Friday, December 16, 2016

The Impact of Advocacy

This blog is a little different from my usual subject matters.  Instead of reporting on the status of various clinical trials, I'm going to discuss a paper by Rachel Kahn Best entitled Disease Politics and Medical Research Funding: Three Ways Advocacy Shapes Policy.   This paper is about how the US government funds research into diseases.

Here is the paper:
but it might require payment to see by the time I post this blog entry.  Here is some coverage of the paper:

My Summary of Best's Paper:
  • Prior to 1980s funding of medical research:
    • Was viewed as a benefit to the researchers being funded
    • Was allocated based on perceived quality of the proposed research
  • During the late 1970s to 1980s there were large social movements (largely focused on AIDS and breast cancer) which changed governmental thinking and policies
  • Starting in the 1990s funding of medical research:
    • Was viewed as a benefit to the people with the disease being researched
    • Was allocated based on impact of the disease being researched
  • Advocacy organizations can have a large impact in government funding of medical research. There is a strong link between advocacy and funding.
Some Details

Here is a key quote on funding:
Increases in the number of nonprofits and lobbying expenditures are both significantly associated with increases in research funding, with each $1,000 spent on lobbying associated with a $25,000 increase in research funds the following year.
Underfunding of Diseases Common to Women and African-Americans

Most of the news coverage of this paper has focused on the "underfunding" of women's and African-Americans' diseases.  This paper discusses the idea that research into diseases of women and African-Americans are underfunded in comparison to diseases of men and whites, including possible reasons for this.  Based on the available data, the paper suggests that the difference is caused by a lack of advocacy organizations.  That funding is based on advocacy organizations, and there are fewer advocacy organization for diseases of women and African-Americans as compared to men and whites.  (Put bluntly: the difference is more directly caused by economic discrimination rather than sexism or racism.)

However, rather than discuss this conclusion, I think it is more important to discuss the weaknesses of the basic idea that diseases of women and African-Americans are underfunded.  The paper lists these weaknesses very clearly:

First, women's diseases are NOT underfunded with respect to men's diseases.    A more accurate statement is that, for women's diseases, breast cancer is funded at a much higher level than men's diseases, and all other women's diseases are funded at a lower level, and everything averages out.  A serious argument can be made that funding should be allocated more evenly among women's diseases, but not that women's diseases as a whole are underfunded.  (Remember that breast cancer has several very strong advocacy organizations, which likely leads to it's "overfunding".)

Second, when the study talked about African-American's diseases being underfunded compared to others, it is very important to remember that only one disease uniquely common to African-Americans was included in the analysis: sickle cell anemia.  So when the study said African-Americans' diseases were underfunded, what it really meant was that sickle cell anemia was underfunded.  (That does sound racist, but it's a single data point, so I'm nervous about reading too much into it.)

Questions for you to Consider

You will notice I'm making no attempt to answer any of the questions below.  Each one of them is a separate "can of worms": worthy of an all night "bull session" in a college dorm room, with some good friends, over some beers.  They are the kind of questions where the discussion is more important than the answer (especially since most of them have no absolute answer).

1. Which model do you think should be the foundation of research funding?  Should research be funded as a benefit to the researchers or to the patients?

2. If you are a proponent of funding based on patient impact, then how do you deal with the problem of diseases which target people who are already discriminated against, being underfunded specifically due to that discrimination?   Early on many believed that AIDS was underfunded specifically because the administration (at the time) didn't care about gays.

3.  If you accept that medical research should be funded based on impact to patients, then how do you measure that impact?
  • Do you measure in terms of number of deaths?  If so, type-1 diabetes will have a relatively lower priority, since it is a less common direct cause of death.
  • Do you measure in terms of number of people with the disease?  If so, minor but common diseases (like the common cold) might get prioritized higher than major (but rare) killers like bone cancer. 
  • What impact should age have?  If two diseases kill the same number of people, but one kills 20 year olds, while the other kills 80 year olds, should they get equal funding?  (This is a classic AIDS vs. cancer argument.)
  • Although mortality and prevalence are common ways to measure impact, from society's point of view, lost productivity might be a better measure.  It does serve to merge depth and breadth of impact into one number.  But then are we going to fund "diseases of the rich" over "diseases of the poor"?  Because when we start measuring economic impact, that's often what it boils down to.
4.  If you accept that medical research should be funded based on impact to patients, then do you take into account other facts about your patients?
  • What impact should preventability have?  Consider three diseases: liver disease, syphilis, and type-1 diabetes:  Liver disease is often (but not always!) caused by alcoholism or drug addiction. Syphilis can be prevented via safe sex.  Type-1 diabetes can not be avoided in any way.  Should these facts impact the funding level for research into these diseases?
  • Many people are willing to underfund research into "diseases" like alcoholism and drug abuse (?are those diseases, or just bad habits?)  But what about lung cancer?  Are you going to fund research into curing the type that smokers get, or just the type that non-smokers get?  What about types that are more common in smokers but occasionally pop up in non-smokers?
Why did I write this blog?
Although we often don't think about it, the federal government is a huge funder of research aimed at curing type-1 diabetes (maybe the largest).  Even research they did not fund directly is often done by programs or sites they did fund.  Therefore, understanding what motivates federal spending is important to understanding research aimed at curing type-1 diabetes.  Even though this is not directly about a clinical trial, I still thought it was interesting and important to blog on.

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. My blog contains a more complete non-conflict of interest statement.
Clinical Trials Blog:

Saturday, November 5, 2016

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

Ustekinumab Is Fully Enrolled

Ustekinumab, an immune modulating drug, started a Phase-II? trial in July 2014.  I previously blogged about it here:

They completed enrollment on May 24, 2016, which means they should finish gathering data by May 24, 2017, because they need to gather data for a year.  Successful results are usually published in less than a year after completion.

This drug was approved in the US in 2009 for treating psoriasis, which is an autoimmune disease (where the immune system self attacks skin cells rather than pancreas cells, as with type-1).  It has also been tested on multiple sclerosis, Crohn's disease, and sarcoidosis (also all autoimmune diseases).  Ustekinumab is thought to work by blocking inflammation, and specifically blocking two immune molecules called IL-12 and IL-23.

Clinical Trial Record:

In July, A Phase-II? Verapamil Trial Was 20% Enrolled
A research group at the University of Birmingham (Alabama) is testing Verapamil on people in the honeymoon period.  The hope is that Verapamil will cause beta cells to naturally regrow.  I've previously blogged on this research here:

They have been recruiting for over a year, but have only enrolled 12 people, out of the 52 they need. At this rate, they will not be fully enrolled within 2 years as they had hoped, and that's a problem.

The drug they are testing is already approved (and pretty widely used) for high blood pressure, so it should not be that hard to recruit for this study.  However, only adults can be recruited (per FDA rules).  Obviously, limiting recruitment to adults still in their honeymoon phase makes this process much more difficult, since most honeymooners are youth, not adults.

Terminated: Leptin by Garg at University of Texas

On June 23, 2015 a Phase-I trial of Leptin being run by Dr. Garg at the University of Texas, was cancelled.  The clinical trial record says terminated at the request of the sponsor.  Since it was being sponsored by JDRF and by Amylin (which makes Leptin), I assume that Amylin shut down the research. You can read my previous blogging here:

At one time they were going to dose 15 people, but they ended up only dosing 7.   It was a Phase-I, pilot study, so there was no control group.  The researchers do hope to publish results, and I'll blog on them when they come out.

Clinical Trial Record:

Joshua Levy 
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, October 19, 2016

Golimumab / SIMPONI Starts a Phase-II? Trial (T1GER)

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

The Study

This study will enroll 81 people.  Half will get the treatment, and half will get a placebo, as the study is double blind.  The treatment is a subcutaneous injection once a week.  This is the same kind of injection used for insulin itself.  Everyone will be followed for two years.  The primary data will be C-peptide generation (a marker for natural insulin production), and the secondary data includes A1c, insulin usage, side effects, more C-peptide data, etc.

They started in August 2016 and plan to run until October 2019.

The researchers are planning on recruiting at 30+ different locations throughout the United States. Their clinical trials page says that right now they are only active in Atlanta, Georgia and Lexington, Kentucky. However, I do think they are actively recruiting in Walnut Creek, California as well. (People often forget to update their clinical trial record as they add more sites.)   The contact point for enrollment is this email address:


Golimumab is a monoclonal antibody (meaning it very specifically targets one type of cell). In particular, Golimumab targets TNFα (Tumor Necrosis Factor alpha) an immune signalling protein, which triggers several immune responses, including inflammation.  This is slightly controversial because researchers such as Dr. Faustman are trying to cure type-1 diabetes by increasing the levels of TNFα, while these researchers are trying to cure type-1 diabetes by decreasing the levels of TNFα. This issue came up in 2009, when Embrel (which lowers TNFα) had a mildly successful Phase-I trial. I discussed the "TNFα: Friend or Foe" at that time:

This study is being done by Janssen Research and Development, which is a large pharmaceutical company.

Clinical Trials Registry:
Drug Web Page:
Drug Wikipedia Page:
TNF  Wikipedia Page:

Joshua Levy
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, October 5, 2016

JDRF Funding for a Cure 2016

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

Let me give you the punch line up front: 71% of the treatments currently in human trials have been funded by JDRF. (And the number is 83% for the later phase trials) This is a strong impact; one that any non-profit should be proud of. This summary does not include Artificial Pancreas research or stem cell growth trials, because there are so many of those that it would be hard to include them all.

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

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

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

New This Year: Phase-II? Trials
Starting this year, I'm dividing Phase-II trials into two groups.  Phase-II trials are "classic" phase-II trials; they are done after a successful Phase-I trial in type-1 diabetes.  What I call Phase-II? trials are done with treatments which are known safe, so they don't need Phase-I trials, but have never been tested on type-1 diabetes before.  These Phase-II? trials might be Phase-II from the point of view of safety, but they are Phase-I in terms of effectiveness, so I'm putting them in their own category.

Cures in Phase-III Human Trials
Summary: currently there are no treatments aimed at curing type-1 diabetes which are in phase-III trials (under the definition of cure that I use). This is the fourth year in a row there have been no phase-III trials underway, and it's not a good thing. Even worse, I don't see a phase-III study starting even next year.  Some people might be discouraged by that, but for me, it's a reason to donate.  Money is the thing that is going to move the Phase-II studies listed below into Phase-III studies, and the Phase-I studies to Phase-II, create more Phase-I studies, and so on.

Cures in Phase-II Human Trials
Summary: there are 24 trials in phase-II, and 20 of them have been funded by JDRF, while 4 have not. Here are the treatments that have been funded by JDRF:
  • AAT (Alpha-1 Antitrypsin) by Grifols Therapeutics and also Kamada 
  • ATG and GCSF by Haller at University of Florida (Established) 
  • Abatacept by Orban at Joslin Diabetes Center 
  • Abatacept by Skyler at University of Miami (Prevention) 
  • Aldesleukin (Proleukin) at Addenbrooke’s Hospital, Cambridge, UK 
  • Diabecell by Living Cell Technologies (Established) 
  • Diamyd, Ibuprofen ("Advil"), and Vitamin D by Ludvigsson at Linköping University
  • Diamyd, Etanercep, and Vitamin D  by Ludvigsson at Linköping University
  • Diamyd and Vitamin D by Larsson at Lund University (Prevention)
  • Gleevec by Gitelman at UCSF 
  • Gluten Free Diet: Three Studies  (Preventative)
  • Oral Insulin (Preventative) 
  • Polyclonal Tregs by both Trzonkowski and Gitelman  
  • Stem Cell Educator by Zhao (Established) 
  • Teplizumab (AbATE study team) 
  • Teplizumab by Herold/Skyler/Rafkin (Prevention)
  • Tocilizumab by Greenbaum/Buckner at Benaroya Research Institute 
  • Umbilical Cord Blood Infusion by Haller at University of Florida 
  • Ustekinumab by University of British Columbia
  • Verapamil by Shalev/Ovalle at University of Alabama at Birmingham
Not funded by JDRF:
  • ATG and autotransplant by Burt, and also Snarski, and also Li 
  • BCG by Faustman at MGH (Established) 
  • Dual Stem Cell by Tan at Fuzhou General Hospital 
  • Vitamin D by Stephens at Nationwide Children's Hospital (Prevention)
Cures in Phase-II? Human Trials
Summary: there are 4 trials in phase-II, and 1 of them has been funded by JDRF, while 3 have not. Here are the treatments that have been funded by JDRF:
  • Rituximab by Pescovitz at Indiana University
Not funded by JDRF:

  • Albiglutide by GlaxoSmithKline
  • Ladarixin by  Emanuele Bosi of Dompé Farmaceutici 
  • Rapamycin Vildagliptin Combo by IRCCS (Established)
Cures in Phase-I Human Trials
Summary: there are 24 trials in phase-I, and 16 of them are funded by JDRF, while 8 are not. Here is the list funded by JDRF:
  • Alefacept by TrialNet 
  • ßAir by Beta-O2's at Uppsala University Hospital in Sweden (Established) 
  • TOL-3021 by Bayhill Therapeutics (Established) 
  • CGSF by Haller at University of Florida 
  • Trucco at Children’s Hospital of Pitt / Dendritic Cells (DV-0100) by DiaVacs (Established) 
  • Exsulin and Ustekinumab by Rosenberg at Jewish General Hospital, Canada (Established) 
  • IBC-VS01 by Orban at Joslin Diabetes Center 
  • Leptin by Garg at University of Texas 
  • Metformin by Littleford at The University of Exeter (Prevention)
  • MultiPepT1De (Multi Peptide Vaccine) by Powrie at King’s College London
  • Nasal insulin by Harrison at Melbourne Health (Prevention)
  • Smart Insulin (MK-2640) by Merck (Established) 
  • Tauroursodeoxycholic Acid (TUDCA) by Goland at Columbia University
  • Polyclonal Tregs by both Trzonkowski and Gitelman 
  • Pro insulin peptide by Dayan at Cardiff University 
  • VC-01 by Viacyte (Established)
Not funded by JDRF:
  • CGSF and autotransplant by Esmatjes at Hospital Clinic of Barcelona (Established) 
  • Encapsulated Islets at University clinical Hospital Saint-Luc (Established) 
  • Mesenchymal Stromal Cell by Carlsson at Uppsala University
  • Microvesicles (MVs) and Exosomes by Nassar at Sahel Teaching Hospital 
  • Monolayer Cellular Device (Established) 
  • Rilonacept by White at University of Texas 
  • Substance P by Vanilloid Genetics at Hospital for Sick Children Toronto (Established)
  • The Sydney Project, Encapsulated Stem Cells (Established) 
    Summary of all Trials
    52 in total
    37 funded by JDRF
    So 71% of the human trials currently underway are funded (either directly or indirectly) by JDRF. Everyone who donates to JDRF should be proud of this huge impact; and everyone who works for JDRF or volunteers for it, should be doubly proud.

    Just Looking at Trials on Established Type-1 Diabetics
    15 of these treatments (29%) are being tested on established type-1 diabetics.
    Of these, 9 are funded by JDRF
    So 60% of the trials recruiting established type-1 diabetics are funded by JDRF.

    Compared to Last Year
    In 2015 there were 42 treatments in clinical trials, in 2016 there are 52 (growth of 24%)
    In 2015 there were no treatments in Phase-III trials, in 2016 there are none (no change).
    In 2015 there were 22 treatments in Phase-II and Phase-II? trials, in 2016 there are 28 (growth of 27%).
    In 2015 there were 20 treatments in Phase-I trials, in 2016 there are 24 (growth of 20%).

    How I Count Trials for This Comparison
    • I give an organization credit for funding a cure if it funded that cure at any point in it's development cycle. 
    • I mark the start of a research trial when the researchers start recruiting patients (and if there is any uncertainty, when the first patient is dosed). Some researchers talk about starting a trial when they submit the paper work, which is usually months earlier. 
    • If there are different clinical trials aimed at proving effectiveness as a cure and as a preventative, or effectiveness in honeymooners and established diabetics, then those are counted separately. 
    • For trials which use combinations of two or more different treatments, I give funding credit, if the organization in the past funded any component of a combination treatment, or if they are funding the current combined treatment. Also, I list experiments separately if they use at least one different drug. 
    • The ITN (Immune Tolerance Network) has JDRF as a major funder, so I count ITN as indirect JDRF funding. 
    • I have made no attempt to find out how much funding different organizations gave to different research. This would be next to impossible for long research programs, anyway. 
    • Funding of research is not my primary interest, so I don't spend a lot of time tracking down details in this area. I might be wrong on details. 
    • I use the term "US Gov" for all the different branches and organizations within the United States of America's federal government (so includes NIDDK, NIAID, NICHD, etc.) 
    • I don't work for the US Gov, JDRF, or any of the other organizations discussed here. I have a more complete non-conflict of interest statement on my web site. 
    Some Specific Notes:
    • Serova's Cell Pouch and DRI's BioHub: These two clinical trials are both testing one piece of infrastructure which might be used later in a cure. They are testing a part of a potential cure. However, in both cases, the clinical trials being run now require immunosuppression for the rest of the patient's life, so I'm not counting them as testing a cure.
    • Substance P at Hospital for Sick Children Toronto: This trial is avoiding the honeymoon period by tested for insulin production.  Patients must inject more than 1/2 unit/kg to be accepted, therefore they will accept recently diagnosed people, if they are injecting enough insulin to be passed the honeymoon.  I'm counting this as "Established".
    Treatments Removed This Year:
    • Etanercept (ENBREL) by Quattrin at University at Buffalo (no movement since 2008)
    • Brod at University of Texas-Health Science Center (no movement since 2009)

    This is an update and extension to blog postings that I've made for the previous seven years:
    Finally, please remember that my blog (and therefore this posting) covers research aimed at curing or preventing type-1 diabetes that is currently being tested in humans. There is a lot more research going on, not covered here.

    Special Note: The JDRF's Role in The First Artificial Pancreas Approval by The FDA
    Although not strictly a "cure" the artificial Pancreas is clearly a huge breakthrough in diabetes treatment which will vastly lower complications, hassle, and "dead in bed" situations.  The JDRF deserves a lot of credit for getting an AP to market now.   First, the JDRF funded a lot of the basic research (and some not-so-basic research as well).   But it also helped clear the regulatory hurdles.  Even five years ago, the FDA's policies and procedures made it very difficult to get an AP approved (even one that worked well).  Simpler medical devices were approved in the EU many months before they were approved in the US.  The JDRF was instrumental in changing that.  The JDRF organized and led an informal consortium of diabetes advocates which, on the one hand, assembled scientific evidence and, on the other hand, applied grassroots political pressure which together resulted in the FDA adopting reasonable policies, and (eventually) this AP approval.

    Please think of this posting as being my personal "thank you" note to all the JDRF staff, volunteers, and everyone who donates money to research a cure for type-1 diabetes:
    Thank You!
    Finally, if you see any mistakes or oversights in this posting, please tell me! There is a lot of information packed into this small posting, and I've made mistakes in the past.

    Joshua Levy
    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.

    Saturday, October 1, 2016

    Rapamycin Vildagliptin Combo Start a Phase-II? Clinical Trial

    These researchers are running a three-armed clinical trial.  One group will get two drugs: Vildagliptin and Rapamycin.  Another group will get Rapamycin and a placebo, while a third group will get two placebos.

    Rapamycin is an immune modulator, so (I assume) it is being used to shut down the autoimmune attack. Vildagliptin is given to type-2 diabetics because it increases their insulin output.  Recent research suggests that it does this both by encouraging beta cell replication and by reducing natural beta cell death (see more discussion below).  Both of these would be valuable if Rapamycin is successful in lowering the autoimmune attack on beta cells.

    There will be 20 people in each group.  All patients will be adults (over 18 years old), who have had type-1 diabetes for five years or longer.  This is NOT a honeymoon trial.  Data will be collected over a 12 week period.  The trial started in May of 2016 and they hope to finish by December 2018.

    The primary outcome is C-peptide response (a marker for natural insulin production), and secondary outcomes include insulin use, A1c numbers, more C-peptide data, and adverse reactions.

    This trial is recruiting in Milan, Italy:
        IRCCS San Raffaele Scientific Institute
        Contact: Lorenzo Piemonti, MD    phone: 0226432706 ext +39
        Contact: Andrea Bolla, MD    phone: 0226432822 ext +39

    Clinical Trial Record:
    Wikipedia entries:


    There is a lot to like about this study.  First, the people being treated have had type-1 for a long time. Second, it's the kind of combination therapy (one drug to lower the immune attack, another to spur beta cell regrowth) that a lot of researchers have been talking about for years.  Finally, it's quick.  They will follow people for about 3 months, which means results will be available soon.  Also, the drugs are already approved for use (one in the US the other in Europe) which should make them easier to get.

    The official title for this study is "Monotherapy With Rapamycin in Long-standing Type 1 Diabetes (MONORAPA)", but I have no idea why, as it's clearly testing a combination therapy, not a monotherapy.

    I'm considering this trial to be a Phase-II? ("Phase-II previously untested") trial, because these two drugs have never been tested together for type-1 diabetes, but Rapamycin/Sirolimus alone is being actively tested in several different clinical trials, which I've blogged about before:

    Vildagliptin (sold as Galvus) is approved in Europe as a treatment for type-2 diabetes.  It is a member of a class of drugs called DPP-4 inhibitors.  More famous members of this class include Januvia and Tradjenta.  Another name for DPP-4 is CD26.

    Sirolimus (also known as Rapamycin) is an IL-2 inhibitor and immunosuppressant.  It was approved in the US in 1999 for organ rejection and cancer.

    About "Natural Cell Death"

    It's important to remember that individual cells do not last as long as people live.  Cells naturally die and new cells grow within your body all the time.  Research (mostly in animals) has suggested that Vildagliptin might have two separate effects on beta cells.  On the one hand, it seems to cause beta cells to naturally divide and grow, and on the other hand, it seems to delay beta cell's "natural death", so they live longer.    Both of these effects may be important to curing type-1 diabetes, but it is not clear.  This is why research is important.  For example, even if Vildagliptin triggers a divide-and-grow reaction, it will only be effective if there are some beta cells to start with, and we just don't know if there are enough to get things started.  On the cell death side, if the autoimmune attack directly kills beta cells, then stopping natural cell death may have little impact.  Those cells will be killed by autoimmunity before they can die of "old age".  However, if the autoimmune attack works by triggering natural cell death (which some researchers believe) then slowing natural cell death could have a large impact.

    Joshua Levy
    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, September 15, 2016

    Substance P Starts a Phase-I Clinical Trial

    Substance P is a peptide (a part of a protein) which is used by several different organs and for several different purposes.   Research done in the early 2000s found that a specific type of neuron (called "TRPV1(+) pancreatic sensory neurons") control islet inflammation and insulin resistance. Removing these neurons from NOD mice prevented diabetes from developing.  Injecting NOD mice with Substance P, which affects these neurons, cured diabetes.   This clinical trial will test this same treatment in people, rather than mice.

    People who have followed type-1 diabetes research for a long time might remember the news stories that injecting capsaicin (the active ingredient in hot chilis) would cure type-1 diabetes.  They were first published in 2006 and get recycled every now and then.  (Usually as examples of the grand conspiracy to suppress type-1 cures, especially cheap, natural cures.)  Anyway, the idea that capsaicin would cure type-1 diabetes comes out of this same line of research in NOD mice.  Capsaicin and Substance P are different, but they affect the same neurons in the pancreas, and the researchers tested both and reported on both in the same journal article.  The clinical trial is Substance P only, no capsaicin.

    The Study

    This Phase-I trial will start out enrolling 12 kids (between 10 and 18 years old) and later expand to 40 kids.  They are looking for people who were diagnosed "recently" but have already passed through their honeymoon period.  Their definition of "done with the honeymoon" is needing to inject more than 1/2 a unit of insulin per kilogram of body weight per day.  

    They are testing four different doses of Substance P.  So no one will get a placebo, everyone will get the treatment, just at different doses.  People will get a single intravenous dose of Substance P, and will be followed for 6 months.  The primary outcome for this study is safety (prevalence of side effects), while the secondary outcomes are measuring effectiveness (C-peptide, a surrogate for natural insulin production).

    The study started in May 2016 and they hope to finish in September 2017 (I assume that is for the 12 person part of the study).

    They are recruiting at one location in Canada: Hospital for Sick Children  Toronto, Ontario
    Contact: Holly Tschirhart    416-813-7654 ext 204517
    Contact: Catherine Pastor    416-813-7654 ext 204396

    A Little History

    The history of this research really brought home to me the slow pace of research in general.  Here is a brief timeline:

    1990s Earliest research into Substance P and type-1 diabetes.
    2000 People with type-1 diabetes have less Substance P.
    2006 Publication of cure results in NOD mice.
    2007 "We expect to begin intervention studies in 2008"
    2016 Intervention studies actually start.

    If you want a single golden example of why there is so much false hope that a cure for type-1 diabetes is just around the corner, read this article, originally published in 2006:
    Note the last sentence:
    "Dosch and Salter expect to complete human trials of the treatment in the next year."
    But also consider the general level of optimism and simplicity in the news report.  But the truth was completely different.  Now, 10 years after this news article, the research is just starting clinical trials.

    This is the first clinical trial run by this company, Vanilloid Genetics Inc, which was founded by Dr. Dosch (and others), one of the original researchers from the NOD mice work in 2006.

    Clinical Trial Registry:

    Joshua Levy
    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.

    Sunday, August 28, 2016

    Ladarixin Starts a Phase-II? Clinical Trial

    You'll notice that the title of this blog refers to a "Phase-II?" trial, rather than the more usual "Phase-II"  trial.  That's because I'm experimenting with new terminology.

    Researchers usually call a trial "Phase-II" because it is larger than a Phase-I trial, and because it is focused on effectiveness while Phase-I trials are focused on safety.  However, I have long been frustrated by two different types of Phase-II trials.  Some Phase-II trials are run after a Phase-I trial. Generally, there was good news from the Phase-I trial, so it is reasonable to be hopeful about the follow on trial.  However, other Phase-II trials are run on drugs which have already gone through safety testing for another disease.  These trials are also called "Phase-II" because the treatment has already been tested for safety.  However these treatments have never been tested for type-1 diabetes, so they are much less likely to be successful.

    So there are Phase-II trials for treatments that have already shown some success in Phase-I trials, and then there are Phase-II trials for treatments which have never been tested on type-1 diabetes, but they both have the same name.  I don't like that.  So, I'm going to refer to these trials by different names.

    Trials run after a Phase-I trial will be called Phase-II.  Trials that are the right size for a Phase-II trial, but are being run on people with type-1 diabetes for the first time, will be called Phase-II? trials.  You can think of the question mark as meaning "no previous type-1 results".

    Ladarixin Starts a Phase-II? Clinical Trial

    Ladarixin targets two specific immune system chemicals: IL-8a and IL-8b. The idea behind this trial is that suppressing this part of the immune system will stop the autoimmune attack which causes type-1 diabetes.

    Ladarixin has previously been tested for several conditions unrelated to type-1 diabetes (Bullous Pemphigoid, Malignant Melanoma, and spinal cord injuries) but did not show promise in treating any of them.  Adis Insight (a drug database) claims that a phase-I trial is underway in Italy, but I cannot find any official record of it, nor any results.  (But European clinical trial registries often don't include Phase-I trials.)  So for this posting, I'm assuming there is no phase-I trial.  I'll update it if I find out about such a trial.

    Ladarixin is also sometimes known as DF-2156A, DF-2156Y, or Meraxin.  It is being developed by the Italian pharmaceutical company Dompé Farmaceutici.

    The Study

    The study will include 72 honeymooners (within 100 days of diagnosis).  Two thirds will get the treatment and one third will get a placebo. The treatment is a daily pill, which people will take for two weeks, and then two weeks off with the cycle repeating three times.  People will be followed for a year afterwards.  The study started in June 2016 and they hope to finish by November 2018.

    They are currently recruiting in two location in Italy:
    • Internal Medicine - Diabetes and Endocrinology Unit, San Raffaele Hospital Milan
      Contact: Emanuele BOSI, MD   
    • Unità Operativa Complessa di Endocrinologia e Dialettologia. Università Campus Bio-Medico di Roma
      Contact: Paolo POZZILLI, MD   
    They hope to start recruiting in Belgium and more sites in Italy.


    Needless to say, Ladarixin prevents and cures type-1 diabetes in mice, and you can read that study here:

    I'm not aware of any previous work suggesting that IL-8 is involved in type-1 diabetes, so this is a unique line of research.

    Note that both trial registry entries refer to the same trial:
    US Clincal Trial Registry:
    EU Clinical Trial Registry:

    Joshua Levy
    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, August 5, 2016

    Atorvastatin (Lipitor) Unsuccessfully Completes a second Phase-II Trial

    Atrovastatin (much better known as Lipitor) has now finished it's second phase-II trial.  The previous trial was unsuccessful, and this trial is unsuccessful, so I think that Lipitor is probably done as a potential cure for type-1 diabetes.  You can read my previous blogging here:

    This clinical trial started recruiting patients in July 2007, finished collecting data in July 2011, and finished completely in July 2013.  It's now been 3 years since that date, and I cannot find a publication reporting on the results of this trial.  In my experience trials with successful results are usually published within a year of completion, while those which are unsuccessful often languish for years, unpublished.

    Clinical Trial Record:

    The previous Lipitor paper is here:
    Conclusion from this previous paper:
    Atorvastatin treatment did not significantly preserve beta cell function although there may have been a slower decline of beta-cell function which merits further study.

    The problem of researchers not publishing results from unsuccessful clinical trials has been getting some press recently.  For example:

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

    Saturday, July 16, 2016

    Polyclonal T-Regs Start A Phase-II Trial (T-Rex)

    T-Rex is a phase-II study of polyclonal T Regulator ("T-Reg") cells.  It is a follow on study to work done at UCSF and in Poland which I've blogged about in the past:

    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.

    The Study

    This study will enroll 111 people divided into three groups (low dose, high dose, and placebo). Patients must be between 12 and 17 years old and be honeymooners (within 100 days of diagnosis). They will be followed for two years.  The primary endpoint is C-peptide generation (the body making it's own insulin) after one year, while secondary endpoints are A1C, insulin usage, adverse effects, and C-peptide at two years.

    The study started recruiting in February 2016 and is expected to finish in March 2020.

    In previous studies, the treatment involves two trips to the clinic (the second being an overnight stay), about two weeks apart.

    Currently, this study is recruiting in two locations, but they hope to add more in the future:

    Fargo, North Dakota, United States, 58122
        Contact: Kathryn McEvoy    701-234-3722
        Contact: Vicki Oberg    701-234-6722
    Sioux Falls, South Dakota, United States, 57104
        Contact: Lynn M Bartholow, BA    800-305-5059
        Contact: Alycia Brantz    605-328-1369


    This is a study where speed of recruitment is going to directly impact how long the study takes. This study gathers data for 2 years, so all data will be collected 2 years after the last patient is recruited. However, recruiting 111 teenagers from just two (relatively low population) sites, such as Fargo, North Dakota and Sioux Falls, South Dakota is going to take years.   The sooner they can recruit from more places, and especially higher population cities, the sooner they can finish recruiting, and the sooner we can see if this works.

    This study is sponsored by Caladrius Biosciences, Inc. in collaboration with Sanford Health (which is different than Stanford University).  Caladrius Biosciences is a small pharma company specializing in bringing cellular therapies to market.

    The term "cellular therapy" refers to treatments that use whole cells.  Cellular therapy itself is a broad topic and can include stem cell therapies, cellular transplants, etc.  In this case it refers to cellular "self transplants" where the patient receives cells that originated inside himself, but have been processed (in this case, grown out) outside his body.

    The Company's web site:
    Newspaper Article:
    Clinical Trial Registery:

    The same group of researchers are planning to start a another trial, which will combine Polyclonal Tregs and IL-2.  I'll blog on that trial when it starts recruiting.

    Joshua Levy
    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.

    Monday, July 4, 2016

    Research In The News (July)

    This is a combination of updates from the last month or two.

    DILfrequency Completes Data Collection

    In late may, the DILfrequency research team announced that they had finished collecting data, and were now starting to analyse that data.  Of course, that's great news, because it implies that results will be published in the next year or two.  (In my experience successful results are published within a year, unsuccessful results often take longer, if they are published at all.)

    This study is testing Aldesleukin (also called Proleukin or IL-2) by giving it to adults within 5 years of diagnosis.  IL-2 is a component of the immune system, and they hope that more it will either improve or cure type-1 diabetes.  Are are looking for changes in the immune system which occurs quickly (ie. in a few weeks), or changes in insulin, A1c numbers, or C-peptide over a three month period.

    I previously blogged on this study here:

    These researchers seem to be months ahead of schedule.  Previously, they expected to finish data collection by October 2016, but they have actually finished in May 2016, which is a testament to their ability to recruit people with type-1 diabetes.  Even better, they enrolled more people than expected: 36 expected vs. 41 actual, that's 14% bigger than planned for.  This group is very media-savvy, with lots of tweeting, facebook posting, a pinterest page, etc.  I suspect that this media focus helped them recruit, and I hope it represents the future of clinical trial recruiting techniques.

    New To Me: Cord Stem Cells In A Phase-II Clinical Trial

    This trial started in 2009, but it registered with the US FDA's clinical trial registry in April 2016, and I did not know about it before then.  The basic plan is to give a total of 30 people a transplant of 3rd party umbilical cord stem cells (called allogeneic umbilical cord mesenchymal stem cells).  The people treated will be honeymooners (within 12 months of diagnosis), and must have had DKA when diagnosed.  There is no control group; everyone will get the treatment.  People will be followed for three years after transplant.  Primary outcome will be insulin usage, and secondary outcomes will be C-peptide, A1c, and autoantibody counts.  The researchers hope to finish collecting data in Dec 2019.

    They are recruiting at one site:
    Nanjing Drum Tower Hospital of Nanjing University Medical School. Nanjing, Jiangsu, China, 210008
    Contact: Dalong Zhu, MD.PhD.    86-25-83106666 ext 61430  
    Contact: Jing Lu, PhD.    86-25-83106666 ext 61431  

    Clinical Trial Registry:


    This research is similar to Haller's work at the University of Florida, which completed a phase-I and started a phase-II clinical trial also in 2009.  I've blogged on that research here:

    Unfortunately, the phase-II study (which included a control group) completed in 2012 and was published in 2013, but was unsuccessful.  Exact quote was "Autologous UCB infusion followed by daily supplementation with vitamin D and DHA was safe but failed to preserve C-peptide.".

    ATG Is Unsuccessful in a Phase-II Trial

    58 people recently diagnosed with type-1 diabetes were given antithymocyte globulin (ATG) in the hopes that it would modulate the autoimmune attack on the pancreas's own beta cells.    The primary end point was C-peptide generation after 2 years (a measure of the body's ability to generate it's own insulin).  People who got the treatment did no better than people who did not.

    Trial Registration:


    Although there was no improvement if the researchers looked at everyone in the study, if the researchers only looked at older patients (between 22 and 35 years old), then they did see a statistically significant improvement in C-peptide levels as compared to untreated patients of the same age.  The researchers were hopeful that future testing might show that ATG is helpful for older patients.

    Diabetes Care Has A Section On Artificial Pancreas Papers

    You can read 9 AP papers in one place:
    Diabetes Care is published by the ADA.

    Losing Autoantibodies: Does It Happen And What Does It Mean?

    It is now well established that people test positive for autoantibodies before they are diagnosed with type-1 diabetes, and (statistically) more autoantibodies are detected over time as people move closer to diagnosis.  Also, there is a big difference between having one autoantibody and having more than one.  I'm sometimes asked: can someone lose an autoantibody that they previously had?  Put another way, are autoantibodies a one way progression to type-1 diabetes? Or can people move closer or farther away from diagnosis (at least as measured by number of autoantibodies).

    The answer, according to this paper:
    is "its complicated".  Basically, some people do lose an autoantibody that they previously had and therefore, at least on paper, move away from type-1 diabetes.  However, in real life, most of the people who lose an autoantibody only had one to start with, and therefore were unlikely to ever be diagnosed with type-1 diabetes.  The people with more than one autoantibody (and who are likely to be diagnosed) rarely lose an autoantibody.

    Joshua Levy
    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, June 22, 2016

    Summary of ADA 2016

    Every year the American Diabetes Association holds the largest diabetes conference of the year.  This year it was in New Orleans.  Attendance was over 16,000 people with 58% international participation. Although I did not attend, I did read (or at least skim) all the abstracts, and read all the tagged tweets that came out of the meeting.  This is my summary.  There were 100s of abstracts, scores of talks, and 1000s of tweets, so I'm only mentioning the most interesting items here.  I've divided this posting into four sections:

    • A very quick summary of the most important findings.
    • Coverage of clinical trials aimed at curing type-1 diabetes.
    • Coverage of research aimed at curing type-1 diabetes (but not yet in people).
    • Other items of interest.
    A Very Quick Summary

    The big type-1 news was all about artificial pancreas research.  The "Do It Yourself" artificial pancreas crew had a poster or two, plus a few meetings, but they dominated the buzz for the first day of the convention.  The commercial / professional artificial pancreas developers took over for the second day, with lots of published data.  

    There was also more focus this year on "Quality of Life" issues.  Not just better numbers, but a better life.  More discussion of the whole person, and not just BGs and A1Cs.  Memorable quote was "The data alone can't be enough to make a decision", but I did not write down who said it.  There was also some discussion of using more patient friendly terminology (especially in the type-2 world).

    In the world of type-2, the LEADER study showing several good outcomes from using liraglutide‎/Victoza and more data from EMPA-REG (both huge studies) made big news.  Everyone was talking about Metformin as though it was the next Vitamin-D (or the Vitamin-C of the 1970s...).

    You'll notice I didn't mention much about clinical trials aimed at curing type-1 diabetes, or even curing type-1 at all.  There were two posters on clinical trials aimed at curing type-1 diabetes, and less than 10 talks aimed at curing type-1 diabetes, and that was about it.

    This is DiabetesMine's summary of ADA 2016 (they cover a lot of topics which I do not):

    Reports From Clinical Trials Aimed At Curing Type-1 Diabetes 

    Combination Therapy with ATG + GCSF in Established Type 1 Diabetes: Two-Year Outcomes
    Poster 1676-P:  
    These researchers had previously reported beta cell preservation at 12 months.  (Meaning that most diabetics lost beta cells over time, but for those treated with ATG and GCSF their beta cell count remained constant.)  The result here is that after two years, treated and untreated people with type-1 diabetes had the same C-peptide numbers, so whatever advantage was seen after a year was not seen after two years.  (There were some immunological differences seen, but the C-peptide numbers, which are the most important in terms of a cure for type-1, were the same.)

    Update on BCG Clinical Program for Reversal of Established Type 1 Diabetes

    This is an update on Dr. Faustman's  phase-II study of BCG, which I've blogged on before.  The key new information is that they have recruited 125 patients out of the 150 people they need.  For one year of recruiting at one site, that is strong progress.  It suggests they will be fully enrolled by the end of the year.  Since the study runs for 5 years, we can expect completion in late 2021 and publication thereafter.  

    Also, there is a single line on the poster about "Clinical Program 3" which is a new study.   It will give repeat doses of BCG to people who were already in the phase-I trial.  I think of it as a follow on study to the phase-I trial.  Since only three people got BCG in the phase-I trial, this clinical program will be tiny.

    5-IT-SY03 - What Is the Future of Immunotherapy for Type 1 Diabetes?
    This session contained about 5 talks which focused on using immunology to cure type-1 diabetes. Unfortunately, there were no abstracts for the talks, and no information about them at all.  So my only knowledge is a few tweets and web articles.
    1. Here is the official ADA preview of the session:
    2. There was general optimism about IL-2 (which I just recently blogged about).
    3. There was pessimism about antigen-based therapies (ie. blocking the immune system's reaction to a specific target):  "Antigen-based new onset and Immunomodulatory onset studies have really not showed any positive substantial results.  --Jay Skyler MD"
    Safety and Tolerability Results from a Phase-I study of Phizer's PF-06342674
    PF-06342674 is a antibody that blocks a part of the immune system (IL-7 binding). This trial is testing physical properties of the treatment (how much ends up in the body, how quickly the body sheds it, any adverse effects, etc.) This is called "safety and tolerability". This trial is not in any way testing that PF-06342674 will treat or cure type-1 diabetes, but based on what is learned here, future studies could test this as either a treatment or a cure.

    Optimistic Overview of Transplanting Pig Islet Cells Into People
    My comments: LCT is the company farthest along in transplanting pig islet cells.  They have done several phase-I and phase-II clinical trials, but the results have not led to a cure as yet.  As for islets from stem cells, Viacyte has started a phase-I trial.  Neither LCT nor Viacyte announced new data at ADA 2016 (that I know of).

    Leptin (Metreleptin) In Patients With Type-1
    We conclude that metreleptin was not efficacious in improving glycemic control in T1DM although it reduced body weight and daily insulin dose modestly.
    My comments: In the past I have covered Leptin as a possible cure for type-1 diabetes.  However, this study suggests that, while it might lower insulin usage, it is not a cure.

    Other Cure Research 
    (I'm including a few AP papers here, but nowhere near all of them.)  From here down, this posting is mostly links to other sources of information.  Different people will be interested in different topics, so I encourage you to read the source material for the topics you care about.  My few comments are in italics.

    Transplants  (But Still Need Lifetime Immunospressive Drugs)!/4008/presentation/44271
    My comments: one patient, but successful.

    873-P / 873 - Pilot Study of Tidepool’s Blip Application for Data Visualization in Type 1 Diabetes (T1D)!/4008/presentation/39609

    AP Papers, Posters, Tweets, etc.

    What do people think an AP is?  (It turns out to be totally different than what I think it is.)!/4008/presentation/39746

    More commerical AP links:

    DiabetesMine @DiabetesMine
    In designing AP pivotal trials, discussion is to make them 6-12 months to pursuade payers. Beyond FDA's 3-month requirement. #2016ADA
    My comment on this last tweet: The FDA has made it clear that they will approve APs based on 3 month clinical trials.  (I think this even covers bihormonal APs, which would include approving a lifetime of Glucagon micro doses with only 3 months of testing.)  However insurance companies may not pay for APs based on 3 months of data.  They might argue for more data to show it really is better.  Therefore there is pressure to run longer phase-III trials, so that one trial can lead to both FDA approval and insurance company payment.  But that would delay initial FDA approval while the longer trials completed.  There was a similar issue in CGMs.  They were approved by the FDA, but some insurance companies would not reimburse until the JDRF funded a longer study that showed benefits that the insurance companies could accept.

    More "we are not waiting" (Homebrew AP) links:
    While using #OpenAPS: self-reported outcome measures showed median HbA1c dropped from 7.1% (SD 0.8%) to 6.2% (SD 0.5%). #2016ADAWhile using #OpenAPS: self-reported outcome measures showed median HbA1c dropped from 7.1% (SD 0.8%) to 6.2% (SD 0.5%). #2016ADA
    #OpenAPS self-reported outcome measures showed median percent time in range (80-180 mg/dL) increased 58% (SD 14%) to 81% (SD 8%). #2016ADA
    Of note: user growth of #OpenAPS is doubling every 3 months, even though users must self-build these AP systems. #2016ADA
    My comment: that is a growth curve that any high-tech start up would be proud of.

    Other Interesting Research
    There were vast amounts of "my new insulin is better than your existing insulin" research.  None of that is included here.  If you care about the new insulins, I would search the ADA material directly, or wait for the press release announcing it is for sale in your country.

    Easing the Child to Young Adult Transition
    Two good tweets from Dan Browne:
    Monaghan: for young adults, shared responsibility w/ parents for t1d care correlates with worse hbA1C. #2016ADA @collegediabetes
    #2016ADA Monaghan: protective factors for YA A1C: pers. responsibility, contact w providers, fear of hyperglyc. #2016ADA @collegediabetes
    My comment: what this seems to say is that giving young adults personal responsibility for their BG is a better strategy than shared responsibility.  I don't think that is conventional wisdom, however.  I do think this talk will be available on line in the future, and will be worth viewing when it is.

    Systematic Population Screening, Using Biomarkers and Genetic Testing, Identifies 2.5% of the U.K. Pediatric Diabetes Population With Monogenic Diabetes.
    via Eleen Ullman's tweet:

    CGMs Beat Diabetic Alert Dogs 
    Basically, CGMs detected lows earlier than dogs, and dogs often alerted when there was not a low situation.  You can read more in this news article:
    And three tweets on that talk:

    Causes of Death for People With Type-1!/4008/presentation/40218
    1473-P / 1473 - Causes of Death in the First 100 Type 1 Diabetes (T1D) Donors in the Network for Pancreatic Organ Donors with Diabetes (nPOD)
    My comment: the link above goes to an abstract.  It is tough to read but important.  Deaths directly caused by type-1 were very common.  So was suicide and drug use.  This is very cautionary data which should not be ignored.

    Inhaled Insulin
    MannKind announces more data (six posters) on their inhaled insulin: 

    Dosing For Protein
    Pratik Choudhary tweeted:
    #2016ADA - preliminary results show 60 gms protein require 25% more insulin - practically - % increase of bolus with increased fat or prot

    Nasal Glucagon

    Type-1 Diabetes and Autism!/4008/presentation/40873!/4008/presentation/40901

    Type-1 Diabetes and Sleep Apnea!/4008/presentation/39594

    Metformin (there was far more than this)!/4008/presentation/39832

    Shaming Is Common:
    LEADER data:
    My comments: If you have type-2, you may want to discuss this with your doctor.  (And even if you don't, your doctor may want to discuss it with you. :-)
    EMPA-REG data:
    Position paper on terminology for "Diabetes"
    My comments: This statement misses what I consider the two most important rules:
    Differentiate between type-1 and type-2 diabetes! (when appropriate)
    Do not say "diabetes" when you mean "type-2 diabetes" or when you mean "type-1 diabetes".

    More Interesting Tweets:

    Doctor Deena @Doctor_Deena
    Amazing #technology for #diabetes-- a skin patch using wavelengths to deliver #insulin into skin pores. #2016ada

    Mark Harmel MPH, CDE @MarkHarmel
    Results of DiaMonD study (CGM in MDI users) impressive. #2016ADA Fewer highs, lows and reduced variability. + Lower A1C by 0.9% at 24 weeks
    My comment: MDI is multiple daily injections.  What this study is showing is that even people who are not using a pump will benefit from using a CGM.  While I suspect this is true, I'm not sure it is useful, because I suspect these people don't want or cannot use a CGM for the same reason they don't want or cannot use a pump: they don't want an attachment or can not afford it.  Telling non-users "it is good for you" will not make them users: they know it is good for them.  They have other reasons for not using it.

    Dr.Harsha Doddihal @Harshadod
    Consuming #proteins followed by carbs could be beneficial in #glycemic control! Poster 62-LB
    My comment: is this news?  I always thought eating carbs after non-carbs led to smaller post meal BG spikes.

    Joshua Levy
    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.

    Sunday, June 5, 2016

    Metformin Starts a Large Trial To Prevent Type-1 Diabetes

    This blog describes a single large, complex trial called adAPT (Accelerator Prevention Trial).  The simple summary for this trial is: The researchers intend to recruit people who have a higher chance of getting type-1 diabetes (because they have a close relative with the disease) and then give some of those people Metformin (the common type-2 drug).  They will then see if the drug prevents or delays type-1 diabetes onset (by comparing the people who got the Metformin to those who did not).  The researchers hope to contact every family in Scotland impacted by type-1 diabetes, and will run the main part of the trial for 5 years.

    However, this trial is based on a non-standard theory about the root cause of type-1 diabetes, plus it is complex.  Throughout this blog posting, I have put reference footnotes (such as [r1] and [r2]) at the bottom, along with extra discussion footnotes, which look like [d1] and [d2].

    Why Metformin As Preventative?

    To summarize: these researchers believe that type-1 diabetes is caused by three factors (called "accelerators") and that Metformin will protect the beta cells from at least one of these accelerators and therefore prevent or slow down type-1 diabetes.

    The Accelerator Hypothesis

    This trial is motivated by the "Accelerator Hypothesis" which is an alternate theory on the root cause of type-1 diabetes.  The standard theory holds that the immune system's mistaken attack on beta cells in the pancreas is the cause of type-1 diabetes [d1].   The Accelerator Hypothesis holds that both type-1 and type-2 diabetes are caused by the same three factors:
    1. Lower beta cell replacement rate (sometimes called "constitution")
    2. Modern environments which make higher demands on beta cells  (this might be more overweight people, an environmental toxin, etc.)  
    3. An immune system which aggressively attacks stressed beta cells.
    The important difference between these theories is that in the standard theory, the autoimmune attack is the cause of type-1 diabetes, while in the Accelerator Hypothesis, the immune system's attack on beta cells under stress accelerates the problem, but does not cause it.

    It also changes how we think about curing type-1 diabetes.  In the Accelerator Hypothesis, the immune system is triggered by stressed beta cells sending signals which the immune system responds to.  This response might be overly aggressive, but it is not fundamentally in error.  So changing the immune system is not going to cure type-1 diabetes (although it may change its progression somewhat).  This contrasts with the standard theory, where fixing the immune system will cure the disease.

    Factor 3 above (the immune system) results in the different symptoms between what we call type-1 and type-2 diabetes.  If the immune system is highly aggressive, there is a faster and younger onset of diabetes, which we call type-1.  If the immune system reaction is smaller or nonexistent, then onset is slower and older, which we call type-2.

    The Accelerator Hypothesis was first proposed about 15 years ago by Dr. Terence Wilkin, and it has evolved slightly over that time.  Some discussion of how the theory has changed is in [d2], and the original wording is in [d3].

    According to this theory, all three accelerators impact everyone with diabetes, although different people will have different "mixes" of the accelerators.


    You might think this theory is just word games: if the main accelerator is factor 2 (insulin resistance, over demand (often caused by overweight), or environmental factors, then that's just a different name for type-2 diabetes.  If the main accelerator is factor 3 (the immune response) then that's just a name for type-1.  And no one has ever measured beta cell replacement rate (factor 1), anyway.

    But it's not just name changes.  For one thing, the theory holds that slowing down any of the accelerators will slow down the diabetes, so if someone with a broken immune system was very thin, their diabetes would be delayed, and maybe even be more like type-2.

    A digression on weight: I know what you are thinking.  You are thinking "my kid wasn't overweight when first diagnosed with type-1 diabetes".  Some of you were thinking "I wasn't overweight when I was diagnosed with type-1 diabetes".  This theory doesn't mesh with my experience either and that does bother me, even if theories are not disproven by personal experiences.  Supporters point to (at least) five studies which show that people diagnosed with type-1 diabetes have higher BMIs (a measure of over weight) than others.  The [r7] paper has references to these studies [d4].  I'm not going to get into the non-scientific aspects of this theory [d5].

    Obviously, this theory is controversial [d6].  Diapedia (an on-line, curated diabetes encyclopedia) has a generally negative summary of this theory [r8] or you can read this negative editorial [r9].  You can compare those articles to the researcher's 2009 summary of supporting data [r7].  It's a classic scientific argument with both sides pointing at their data.

    But the bottom line is that it doesn't matter who thinks this theory is correct or who thinks it is wrong. What matters is that the researchers have gotten the money and regulatory approval to actually test it.  ("One experiment is worth a thousand expert opinions" -- Robert H. Mathies.)  Arguing about the theory is a waste of time right now.  They are testing it, and the only thing that makes sense is to wait for the results from the trial, and see what they show. 

    This theory is similar to the "Inflammation Theory" as a cause of type-1 diabetes [d7].

    Trial Structure

    This trial will start in early 2016, and is expected to publish final results in 2022.
    Children between 5 and 16 will be screened, and can enroll if they have two or more autoantibodies.
    They hope to enroll at least 90 people in the pilot phase, and more later.

    The contact listed in the clinical trials registry is Pauline Armory:
    And the trial manager is Ann Turner:
    The general contact email is: Info@adaptdiabetes.orgAnd much more information is available on their web site:
    The news coverage lists a large number of doctors working at many different clinics, so my guess is that if you are in Scotland or Northern England, you won't have to travel far to participate.

    (Note: my description of this clinical trial is based on information from the trial's web page [r1], two clinical trial records [r4,r5] and several news reports [r2], and these sources do not all agree with each other. I'm doing the best that I can, to combine these sources, but it is possible that some of the information here is out of date.)

    For those who are enrolled, during the first four months, blood glucose levels will be tested after a meal.  At this point, the researchers want to see that Metformin is successful in lowering those peak blood glucose levels.  This is their signal that Metformin is having the effect that they want to test.

    After this, people will be followed for five years, with regular autoantibody tests.  The researchers hope to see less autoantibody progression.  Also, they want to see slower progression.  Ideally, they would like to see both of these things.  Since more autoantibodies are seen in people actually diagnosed with type-1 diabetes, fewer/slower autoantibodies would be a clear signal that the treatment is working.

    Finally, these people will be followed to track how many are diagnosed with type-1 diabetes via the traditional symptoms (high BG, etc.)  The researchers hope that fewer treated patients will actually come down with type-1 diabetes as compared to the control group.

    This trial will take a long time:  recruiting the people + four months + five years.  The researchers are aiming to finish in 2022.  The autoantibody data will be available sooner (although I don't know if it will be published early).  Of course, the screening data (peak BG after a meal) will be available much earlier, but I'm not sure that will be published and even if it is, I don't think (by itself) it's critical to a cure.

    The trial is being funded by JDRF.

    Extra Discussion

    [d1]  This is called "autoimmunity" or "autoimmune attack" because the immune system is attacking the body's own cells, rather than foreign cells, as it should.

    [d2] If you compare the more recent wording of the hypothesis to the original wording, you can see the following differences:
    • Recently, factors 2 and 3 are emphasised more while factor 1 is downplayed.
    • Earlier, weight gain was described as the primary cause of factor 2.  Later, this was changed to insulin resistance, and even more recently to environmental factors in general.
    • Earlier descriptions of the hypothesis focused on both types of diabetes as being "the same" disease.  Later descriptions focus on both types of diabetes have shared causes, but does not describe them as being the same disease.
    The original 2001 definition is in the "extra discussion" section [d3] below.

    [d3] Quoted from [r8] but originally from [r6], this is the original 2001 hypothesis:
    The ‘Accelerator Hypothesis’ argues that Type 1 and Type 2 diabetes are one and the same, distinguished only by their rate of beta cell loss and the accelerators responsible. The first accelerator, a constitutionally (intrinsically) high rate of beta-cell apoptosis [cell death or cell "turnover"], is necessary for diabetes to develop but in itself rarely sufficient to cause it. Insulin resistance, the second accelerator, results from weight gain and physical inactivity which further increases the rate of beta-cell apoptosis and accounts for the rising incidence of Type 1 as well as Type 2 diabetes in industrially developed societies. Finally, a small and genetically defined subset of patients with both intrinsic lesion and insulin resistance develops beta-cell autoimmunity, the third accelerator.
    [d4] As you can imagine, measuring BMI at type-1 diabetes at diagnosis is not a simple thing. Because weight loss is a classic sign of type-1, these researchers actually compared BMI at some point after diagnosis to a control group, but that is not perfect, either.  They were weighing people during the earliest phase of the honeymoon, and I'm not sure that really represents weight just before onset.  (Plus, the whole idea of "onset" is being reevaluated based on the TrialNet data.)

    [d5] Many in the type-1 community have been complaining for years that media and many doctors do not differentiate between type-1 diabetes and type-2 diabetes, when they should.  This theory postulates that there is only one diabetes, and there really is no fundamental difference between type-1 and type-2.  Even worse, the type-1 community has argued for years that type-1 is not a "lifestyle disease" caused by being overweight, but this theory holds that it is (or at the very least, being overweight contributes to the disease).  So there are plenty of non-scientific reasons to hope this theory is wrong.

    [d6] Indeed, one editor who published an update to the theory revealed that two of his peer reviewers had rejected the paper. However, the the editor was publishing it anyway, because he felt minority viewpoints should be aired publicly.  He accompanied the article with an opinion piece by the editor himself stating that he personally thought the theory was wrong.

    [d7] The Inflammation Theory holds that beta cells become inflamed, and this inflammation triggers the autoimmune attack.  The Accelerator Hypothesis hold that beta cells are under metabolic stress which causes them to be attacked by the immune system (although this attack may be more or less aggressive).  I view "metabolic stress" and "inflammation" as related concepts, although not everyone does.

    The Inflammation Theory was quite popular several years ago, and motivated several clinical trials. However, as of now, I think that only one of those inflammation based prevention treatments is still being tested. That is AAT.  

    References and Sources

    [r1] Trial Website:
    [r2] News Article:
    [r3] Press Release:

    [r4] EU Clinical Trial Registry:
    EudraCT Number: 2015-000748-41  (this is a European clinical trial registry number)
    [r5] UK Clinical Trial Registry:
    The UK trial registry lists this trial ID as 20540, but the query above uses 34351, and I don't know which one is correct.

    [r6] Here is the original paper on the theory, from 2001:*~hmac=2a7ec6140ae9ef099ca55256b1e12795f78cb39c2aa342820a7705fb547a038d

    [r7] Much more detail on the Accelerator Hypothesis of type-1 diabetes in included the following 2009 review article, written by the same researcher who is running this trial:



    Joshua Levy
    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.