing type-1 diabetes, not curing it.

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 also include indirect funding of various kinds. The JDRF funds nPOD,  ITN, and several other organizations, so I include research done by these other groups as well.

The Difference Between Phase-II and Phase-II? Trials
Phase-II trials are "classic" phase-II trials; they are done after a successful Phase-I trial in type-1 diabetes.  What I call Phase-II? trials are done on known safe treatments, so they don't need Phase-I trials, but have never been tested on type-1 diabetes before.  These Phase-II? trials might be Phase-II from the point of view of size and safety, but they are Phase-I in terms of effectiveness, so I'm putting them in their own category.

Cures in Phase-III Human Trials

Summary: currently there is only one treatment in a phase-III clinical trial, and that is aimed at prevention.  It is funded by JDRF:

• Oral Insulin (Preventative)

Cures in Phase-II Human Trials

Summary: there are 22 trials in phase-II, and 18 of them have been funded by JDRF, while 4 have not. Here are the treatments that have been funded by JDRF:

• AAT (Alpha-1 Antitrypsin) by Kamada 
• ATG and GCSF by Haller at University of Florida (Established) 
• Abatacept by Orban at Joslin Diabetes Center 
• Abatacept by Skyler at University of Miami (Prevention) 
• Aldesleukin (Proleukin) at Addenbrooke’s Hospital, Cambridge, UK 
• Diamyd, Ibuprofen ("Advil"), and Vitamin D by Ludvigsson at Linköping University
• Diamyd, Etanercep, and Vitamin D  by Ludvigsson at Linköping University
• Diamyd and Vitamin D by Larsson at Lund University (Prevention)
• Gleevec by Gitelman at UCSF 
• Gluten Free Diet: Three Studies  (Preventative)
• Polyclonal Tregs by both Trzonkowski and Gitelman  
• Stem Cell Educator by Zhao (Established) 
• Teplizumab (AbATE study team) 
• Teplizumab by Herold/Skyler/Rafkin (Prevention)
• Tocilizumab by Greenbaum/Buckner at Benaroya Research Institute 
• Umbilical Cord Blood Infusion by Haller at University of Florida 
• Ustekinumab by University of British Columbia
• Verapamil by Shalev/Ovalle at University of Alabama at Birmingham

Not funded by JDRF:

• ATG and autotransplant by Burt, and also Snarski, and also Li 
• Dual Stem Cell by Tan at Fuzhou General Hospital 
• Stem Cells of Arabia (Established)
• Vitamin D by Stephens at Nationwide Children's Hospital (Prevention)

Cures in Phase-II? Human Trials
Summary: there are 12 trials in phase-II, and 7 of them has been funded by JDRF, while 5 have not. Here are the treatments that have been funded by JDRF:

• Alpha Difluoromethylornithine (DFMO) by DiMeglio
• GABA by Diamyd
• GNbAC1 by GeNeuro (Established)
• Golimumab by Janssen
• Golimumab by Greenbaum (Established)
• Intranasal Insulin by Harrison at Melbourne Health (Prevention)
• Rituximab by Pescovitz at Indiana University

Not funded by JDRF:

• Albiglutide by GlaxoSmithKline
• Ladarixin by  Emanuele Bosi of Dompé Farmaceutici
• Liraglutid (Presymptomatics)
• NNC0114-0006 and Liraglutide by Novo-Norsk
• Rapamycin Vildagliptin Combo by IRCCS (Established)

Cures in Phase-I Human Trials
Summary: there are 24 trials in phase-I, and 15 of them are funded by JDRF, while 9 are not. Here is the list funded by JDRF:

• Alefacept by TrialNet 
• ßAir by Beta-O2's at Uppsala University Hospital in Sweden (Established) 
• TOL-3021 by Bayhill Therapeutics (Established) 
• CGSF by Haller at University of Florida 
• Exsulin and Ustekinumab by Rosenberg at Jewish General Hospital, Canada (Established) 
• Golimumab by (Presymptomatics)
• IBC-VS01 by Orban at Joslin Diabetes Center  
• Metformin by Littleford at The University of Exeter (Prevention)
• MonoPepT1De by Cardiff University
• Mozobil by University of Alberta (Established)
• MultiPepT1De (Multi Peptide Vaccine) by Powrie at King’s College London
• Nasal insulin by Harrison at Melbourne Health (Prevention)
• Tauroursodeoxycholic Acid (TUDCA) by Goland at Columbia University
• 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) 
• Gluten Free Diet by Carlsson at Lund University
• IMCY-0098 by Imcyte
• Mesenchymal Stromal Cell by Carlsson at Uppsala University
• Microvesicles (MVs) and Exosomes by Nassar at Sahel Teaching Hospital 
• Monolayer Cellular Device (Established) 
• ProTrans by NextCell (Established)
• Substance P by Vanilloid Genetics at Hospital for Sick Children Toronto (Established)

Summary of all Trials
59 in total
41 funded by JDRF
So 69% 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
16 of these treatments (27%) are being tested on established type-1 diabetics.
Of these, 9 are funded by JDRF.
So 56% of the trials recruiting established type-1 diabetics are funded by JDRF.

Compared to Last Year
In 2017 there were 55 treatments in clinical trials, in 2018 there are 59 (growth of 7%).
In 2017 there was 1 treatment in Phase-III trials, in 2018 there is one (no change).
In 2017 there were 22 treatments in Phase-II trials, in 2018 there are 22 (no change).
In 2017 there were 8 treatments in Phase-II? trials, in 2018 there are 12 (growth of 50%).
In 2017 there were 24 treatments in Phase-I trials, in 2018 there are 24 (no change).

A Little Discussion
This year there are no phase-III trials aimed at curing type-1 diabetes, and that's been true for many years.  Indeed, since I've tracked research, there has never been a phase-III trial aimed at people with established type-1.  Back in the 2000s, there were a couple aimed at curing honeymoon type-1, but none were successful, and none have started for years.

That's discouraging, because it means we are a long way from a cure.  However, for me, it's a reason to donate.  Money is the thing that is going to move the Phase-II studies into Phase-III studies, and the Phase-I studies to Phase-II, create more Phase-I studies, and so on.  And if we think "nothing looks promising in the next few years, so I won't give money" that results in nothing looking promising in the future, either.  If you're worried about your money going to non-research, then you can do what I do: fill out the attached form or go to the following website and send it in with your donation:  http://thejdca.org/good-giving-landing-page/  (Unfortunately I don't know how to do this for on-line donations.)

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:

• GNbAC1 by GeNeuro used JDRF's nPOD project.
• NextGen's ProTrans product is a form of Wharton's Jelly, and JDRF has funded related research into Wharton's Jelly, but has not funded this program specifically, so it is listed as non-JDRF.
• I'm removing Dr. Faustman's BCG research from my list of potential cures.  For more information read this blog:
  https://cureresearch4type1diabetes.blogspot.com/2018/09/every-year-in-september-or-october-i.html and for even more details
  https://cureresearch4type1diabetes.blogspot.com/2018/07/dr-faustman-publishes-follow-on-bcg.html
• Oral Insulin: This trial was a phase-III trial, meaning that it was large and designed to provide enough information so that if, if successful, the treatment could be widely used. However, as it turned out, only part was successful, and that part was phase-II sized, so I don't think we will see widespread use based on this trial alone. You can think of this as a phase-III trial with phase-II results.
• 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.
• Substance P at Hospital for Sick Children Toronto: This trial is avoiding the honeymoon period by testing for insulin production.  Patients must inject more than 1/2 unit/kg to be accepted, therefore they will accept recently diagnosed people, if they are injecting enough insulin to be passed the honeymoon.  I'm counting this as "Established".

This is an update and extension to blog postings that I've made for the previous seven years:

• https://cureresearch4type1diabetes.blogspot.com/2017/10/jdrf-funding-for-cure-2017.html
• http://cureresearch4type1diabetes.blogspot.com/2016/10/jdrf-funding-for-cure-2016.html
• http://cureresearch4type1diabetes.blogspot.com/2015/10/jdrf-funding-for-cure-2015.html
• http://cureresearch4type1diabetes.blogspot.com/2014/09/jdrf-funding-for-cure-2014.html
• 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

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 than is counted 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.  As in previous years, I'll be at the Santa Clara (California) JDRF One Walk. New this year, I'll be part of the Bigfoot Team.  Come by and say "hi", or strike up a conversation about research.  I love to talk about research!

Joshua Levy 
https://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 Bigfoot Biomedical news, views, policies or opinions. In my day job, I work in software for Bigfoot Biomedical. 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.

Dropping Four Research Programs

Every year in September or October I write a blog posting which summarizes all research being done in humans, aimed at curing type-1 diabetes.  That blog is going to be published in 2-4 weeks.   While putting that blog together I have found several research projects which I should not cover any more, and I'm listed those here, with a brief note on why they are no longer of interest.

I understand that this posting is a downer, and I'm sorry for that, but it is important to know what studies are no longer looking promising, and why.  Research naturally gets a lot of press when there is good news, but it's important to keep track of the bad news, and the "no news is bad news" situations as well.

Dendritic Cell Therapy  (DV-100) by DiaVacs
This trial was supposed to start in 2013, but never did.  The company is working on a follow on product, DV-200, and when that starts clinical trials I will follow it.  But since there has been a five year break between DV-100 and DV-200, I'm going to wait until a trial actually starts before restarting coverage.

BCG by Faustman at Harvard
This research is being removed for two reasons:

• Her phase-II trial is not using C-peptide data as either a primary or secondary outcome.  C-peptide is the standard measure for progress to a cure, so not having it as a primary or even secondary outcome means this research is no longer "aimed a curing type-1 diabetes".  (I will continue to follow it, and especially any C-peptide data that comes out, but unless C-peptides are a primary or secondary outcome, it is not cure focused for me.)
• The phase-I trial extended results show that Dr. Faustman's original theory (the TNF theory) of how BCG might cure type-1 diabetes is wrong.  The paper said specifically that the theory did not explain the results seen, and presented a new theory.  However the new theory is based on how the body digests carbs (not regenerating beta cells), and therefore is not a cure focused theory.  (Indeed, several type-2 diabetes treatments are based on similar theories).  So even if this theory is correct, the result would be treatment, not cure.

Obviously, this research group is continuing to talk about curing type-1 diabetes, but one the rules of my blog is "Actions speak louder than words" and if the clinical trial is not focused on C-peptide data, I don't think they are focused on a cure, no matter what is said.

Rilonacept by White at University of Texas

This group published their phase-I results in June 2018, but they were unsuccessful: "Rilonacept treatment for 6 months is well-tolerated in individuals with T1D of recent onset, but is unlikely to be efficacious as a single agent in preserving beta cell function."  So I don't expect any follow up work.

The Sydney Project (Encapsulated Stem Cells)
I can not find any recent references to this project.  The closest I can find is an encapsulated stem cell project being funded by the Australian Foundation for Diabetes Research.  It is doing animal research right now, so not clinical trials.


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 Bigfoot Biomedical news, views, policies or opinions. In my day job, I work in software for Bigfoot Biomedical. 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.

NextCell Starts a Phase-I Study of Mesenchymal Stromal Cell Treatment

NextCell pharma is running a clinical trial of their ProTrans product.  This is a stem cell product derived from "Wharton´s Jelly", which is a specific part of the umbilical cord.  ProTrans is made from umbilical cords from third parties, not the person receiving the transplant.  (So this is not self transplants, where the person gets stem cells which were originally harvested from themselves.)

The difference between ProTrans (the product being tested), and generic stem cells from Wharton's Jelly in the umbilical cord, is some proprietary testing.  NextCells thinks they have a way of identifying which batches of stem cells will be more effective, so they test each batch of stem cells, and the ones that pass are used to make ProTrans.

The Clinical Trial

The clinical trial being run right now, can be thought of as two mini-trials, being run one after the other.  They were both approved at the same time, which is why there is only one clinical trial registry.  However, when you read it, it is very clear that there is a 9 person trial, followed by a 15 person trial.  The first part is focused on finding the best dose, and the second part is focused on finding how effective that dose is.  The researchers have published their entire study protocol, which you can read here:
http://www.clinicaltdd.com/article.asp?issn=2542-3975;year=2018;volume=3;issue=2;spage=32;epage=37;aulast=Carlsson
Note that this published protocol description is not the same as the FDA clinical trial registry description.  I'm assuming that the published protocol is correct, as it was published months after the FDA registry was last updated.

Both parts of this study are limited to adults (18-40 years old) who are within 2 years of diagnosis.
The first part will be men only, the second part will be men and women.  The treatment is one intravenous infusion.  No immune supressives will be given.  The primary end points are safety and C-peptide generation (this measures the body's ability to generate insulin) after a year.  Secondary end points include insulin independence, insulin use, A1c numbers, and more C-peptide results.

Part 1

This part of the study is not blinded, and will include three groups of three people each, all of whom will get the treatment (no control group).  Each group will get a different dose of stem cells.  The first group will get 25 million cells, the next 100 million cells, and the third will get 200 million.

Results: No serious adverse effects as of June-2018.  Initial (one-month) results expected Oct-2018.

Part 2

This part of the study is double blind.  Ten people will get the treatment and five will get a placebo as a control group.  Everyone in this group will get the same dose, and that dose will depend on which one gives the best results in the first part of the trial.

Results:  Full results expected 2020.

NextCell's web site: http://www.nextcellpharma.com/
Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT03406585
Paper on Wharton's Jelly in general:
https://stemcellsjournals.onlinelibrary.wiley.com/doi/full/10.1002/sctm.16-0492


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 Bigfoot Biomedical news, views, policies or opinions. In my day job, I work in software for Bigfoot Biomedical. 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.

Results from a Phase-II Verapamil Trial

Verapamil is a drug which has been used in the US since 1982 for high blood pressure, migraines, and heart problems.  It also lowers levels of a protein called TXNIP.  The researchers running this trial believe this is important because they believe TXNIP kills beta cells as part of the onset of type-1 diabetes.  So giving Verapamil should lower TXNIP which should improve beta cell survival, and stop type-1 diabetes.

I previously blogged about this trial when it started:
https://cureresearch4type1diabetes.blogspot.com/2015/03/verapamil-starts-phase-ii-trial.html

This included 32 people.  The treatment was a Verapamil pill once a day.  The study was done on honeymooners and was double blind.  The primary end point was C-peptides, which are key for a cure, as they measure the body's ability to create insulin.  You can see the results below:

Graph is from the published paper, and is presented
 for educational purposes only.

Remember these are honeymooners, and they were given Verapamil for the entire time.   Normally, people continue to loose C-peptide during the year after diagnosis, and you can see that in the placebo (untreated) group in black above.  But the treated people (in red above) improved their C-peptide production for the first three months, and still produced more C-peptide than untreated people after 12 months.

Discussion

Having the C-peptide numbers go up noticeably in the first three months is a good outcome, but it is not -- by itself -- a cure or a prevention.  The treated people were still doing much better than the untreated group after a year, but again, that's not a cure by itself.  So the real question is how to move these good results forward to a cure, and I think there are four ways to think about that question:

One big question is, why did C-peptide production (and thus insulin production) improve so much for the first three months, but then stop improving?  Remember, that the drug was given for 12 months, but the improvement was seen only in the first 3 months.  Obviously, if we could make the Verapamil continue to help insulin production for longer, it would be much closer to a cure.

Another question is, what would happen if Verapamil was given to people who had two autoantibodies, but were not showing any symptoms of type-1 diabetes?  Would Verapamil result in a delay of onset, or could it prevent type-1 completely?  Current research shows that essentially everyone who has two autoantibodies will eventually show symptoms of type-1 diabetes, but this study shows that for the length of time of the study, C-peptide generation was basically the same at the end of the trial as at the beginning.  If people without symptoms were treated, would they continue to be symptom free as long as they were treated?  That would be a preventative (and possibly the first step to a cure).

A third option would be to try to improve the treatment, either by combining Verapamil with another drug which helps preserve beta cell function, or by finding a better dosing regimen, with results in a better outcome.

Finally, this study was done on recently diagnosed adults, and the researchers mention that running a similar study on recently diagnosed children in the honeymoon phase be worthwhile.
Paper: https://www.nature.com/articles/s41591-018-0089-4 (behind a paywall)
Trial Registry: https://clinicaltrials.gov/ct2/show/NCT02372253

I'd like to thank the authors for sending me a copy of the paper, which is otherwise 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, JDCA, or Bigfoot Biomedical news, views, policies or opinions. In my day job, I work in software for Bigfoot Biomedical. 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.

GABA Starts A Phase-II? Clinical Trial in Honeymooners

This blog has two parts.  The first part describes a phase-I clinical trial in honeymooners which started recently.  The second part summarizes the rest of the GABA (Gamma-Aminobutyric Acid) research done so far in people.  GABA is well known as a neurotransmitter, but it also is generated by pancreatic beta cells and also the immune system, both of which are heavily involved in type-1 diabetes.

GABA is widely available as a "dietary supplement", and you can read a lot more about it here:
https://en.wikipedia.org/wiki/Gamma-Aminobutyric_acid
There are several mouse studies that show effectiveness against type-1 diabetes.

The Current Clinical Trial

This trial will enroll 95 people with honeymoon type-1 diabetes into three groups as described below.  It is recruiting children aged 4 to 18.  They plan to finish in June 2019.  Primary outcomes are insulin usage and C-peptide generation, while secondary outcomes are levels of diabetes autoantibodies.  All of these will be measured one year after dosing.  People will get two injections of GAD, one month apart.  They will take GABA pills twice a day.  I think the pills will be for a year, but I might be wrong about that.

The three patient groups are:
    Some people will get two different placebos, and be a control group.
    Some will get GABA and a placebo for GAD.
    Others will get both GABA and GAD.

GAD is developed by Diamyd corporation, and has been tested for at least 10 years.  I've blogged on it in the post many times:
https://cureresearch4type1diabetes.blogspot.com/search/label/Diamyd
It has a long history of safety, but also of not being effective.  So I don't hold out much hope for the GAD alone being effective.  But that doesn't really matter, because GAD alone is not being tested.  Since two different arms will get GABA, if that is effective, it will be obvious.  If the GAD + GABA arm is more successful than the GABA only arm, that would breathe new life into GAD research.  In animals, GAD is part of the biochemical mechanism which creates GABA, so the two are related.

This trial is marked in the FDA registry as still recruiting at one site, however the press release from Diamyd says it is already fully enrolled:
    Children's [Hospital] of Alabama, Birmingham, Alabama, United States, 35233
    Contact: Sharon D. May, BSN    205-638-5031    smay@peds.uab.edu 
    Contact: Heather Choat, MD    205-638-9107    hchoat@uab.edu 
    Web page: https://www.childrensal.org/endocrinology-research

The researchers considered this a phase-I trial, but because of the size and the previous GABA clinical trials, I'm treating it as a phase-II? trial, meaning a trial big enough to be phase-II, but without results from a previous phase-I trial done on people with type-1 diabetes.

Press Release: https://www.diamyd.com/docs/pressClips.aspx?ClipID=2827171
USA Clinical Trial Registry: https://clinicaltrials.gov/ct2/show/NCT02002130
WHO Clincal Trial Registry: http://apps.who.int/trialsearch/Trial3.aspx?trialid=NCT02002130

This research is funded by JDRF and the companies that manufacture GAD (Diamyd / Johnson and Johnson) and GABA (NOW foods).

Preview of Coming Attractions: Diamyd, the company that researched GAD is now also working on a GABA based drug called Remygen.  A research group in Sweden is planning to start a trial of this drug in people with established type-1 diabetes in Sept 2018. I'll blog on these trials when it starts.  Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT03635437

A Little History

Back in 2012 Penny Jester, a researcher at the University of Alabama at Birmingham, tried to start a clinical trial in GABA.  However, the FDA did not approve her IND (Investigational New Drug) application, and so the trial was never started.  You can see the registration here:
https://www.clinicaltrials.gov/ct2/show/NCT01561508

In 2013 Zhaoyun Zhang and fellow researchers at Huashan hospital in Shanghai, China ran a small study (confirming safety) on GABA in healthy people, reported here:
https://www.ncbi.nlm.nih.gov/pubmed/26617516

and  registered here:

https://clinicaltrials.gov/ct2/show/NCT01917760

Then in 2013 the same group started a 60 person phase-II? study of GABA on people with honeymoon type-1 diabetes, but I have not been able to find published results.

You can read Dr. Zhang's rational for testing GABA in this paper:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4322886/

More Reading

Because both GABA and GAD have long histories as potential cures for type-1 diabetes, there is lots of previous research to read, if you want:

    https://www.the-scientist.com/news-opinion/studies-unable-to-reproduce-results-of-two-diabetes-papers-64630

    http://diabetes.diabetesjournals.org/content/62/11/3674.full

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3136292/ (mice)
    https://www.uu.se/en/news-media/news/article/?id=10440


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 Bigfoot Biomedical news, views, policies or opinions. In my day job, I work in software for Bigfoot Biomedical. 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.

Dr. Faustman Publishes Follow On BCG Data From Phase-I Trial

Dr. Faustman published a paper [r2] and a poster [r1] that contained results from an extension to her Phase-I trial [r17].  These results have generated a lot of buzz, and the study was complex, so this is going to be a long post with four sections:  First, a quick summary.  Second, a more detailed discussion of her results.  Third, a discussion of the buzz surrounding those results.  And fourth, a discussion of where her research goes from here.  The [dN] marks mean that there is more discussion about this point at the end of the blog post, and the [rN] marks are references which are also at the end of the posting.

I've written a total of 18 blog entries on this line of research over the last 10+ years, and you can read them all here:  https://cureresearch4type1diabetes.blogspot.com/search/label/Faustman

The short history is this: Dr. Faustman is trying to cure type-1 diabetes by using BCG, a widely used tuberculosis vaccine.  Dr. Faustman published phase-I clinical trial data in 2012, and is now publishing data from an extension to that trial. 

Quick Summary of Results and Importance

All of these points are discussed in a lot more detail below, especially including the data they are based on, and how I got from the data to these summary points:

1. C-peptide is the FDA, researcher, and industry standard for evaluating cures for type-1 diabetes, and the C-peptide data reported here shows the BCG did not cause a rise in C-peptide levels.  These results mean that this extended phase-I trial has worse results/is farther away from a cure, than the initial phase-I study reported years ago.   The first phase-I showed tiny increases in C-peptide, but here, no clinically significant increases are seen.
2. A1c data is generally used to evaluate treatments for type-1 (not cures).  The A1c data is the best data reported here (an improvement of about 0.8), and is similar to several other treatments already available or in later phases of clinical trials.  All the data presented here is based on a very small number of people who actually got BCG (3 people in some cases 12 in others).  Furthermore, it is inconsistent.  At some points in time the BCG group did worse than the control groups, while at other times they did better. 
3. Dr. Faustman had a theory as to why BCG could cure type-1 diabetes.  The paper is clear that the A1c results seen here are not caused by this theory.  The paper presents a new theory to explain the cause of these results.  
4. There is a phase-II trial underway (with results expected in 2023), so we will have more data then.
5. And finally, the primary end point for the phase-I trial was autoreactive t-cells, and this extension to the phase-I trial did not include data on autoreactive t-cells, which means the clinical trial was unsuccessful.

Results and Discussion

As with all science, the important information is the results of the study, so let's take a look at the data presented (and the data that was not presented):

A1c Data

Graph is from Dr. Faustman's paper, and is presented
 for educational purposes only.

The best data in the paper was A1c data.  The graph at the right (taken from the paper) shows the A1c numbers for the people treated with BCG (in red) vs. two types of control groups (in black). [r2]

You can see that the people treated with BCG had worse A1c numbers for the first two years after the treatment.  They then improved noticeably for the next two years, and then gradually increased for the next four years.  Overall the patients had worse A1c numbers for the first two years, and better for the next six years.

Importance of the A1c Data

For me, this data does not support the idea that BCG is a cure for type-1 diabetes.  It doesn't even support the idea that BCG is a treatment for type-1 diabetes.

First and most importantly, A1c data is typically used to measure treatments not cures [d1].  This is for a very good reason: many things, unrelated to a cure, impact A1c numbers.  Being more aggressive about insulin dosing,  going on a low carb diet, using a CGM, or taking an SGLT or GLP-1 drug can all impact A1c numbers as seen here [d2], but none of them are a path to a cure.

On the other hand, the only thing that impacts C-peptide numbers is the body generating its own insulin [d3].  That is why researchers commonly use (and the FDA expects) C-peptide as the end point for clinical trials aimed at curing type-1 diabetes [d5].   Generating your own insulin and maintaining that production is what cures type-1 diabetes, and it is exactly what C-peptides measure.  This is an important point and discussed in detail in [r9] (the conclusions of the D-Cure workshop).

Second, the data above in inconsistent: worse for two years and better for six.  If you are going to argue that the good numbers (3-5 years out) are really caused by BCG, then you have to assume that the bad numbers (0-2 years out) are also caused by the BCG.  After all those numbers are closer to the BCG dose.  It seems much more reasonable to me to assume that neither the bad numbers nor the good numbers had much to do with the BCG dose.

Third, existing treatments have already shown better and more consistent improvements in A1c than are seen here.  These are described in more detail in [d2] and [r11-13].  If I wanted to get excited about new treatments for type-1 diabetes, BCG would get in line with the many treatments which have stronger evidence in larger clinical trials [d10].

Fourth, the eight year data is based on 3 people, and the five year data on 12 people, and there are two problems with these numbers.  The big, obvious problem is that they are tiny, especially the 8 year data [d6]. The second issue is that more people were added after the end of the phase-I trial.  This is unusual.  Normally an "extension" or a "follow on" trial simply follows the same group of people (or a subset) for a longer period of time.  It's quite unusual to see new patients added after the end of the trial as described by the clinical trial registry.   

The A1c results also have a serious problem with "results switching" described [d7] and [r16].

As a side note, even as a measure of treatment success, A1c is falling out of favor as compared to "time spent in range" and quality of life measures as proposed by the "Beyond A1c" movement:
https://diatribe.org/public-workshop-outcomes-beyond-a1c-brings-patient-preferences-fda

C-Peptide Data

As stated previously, C-peptide numbers are the best measure of progress towards a cure [d4], so these are the numbers we should pay the most attention to.  Here are a few quotes from the paper: 

"The BCG-treated type 1 diabetic subjects at year 4 after glucagon challenge had a negligible to no return of clinically significant C-peptide. "

"The human pancreas after BCG even at four years after repeat vaccinations did not secrete significant insulin as clinically measured by C-peptide."

"Therefore we concluded that BCG vaccinations did not induce a clinically meaningful return of C-peptide levels in the pancreas by regeneration" [r2]

The paper reported that at 4 years (the point of highest A1c effect) the C-peptide numbers for the treated patients were "in the range of 2–3 pmol/L."  Table 1c in the paper included C-peptide numbers, but the numeric data was not included in the paper or the supplemental materials.  My eyeballing of the data is that the control group started off just below 2 pmol/L and the treated group started off just above 2 pmol/L.

Importance of the C-Peptide Data

In terms of measuring progress towards a cure, C-peptide data is the most important data.  When the FDA, EMA, or other researchers evaluate this study, it is the key data they will look at [d11].  It shows no progress towards a cure.  That is bad news for BCG-as-a-cure research.

Several Additional Metabolites

In addition to A1c and C-Peptide data, the paper also reported on a variety of metabolites.  These are various chemical markers of what is happening inside the body.  The purpose of these measurements is to try to figure out what was causing the changes to A1c seen in the study.  If you care about these details, then I urge you to read the paper [r2].

The statistically significant differences between people with type-1 who were given and not given BCG are summarized as follows:

In the purine pathway, adenine, N6-carbamoylthreonyladenosine, 7-methylguanine and N2,N2-dimethylguanosine all statistically showed significant increases in BCG-treated T1Ds compared to untreated T1Ds [r2]

Autoreactive T-Cell Data

This study reports on an extension to the phase-I trial, but it does not report on the primary outcome of that study (autoreactive t-cells) [r6].  In the world of clinical trials, this means this extension to the phase-I trial was unsuccessful.

A clinical trial is considered successful if there are good, statistically significant results for the primary outcome, using standard data analysis.  You can read a lot more about this definition here:
https://cureresearch4type1diabetes.blogspot.com/p/recently-on-couple-of-occasions-ive.html
The key point is that not reporting on a primary end point, means the trial has failed.

The autoreactive t-cells results were involved in the "results switching" described [d7] and [r16].

The Change of Theory

Until this publication, Dr. Faustman believed that BCG worked by causing the body to generate more TNF, and this TNF caused the body to generate fewer autoreactive T-cells [r17].  Fewer of these bad T-cells resulted in a cure [d9].  She has published a few papers and edited a book on this theory [r10].

However, in this paper she makes it clear that this theory is not causing the A1c changes.  To quote her paper:

"The mechanism for lowered HbA1c values was not equivalent to the NOD [non-obese diabetic] mouse pancreas regeneration after BCG treatment" [r2]

And the paper describes a replacement theory:

"[BCG causes] a cellular switch from primarily oxidative phosphorylation, a low glucose utilization state, to augmented early aerobic glycolysis, a high glucose utilization state associated with high purine metabolism" [r2]

BCG lowers A1c by changing the way the body uses glucose, so that it burns more, which lowers blood glucose levels and therefore A1c numbers.  The new theory and the old theory are completely different.  Among other things, the old theory was based on immunology, while the new theory is based on glucose metabolism.  The new theory could replace the old theory, or both could be happening in parallel.

The Importance of The Change In Theory

Initially, I didn't think this change mattered much.  I'm much more focused on the question of effectiveness than mechanism.   (Put another way: I want a cure for my daughter, and I don't care exactly why it works, so long as it does work.)  But then I realized the implications of this change in theory.

BCG has finished a phase-I clinical trial.  At this point, most drugs would have two reasons to think they might be successful: the results of their phase-I trial and the results of the previous animal experiments.   That means that even if the phase-I trial was unsuccessful, the researcher could still rely on the animal trials for motivation, and try another human trial to capitalize on whatever good results were seen in the animal studies.   This is particularly important for BCG because the phase-I trial did not lead to successful C-peptide numbers.

However, Dr. Faustman is now saying that the TNF theory did cause the good results in mice, but is not causing the good results in people.  So therefore, it is hard to go back to her animal research to get support for her current human research.  And the human research itself is not yielding good results [r21].

Why The Hype?

A big part of the reason this study is important, is because of the buzz it has generated.  Therefore, understanding where that buzz comes from is important.  In my opinion, the results from the paper don't merit much excitement.  The hype comes from the news coverage of the press release, and I think it is always a mistake to react to hype in press releases when the underlying paper does not generate the same level of excitement.  This is a general problem in medical research and I'd recommend reading the articles listed here [r14].  Those articles cover the problem from several different points of view.

 The press release starts out with this sentence:

"Long-term follow-up of participants in clinical trials of a generic vaccine to reverse advanced type 1 diabetes finds significant clinical benefits, including restoration of near-normal blood sugar levels." [r3]

Consider the word "reversal", which is often interpreted to mean "cure".  (Compare "drug X reverses disease Y to "drug X cures disease Y".  Same meaning.)  Reversal is also in that first sentence to refer to results in people.   However, in the body of the paper, different forms of reversal are used 5 times (3 times for mice, 1 time to say the results did not include reversal, and 1 time for speculation about reversal).  Never in the paper was the word "reversal" used to describe the results in people, yet it was used in exactly that way in the first sentence of the press release.

Also, the press release uses the term "near-normal blood sugar levels" repeatedly.  Many newspapers interpreted this to be near-cure, and wrote their headlines accordingly.  But let me ask you a simple question:  If someone has type-1 diabetes and uses a lot of technology and generally works hard at treating their type-1, and has an A1c in the mid or low 6s, would you describe that as "near-normal blood sugar levels"?  Maybe.  But that says nothing about if they are close to a cure for type-1 diabetes.  Saying "near-normal" generates a lot of hype, but a cure is based on not needing to constantly treat your type-1 diabetes.  And the study is clear:  No one treated their type-1 diabetes any less because of the BCG: not fewer blood checks, not less insulin.  Everyone continued their standard care: dosing for what they ate, counting carbs, and anything else that we would associate with type-1 diabetes [d8].

The subtitle of the press release is:

"Mass. General study finds novel mechanism underlying stable, durable blood sugar control" [r3]

Now take a look at the previous graph of A1c numbers.  Does that look stable to you?  Does it look durable?  Not to me.  Quite the opposite, the good results are completely dependent on when you look at the data.  Two years after treatment the numbers are bad.  Between four and six years they are good.  At the end of the study, they are heading back towards where they started.  This is neither stable or durable.

The press release gives specific A1c data for 3 years and 4 years, and the average for the four year period from 3-7 years.  The 4 year numbers are the best found in the study, the 3 year second best, and the 3-7 year time frame the "good years" of the study.  However, the 1st and 2nd years (when results are bad) are not mentioned, and the average presented in the press release specifically excludes those years. It's like calculating a child's GPA but excluding their worst grades.  Of course it looks good, but it doesn't represent their real level of accomplishment.

Where BCG Research Goes From Here

One answer to this question is simple: a phase-II study is already underway, so we just wait until 2023 for those results to be published.  For BCG to be successful as a cure, it needs a specific kind of good news from the phase-II study: C-peptide data which is both statistically significant and clinically significant, and which comes from a large group of people with a good control group.  As a treatment (something taken in addition to insulin) then A1c data is enough.  It would still need to be statistically significant and clinically significant, and come from a large group of people with a good control group.  But all of that is possible from the phase-II trial.

Another answer is this: At this point, both publications from the phase-I trial were unsuccessful.  While an unsuccessful phase-I trial usually ends the line of research, this is not always true.  My guess is that about 20% of the current current phase-II trials are occurring after an unsuccessful phase-I result.  So there is always some hope.

But the real question is, how optimistic should we be about this line of research?  In my opinion, not very optimistic.  Above, I've described why the C-peptide and A1c data in this specific paper don't give me much hope for success in the future.  However, when I look at the (roughly) 15 year history of BCG trials in people, and put this paper into the context of the previous BCG research, I see a couple of additional red flags:

First is the lack of forward progress, given 15+ years / 34 million dollars [r20].  Fifteen years is enough time to get from the start of a phase-I to end of phase-III trials, and $34 million is more money than most academic researchers can spend on one line of research.  But for all that, I don't see any forward progress.  In 2003, we had no data on BCG's curative effect on people.  Now, we still don't have any positive C-peptide data to answer that question.  The hope is that the phase-II trial will answer it in 2023 or so.

Second, is the changing target of the research.  Successful research tends to have one target ("primary end point"), and gathers more evidence and stronger evidence on that target over time.  That is the progress that researchers expect.  However this line of research has changed its target repeatedly.  When the phase-I study started, the primary end point was autoreactive t-cells [r6].  When the phase-I study ended, the headline data was C-peptides [r17], and now this extension headlines A1c data [r2].

Even worse, this paper conflicts with the previous paper, even though they are both based on data from the phase-I trial. The initial phase-I paper showed: small, good results for C-peptide, no good results for A1c data, and support for the TNF hypothesis.  This paper shows no good results for C-peptide, mild, good results for A1c data, and support for a sugar metabolism hypothesis, but not a TNF hypothesis.  Good science builds on itself: the first results might be small, but the next results are stronger.  But here, the next results are not bigger, they are different.  That is not the normal course of scientific progress.

Personal Note

Many people, with wildly different viewpoints, reviewed this blog posting.  I want to thank everyone who spent time on it.  It needed a lot of work, and benefited from every reviewer's feedback.   All mistakes are my own.

Extra Discussion [d-Numbered] Footnotes

[d1] Consider a simple example: injecting insulin.  If you inject more insulin your A1c will go down, but your C-peptide numbers will not change.  A researcher who is treating A1c as progress toward a cure will see injecting more insulin as progress towards a cure.  That is why researchers measure C-peptide to evaluate progress to a cure.

Or consider this: "in the 1990s, the FDA began to approve drugs for the treatment of diabetes based upon hemoglobin A1c (HbA1c) as the outcome. The prevailing belief was that risk reduction could be achieved by a clinical focus on reaching target values of HbA1c" [r18]

[d2]  For instance this slide [r20] presents data from four different groups treated with different type-2 diabetes medicines (two medicines at two doses).  All four of these groups dropped the same or more as is seen here.  And [r21] shows that simply using CGMs can lower A1c numbers in pregnant women about the same as seen here.  And [r22] shows that a new class of drugs (approved in type-2s and being tested in type-1s) called SGLTs lower A1cs about as much as seen here.  And the list goes on.

The bottom line is that the average improvements seen in this study are similar to the average improvements seen in many other treatments, which are much closer to FDA approval (or already have EMA approval) for type-1 diabetes. 

When we look at A1c for people who got BCG over the life of the study, it averages about 6.6 which is about 0.8 below the 7.4 where it started.  (The result is a little worse (about 0.5) if we compare it to the control group, which started at about 7.1).

For comparison, all of these treatments have gotten results similar to the 0.8 improvement seen here in either type-1 diabetes, type-2 diabetes, or both:
    Semaglutide: A1c improvement of 1.5 [r20]
    Delaglutide: A1c improvement of 1.2 [r20]
    CGM use during pregnacy: A1c improvement of 0.6 [r21]
    SGLT2 inhibitors: A1c improvements of 0.5 to 0.8 [r22]

[d3] As an example, When was the last time your doctor said "If you do X, Y, or Z you will have better A1c numbers next time?  We get it all the time.  But when was the last time your doctor said "If you do X, Y, or Z your c-peptide number will be better"?  Never.  This shows both that A1c is a measure of treatment, and why it is not a good measure of a cure.

[d4]  For example the following quote is from the D-Cure workshop of international experts held in Barcelona in April 2007 [r9]:

"It is now an accepted approach to evaluate endogenous insulin secretion by measuring C-peptide levels (with highly sensitive and normalized measurement methods) in response to a physiologic stimulus (liquid mixed-meal) under standardized conditions."

This report goes on to specifically to consider and reject A1c as a measure of a cure:

"differences in HbA1c between treatment and placebo groups are minimal and thus cannot serve as robust measures of efficacy"

[d5] I reviewed all phase-III clinical trials aimed at curing type-1 diabetes in the last 15 years.  These are in the final stage of clinical trials, which lead (if successful) to FDA approval.  There have been 11 by my count, testing a total of 4 different treatments.   Of these, 6 used C-peptide as their sole primary outcome.  None used A1c alone as their sole primary outcome.  One used it as part of a dual primary outcome. Four used other measures as their primary outcome.

[d6]  It was not supposed to be that small.  The phase-I trial was supposed to have 12 treated people and 12 control [r6].  However, for reasons never published, the original trial only gave 3 people BCG.

[d7] Finally, these A1c results represent what is commonly called "results switching" in clinical trials, and this is very dangerous in reporting results.  Results switching is when the researcher says they are going to report one result (and designs the trial to do this), but then ends up reporting on a different result.  One of the reasons the FDA has a public clinical trial registry [r19] is specifically so that researchers need to publicly announce what their end points are ahead of time.  This prevents them from selecting end points to create success after the data is gathered.

Obviously, it is bad when secondary results are switched, and worse when a secondary result is used to replace an unsuccessful primary result.  However, in this study we see the worse form of "results switch" where an unsuccessful primary end point (autoreactive t-cells) is not reported, and replaced with a better, but still mediocre, result (A1c) which was previously not part of the study at all!

There are several articles on results swapping listed here [r16].

[d8] Compare Dr. Faustman's use of language in the press release with Dr. Bernstein's use of language.  Dr. Bernstein uses a low carb diet and aggressive insulin dosing to achieve A1c numbers lower than those reported in Dr. Faustman's research.  His target A1c is 4.5, much lower than Dr. Faustman achieved here.  However, Dr. Bernstein never refers to curing type-1 diabetes.  He is very clear that the low A1c numbers he aims for might be the same as someone without type-1 diabetes, but that is in no way a cure.

To put it bluntly: if you think Dr. Faustman's A1c numbers in the mid-6s represents a near cure, then you would have to agree that Dr. Bernstein's A1c numbers in the mid-4s would represent an actual cure, but no one does that.

[d9] The essence of Dr. Faustman's older theory on how to cure type-1 diabetes is:

• BCG causes the body to generate TNF
• TNF causes fewer autoreactive T-cells
• Fewer autoreactive T-cells results in natural beta cell regrowth and more insulin generation
• More insulin generation is the path to curing type-1

BCG (Bacillus Calmette–Guérin) is a biologic that has been given to over a billion people (in low dose) as a tuberculosis vaccine, and is also approved (in much higher doses) as a bladder cancer treatment. It is a generic drug with a very long record of safety.

TNF ("Tumor necrosis factor" or TNF-alpha) is a naturally occurring protein that can cause cells to die. It is involved in the natural regulation of immune cells.

"Autoreactive" refers to immune cells that mistakenly attack the body's own beta cells. The destruction of these beta cells leads to type-1 diabetes. This is sometimes referred to as an "autoimmune attack" because the body's own immune system attacks the body itself.

Many more details are available here [r10].

[d10] For A1c improvements, my standard (which I think is pretty common among both researchers and the FDA) is that changes below 0.5 are not of importance, changes above 1.0 are definitely important, and numbers between these are of mild importance.  So the BCG results (if supported by larger trials) would be in the mild interest area.

[d11]  Here are three supporting quotes:

Clinical studies aiming at preservation of beta cell function should be randomized, preferably double-blind and placebo-controlled and should include patients with a documented residual beta cell function. The primary outcome should preferably consist of co-primary endpoints including not only the change from baseline in C-peptide (e.g. C-peptide AUC) or, if appropriately justified, the percentage of patients with C-peptide increases above a clinically meaningful threshold following a physiological stimulus (e.g. liquid mixed meal) under standardized conditions but also HbA1c, frequency of hypoglycaemic episodes, particularly severe events, or the percentage of patients not requiring insulin therapy or with a relevant reduction in insulin requirements. Any of these endpoints not included as co-primary endpoint should be evaluated as important secondary endpoint. [r22]

FDA and EMA stand ready to approve disease modifying therapies for T1D. and have expressed reasonable expectations for demonstrating efficacy of therapies aimed at preserving insulin secretion in new onset patients. It is unclear what minimum treatment effect on preservation of C-peptide secretion, the regulatory primary efficacy endpoint, would be considered clinically meaningful for a new onset intervention. A small effect size (10-20% at two years) might be enough if the safety profile is very benign. [r23]

And finally, compare these two quotes from [r24]:

Efficacy endpoints. Stimulated C-peptide response is accepted as the regulatory primary endpoint because it is a direct measure of reducing the hormonal deficiency state of T1DM.

Secondary endpoints and their considerations. HbA1c is the gold standard measure of glycemic control, but it is an insensitive measure of improved beta cell function resulting from an intervention. 

Reference [r-Numbered] Footnotes

[r1] The Press Release: https://www.massgeneral.org/News/pressrelease.aspx?id=2262
and the Faustman lab FAQ is here:
https://www.faustmanlab.org/wp-content/uploads/2018/06/FAQs.pdf

[r2] The Paper: https://www.nature.com/articles/s41541-018-0062-8  and this includes supplementary data here: https://static-content.springer.com/esm/art%3A10.1038%2Fs41541-018-0062-8/MediaObjects/41541_2018_62_MOESM1_ESM.pdf

[r3] Abstract of The Poster:
https://plan.core-apps.com/tristar_ada18/abstract/5188446740e191fd289345d56a7ee704
This tweet contains the poster and a little discussion:
https://twitter.com/HangryPancreas/status/1011294476260831233

[r4] Medical Press Coverage:
https://www.medpagetoday.com/meetingcoverage/ada/73696
https://www.statnews.com/2018/06/21/type-1-diabetes-vaccine-denise-faustman/

[r5] ADA/JDRF Response:
http://www.diabetes.org/assets/pdfs/news/joint-statement-from-ada-and-jdrf.pdf
and coverage:
https://www.healthline.com/diabetesmine/denise-faustman-research-pushback-ada-jdrf

[r6] The FDA clinical trial record for the phase-I study:
https://clinicaltrials.gov/ct2/show/NCT00607230

[r7] The FDA clinical trial record for the phase-II study:
https://www.clinicaltrials.gov/ct2/show/NCT02081326

[r8] More than you ever wanted to know about how the FDA evaluates clinical trial end points:
https://www.fda.gov/downloads/Drugs/.../Guidances/ucm071624.pdf

[r9] This report summarizes the conclusions of the D-Cure workshop of international experts held in Barcelona in April 2007 and the current recommendations and updates in the field:
https://pdfs.semanticscholar.org/c337/5ee9865135c7e312417fa7b8b04b9564c776.pdf

[r10] Dr. Faustman's most recent paper describing TNF as the mechanism of a cure was published in 2017:
    https://www.ncbi.nlm.nih.gov/pubmed/28843039
And she had edited an entire book on the subject in 2014:
    https://www.elsevier.com/books/the-value-of-bcg-and-tnf-in-autoimmunity/faustman/978-0-12-799964-7
And she had several earlier publications on the same (now defunct) theory:
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3870411/
    http://www.pnas.org/content/105/36/13644

[r11] https://twitter.com/snp_io/status/1010616966523088896
[r12] https://twitter.com/Fallabel/status/1011280750967246848
[r13] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4265871/

[r14] https://www.theguardian.com/science/blog/2014/dec/10/science-health-news-hype-press-releases-universities
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3735615/
https://www.scidev.net/global/health/practical-guide/progress-or-pr-how-to-report-clinical-trials.html
https://www.healthnewsreview.org/2018/04/a-cancer-doctor-speaks-out-how-premature-hype-about-experimental-drugs-fails-patients/

[r16] These are general references for results switching:
    http://compare-trials.org/blog/are-your-results-unusual-or-how-often-are-outcomes-switched/
    https://www.bmj.com/content/356/bmj.j396
    https://www.enago.com/academy/issue-at-hand-outcome-switching-in-clinical-trials/
    https://www.psychologytoday.com/us/blog/side-effects/201604/how-outcome-switching-is-corrupting-medical-research
And this organization:
    http://compare-trials.org/
This abstract is an interesting read as well:
    https://www.nature.com/articles/s41598-017-09553-y

[r17] Initial results of the BCG phase-I clinical trial:
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0041756

[r18] This paper argues that A1c is the right end point to measure treatments for type-2 diabetes:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5350060/

[r19] This is a link to the US FDA's Clinical Trial Registry Site, plus an article about it:
    https://clinicaltrials.gov
    https://www.vox.com/2014/12/6/7344357/clinical-trials-transparency

[r20] Dr. Faustman's Lab has raised about $11 million for their phase-I trial and about $23 million for their phase-II trial:
    https://www.bizjournals.com/boston/news/2016/11/03/mgh-looks-to-reverse-diabetes-with-funding-from.html
    https://www.bizjournals.com/boston/news/2018/06/21/mgh-study-finds-generic-drug-can-reverse-type-i.html

[r21] The two key quotes from her paper are:

As previously published, the elevations in tumor necrosis factor (TNF) from the BCG vaccine stimulate cytotoxic T cell death and beneficial Treg expansion [in live mice and isolated human tissue]

and then:

The mechanism for lowered HbA1c values [in people] was not equivalent to the NOD diabetic mouse pancreas regeneration after BCG treatment

[r22] http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129256.pdf

[r23] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748875/

[r24] https://www.tandfonline.com/doi/pdf/10.4161/hv.7.1.14527

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 Bigfoot Biomedical news, views, policies or opinions. In my day job, I work in software for Bigfoot Biomedical. 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.