Monday, August 14, 2017

Possible Cures In The News (August)


The blog posting is a collection of small updates to existing clinical trials.

The TN20 (Oral Insulin) Phase-II Clinical Trial Completes Enrollment 

TN20 is the name of a specific oral insulin clinical trial, which completed enrollment in March 2017. Since this study will follow people for one year, they should finish collecting data in March 2018.

The following blog post:
https://cureresearch4type1diabetes.blogspot.com/2017/07/phase-iii-results-from-oral-insulin.html
covers oral insulin in detail, describing why people think it might prevent type-1 diabetes, and the other clinical trials (and there are several) currently running.

Clinical Trial Registery: https://clinicaltrials.gov/ct2/show/NCT02580877

T-Rex Study Is Half Enrolled

I've previously blogged on the T-Rex study (sometimes under the name "Polyclonal T-Regs"):
https://cureresearch4type1diabetes.blogspot.com/search/label/Polyclonal%20Tregs

It is currently in a phase-II clinical trial, and that trial is now half enrolled (56 people out of 111).

This study is unusual in that it can enroll kids as young as 8, and is recruiting people at over a dozen different sites in the US: https://clinicaltrials.gov/ct2/show/study/NCT02691247#contacts

News: http://www.diabetes.co.uk/news/2017/jul/pioneering-t-rex-study-reaches-milestone-in-treating-children-with-type-1-diabetes-96973185.html

A quick summary of this treatment is as follows: remove one specific type of T regulator cell (called "CD4(+)CD25(+)CD127(lo)") from a person with type-1 diabetes.  Grow them out so you have about 500 times more, and then put them back in the same person.  Since regulatory T cells naturally regulate the body's immune system, and the patient now has more of them, the hope is that they will prevent the autoimmune attack which causes type-1 diabetes.

Results from the previous phase-I trial found that this treatment preserved beta cells.  C-peptide levels remained constant in the treated group.  Since C-peptide levels drop during the honeymoon period, these treated people did better than untreated people would be expected to do.  The previous phase-I study did not have a control group, but the current phase-II study does.

Results of Phase-I Clinical Trial of REMD-477 for T1D

I probably will not cover this moving forward, because it is more treatment than cure. REMD-477 is a  Glucagon Receptor Antibody.  The hope is that giving this to people with type-1 will cause them to produce less glucagon and therefore use less insulin.   This was a 21 person trial, where half the people got the treatment and half did not.  The people spend a few days in a hospital, and then were followed for a few weeks "in the wild".

They found that glucagon levels did go down (20-30%), insulin requirements did go down (about 10%), and people did spend more time in their target BG range (about 15%), for a few weeks after treatment.

Slides: https://professional.diabetes.org/sites/professional.diabetes.org/files/media/2017_press_program_ppt_pettus-final.pdf
Several Press Releases: http://sashayan.edicy.co/new-media
Clinical Trial Registry: https://clinicaltrials.gov/ct2/show/NCT02715193

They have started a follow up study, which will enroll 75 people and last 24 weeks.  They hope to finish it in Sept-2018: https://clinicaltrials.gov/ct2/show/NCT03117998

I suspect that any treatment which lowers glucagon levels is going to have some impact on people who play sports, and anyone who has an unexpected low (especially if they need a Glucagon injection, but even if not).  This study did not address either of those issues, but I suspect that follow on studies will need to, if they want FDA approval for this as a treatment for type-1 diabetes.

Diamyd Unsuccessful in Phase-II Clinical Trial on Presymptomatics 

This study is another testament to the optimism of researchers.  Diamyd ("GAD Vaccine") has been tested for over 10 years.  None of these trials has been particularly successful.  They culminated in an unsuccessful Phase-III trial years ago.  You can read my previous blogging on Diamyd here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Diamyd

However, researchers are natural optimists.  And it is important that they are.  Society needs optimistic researchers so that they will repeatedly attack problems, and not give up, even in the face of adversity.  Previous Diamyd trials had been done on honeymooners, so this trial was done on presymptomatics. Unfortunately it failed.

News Coverage: http://www.diabetesincontrol.com/ada-alum-gad-diamyd-vaccine-fails-to-prevent-type-1-diabetes
Press Release: http://www.diabetes.org/newsroom/press-releases/2017/larsson-scientific-sessions-2017.html
Clinical Trial Registry: https://clinicaltrials.gov/ct2/show/NCT01122446

Discussion

This trial reminded me that, in the world of type-1 diabetes, if the headline reads "new treatment shown safe" that really means "new treatment is not effective".  Almost all clinical trials aimed at type-1 diabetes measure both safety and effectiveness. This is especially true of phase-II trials, like this one, and phase-III trials. Since effectiveness data is obviously more news worthy than safety data, if the headline talks about safety, that means the treatment was ineffective.

The headline for the press release above is classic that way "Autoantigen GAD-Vaccine is Safe for Children at High Risk for Developing Type 1 Diabetes", while the headline for the news coverage is much more accurate "ADA: Alum-GAD (Diamyd) Vaccine Fails to Prevent Type 1 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.

Friday, July 14, 2017

Update On Dr. Faustman's BCG Research

There was some media buzz about Dr. Faustman's BCG research as reported on a poster at ADA 2017.  I can't link directly to it, but you can go to this page:
https://ada.apprisor.org/epsSearchADA.cfm
and search for Faustman to see the poster and the abstract.

Dr. Faustman's research has about 15 years of history, which I've blogged about before, here:
http://cureresearch4type1diabetes.blogspot.com/2014/04/dr-faustman-starts-phase-ii-trial-for.html
http://cureresearch4type1diabetes.blogspot.com/2012/08/summary-of-drfaustmans-phase-i-results.html
And in several other blogs.

But to summarize very quickly: Dr. Faustman's previous research was based on the idea that BCG (a Tuberculosis vaccine) increases the levels of TNF, and higher TNF levels could result in less autoreactive T cells, and this would lead to a cure for type-1 diabetes.  Unfortunately, this did not pan out.  Her phase-I trial showed that BCG did not change the levels of live autoreactive T cells in circulation.  However, using some non-standard data analysis, Dr. Faustman interpreted the phase-I study to show that there was an increase in T-reg immune cells.  T-reg cells get rid of the autoreactive T cells, so increasing the T-reg cell count could also lead to a cure for type-1 diabetes.

What is the New News?

The poster presented at ADA 2017 contained data on a possible mechanism whereby BCG could increase the level of T-regs in a type-1 diabetic.  This mechanism involved changes to how genes are used in the body (called "epigenetic changes").  These changes can be long lasting.  Obviously, a long lasting treatment is better than a short lasting one, so (if this finding is confirmed by more research) this is good news.

Also, although not required, it is nice to have a theoretical basis for why a treatment should work, if you are going to test that treatment. This is particularly true of the BCG research, since the phase-I trial showed pretty clearly that the previous theory was wrong, so having a new theory is good.

How Important Is This?

In my opinion, it is not very important. Why not?  In a nutshell:
1. It's a finding about a possible mechanism of how a cure works, not evidence of effectiveness, for a treatment where effectiveness is the important, unanswered question.
2. It's based on data from 3 people.
3. It's a poster, not a presentation (or a paper).

1. It's a mechanistic finding so it is aimed at answering the question "how does BCG work?", but the important question is "does BCG work?"  That needs to be answered before the "how" question is important.  The results from the phase-I trial were not successful (see discussion below).  Therefore, for me, research into the mechanism of how it might work is less important until we get some evidence that it does work.

2. Dr. Faustman's phase-I study gave BCG to only three people.  It is the smallest phase-I study I have ever covered in the field of type-1 diabetes.  This poster is based on data from those same 3 people, and that is not a large enough foundation to get me excited.

3. As a poster, this is a lesser form of publication, than a journal article or a presentation.  That is not fatal, of course, but it is a handicap.  For comparison, Gleevec and Oral Insulin both merited presentations, so the organizers of the ADA scientific sessions clearly thought that those studies were more important than this BCG result.  (And I agree with them.)

Some Discussion on The Results From the Phase-I Trial

Obviously, Dr. Faustman considers the phase-I trial to be a success, which is why she has started a phase-II trial, so why do I consider it unsuccessful?  For two reasons:

First, the normal definition of success for a clinical trial is successful results from the primary outcome.  Her phase-I trial's primary outcome was autoreactive T cells, and there was no difference between the the treated group and the control group.  So that's an unsuccessful result.

She did report two tiny successful outcomes in her secondary results.  But to get those, she had to do two different data manipulations.  I discussed those in detail in 2012 when the original results were published:
http://cureresearch4type1diabetes.blogspot.com/2012/08/details-of-dr-faustmans-phase-i-results.html
See the section called "Weaknesses in Data Analysis".

A very short summary is:
1. She shifted 1/3 of her control group to be analysed as though it were in the treatment group, after she had seen the results, and saw that would change the outcomes.
2. She did not use a single control group.  Rather, she used different control groups for different outcomes, including (in some cases) pulling data from other studies.

My older blog posting describes in detail how damaging these are to her analysis.  But suffice it to say, if the data shows success, there is no reason to do those manipulations.  And if the data is successful (even at a tiny level), only after those manipulations, then how real is it?

Now, if her phase-II study (which is expected to enroll about 150 people) is successful using standard data analysis techniques, then she can rerun this poster study with data from those 150 people.  She will then have more people and a successful treatment and at that point, a mechanistic study would be interesting. The phase-II study is expected to end around 2023.


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.

Phase-III Results from an Oral Insulin Clinical Trial In Presymptomatics


A Quick Introduction to Oral Insulin to Prevent T1D

Obviously, all type-1 diabetics need to take insulin in order to process carbohydrates. This insulin must be injected, because if it were taken orally it would be digested into smaller pieces and would not work as insulin [d1]. Injecting insulin in this way does not cure or prevent type-1 diabetes, it just treats it.

However, one of the autoantibodies that is associated with type-1 diabetes targets insulin molecules[d2]. Therefore, there is a theory that giving insulin to people with T1D might prevent or delay the onset of type-1 diabetes by training the body not to produce this autoantibody. The process is vaguely similar to giving small amounts of peanut proteins to people with peanut allergies[d3]. Insulin pills may work for this purpose even though they would not work as a treatment for type-1.

The Phase-III Study (Structure and Results)

These researchers started with 10,000s of TrialNet participants, and enrolled 560 people who were "presymptomatic". They showed two autoimmune markers, but no symptoms of type-1 diabetes. All of these people tested positive for one particular autoantibody associated with T1D (micro insulin autoantibody) [d2], but they were further subdivided into four groups based on the other autoantibodies they tested positive for, and how much insulin they were producing.

Each subgroup was split in half. One of these halves got oral insulin twice a day, and the other half got a placebo. They were followed for a year or longer to see how many people in each group developed type-1 diabetes as measured by "classic" symptoms.

If you look at the entire study, oral insulin did not have a statistically significant effect. However, if you looked at one subgroup specifically [d4], that subgroup did show a statistically significant effect. For that one subgroup, about 18% of the treated group came down with T1D, while 34% of the untreated group did. The researchers viewed this as delaying the onset of type-1 diabetes by 2.5 years (on average) for this subgroup.

Presentation Slides:
https://professional.diabetes.org/sites/professional.diabetes.org/files/media/2017_press_program_ppt_greenbaum-final.pdf

News Coverage:
https://www.healio.com/endocrinology/diabetes/news/online/%7Bbdefed06-5c4e-442f-8724-972e380cdbcb%7D/oral-insulin-therapy-fails-to-prevent-type-1-diabetes-but-some-see-disease-delay
http://www.diabetesincontrol.com/ada-oral-insulin-may-delay-type-1-diabetes-onset/

Clinical Trial Record:
https://clinicaltrials.gov/ct2/show/NCT00419562

Discussion Of This Study

The results of this study are clearly "bad news on one hand, good news on the other". If you look at the study as applied to all presymptomatics, it was not successful. On the other hand, if you look at it for one specific subgroup, then it was successful. So the obvious thing to do is to try to replicate the results on the specific subgroup where it was previously successful. If so, this could turn into a delaying or preventative treatment for the 10% of patients who fall into this group. Since this subgroup had a specific combination of autoantibodies, it is straightforward to test ahead of time, and give oral insulin to people with this same combination, but not other combinations (where it did not work).

This trial was the size of a phase-III trial. However, the success was only seen in a subgroup, and that subgroup was the size of a phase-II trial. So I would not think of this as a successful phase-III trial, but rather as a successful phase-II trial (meaning that at least two phase-III trials should be expected before it becomes commonly available) [d5].

It is also important to remember that as group size gets smaller, the chance for accidental correlation gets bigger. With these sorts of subset analysis, it is always possible that the effect seen is cause by luck rather than effect. In this particular case, the results were statistically significant even for the smaller group, which is a good sign, but only larger studies will be conclusive.
The History of Oral Insulin

Oral Insulin has a long, complex history of clinical trials, and the results are very mixed (like this study). Just before I started my blog (so 10+ years ago), the results of an oral insulin for prevention trial were announced, and the trial was unsuccessful. However, the researchers analysed the data in more depth after the study concluded, and realized that it had worked for one subgroup (sound familiar?) That was the micro insulin autoantibody subgroup, and that's why everyone in this study had that antibody.

But the idea that oral insulin might prevent/delay type-1 is a popular one, and there are at least three clinical trials running right now. All three of these studies are similar, except for size: the first is 44 people, the second is 220, and the third is 92.

Oral Insulin Starts a Phase-II Trial In Germany (pre-POINT Early)
Recruiting:
Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Lehrstuhl für Diabetes und Gestationsdiabetes der Technischen Universität München, München, Germany, 80804
Started in Aug 2015 and expected to finish in Aug 2017
News: Vaccination against type 1 diabetes may soon be available to young children:
Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT02547519

Phase-II Oral Insulin Trial In Germany (Fr1da)
Recruiting:
Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Lehrstuhl für Diabetes und Gestationsdiabetes, der Technischen Universität München, München, Deutschland (DEU), Germany, 80804
Anette-G. Ziegler, Prof. Dr., MD +49 (0)800 464 ext 8835 diabetes.frueherkennung@helmholtz-muenchen.de
Started in Dec 2015 and expected to finish in June 2021
Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT02620072


Phase-II Oral Insulin Trial In The US (TN20)
Not recruiting.
Started in Jan 2016 and expected to finish in Dec 2017.
Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT02580877
Extra Discussion

[d1] To complicate things, several researchers are working on creating a form of insulin which could be eaten, but which would avoid digestion, so that it could be used to treat type-1 diabetes. This is also called "oral insulin" research. In this blog posting, I'm talking about oral insulin as a cure or preventative for T1D, not as a treatment.

[d2] Autoantibodies are the malfunctioning antibodies which cause the immune system to attack beta cells. There are five autoantibodies associated with type-1 diabetes, and there may be more that we haven't discovered yet. The five we know about are:
* micro insulin autoantibodies (mIAA or just IAA)
* islet-cell antibodies (ICA)
* glutamic acid decarboxylase (GAD) antibodies
* islet antigen-2 (IA-2) antibodies
* zinc-transporter 8 (ZnT8) autoantibodies
The last one was not used in this study, possibly because it tends to show up later in the disease process.

[d3] It is important to realize that type-1 diabetes is NOT a conventional allergy to insulin. It is similar to allergies in that it is the body's immune system overreacting to something that it should not react to, but other than that, is quite different. Allergies involve the immune system overproducing histamines. These histamines attempt to get physical irritants, like pollen, out of your body. You can counter this histamine reaction by taking antihistamines. Type-1 diabetes involves the immune system overproducing malfunctioning killer T-cells (or perhaps under producing regulatory T-cells). These malfunctioning killer T-cells mistakenly kill beta cells, thinking they are foreign cells (ie. living creatures like viruses, that have invaded the body). So the mechanism is different (histamines vs. T-cells), and the mistaken target is different (physical things, like pollen or wheat vs. living organisms, like viruses).

[d4] The subgroup that showed the effect was the micro insulin autoantibody (which everyone in this study had), and either the ICA autoantibody or both the GAD and IA-2 antibodies, and also low insulin secretion at the start of the study.

[d5] As far as I can tell, oral insulin is not approved for the treatment of any disease in the US, and is not available either by prescription or "over the counter". Therefore, it will need to go through full US FDA approval, which requires two phase-III trials. I don't know if the FDA would consider this a phase-III trial for approval purposes.

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.

Wednesday, July 5, 2017

Presymptomatics and Two Clinical Trials for Victoza / Liraglutide

First, a new word: "Presymptomatic". This refers to people who have tested positive for two autoantibodies, but who have no other symptoms of type-1 diabetes. Their blood glucose levels are normal (not elevated), etc.

Presymptomatics are not yet diagnosed with type-1 diabetes in the classic way, but current theory is that all of these people will eventually be diagnosed. It is just a matter of time. So in the same way I might say "Drug X starts a phase-I trial in honeymooners" or "Treatment Y starts a prevention trial" or "Drug Z starts a trial in people with established type-1 diabetes", I will also start to report "Drug W starts a phase-I trial in presymptomatics".

You can think of presymptomatics as pre-honeymooners.  They are like honeymooners, but even earlier in the disease process.

I also want to stress that although the JDRF, the ADA, and the Endocrine Society agree that two autoantibodies is the earliest diagnostic for type-1 diabetes, this is not universal agreement, and what agreement there is, is only about 2 years old.  Here are some web sites which describe this view of the stages of type-1 diabetes:
This also changes when "diagnosis" occurs.  In the past, diagnosis occurred when symptoms were seen, and confirmed with a blood glucose measurement.  However, now diagnosis occurs when two autoantibodies are measured, and this is often years before symptoms are seen, or blood glucose levels are noticeably abnormal.

So, moving forward, I will use the term "classic diagnosis" or to refer to people who were diagnosed because they showed symptoms, as was done in the past, so it's obvious what kind of diagnosis I'm talking about.

Discussion

I expect there will be more studies like the two described below, that specifically target presymptomatics. After all, any treatment that researchers thought might work for honeymooners (but did not), should now be retested on presymptomatics. This is especially true of treatments which change the immune system.

In the past, it's generally been understood that to cure type-1 diabetes, you needed to change the immune system (so it stopped generating autoantibodies and stopped attacking beta cells), but you also needed to regrow beta cells.  However, presymptomatics have enough beta cells so that they can regulate their own blood glucose levels.   To cure them (ie. to prevent symptoms from ever showing up), "all" you need to do is change the immune system.  No need to regrow any beta cells.

That sounds important, and it is, especially when you think about treatments that have already been shown to stop the destruction of beta cells.  In the last 5-10 years, several treatments have been shown to "preserve beta cells" meaning that once given, beta cells stop being killed off by the immune system.  Since these studies were typically done in honeymooners, this did not cure anybody, it just extended the honeymoon.

But if those same treatments showed the same results in presymptomatics, then it could be said that they prevented type-1 diabetes.  I very much hope that every treatment which has previously been found to preserve beta cells, will now be tested on presymptomatics. Some of the treatments which have preserved beta cells in honeymoon diabetics (at least to some degree) are: T-Rex (polyclonal Tregs), Abatacept (Orencia), Etanercept (ENBREL), and Teplizumab. 

Victoza / Liraglutide Starts A Phase-I Trial In Presymptomatics

About this trial: it's testing the theory that Liraglutide (sold as Victoza) might help people use less insulin or delay their use of insulin, when given to people before they are classically diagnosed with type-1 diabetes.  This is an early phase-I trial.  Only 10 people will be enrolled, and there is no control group.   This trial recruits people who have started to have trouble generating insulin in response to food that they've eaten.  They will be followed for one year.  The trial started in March 2016 and they hope to finish by July 2018.

They are recruiting only by invitation at several nordic hospitals:
  • University of Oulu and Oulu University Hospital, Dept of Children and Adolescents Oulu, Finland, 90029
  • University of Tampere and Tampere University Hospital Tampere, Finland, 33520
  • University of Turku and Turku University Hospital Turku, Finland, 20520
  • Lund University and Skåne University Hospital Malmö, Sweden, 205 02
Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02908087

Discussion

The Clinical Trial Record lists this as a phase-II trial, but with only 10 people included and no control group, I consider it a phase-I trial.

I don't see how this trial could ever prove any level of effectiveness.  We don't know how many people eligible to enroll in this study would "naturally" have type-1 diabetes symptoms within the one year study time.   And, this trial has no control group.  So there is no way to compare the results from this study to "normal" results to see if it worked or not.

It could show safety, but the drug being tested has been approved for use in overweight people and also people with type-2 diabetes for years, and is used "off label" by some people with type-1 diabetes, so safety is not really an issue.

Victoza / Liraglutide Starts A Phase-I Trial In Presymptomatics

This trial is similar to the one above, except that it is much larger, and recruiting a slightly different population.  This second trial recruits people who have two autoantibodies and one of several different glucose abnormalities, so it's a larger group of people, and also more in tune with the "two autoantibodies means type-1 diabetes" definition of Presymptomatic.  

This is an phase-II- trial which will enroll 82 people with half in a control group and half getting the treatment.  People will be followed for one year.  The trial started in 2016, and is expected to finish in mid 2019.  They are recruiting by invitation only at the same hospitals listed in the previous trial.


Discussion

(As you read this remember that I'm not a statistician, and have never take a college level class in statistics.)
I'm a little worried about the statistical power of this study.  They are going to have 41 people in their treatment group, and will follow them for one year.  The data I've seen suggests that about 10% of the people with two more more autoantibodies will show classic type-1 diabetes systems each year.  So that means that we should expect about 4 from this group to show symptoms by the end of the study. If this treatment were perfect in preventing type-1 diabetes, then 0 in the treated group would show symptoms.   But the difference between 0 and 4 is not that large.   And the treatment is unlikely to be perfect the first time it is tested.  Let's say that 2 people in the treated group get symptoms, but 4 people in the untreated group get them.  Is that a 50% reduction in diagnosis (which would be huge) or is that just a little good luck involving two patients?  It's hard to tell, and that is what I'm worried about.

On the other hand, this is a phase-II study, so will not be the last word, in any case, and Victoza is already approved, so is not a particularly risky drug.  Also, if the results for the first year are good, then it would be relatively easy to extend this trial for another year (or longer) which would increase its statistical power.

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.

Friday, May 19, 2017

Possible Cures for Type-1 in the News (May)


Phase-I Study of Of Gluten Free Diet In Honeymoon Type 1 Diabetes (Diabglut)

This trial will recruit 160 children, aged 3 to 18.  It started in December 2015, and is expected to end in December 2020. Half of the people will be put on a gluten free diet within one month of diagnosis, and the other half will not (and will be the control group).

This study is being done in Skanes University Hospital, Lund, Region Skane, Sweden, 22185
Contact: Annelie Carlsson, MD PhD    +46768267170    annelie.carlsson@med.lu.se
Contact: Iren Tiberg, PhD, nurse       iren.tiberg@med.lu.se

Clinical trial registry: https://clinicaltrials.gov/ct2/show/NCT03037190

Discussion

My first thoughts when I saw this study were: "Why do a study like this?  Does anyone really believe that a gluten free diet will cure/improve type-1 diabetes?"

The researchers included four previous studies as references for this work, but I think the one that mattered was this one:
https://www.ncbi.nlm.nih.gov/pubmed/22729336
This is the case study of a single patient (a five year old boy).  He was was put on a gluten free diet a few weeks after diagnosis, and remained off insulin for 20+ months.  That's an unusually strong honeymoon, and I think it is reasonable to say that the researchers are hoping that they can create that kind of honeymoon in other newly diagnosed people.

For me, case studies (like this one) represent a middle ground between anecdotes and scientific studies.  I don't think they are very strong by themselves, but I do think that following them up with a research study is a good way to proceed.

The other three studies cited by the researchers as background for this research were much less dramatic. One study tried delaying introduction of gluten in the diet of babies: no effect. Another tried putting people with two antibodies on a gluten free diet before diagnosis: no effect on eventual diagnosis, but might have a small effect on beta cell survival after diagnosis. The third study was population based, and suggested that introducing gluten earlier (at 4 months, rather than later) might lower the rate of celiac diagnosed at 12 years. As a population study, I don't put a lot of weight on it, and the impact was to celiac and not type-1, in any case.

Minimal Islet Transplant at Diabetes Onset (MITO)

This is mostly a transplant trial, so I don't expect to follow it moving forward, but it is a different type of transplant, so I'm describing it here.

Most transplants are done on the most seriously impacted people with type-1 diabetes.  These people often have a lot of trouble controlling their type-1, they are often already having serious complications, and are generally on the worst side of the type-1 spectrum.  These are the people who often volunteer for transplantation.

This study is targeting the opposite: people who within 6 months of type-1 diagnoses, and are still generating some residual insulin.  The idea is to transplant some islet cells in combination with ATG, G-CSF, and Rapamycin treatments. It's a "kitchen sink" approach.  All of those treatments are in active clinical trials right now, but none of them has been shown effective so far.

I do think that it will be valuable to get data from people who are not so extremely sick when they get their transplant, although I doubt this will lead to a cure in the short term.

They are recruiting 6 people in Italy:
IRCCS San Raffaele Scientific Institute   Milan, Italy, 20132
Contact: Lorenzo Piemonti, MD   0226432706 ext 39    piemonti.lorenzo@hsr.it
Contact: Paola Maffi, MD       paola.maffi@hsr.it
Contact: Emauele Bosi, MD 0226432818 ext 39 emanuele.bosi@hsr.it

Clinical trial registry: https://clinicaltrials.gov/ct2/show/NCT02505893

T-Rex Now Can Enroll People 8 Years Old, and Older

Previously, they could enroll people as young as 12, but they have enough safe results with those kids, so that the FDA will now allow kids as young as 8 to enroll. You can read all about the technique they are using and who is eligible in my previous blogging:http://cureresearch4type1diabetes.blogspot.com/search?q=T-Rex

Also, the last time I blogged, this study was only recruiting in two locations, but now they are recruiting all over the US, from Oregon to Connecticut to Florida to UCSF, not to mention Tennessee, Missouri, Massachusetts, Indiana, and that is not a complete list.  (See the Clinical Trial Record, link below, to get a complete list.)

This is a phase-II trial which is a follow on to the previous "Polyclonal T-Reg" study, which I also blogged about here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Polyclonal%20Tregs
(Look at all the postings in this link, except the first one, in order to see the history of this treatment.)

Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02691247

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.

Thursday, May 11, 2017

Update on the University of Jordan's Stem Cell Project

The University of Jordan recently announced the start of a phase-I trial of stem cells. While researching that, I found that they had already published results from a pilot study done at Stem Cells of Arabia (also in Jordan). So in this blog posting, I will first discuss the results of the pilot study, and then the phase-I study they are starting now. Even though these trials were sponsored by different organizations, I consider them part of the same research program.

What Is Being Tested?

These researchers are taking someone's own blood, and then process it before putting it back into the person's body.  I'm not sure the exact nature of this processing.  The pilot study makes it sound similar to Dr. Zhao's work (exposing the patient's cells to stem cells).  However, an interview in ASweetLife.com makes it sound like a filtering process.  It may be both.  The description in the FDA Clinical Trial record for their upcoming phase-I study talks about donors and "passaging" the cells, which might be a shorthand for the same process used in the pilot study.  Whatever their process is, it focuses on three types of immune cell markers: CD34+, CD133+, and CD271+. The process is similar to Dr. Zhao's and also to the T-Rex study. This is not a classic transplant, because the patient is getting their own cells back, and immune suppression drugs are not used.

Results from Stem Cells of Arabia's Pilot Trial of Stem Cells

The only information I have is from an abstract. I think it is from a talk given at the 2015 International Cord Blood Symposium conference, and was published in the journal Transfusion (abstract only).
The patients' average age was 35 years old, but ranged from 13-52, but there was no information on their honeymoon status.  The average A1c at start was 9.0, average Fasting Blood Sugar 350 (although I'm not sure what that means in a type-1 diabetic), C-peptide average was 0.06 (three people had 0.00 and one had 0.23.
Here is the complete results section of the abstract: 
There were no complications over the follow up period (14-51 months). Three out of four patients completely stopped their insulin requirement at 6 months. All 4 patients showed significant improvements in Fasting Blood Sugar (average 145), C-peptide (average 1.01), and HbA1c (average 7.0), during 12 months post transplantation.
Discussion

This is a study where only having the abstract really hurts.  Obviously, these results look very good, but there are key details missing. If the reported C-peptide numbers are fasting, and measured in ng/ml, those are excellent, but if they are in response to eating, then they are not particularly strong. (The abstract does not say.) Having 3 out of 4 patients not using insulin at six months is great, but there is no information on how long each person did not need to use insulin.  The results are great for established type-1 diabetes, but the abstract doesn't say how many people are established vs. honeymooners.

Based on those results, it is easy to see why this group is excited about doing a larger study. I'm excited too!

   University of Jordan Starts a Phase 1 Trial of Stem Cells

This is the start of the study which was previously discussed on ASweetLIfe:
https://asweetlife.org/jordanian-researchers-working-on-stem-cell-treatment-for-type-1-diabetes/
Now the study has officially started and there is a FDA Clinical Trial Record with the details of how the study will work.

This is a 20 person study, which will enroll adults (between 18 and 35) who have been diagnosed within 3 years, or are still generating C-peptide at a rate of 0.5 ng/ml or more. They expect to finish the study in July 2018.  Some people will get a small dose of stem cells, while others get a larger dose.  There is no control group.  Patients will be followed for 36 weeks.  The primary outcome is safety after 6 months.  No effectiveness outcomes are mentioned.

Cell Therapy Center,  Amman, Jordan, 11942
Contact: Abdalla Awidi, MD    0096265355000 ext 23960    abdalla.awidi@gmail.com
(I think this phone number would be  +96265355000 ext 23960, where + means "whatever you need to do to get an international number".)

Web site: http://www.stemcellsarabia.net/ and http://centers.ju.edu.jo/en/ctc/Home.aspx
Clinical trial registry: https://clinicaltrials.gov/ct2/show/NCT02940418

Discussion

This is a quick study.  Expecting to have results in less than 18 months is much faster than most clinical trials, and from my point of view, that's a good thing.  On the other hand, there is no mention of reporting on the things that people with type-1 would care about.  No A1c data, no C-peptide data, and no insulin usage data is listed in the secondary outcomes.  Hopefully those things will be reported on, but most studies (even phase-I studies) list these as secondary outcomes.

This research is based on the same basic ideas which also led to Dr. Zhao's "Cell Educator" research, but the two approaches are not the same treatment.  Dr. Al-Zoubi's group is taking stem cells from a person with type-1 diabetes, treating them, and then injecting them back into that patient.  Dr. Zhao is taking stem cells from third parties, and then exposing people's immune cells to proteins made by those cells, but the stem cells themselves are never injected into the patient.   But both approaches are trying to harness proteins created by stem cells.

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.

Friday, April 28, 2017

Vaccination and Type-1 Diabetes (part 2)

 Results from the Studies and References (continued)

[r6] The Swedish childhood diabetes study (1991)
http://www.springerlink.com/content/m7j8j541414urn4r/
When vaccinations were considered as possible risk factors for diabetes, a significant decrease in relative risk estimated as odds ratio (OR) was noted for measles vaccination (OR=0.69; 95% confidence limits 0.48–0.98). For vaccination against tuberculosis, smallpox, tetanus, whooping cough, rubella and mumps no significant effect on OR for diabetes was found. ... In conclusion, a protective effect of measles vaccination for Type 1 diabetes in childhood is indicated
[r7] No major association of breast-feeding, vaccinations, and childhood viral diseases with early islet autoimmunity in the German BABYDIAB Study.(2000)
http://care.diabetesjournals.org/content/23/7/969.abstract
RESULTS: In offspring from mothers with type 1 diabetes, duration of exclusive and total breast-feeding did not differ between islet antibody-positive and -negative children, regardless of HLA genotype, and breast-feeding of 3 months or longer was not associated with protection from antibody development or diabetes onset. In offspring from diabetic fathers, non-statistically significant reductions in exclusive and total breast-feeding times were observed in the antibody-positive cohort. Neither type nor quantity of vaccinations (including Bacille Calmette-Guerin vaccine; haemophilus influenzae vaccine; diphtheria, tetanus, and pertussis vaccine; tick-born encephalitis vaccine; or measles, mumps, and rubella vaccine) were associated with the development of islet antibodies and diabetes. Measles, mumps, and rubella were not reported in children with islet antibodies or diabetes. CONCLUSIONS: This study showed no evidence that proposed environmental factors affect islet antibody development in the first 2 years of life in offspring from parents with type 1 diabetes.
[r8] Lack of association between early childhood immunizations and beta-cell autoimmunity.
http://care.diabetesjournals.org/content/22/10/1694.abstract

RESULTS: There was no difference between cases and control subjects in the proportion receiving hepatitis B (HBV), Haemophilus influenzae b (Hib), polio, or diphtheria tetanus pertussis (DTP) vaccines before 9 months of age; in the proportion receiving HBV at birth rather than later; or in the median age at first HBV, Hib, polio, or DTP vaccination. CONCLUSIONS: The results suggest that changing the early childhood immunization schedule would not affect the risk of developing beta-cell autoimmunity or type 1 diabetes.
[r9] Lack of association between receipt of conjugate Haemophilus influenzae type b vaccine (HbOC) in infancy and risk of type 1 (juvenile onset) diabetes: long term follow-up of the HbOC efficacy trial cohort (2002)
http://journals.lww.com/pidj/Citation/2002/06000/Lack_of_association_between_receipt_of_conjugate.18.aspx
https://www.ncbi.nlm.nih.gov/pubmed/12182385
We found no evidence that vaccination with Hib conjugate vaccine in infancy is associated with risk of [type-1] diabetes later in life.

[r10] Cumulative incidence of childhood-onset IDDM is unaffected by pertussis immunization. (1997)
http://care.diabetesjournals.org/content/20/2/173.short

RESULTS: No difference in cumulative incidence rate of IDDM up to the age of 12 years was found when the birth cohorts for 1978 and 1979 with high DTP vaccination coverage were compared with the cohorts of 1980 and 1981 with low pertussis vaccination coverage. CONCLUSIONS: The comparison of the cumulative incidence of IDDM, up to the age of 12 years, in birth cohorts with high and low exposure to pertussis vaccine does not support the hypothesis that pertussis could induce autoimmunity to the beta-cell that may lead to IDDM.
[r11] Previous Exposure to Measles, Mumps, and Rubella but Not Vaccination During Adolescence Correlates to the Prevalence of Pancreatic and Thyroid Autoantibodies (1990)
http://pediatrics.aappublications.org/cgi/content/abstract/104/1/e12
Note that this title is a little tortured, but what they are trying to say is that vaccinations did not have an impact into the Prevalence of Pancreatic and Thyroid Autoantibodies, although people who were exposed to the actual disease (not the vaccination) did have a higher incidence of autoantibodies.
Results. The vaccination changed neither the prevalence nor the level of autoantibodies. Children with rubella antibodies before vaccination had higher levels of ICA than did the rubella seronegative children. In contrast, thyroid autoantibody levels and prevalence were lower in children with antibodies against measles, mumps, or both before vaccination than in children without those antibodies.
Conclusions. Previous natural infection or vaccination against measles, mumps, or both seemed to have an inhibitory effect on the development of thyroid autoantibodies. In contrast, children with previous exposure to rubella had higher levels of ICA. No evidence was found that MMR vaccination during adolescence may trigger autoimmunity.
[r12] Vaccination and autoimmune disease: what is the evidence? (2003) Review Paper
Diabetes
Over the past few decades, there has been a regular increase in the incidence of type 1 diabetes in most countries of the world. That childhood vaccines have been identified as a potential trigger event for this disease is, therefore, not surprising.  This possibility has been assessed in a few epidemiological studies. Results of a case-control study done in Sweden in the mid-1980s did not indicate any great effect of vaccination against tuberculosis, smallpox, tetanus, pertussis, or rubella on risk of diabetes.
  
[This next paragraph refers to the Claussen paper discussed here as [r5].  Note that paper did not find different rates of type-1 diabetes between people vaccinated for HiB, and those not vaccinated.] However, one group has suggested that the timing of vaccination could be of importance, and that certain vaccines—eg, Haemophilus influenzae type b (Hib)—might increase the risk of type 1 diabetes if given at age 2 months or older. This theory was not confirmed by a 10-year follow-up study of more than 100000 Finnish children involved in a clinical trial of the Hib vaccine. In this study, there was no increased risk of diabetes when children who had received four doses of vaccine at age 3, 4, 6, and 14–18 months were compared with those who received only one dose at age 2 years. Furthermore, the risk of diabetes did not differ between children in the latter two cohorts and those in a non-concurrent unvaccinated group.
Additionally, findings of a study undertaken in four large health-maintenance organizations in the USA did not suggest an association between administration of routine childhood vaccines and increased risk of type 1 diabetes, irrespective of the timing of Hib or hepatitis B vaccination. Therefore, at this time, there are no serious indications of any great effect of childhood vaccines on the occurrence of type 1 diabetes.
[r13] Risk factors for type I diabetes mellitus in children in Austria (1999) 
Conclusion ... No correlation could be found with dietary intake of cow's milk products in early infancy, vaccination and other environmental factors.
[r14] No evidence that vaccines cause insulin dependent diabetes mellitus (1998) Meta Analysis
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1756616/pdf/v052p00674.pdf
We conclude that at present there is no evidence of a link between IDDM and vaccination in humans.
[r15] Consequence or coincidence?: The occurrence, pathogenesis and significance of autoimmune manifestations after viral vaccines (2004)
http://www.sciencedirect.com/science/article/pii/S0264410X05003506
This review included a Medline search from 1966 to 2004, so it included a huge number of papers.
Whenever controlled studies of autoimmunity following viral vaccines were undertaken, no evidence of an association was found.
No evidence linking viral vaccines with type 1 diabetes, multiple sclerosis (MS) or inflammatory bowel disease can be found.

Why Do People Believe That Vaccines Cause Type-1 Diabetes? (Or Might Cause It?)

This is a subject much to broad to cover in a blog posting.  However, I think there are some reasons to mention briefly:

First, since almost everyone gets vaccines, almost everyone who is diagnosed with type-1 diabetes has been vaccinated. And since almost everyone who is diagnosed with type-1 has been vaccinated, some of them will be recently vaccinated, just by chance.

Second, research which shows something is safe or does not cause a problem does not cause a big splash in newspapers, web sites, etc. That really came through as I searched for papers that showed vaccine safety. Many of them had no press/web/blog/facebook/twitter coverage at all!
Third, genetics, or lack of them.  People understand that type-1 diabetes is a genetic disease, and they often notice that they don't know about any history of type-1 diabetes in their family.  They think to themselves "I was told it was genetic, but it's obviously not in my case, so maybe it's vaccines.  After all, I was vaccinated."  This is bad logic on a number of levels.  First, there are lots of environmental factors which have nothing to do with vaccines.  Second, unless you know exactly how all your grandparent's (and great-grandparent's) descendants died, then you don't really know about type-1 in your family.  If any of those descendants died young, it might well have been type-1 diabetes. Finally, remember that most people diagnosed with type-1 diabetes do not have a known history of type-1 in their families. But these same families often do have a history of other autoimmune diseases (with related genetics).  In short, the lack of a family history of type-1 diabetes does not mean that vaccines are involved.

Fourth, and most importantly, there is clearly an infrastructure of people who think vaccines cause all kinds of problems.  These people (and their web sites) are very vocal in pushing the idea that vaccines cause all kinds of problems (Autism, Type-1 Diabetes, ADD, bad test scores, allergies, Asthma, and on and on and on).  They tend to seize on questionable (or outright fraudulent) research, while ignoring much better research which contradicts them.  I want to stress that in these two blogs, I did not selectively report on the research.  I included all the studies which I found.

I took a look at several of these  web sites (Age Of Autism, NVIC, etc.) looking for studies which showed higher occurrence of type-1 diabetes in vaccinated people as compared to unvaccinated people.  The only such studies I was able to find were two Claussen studies.  One of those studies is discussed above.  The other study was not a direct comparison study (that is, it did not compare people who got a vaccine to people who did not).  Instead it mined other people's population studies for information.  So while population studies are generally worse than direct comparison studies, this study was even worse than a population study.

Always Looking For More Studies

I'm always looking for more studies!  So if you find any study not listed here, which compares type-1 diabetes rates in otherwise similar vaccinated and non-vaccinated populations (or to delayed-vaccination populations), please email me!

Joshua Levy
http://cureresearch4type1diabetes.blogspot.com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions.


Vaccination and Type-1 Diabetes (part 1)

Every now and then I see a posting where someone asks if maybe vaccinations have something to do with causing type-1 diabetes. The following is my collection of data showing that they do not.  It is in two parts because it is too long to be posted on some forums as a single post.

The r-numbers in the text below are references to specific studies later in the text.

Do Vaccinations Cause Type-1 Diabetes or Make It More Common?

In order to answer this question I searched through all the research I could find on humans which was published in peer-reviewed indexed journals, which compared type-1 diabetes rates in vaccinated vs. unvaccinated populations or which compared vaccinated on the standard schedule to vaccinated on a slower schedule.  I do think people with specialized tools might be able to find more research, so if you find any more studies on people, please tell me about them.  I did not include population based studies, as these are much less reliable than studies which directly compare groups.  I must say I was surprised at how much research was out there showing that vaccines did not cause type-1 diabetes.  I had never heard of one such paper, but it turns out there are many.  I view this as reporting bias: papers showing things are safe don't make the news, so the public never hears about them.  I grabbed the first 15 studies I found, and they are listed (with results) below.  

Summary
The bottom line is that there are 12 studies which find that vaccines do not increase the rate of type-1 diabetes.  Of these, 2 actually find that vaccines lower the rate of type-1 diabetes, probably by lowering the rates of mumps or rubella in the population [r3, r6].  There are also two review articles [r12, r15], and one meta analysis [r14] which come to the same conclusion: vaccines do not cause type-1 diabetes. Note that one study [r5] claimed that it "supported" the idea that a causal relationship existed.  However the paper's abstract reported that there was no statistically significant difference between type-1 diabetes rates between children who got influenza B immunization and those who did not.   

Now the democratic thing to do is to say 12 studies show vaccines don't cause type-1, 0 show that they do, so the "does not cause" side wins in a landslide.  Or to look at the studies which summarized the findings of all the other studies available when they were written: these were 2 showing vaccines are safe vs. 0 showing they might cause type-1 diabetes.  

Some of the papers looked at the question of timing: did delaying vaccinations result in a lower type-1 diabetes rate?  A total of 3 papers looked at that issue and all of them found that delay did not result in lower rates of type-1 diabetes [r2, r4, r8]. 

One paper [r7] looked at the overall number of vaccines given to one person, to see if that was associated with higher type-1 diabetes rates.  It found no relationship.


Finally, as a separate area of interest: at least 2 of these papers looked at the relationship between breastfeeding or early introduction of cow milk and type-1 diabetes and found no connection [r7,r13].


If you have any doubts about this I urge you to read the quotes from the abstracts below; they are really very strong in showing that vaccines do not cause type-1 diabetes.

Discussion of the Claussen Paper

The Claussen paper [r5] does not show an increased rate of type-1 diabetes after immunization.  Dr. Claussen says that it does, and refers to it that way, but if you look at the actual abstract, you see this:

The difference in cumulative incidence between those receiving 4 doses and those receiving 0 doses is 54 cases of IDDM/100,000 (P = 0.026) at 7 years, (relative risk = 1.26).
And a relative risk of 1.26 is too low to be considered a correlation.  (Most researchers want to see a relative risk of 2, others will accept a relative risk as low as 1.5, but that is rare.  But in any case 1.26 is well below the correlation threshold.  (There is also some discussion of clustering in the abstract, but no numbers are given.)

Results from the Studies and References


Each entry in this list contains a reference number, the title of the paper, the year it was published, a URL where you can see the whole abstract (sometimes the whole paper), and the results and/or conclusions section which you can read.  The indented text is quoted from the study.

[r1] Childhood Vaccination and Type 1 Diabetes (2004)
Results Type 1 diabetes was diagnosed in 681 children during 4,720,517 person-years of follow-up. The rate ratio for type 1 diabetes among children who received at least one dose of vaccine, as compared with unvaccinated children, was 0.91 (95 percent confidence interval, 0.74 to 1.12) for Haemophilus influenzae type b vaccine; 1.02 (95 percent confidence interval, 0.75 to 1.37) for diphtheria, tetanus, and inactivated poliovirus vaccine; 0.96 (95 percent confidence interval, 0.71 to 1.30) for diphtheria, tetanus, acellular pertussis, and inactivated poliovirus vaccine; 1.06 (95 percent confidence interval, 0.80 to 1.40) for whole-cell pertussis vaccine; 1.14 (95 percent confidence interval, 0.90 to 1.45) for measles, mumps, and rubella vaccine; and 1.08 (95 percent confidence interval, 0.74 to 1.57) for oral poliovirus vaccine. The development of type 1 diabetes in genetically predisposed children (defined as those who had siblings with type 1 diabetes) was not significantly associated with vaccination. Furthermore, there was no evidence of any clustering of cases two to four years after vaccination with any vaccine.

Conclusions These results do not support a causal relation between childhood vaccination and type 1 diabetes.
[r2] Childhood Vaccinations, Vaccination Timing, and Risk of Type 1 Diabetes Mellitus (2001)
http://pediatrics.aappublications.org/cgi/content/abstract/108/6/e112
Conclusions. In this large, population-based, case-control study, we did not find an increased risk of type 1 diabetes associated with any of the routinely recommended childhood vaccines. Our study adds to previous research by providing data on newer vaccines, including hepatitis B, acellular pertussis, and varicella vaccines. For the older vaccines, our results are generally in agreement with previous studies in not finding any increased risks. Ours is the first epidemiologic study to evaluate the possibility that timing of vaccination is related to risk of clinical diabetes in children. Our results on hepatitis B vaccine do not support the hypothesis; risk of type 1 diabetes was not different between infants vaccinated at birth and those who received their first vaccination later in life. The results of our study and the preponderance of epidemiologic evidence do not support an association between any of the recommended childhood vaccines and an increased risk of type 1 diabetes. Suggestions that diabetes risk in humans may be altered by changes in the timing of vaccinations also are unfounded.
[r3] Decline of mumps antibodies in Type 1 (insulin-dependent) diabetic children and a plateau in the rising incidence of Type 1 diabetes after introduction of the mumps-measles-rubella vaccine in Finland (1993)
The results suggest that the elimination of natural mumps by mumps-measles-rubella vaccination may have decreased the risk for Type 1 diabetes in Finland; a possible causal relationship is substantiated by the observed concomitant decrease in mumps antibody levels in diabetic children.
[r4] Association between type 1 diabetes and Haemophilus influenzae type b vaccination: birth cohort study (1999) 
Results: No statistically significant difference was found at any time during the 10 year follow up in the risk of type 1 diabetes between the children born before the vaccination period and those vaccinated at the age of 24 months only (relative risk 1.01). The difference in the risk between the cohort vaccinated first at the age of 3 months and the cohort vaccinated at the age of 24 months only was not statistically significant either (1.06).

Conclusion: It is unlikely that H influenzae type b vaccination or its timing cause type 1 diabetes in children.

[r5] Clustering of cases of insulin dependent diabetes (IDDM) occurring three years after hemophilus influenza B (HiB) immunization support causal relationship between immunization and IDDM.
http://www.ncbi.nlm.nih.gov/pubmed/12482192

The difference in cumulative incidence between those receiving 4 doses and those receiving 0 doses is 54 cases of IDDM/100,000 (P = 0.026) at 7 years, (relative risk = 1.26).

This list is continued in part 2.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions.

Sunday, April 16, 2017

How Does JDRF Decide What Research To Fund?


I've always been interested in how JDRF decides what research to fund. So I was lucky that while attending the recent Bay Area Diabetes Summit  [d1] I attended a talk by Dr. Aaron Kowalski the Chief Mission Officer of JDRF [d2].  After the talk, I was able to ask him how JDRF made those decisions. He did his best, in the few minutes we had, to describe the process too me.  Later on, we followed up with a phone call, which allowed him to answer more detailed questions about the process. This blog is my summary of the process.  As always, any mistakes in this blog posting are mine alone.

Who Is Involved

There are three main groups of people involved in deciding who JDRF will fund:
  • The Research Staff:  This is a group of about 15-20 JDRF employees, most of whom are Ph.Ds, or have other degrees in medicine or science.
  • The Research Committee: More than half of this committee is made up of members of JDRF Board of Directors.  The remaining members bring specific skills and experiences to the table.   There are 13 people on this committee, and they all have close connections to the world of type-1 diabetes: 11 have one or more children with type-1 diabetes, 2 have type-1 themselves, and 2 have spouses with type-1 diabetes.  The total is more than 13 because 2 people fall into more than one category.  Full list is below [d3].  
  • The Board of Directors: More formally, the International Board of Directors.  This group is listed here: http://www.jdrf.org/about/leadership/#board-of-directors.  This is the governing board of JDRF, and is also overwhelming composed of people directly impacted by type-1 diabetes (people with the disease, parents of people with the disease, spouses, grandparents, etc.)
Allocation Funds: Priority, Strategy, Budget

JDRF's research staff makes proposals to the Board of Directors about how to allocate research money and if specific areas of research should be funded or not.  The Board of Directors makes the final decisions about what areas should be funded, and how money should be allocated between areas.  For the last few years, money has been allocated into six basic areas, and the division between these areas is done by the Board: Restoration, Beta Cell Replacement, Artificial Pancreas, Glucose Control, Prevention, and Complications [d4].

For each year, the Board of Directors makes decisions about JDRF's priorities, strategy, and overall budget.  These decisions help guide the Research Staff throughout the year.  Also, as described below, the Board is sometimes asked about specific research when it is significantly different from what JDRF has funded in the past.

You can read more about JDRF's 2017 research priorities here:
http://grantcenter.jdrf.org/information-for-applicants/research-priority-areas/
But the seven priorities are:
  • Beta Cell Replacement
  • Beta Cell Regeneration and Survival
  • Beta Cell Autoantigen-Specific Immune Therapies
  • Prevention of Type 1 Diabetes
  • Artificial Pancreas Device Systems
  • Glucose Modulating Agents
  • Diabetic Kidney and Eye Complications Therapies
But I encourage you to read the whole document, because it includes a high level vision statement, but also more specific goals in each area for 2017.

Specific Research

There are two "paths" that individual research proposals can follow in order to get approval, which I will call the "normal path" and the "unusual path".

The normal path goes as follows:
  1. The researcher submits a summary of the research they want to do.  This is not a detailed proposal, but an overview.
  2. JDRF's research staff reviews this summary focusing on if it fits in with JDRF's priorities, strategies, and budget.  If it does, they ask the researcher for a detailed proposal.
  3. The researcher then submits the detailed proposal.  This contains all the details of what will be done, where it will be done, who will do it, how long it will take, how much money is needed, why it is important, and how it can push forward the goals of JDRF.
  4. The detailed proposal is then reviewed both internally and externally.  The internal review is done by JDRF's research staff.  The external review is done by multiple researchers who work in the field, but are not involved in this specific research.  There are usually three such reviewers and they sign non-conflict of interest statements.
  5. Assuming the internal and external reviewers both like the proposal, it next goes to the Research Committee.  The Research Committee must approve all grants over $500,000.  These grants are each discussed separately, and the committee members can vote yes, no, or request more information for any grant.  They meet about once a month to do this work.  Grants under that amount are approved by staff, but presented to the Research Committee.  That committee can review all documentation of the staff decision (i.e. external reviews, etc.) and can question any grant.
  6. There is a separate group of people, referred to as "Operations Staff" who are responsible for the grant after it has been approved.  In general, this group is not involved in the funding decisions.
The unusual path covers research projects where the research staff is unsure if the project is even the kind of project that JDRF would fund.  These are usually new types of research, especially those requesting a large amount of money.  In these cases, the staff member will sometimes present the project to the Research Committee, prior to reviewing it.  The goal of this early discussion is to decide if the research proposal should even be considered; if it is the sort of project that JDRF would ever fund (regardless of the merits of this particular project).  If the Research Committee decides it is, then it goes through the normal path; if the Research Committee decides it's not, then it doesn't move forward.

Dr. Kowalski  pointed out several strengths of the system: First, nothing can be done based on one person's actions.  Every funding decision involved the Research Committee and multiple external and internal reviews.  Second, everyone on the Research Committee is directly impacted by type-1 diabetes.  Third, everyone on the Board of Directors is also similarly impacted by type-1 diabetes. Points two and three, taken together mean that both the overall policy decisions, and the specific research approvals are in the hands of people who have type-1 diabetes, or who have children, a spouse, grandchildren, etc. who have type-1 diabetes.

Discussion

I'm sure many people will want more details than I've provided here (or different details), and I hope that JDRF will publish a detailed description of the funding process.  This blog includes every scrap of information that I know on the subject.

Dr. Kowalski and I spent some time discussing how to make JDRF more transparent, which we both agreed is important moving forward.  It's a trade off however, because money spent developing web pages which describe how decisions are made takes money away from research.  We both bemoaned the lack of a "funding dashboard", a web site where you could see at a glance a high level overview of where money had been spent.  I'm hopeful that JDRF will get this information on-line soon.

If you want a searchable database of all the research projects which JDRF funds, that is available here:
https://jdrf.smartsimple.us/ex/ex_viewreport.jsp?key=&token=@GgoITRgTeFtYRhpcSRxRQ1BXZ1x8GHFg
(Or, from the main JDRF page, select "Our Work" and then "Search Research Abstracts".)
This is a good resource to find out if JDRF funded a particular researcher or university.  However, it uses a few terms that non-researchers will not be familiar with [d6] and you can search for words only in titles, but not in the body of abstracts or proposals themselves.  It contains information on individual projects only, there is no summary data of any kind.

This information comes directly out of the "SmartSimple" software that JDRF uses to track grant applications, grants, etc, and I do think that is the long term key to providing transparency without spending a lot of money on it.  Since JDRF is already using software to manage their grant process, if that software can be configured to provide summary data to the public, it would provide transparency without the constant work of updating the web pages.

Dr. Kowalski and I also discussed another topic called "funding mechanisms".  These are pools of money allocated for specific types of researchers or specific types of research.  For example, there is a funding mechanism for young researchers (to encourage people to enter the field of type-1 diabetes research).  There is a funding mechanism for early patient research (to help bridge the gap from animal to human trials), for specific projects which JDRF is encouraging [d6], etc.  All of these funding mechanisms go through the same process described above.  You can read more about them here:
http://grantcenter.jdrf.org/information-for-applicants/grant-mechanism-descriptions/

The process described in this blog post does not cover JDRF's recently announced "Venture Philanthropy" fund.  That fund has a similar process (also with a Board of Directors and an Investment Committee).  If there is interest, I'll try to make contact with the director over there, and see if I can write up a similar blog for them.

Finally: I want to say that if you have a question about how JDRF does something, or why JDRF does something, then I encourage you to look on the JDRF web site.  If you can't find what you are looking for, then try searching on google.com and adding "site:jdrf.org" to your search.  This tells google to only return hits on JDRF's site.  You can also add "filetype:pdf" which will only find PDF documents.

Extra Discussion

[d1] The Bay Area Diabetes Summit was a great event.  It was organized by CarbDM, DYF, with help from many other organizations, and everyone did a wonderful job. These Summits happen once a year, and if you are in the area, I strongly recommend attending.  There is lots to learn.   More info here:
https://carbdm.org/events/bay-area-diabetes-summit/

[d2] Dr. Aaron Kowalski is JDRF's Chief Mission Officer.  He's worked for JDRF for 13 years.  Prior to being CMO he was Vice President of Research.  Prior to working at JDRF he earned a Ph.D. in molecular genetics from Rutgers University and the University of Medicine and Dentistry of New Jersey.  He was diagnosed with type-1 diabetes when he was 13 years old in 1984, and so has lived with this disease for a long time.  His brother also has type-1 diabetes (diagnosed in 1977).
https://www.linkedin.com/in/aaron-kowalski-3221a35/

[d3] The current members are: Steve Newman, Randy Anderson, Tom Chapman, Tim Clark, Maarten de Groot, Karen Jordan, Doug Lowenstein, Preetish Nijhawan, Carol Oxenreiter, David Panzirer, Lorraine Stiehl, Jerry Wisler, and Michael White.

[d4] Of course, everyone wants to know how much is spent on each area.  The most recent data I could find myself (and it took me over an hour to find it, and I had to use my best google-fu) was updated in March 2015, but I think it covers the year of 2014:
  • Restoration ($31m)            [Restoration of insulin production in people with type-1 diabetes.]
  • Encapsulation ($13m)        [Recently replaced by the broader "Beta Cell Replacement".]
  • Artificial Pancreas ($16m)
  • Glucose Control ($5m)       [This includes smart insulin.]
  • Prevention ($14m)
  • Complications ($13m)
  • Multi-category Programs ($9m)
Source: https://www.hlc.org/app/uploads/2014/05/2015-JDRF-Fact-Sheet.pdf
which is the most recent fact sheet that has this level of detail.  Note that the total here ($101m) does not exactly match the data from fiscal year 2014 tax forms ($98m).  The fiscal year ends in June. That might be a summation/rounding difference, or this data might be for calendar year 2014, or for the 12 months preceding March 2015, or I might have messed up the numbers in some way.  I'm a software engineer, not an accountant.

[d5] Especially the term "funding mechanism", which I describe below.

[d6] JDRF refers to these as RFAs (Requests For Applications), but another common name is RFPs (Requests For Proposals).  Instead of just sitting back and seeing what proposals come in, the funding organization makes a public request for a specific type of proposal.  JDRF does this on occasion. These proposals go through the same approval process as others. You can see a few recent examples here:
http://www.jdrf.org/wp-content/uploads/2012/12/FY16-Beta-Cell-Replacement-Retrievable-RFA.pdf
http://grantcenter.jdrf.org/wp-content/uploads/2016/12/FY17-Microbiome-RFA-2016.12.21-2.pdf


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

Tuesday, March 21, 2017

Possible Cures for Type-1 in the News (March)

ViaCyte Starts A Three Year Follow-up Safety Study in Subjects Previously Implanted With VC-01™
This clinical trial is studying people who were part of ViaCyte's clinical trial of VC-01™, an encapsulated beta cell cure.  Once the device is removed at the end of the study, the patients can enroll in this follow on study which tracks them for three additional years, looking for adverse effects.

ViaCyte is a commercial company testing an encapsulated beta cell cure.  You can read my previous blogging about them here: http://cureresearch4type1diabetes.blogspot.com/search/label/ViaCyte
They are in the middle of a large Phase-I study, which could finish as early as 2020.

Clinical record: https://clinicaltrials.gov/ct2/show/NCT02939118

Discussion

I'm hopeful that this means that one person has finished the ViaCyte protocol, which is motivating them to start this follow on.  The other option is that they are just planning ahead.  Since there is no control group, the interim data could be published, if ViaCyte wanted.

Two Phase-I Studies Start with Umbilical Cord Treg Cells 
These two studies have a lot in common, so I'm going to discuss them together: first, their similarities, then their differences. Here are the similarities:
  • They are both run by the same researcher (Dr. Zhiguang Zhou) at the same hospital (Second Xiangya Hospital of Central South University).
  • They recruit at the same place: Institute of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China, 410011
    Contact: Zhiguang Zhou, MD/PhD    86-731-85292154    zhouzg@hotmail.com
  • They have already started recruiting 40 people, and expect to finish in 2019.
  • These trials are open to people who have been diagnosed within 3 years and are between 6 and 60 years old.
  • Each has a primary end point which is safety related, and secondary endpoints which are effectiveness related and include C-peptide, A1c, insulin usage, etc.
  • Both studies will work with stem cells which have been harvested from umbilical blood, separated into components, and had the T-reg cells "grown out" for two weeks.  These enriched T-reg cells will be infused into patients.  T-reg cells are regulatory cells which are part of the immune system, and work by controlling other immune cells so that those other cells don't attack beta cells.

The first study is Safety Study and Therapeutic Effects of Umbilical Cord Blood Treg on Autoimmune Diabetes: This study will have two groups, one will get the treatment, and one will be a control group and will not get the treatment.

Clinical trial registry: https://clinicaltrials.gov/ct2/show/NCT02932826

The second study is Safety and Efficacy of Umbilical Cord Blood Regulatory T Cells Plus Liraglutide on Autoimmune Diabetes: This study has four groups.  One will get the treatment and also Liraglutide, another just the treatment, a third just Liraglutide, and a fourth will be a control group.  Liraglutide (sold as Victoza) is similar to exenatide (Byetta), which is a common type-2 medication, but is also sometimes used on type-1.  Victoza is a weekly injection. 

Clinical trial registry: https://clinicaltrials.gov/ct2/show/NCT03011021

Discussion

The researchers are not clear on why they are using Liraglutide, but site its "various benefits for beta cells". They expect it will increase the effectiveness of the new T-regs, possibly by encouraging beta cell growth.

JDCA's Update on Dr. Faustman's Research

An update on Dr. Faustman's BCG research by the JDCA (Juvenile Diabetes Cure Alliance) is here:
http://eepurl.com/cHrGqX

My key takeaway points are:
* The Phase-II trial should finish in 2023.
* They have enrolled 125 out of the 150 they need.
* An 8 year follow up from their Phase-I trial should be published by the end of 2017.

(Remember, I am a fellow of the JDCA and we regularly discuss various research programs, including this one.)
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.

Thursday, February 9, 2017

News From EASD (European Association to Study Diabetes)


Back in October 2016 was the European Association to Study Diabetes (EASD) conference, which is the largest scientific meeting on diabetes in Europe.  Much like ADA, it covers both type-1 and type-2 diabetes. The Europeans are way ahead of the American in terms of on-line access.  The EASD 2016 web site has recordings of many of the talks, and much more content than the ADA web site. You can see it here:
http://www.easdvirtualmeeting.org/

Clinical Trials Aimed at Curing Type-1 Diabetes
The only research which I saw which was directly aimed at curing type-1 diabetes was a talk and a poster given by Dr. Ali from the Cardiff Diabetes Vaccine Development Center (which is part of Cardiff University, Wales, UK).  This is part of the ongoing work by Dr. Peakman and others.

Results of the Monopept1de Phase-I Trial of An Insulin Peptide

This research has been on-going for at least 10 years.  Here is my previous blogging:
http://cureresearch4type1diabetes.blogspot.com/search/label/Proinsulin
The basic idea is to give people with type-1 diabetes an injection containing part of the insulin molecule, which will teach the body's immune system not to attack itself.  The idea is vaguely similar to giving people tiny amounts of peanut protein to desensitize them from peanut allergies.  It is important to remember that type-1 diabetes is NOT a classic allergy.  The analogy is not perfect, but that's the general idea.

The study showed that the treatment was safe and did not trigger any serious adverse effects, or unexpected adverse effects of any kind.  The success/outcome data was weaker.  C-peptide production did NOT increase, but insulin usage went down, and H1c numbers showed a downward trend in treated people.  None of this is strong data for effectiveness, but this trial was aimed at gathering safety data.  The researchers think the safety data is plenty strong enough to support a phase-II study.

Poster: http://www.easdvirtualmeeting.org/resources/proinsulin-peptide-immunotherapy-in-new-onset-type-1-diabetes-is-well-tolerated-and-associated-with-reduced-daily-insulin-usage
11 Minute Talk: http://www.easdvirtualmeeting.org/resources/proinsulin-peptide-immunotherapy-in-new-onset-type-1-diabetes-is-well-tolerated-and-associated-with-reduced-daily-insulin-usage-203021b2-7c50-4239-81b8-84fe0d8a0291
Older Poster On The Same Research: http://www.easdvirtualmeeting.org/resources/proinsulin-peptide-immunotherapy-in-type-1-diabetes-safety-data-of-a-first-in-new-onset-type-1-diabetes-phase-1b-trial--2

This same research group is working on another clinical trial called "MultiPepT1De", which is testing using several different proteins at once.  The trial reported on here only used one. The MultiPepT1De trial was scheduled to finish in Feb-2017, but is running late:
https://www.ukctg.nihr.ac.uk/trials/trial-details/trial-details?trialId=5462
https://clinicaltrials.gov/show/NCT02620332

Other Interesting Talks

Faustman
This was a 15 minute talk by Dr. Denise Faustman, where she discusses a particular chemical pathway (TNFR2):
http://www.easdvirtualmeeting.org/resources/in-vitro-tnfr2-agonism-for-correction-of-treg-activation-defect-in-type-1-diabetes-c96e016f-57c0-4432-9805-9918efcd364e

Viral Infections as Triggers
The talk in the next link discussed looking for viruses in the pancreases of 6 newly diagnosed adults. It is 30 minutes long and has 114 slides: 
http://www.easdvirtualmeeting.org/resources/the-pathogenesis-of-type-1-diabetes-virus-involved-lessons-from-the-divid-study
These researchers are trying to answer the question "does a viral infection trigger type-1 diabetes", by looking at pancreases close to the time of diagnosis.  They did find more viruses in people with type-1 diabetes, but it was low grade persistent infection, not an acute infection.  They were all enteroviruses, no two of the same strain, and the exact virus could not be identified (due to low levels).

Also, they found that 36% of the islets were still producing insulin approximately 5 weeks after diagnosis, which is higher than previous estimates that I'm familiar with.  This definitely comes down on the "viruses are involved in triggering type-1", but the study was a small pilot study, in need of follow up.

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.