Friday, October 6, 2017

JDRF Funding for a Cure 2017

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: 63% of the treatments currently in human trials have been funded by JDRF. (And the number is 81% 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.
    (Presymptomatics) One more more trials are open to people who have 2 or more autoantibodies, but have not yet started showing symptoms of type-1 diabetes.
    (Prevention) This treatment is aimed at preventing type-1 diabetes, not curing it.

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 also 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.

Starting Last Year: Phase-II? Trials
Starting last year, I divided 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 is only one treatment in a phase-III clinical trial, and that is aimed at prevention.  It is funded by JDRF.  While I see the benefit of prevention, this is the sixth year in a row there have been no phase-III trials aimed at curing existing type-1 diabetes, 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.
  • Oral Insulin (Preventative) 
Cures in Phase-II Human Trials
Summary: there are 22 trials in phase-II, and 17 of them have been funded by JDRF, while 5 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)
  • 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 
  • Stem Cells of Arabia (Established)
  • Vitamin D by Stephens at Nationwide Children's Hospital (Prevention)
Cures in Phase-II? Human Trials
Summary: there are 8 trials in phase-II, and 2 of them has been funded by JDRF, while 7 have not. Here are the treatments that have been funded by JDRF:
  • Rituximab by Pescovitz at Indiana University
  • Intranasal Insulin by Harrison at Melbourne Health (Prevention)
Not funded by JDRF:
  • Albiglutide by GlaxoSmithKline
  • Golimumab by Janssen
  • Ladarixin by  Emanuele Bosi of Dompé Farmaceutici
  • Liraglutid (Presymptomatics)
  • NNC0114-0006 and Liraglutide by Novo-Norsk
  • Rapamycin Vildagliptin Combo by IRCCS (Established)
Cures in Phase-I Human Trials
Summary: there are 24 trials in phase-I, and 15 of them are funded by JDRF, while 9 are not. Here is the list funded by JDRF:
  • Alefacept by TrialNet 
  • ßAir by Beta-O2's at Uppsala University Hospital in Sweden (Established) 
  • TOL-3021 by Bayhill Therapeutics (Established) 
  • CGSF by Haller at University of Florida 
  • 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  
  • 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) 
  • Gluten Free Diet by Carlsson at Lund University
  • 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
    55 in total
    35 funded by JDRF
    So 63% 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
    17 of these treatments (31%) are being tested on established type-1 diabetics.
    Of these, 8 are funded by JDRF
    So 47% of the trials recruiting established type-1 diabetics are funded by JDRF.

    Compared to Last Year
    In 2016 there were 42 treatments in clinical trials, in 2017 there are 55 (growth of 31%)
    In 2016 there were no treatments in Phase-III trials, in 2017 there is one.
    In 2016 there were 22 treatments in Phase-II and Phase-II? trials, in 2017 there are 30 (growth of 36%).
    In 2016 there were 20 treatments in Phase-I trials, in 2017 there are 24 (growth of 20%).

    A Little Discussion

    Although the growth of 31% looks really good, I'm a little worried that that high growth number is because of a mistake on my part.  In previous years, I would review the research and remove everything that had failed or was going nowhere for too long.  However, this year, I was hit by some extra work at my real job, and so did not have time to check the older research to see if it was still active.  My guess is that some of the research still listed here really should be removed, and I'll do that over the next few months.  Still, I do think there was growth this year, just not 31% growth.

    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:
    • Oral Insulin: This trial was a phase-III trial, meaning that it was large and designed to provide enough information so that if, if successful, the treatment could be widely used. However, as it turned out, only part was successful, and that part was phase-II sized, so I don't think we will see widespread use based on this trial alone. You can think of this as a phase-III trial with phase-II results.
    • Serova's Cell Pouch and DRI's BioHub: These two clinical trials are both testing one piece of infrastructure which might be used later in a cure. They are testing a part of a potential cure. However, in both cases, the clinical trials being run now require immunosuppression for the rest of the patient's life, so I'm not counting them as testing a cure.
    • Substance P at Hospital for Sick Children Toronto: This trial is avoiding the honeymoon period by testing for insulin production.  Patients must inject more than 1/2 unit/kg to be accepted, therefore they will accept recently diagnosed people, if they are injecting enough insulin to be passed the honeymoon.  I'm counting this as "Established".
    This is an update and extension to blog postings that I've made for the previous seven years:
    Finally, please remember that my blog (and therefore this posting) covers research aimed at curing or preventing type-1 diabetes that is currently being tested in humans. There is a lot more research going on, not covered here.

    Please think of this posting as being my personal "thank you" note to all the JDRF staff, volunteers, and everyone who donates money to research a cure for type-1 diabetes:
    Thank You!
    Finally, if you see any mistakes or oversights in this posting, please tell me! There is a lot of information packed into this small posting, and I've made mistakes in the past.  As in previous years, I'll be at the Santa Clara (California) JDRF One Walk.  Come by and say "hi", or strike up a conversation about research.  I love to talk about research!

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

    Sunday, October 1, 2017

    Important Update For Stem Cells Arabia


    If you are interested in potential cures for type-1 diabetes, then I urge you to read this report from the JDCA about Stem Cells Arabia:
    http://thejdca.org/pc-2017-stem-cells-arabia
    (Note that as a Fellow of the JDCA, I did contribute to their report.)

    Stem Cells Arabia is in the middle of a clinical trial were they combine two stem cell procedures as a possible cure for type-1 diabetes.  However, the real excitement is fueled by the results of a very small pilot study they did previously.  The results from the pilot study were presented at a conference, but not published in a journal.  But those results are very strong: all four treated patients went months without needing to inject insulin and never needed anti-rejection drugs.  If you find that exciting (and I certainly do), then you'll want to read the JDCA report which contains more details, and you'll be looking forward to the results of their larger trial, which is expected to complete in early 2019.


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

    Monday, September 18, 2017

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


    Catching Up With NNC0114­-0006 (Anti IL-21)

    Back in 2015 Novo-Norsk started a clinical trial into a combo treatment of NNC0114-0006 and Liraglutide (which is more commonly known as Victoza).  I ignored this trial, because I thought that NNC0114-0006 was a new form of insulin, and they were testing a treatment for type-1 diabetes. However, I have since found out that NNC0114-0006 targets IL-21 and that Liraglutide may stimulate beta cell growth.  Therefore, this combination could have the effect of stopping the autoimmune attack while at the same time regrowing beta cells, and that would be a path to a cure.

    Liraglutide is approved for use in type-2 diabetes and works by increasing insulin production. Recently, experiments in mice have suggested that it works (at least partly) by helping the body grow more beta cells, and preventing the death of beta cells:
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4418765/

    NNC0114-0006 is an anti IL-21 treatment.  IL-21 is a chemical that the immune system uses for communication, and several experiments have suggested that too much IL-21 is important to creating type-1 diabetes:
    https://www.ncbi.nlm.nih.gov/pubmed/18779574
    https://www.ncbi.nlm.nih.gov/pubmed/19208913
    https://link.springer.com/article/10.1007/s00125-015-3509-8
    (and there are many more such studies.)

    So combining these two treatments provides a possible path to a cure.

    The Current Study

    The study that started in 2015 is a phase-II? trial (the question mark means that it is a phase-II trial, but there has never been a phase-I trial for this combination of treatments).  The basic study design is four groups: one group gets both treatments, one group gets two placebos, one group gets NNC0114-0006 and placebo, and one group gets Liraglutide and a placebo.  So they have all their bases covered. The study is large: 304 people recruited from 100+ sites all over the US and Europe.

    The clinical trial record says that this study is recruiting patients.  However, when I look at the list of locations, every one is marked "Active, not recruiting", "Completed", or "Suspended", so I'm very hopeful that they have recruited all the patients that they need.  That is important, because they expect to collect data for 80 weeks.  Their target completion date is April 2019.

    This is actually the fifth study of NNC0114­-0006.  You can see the list here:
    https://www.clinicaltrials.gov/ct2/results?cond=&term=NNC0114%C2%AD-0006
    The four previous studies were smaller (between 10 and 65 people), and were done on other autoimmune diseases: Rheumatoid Arthritis, Crohn's Disease, and Systemic Lupus Erythematosus.

    Clinical Trial Registry: https://www.clinicaltrials.gov/ct2/show/NCT02443155
    Other Study ID Numbers: NN9828-4150
    2014-001215-39 ( EudraCT Number )
    U1111-1154-7172 ( Other Identifier: WHO )
    REec-2015-1768 ( Registry Identifier: Spanish registry )

    Metreleptin Fails A Phase-I Trial

    Back in the 2008-2010 timeframe there was some hope that Leptin would cure type-1 diabetes, and a clinical trial was started in 2010.  Then in 2015 the trial was canceled by one of the sponsors.  Finally, now in 2017 the results have been published, and the conclusions are:
    Metreleptin is safe but may not be efficacious in improving glycemic control in patients with T1DM, although it reduces body weight and daily insulin dose modestly.
    You can read my previous blogging here:
    http://cureresearch4type1diabetes.blogspot.com/search/label/Leptin
    The abstract is here: http://care.diabetesjournals.org/content/40/5/694?etoc
    Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT01268644

    Interesting Treatment for Multiple Sclerosis

    I usually do not blog on cures or treatments for other diseases.  However, MS, type-1 diabetes and several other diseases are all from the same family of "autoimmune diseases".  They are all caused by the body's immune system attacking a different organ or internal system.  So in theory, research into curing one of these diseases might help cure the others.

    So with that in mind, I thought this study was interesting:
    Multiple Sclerosis Therapy NKTR-358 Begins Phase 1 Clinical Trial:

    Basically, this company has a treatment which causes a person to generate more Treg cells.  Since Treg cells regulate the immune system, having more of them might prevent the immune system from attacking the wrong cells.  In type-1 diabetes, we have several research programs aimed at increasing Treg counts, but usually by growing more Tregs outside the body, and then infusing them into the body (T-Rex, Stem Cell Educator, and Stem Cells of Arabia are all working on similar ideas). NKTR-358 is a treatment which (they hope) will cause the body to generate more Treg cells, itself.

    Also, NKTR-358 works at least partially, by targeting the IL-2 receptor in the immune system, and this receptor is also an active target of research in type-1:
    http://cureresearch4type1diabetes.blogspot.com/2016/05/general-update-on-il-2-research.html
    (and the IL-2 targeted by NKTR-358 is different than the IL-21 targeted by NNC0114-0006 above.)

    Company Information: http://www.nektar.com/pipeline/rd-pipeline/nktr-358
    Some animal data: http://www.nektar.com/application/files/6514/9970/7031/Langowski_NKTR-358_WCI2017.pdf

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

    Monday, September 4, 2017

    ViaCyte Clinical Trial News: VC-01 is Fully Enrolled, VC-02 Starts

    This blog posting covers two important pieces of news from ViaCyte.

    ViaCyte's Phase-II Trial of VC-01 is Not Recruiting
    (But What does that mean?)


    I missed this news, when it was announced back in May 2017, but ViaCyte's Phase-II clinical trial of VC-01 is not recruiting more people.  I'm not sure if this is a "pause" between their phase-I group and their phase-II group, or if they have finished recruiting all people for both groups.  That's important because they are gathering effectiveness data for six months.  So whatever group they finished recruiting in May, they should have effectiveness data in November.  Effectiveness data for 15 people would be good, but from the full 65 people would be even better.  Since this trial is not blinded (and has no control group), they could publish their data as soon as they have it, if they want to.

    Also, they are gathering safety data for two years, so that same group will finish gathering safety data in May 2019.  The same "15 people is good 65 people is better" and "with no control group, they can publish if they wish" applies to this safety data as well.

    Clinical Trial Registery: https://clinicaltrials.gov/ct2/show/NCT02239354

    Differences Between ViaCyte's VC-01 and VC-02 Treatments

    ViaCyte has started a clinical trial for their VC-02 stem cell implantation product, but as this treatment is not a cure (by my definition of "cure"), I will not be following it.  Don't mix up VC-02 with their earlier VC-01 product.  VC-01 is a potential cure, and I will follow it moving forward.

    I found this confusing: why would a company test a non-cure after they had a cure already in the pipeline, and ahead of the non-cure?  Why even bother with the non-cure?

    While VC-01 and VC-02 are encapsulated stem cells, the nature of the encapsulation is completely different.  VC-01 uses a "strong" encapsulation which prevents the body's immune system from attacking the new cells. This prevents both the normal rejection (ie. the foreign organ reaction), and type-1 rejection (ie. the malfunctioning autoantibody reaction) from attacking the new cells.  Therefore, VC-01 does not require anti-rejection drugs.  VC-02 uses a "weak" encapsulation which holds the stem cells together and in one place, and encourages new blood vessels to integrate into the encapsulation, but provides no immune protection.  People getting VC-02 will need to take anti-rejection drugs [d1].

    Both VC-01 and VC-02 have the same cells inside.  They both start with ViaCyte's PEC-01 cells. These are created by harvesting human embryonic stem cells from a long-existing culture and treating them so they differentiate into pancreatic cells.  The cells that are inside the devices are these pancreatic cells.   (There are no "raw" stem cells in the device.)  This process is described on ViaCyte's web site here:
    http://viacyte.com/technology/stem-cell-engineering/

    The obvious question is, why would any person with type-1 diabetes choose to be in the VC-02 trial, if they could be in the VC-01 trial?  The immunosuppression required by VC-02 has known bad side effects, and there are known risks in taking those drugs for decades.

    First is that the VC-01 trial is not recruiting right now.  So if you want an encapsulated ViaCyte stem cell treatment right now, VC-02 is your only option.  I don't know if the VC-01 trial is completely enrolled, or if it will open up again, to gather a second group of patients.

    Second is this: The ViaCyte team believes that the reason some implanted beta cells work and some fail is "vascularization".  Vascularization is the body's ability to grow blood vessels into the new beta cells so that they can get oxygen, remove waste products, and generally integrate with the host person.   ViaCyte believes that the encapsulation used in VC-01 will allow this vascularization and therefore be successful.   However, they also believe that VC-02 will have even better vascularization, and therefore an even higher chance of success.  So if someone currently has type-1 diabetes, they may choose to have VC-02 because it has a higher chance of success (even if this is a trade off against a known higher risk from the treatment).

    The VC-02 Study

    Although there is only one official clinical trial of VC-02, there are two patient groups within this trial (which they call "cohorts"), and these cohorts are really separate phase-I and phase-II trials. It's just that one clinical trial registry covers both. The first cohort will be 15 patients, all of whom will get a low dose version of the treatment. The second cohort will be 40 patients, all of whom will get a higher dose version of the treatment. There is no control group. They expect to finish the second cohort in Dec 2020.

    They are collecting their primary safety data at 4 months post transplant, and primary effectiveness data (C-peptide data) at 6 months post transplant.

    They are recruiting at two sites:

    • University of California San Diego, San Diego, California, United States, 92121
      Contact: Study Coordinator    1-844-317-STEM (7836)    alphastemcellclinic@ucsd.edu
    • University of Minnesota Recruiting, Minneapolis, Minnesota, United States, 55455
      Contact: Study Coordinator    612-626-4993    kreel001@umn.edu

    Clinical Trial Registry: https://clinicaltrials.gov/ct2/show/NCT03163511
    ViaCyte's FAQs: http://viacyte.com/clinical/faqs/

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

    Monday, August 14, 2017

    Possible Cures In The News (August)


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

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

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

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

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

    T-Rex Study Is Half Enrolled

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

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

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

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

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

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

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

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

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

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

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

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

    Diamyd Unsuccessful in Phase-II Clinical Trial on Presymptomatics 

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

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

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

    Discussion

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

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

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

    Friday, July 14, 2017

    Update On Dr. Faustman's BCG Research

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

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

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

    What is the New News?

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

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

    How Important Is This?

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

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

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

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

    Some Discussion on The Results From the Phase-I Trial

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

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

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

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

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

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


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

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


    A Quick Introduction to Oral Insulin to Prevent T1D

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

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

    The Phase-III Study (Structure and Results)

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

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

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

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

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

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

    Discussion Of This Study

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

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

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

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

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

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

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


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

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

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

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

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

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

    Joshua Levy
    http://cureresearch4type1diabetes.blogspot.com
    publicjoshualevy at gmail dot com

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

    Wednesday, July 5, 2017

    Presymptomatics and Two Clinical Trials for Victoza / Liraglutide

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

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

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

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

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

    Discussion

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

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

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

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

    Victoza / Liraglutide Starts A Phase-I Trial In Presymptomatics

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

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

    Discussion

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

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

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

    Victoza / Liraglutide Starts A Phase-I Trial In Presymptomatics

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

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


    Discussion

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

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

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

    Friday, May 19, 2017

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


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

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

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

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

    Discussion

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

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

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

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

    Minimal Islet Transplant at Diabetes Onset (MITO)

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

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

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

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

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

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

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

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

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

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

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

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

    Thursday, May 11, 2017

    Update on the University of Jordan's Stem Cell Project

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

    What Is Being Tested?

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

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

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

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

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

       University of Jordan Starts a Phase 1 Trial of Stem Cells

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

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

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

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

    Discussion

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

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

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

    Friday, April 28, 2017

    Vaccination and Type-1 Diabetes (part 2)

     Results from the Studies and References (continued)

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

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

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

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

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

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

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

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

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

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

    Always Looking For More Studies

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

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