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.