Tauroursodeoxycholic Acid (TUDCA) Starts a Phase-I Trial

Tauroursodeoxycholic Acid (also known as TUDCA or Taurolite) is a chemical found in bile (especially bear bile).  Mouse and rat studies have found that can preserve beta cells, and it is already approved for us in Europe for relatively rare liver diseases.  It is also widely available as a "dietary supplement" in the US.

This study will enroll 20 adult, honeymooning type-1 diabetics.  Half will get the drug, half a placebo.  Treatment will be TUDCA pills each day for a year.  C-peptide levels after a meal are the primary outcome, and will be measured for 18 months.  They will also check liver function, as a safety issue.  They hope to complete the study by December 2018.  This clinical trial is funded by JDRF. (Note that the study is officially phase-II, but I consider it phase-I because of it's size and first-in-type-1 nature.)

This study is recruiting at one site:
    Naomi Berrie Diabetes Center, Columbia University, 1150 St. Nicholas Ave.
    New York, New York, United States, 10032
    Contact: Ellen Greenberg, MA    212-851-5425    emg25@columbia.edu
    Contact: Robin Goland, MD    212-851-5492    rsg2@columbia.edu

Why Test TUDCA? TUDCA has been found to relieve stress in a particular part of the beta cell (called the ER).  The hope is, by lowering this stress, beta cells will not be killed, and either type-1 will not occur, or it will be less severe, or be delayed.  This is based on type-1 diabetes being caused by the following chain of events:

Autoimmune attack  –causes→ ER stress –causes→ Type-1 Diabetes

so if you can stop/lessen/delay the ER stress you can stop/lessen/delay type-1 diabetes.

3 Minute Video: https://vimeo.com/118597801
Information For Patients: http://www.nbdiabetes.org/news/unique-jdrf-funded-clinical-trial-tudca
Press Release and Video: http://jdrf.org/blog/2015/02/09/t1d-trial-looks-to-teach-an-old-drug-new-tricks/
Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02218619
Wikipedia entry: https://en.wikipedia.org/wiki/Tauroursodeoxycholic_acid
Earlier News Article: http://www.hsph.harvard.edu/news/press-releases/newly-discovered-mechanism-suggests-novel-approach-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.

Perle Biosciences Starts a Phase-II Trial Of A Combo Cure

This turned out to be a much longer blog posting than I expected.  Lots of interesting digressions and complexities.

Perle Biosciences is a startup aimed at curing type-1 diabetes.  This is their first trial of a combination therapy: one drug to stop the bad autoimmune attack (Cyclosporine) and another drug to regrow beta cells (Omeprazole).  Both are taken as pills and both are already FDA approved for other uses.  Omeprazole is an antacid more commonly known by the brand name "Prilosec" and is available "over the counter" in the US.  Cyclosporine is an immunosuppressive drug, available by prescription only, and has earned a "black box" warning.

Note: This is the first study that I have blogged on which is registered in the European trial registry, but not the US one.  In the past, even the European trials were registered in the US.  Initially, it looks like the EU registry has at least as much useful information as the American one, I'm happy about that.

A summary of the trial:

• The trial will recruit in Europe.  (Exact locations are still shifting: contact the company to find a site near you.)
• 81 patients between 10-20 years old will be enrolled.  All will be newly diagnosed.
• No control group, but 2/3s of the patients will get both drugs, and 1/3 will only get Omeprazole.
• Dosing for Omeprazole will be 30mg twice daily for children and double that for adults.
• Dosing for Cyclosporine will be 2.5mg/kg twice daily and then later adjusted. 
• Patients will be followed for six months.
• Primary end point will be insulin independence.
• Secondary end points will include A1c, BG highs and lows (via CGM), insulin usage, autoantibodies, and a collection of safety measures.

News: http://www.medscape.com/viewarticle/847379
http://www.news-medical.net/news/20150624/Perle-Bioscience-announces-enrollment-for-Phase-3-trial-of-combination-therapy-in-type-1-diabetics.aspx
Press Release: http://perlebioscience.com/wp-content/uploads/2014/09/Perle_IIT_Release_6.23.15.pdf
Trial Registry: https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-000105-39/ES
EudraCT Number: 2015-000105-39

The Cyclosporine Safety Issue

Cyclosporine's safety profile is a subject complex enough, and important enough, so that I will probably spend some time researching it specifically, and writing a blog focused solely on safety.  I hope to do that before this study reports results (which I would not expect for at least 18 months).

Cyclosporine has two "black box" warnings, which are the strongest warning the FDA puts on drugs.
This drug is approved to prevent organ rejection after transplantation and also to treat two autoimmune diseases: rheumatoid arthritis and psoriasis.  The dose being given in this trial is similar to the dose given for transplantation, which is about twice the dose given for the autoimmune diseases.  (Although doctors are free to change dosing in any case, based on their professional judgement.)  The big difference is that for transplantation, the drug is often given permanently, while in this trial, it will only be given for six months.

I did a very quick look at Cyclosporine long term safety studies.  Using Cyclosporine for two or more years does appear to be associated with increases in certain kinds of cancer, in some studies.  It's hard to make a clear determination for several reasons: there are not many long term studies on Cyclosporine safety, different diseases are treated with different doses, and many (all?) of the diseases that Cyclosporine is used for, also have bad health effects of their own, so separating out the bad effects of long term treatment and bad effects of the disease is hard to do.

This was the only study I found that looked at Cyclosporine in type-1 diabetics.  It found that using Cyclosporine for a year (on average) during the honeymoon was associated with worse kidney function years later.  This was a 40 person study, and I'm not sure how much worse the kidney function was, but it's definitely something to look into:
http://www.researchgate.net/publication/13193142_Cyclosporine_nephrotoxicity_in_type_1_diabetic_patients._A_7-year_follow-up_study._Diabetes_Care_22_478-483

Cyclosporine has several common names, in different countries. It is sold under several brand names, which have different formulations and are NOT interchangeable.  To add to the confusion, there are several drugs with similar names, some of which are quite toxic.  So if you want to do your own research, use Wikipedia to include synonyms and exclude similarly named drugs.  (I'm sure the PhDs will be horrified, but I've never had a problem getting basic drug facts from Wikipedia.) And tell me what you find!  Also remember that "high dose" (which I think generally refers to doses 7.5mg/kg/day and higher) shows more side effects than "low dose" (generally 5mg/kg/day or less).  This trial starts out at the "low dose" of exactly 5mg/kg/day.

Previous Research With These Drugs

Cyclosporine
This drug was tested as a honeymoon cure for type-1 diabetes in the 1980s and early 1990s.  I would summarize the results as this: Cyclosporine caused many patients to go into remission while it was given, but when stopped, type-1 diabetes returned.  Especially in the high dose trials, people did drop out specifically because of the side effects.

Here are abstracts for some of those studies:
* http://www.sciencemag.org/content/223/4643/1362
* http://link.springer.com/article/10.1007%2FBF00403182
* http://www.ncbi.nlm.nih.gov/pubmed/1611143
* http://www.ncbi.nlm.nih.gov/pubmed/9115576
* http://www.ncbi.nlm.nih.gov/pubmed/2210078
* http://www.ncbi.nlm.nih.gov/pubmed/1397785
* http://www.ncbi.nlm.nih.gov/pubmed/20440520 (for trial https://clinicaltrials.gov/ct2/show/NCT00905073).

Proton Pump Inhibitors
Omeprazole is a Proton Pump Inhibitor (which is a specific type of antacid), and this type of drug is known to improve A1c numbers in type-2 diabetics, but only slightly (for example 0.6, so from 7.7 to 7.1).  This might be because these drugs encourage the growth new Beta cells (which would be part of a cure for type-1 diabetes) or it might be because these drugs increase the production of existing Beta cells (which would not help, because type-1 diabetics have too few Beta cells to effect).

Type-2 research (there is a lot more):
* http://www.ncbi.nlm.nih.gov/pubmed/22886351

* http://www.ncbi.nlm.nih.gov/pubmed/22218624

Points of Discussion

Phase-II vs. Phase-III
Perle Bioscience's press release refers to this trial as a phase-III trial, but I make my own determination of phase.  In this case I'm treating it as a phase-II for these reasons:

1. 81 people is solidly in the phase-II size (around 100 people), and far short of the common phase-III size (around 300 people).
2. There is no control group, most phase-II and all phase-III trials that I'm familiar with, have a control group.   Only phase-I trials commonly don't have control groups.
3. This is the first trial anywhere by anyone on this combination of drugs.
4. The clinical trials registry for this trial lists it as a "Phase-IIb/III" trial, and I generally use the lower number phase, when two are given, because that is where they are starting.

I consider phase-III trials to be the pivotal trials that give the FDA enough information for approval, and I don't see that happening for this trial.  (Of course, since both of these drugs are already available for other uses, they could be used "off label" without any formal FDA approval.)

Primary End Point
The primary end point for this trial is "insulin independence, defined as use of exogenous insulin of [less than] 0.2 units/kg body weight/day and hemoglobin A1c [less than] 6.5%".  For comparison common doses for type-1 diabetics are between 0.5 and 1.0 units/kg/day.

Since I've been following type-1 diabetes research, I've never seen a trial which used insulin usage coupled with A1c numbers as a primary outcome; they usually use C-peptide.  I think insulin plus A1c is a harder to reach milestone, and makes it harder to see incremental progress.  C-peptide is particularly good at seeing a tiny step forward.  But I'm not sure that's been a good thing.  Several recent studies have shown a tiny step forward, but have not been extended to something a person would care about.  Obviously, not needing insulin is something every patient would care about, but is changing from 0.7 per day to 0.2 per day a successful outcome?  For an initial trial, a drop down to 1/3 or 1/4 the insulin you used to use would be a great result.

Taken together, I'm a little mystified by this choice of primary outcomes.  In some ways, I think they have selected a higher bar than other studies, and certainly a non-standard one.  But if they are successful against this higher bar, so much the better.

History
Perle Biosciences first filed paperwork related to a combination clinical trial in January 2013.  At that time they envisioned two large (200 person) trials, one for honeymooners and one for people with established type-1.  Each trial would include four treatment groups (both drugs, both placebos, one drug and placebo, and the other drug and placebo).  Also they were going to use Lansoprazole rather than Omeprazole.  They are similar drugs: both PPIs (proton pump inhibitors), and I don't know why they switched.

Finally, I started researching this blog before the European trial registry was completed.  Therefore I started out getting my information from emails with Perle Biosciences, their facebook page, and a press release.  I'd like to thank them for replying quickly to my emails.  The information here comes from all of these sources (trial registry, email, facebook, and press release).

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.

Research In The News (November)

MK-2640 ("Smart Insulin") Completes Enrollment Collection of a Phase-I Clinical Trial And Then Adds a New Part

MK-2640 is the Merck identifier for what we all know as Smart Insulin.  It is the only "self dosing" insulin currently in human trials.  The idea behind this drug is that you could inject it (maybe twice a day, maybe once a day, maybe once a week), and then it would release insulin if your BG numbers were high, and not if they were low.  It is sort of a chemical artificial pancreas.

Because there is no data from human testing (nor have I seen any animal data), there is no way for me to know if MK-2640 is going to turn into a "lantus killer" (i.e. a great basal insulin), or if it is going to turn into something much closer to an artificial pancreas.   For example, something you take once a week and not count carbs or otherwise worry about type-1 diabetes.

The First News 

On 29-June-2015 Merck updated the clinical trial record to show that they were no longer recruiting people for this trial.   Since this trial collects data for 37 days, that tells me that they finished in August. However, a different part of the record suggests they might have finished collecting data even earlier.  Yet another part of the record was updated to show an "Estimated Study Completion Date" of October 2015.  So that was all good news, and I was looking forward to them publishing results.

The Second News

Then (in September) they added a third part to what had previously been a two part clinical trial. Part three seems to be a continuation of part two (meaning they are testing in type-1 diabetics and are comparing MK-2640 to regular insulin.  They are now recruiting again (presumably for part three), and have pushed out the completion date to early 2016.  Part three will add 16 people to the test (from 58 to 74), but the testing looks pretty similar to part two.

A (Very Little) Discussion

Most of this clinical trial involves giving people MK-2640 (different groups of people getting three different doses), and then dripping sugar into them for 9 hours (7 hours in part three) and seeing what happens.  The sugar is an IV drip ("intravenous infusion"), not eaten in a meal.  In this case "what happens" means things like: side effects, BG levels, how quickly the body "clears" the drug out of the system, etc.

For me, the most important data will be how quickly MK-2640 lowers BG levels when sugar first starts hitting the bloodstream. If it lowers BG levels quickly, that means that it will work for meals (and is more of an AP replacement). However if it is slow to lower BG levels, that implies that it is more of a Basal insulin, and might replace Lantus/Levemir in the market, but not replace pumps/APs.

However, as I am an optimist, I will not forget that IV sugar is much faster acting than carbs eaten in a meal, so even if the results are so-so for IV sugar, I would expect better results from a real meal.  Of course, it could turn out exactly the opposite: the slower sugar absorption might result in slower MK-2640 reaction times.  I guess we'll have to wait for the first "real world food" tests.  I only hope it gets that far.

I interpret adding the new part three section to be all good news.  They added that after they had run the first two parts, and I don't think they would do more testing if the first parts did not look good.  (A pessimist might say that if part two was not good, they were hoping to save the trial with data from the new part.  However, I am an optimist so I think if part two was not good they would have just stopped, and since they pushed ahead, that is good news.)

Similarly, part two followed people for 9 hours, but part three only followed them for 7 hours.  Is that good news, because it means that Smart Insulin reacted quickly?  Or is it bad news because, Smart Insulin lost effectiveness after that?  There is no way to tell, until they publish.

Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02269735

MultiPepT1De (Multi Peptide Vaccine) Starts A Phase I Study

This is a follow on study to one of the very first clinical trials I ever followed:
http://cureresearch4type1diabetes.blogspot.com/search/label/Peakman
That older trial injected a peptide (part of an insulin molecule) in the hopes that the immune system would learn not to auto-attack.  This new study injects a mix of peptides to provide a broader education to the immune system.  The basic idea is like injecting peanut proteins to teach the immune system not to be allergic to peanuts.

The study will enroll 24 adults, within four years of diagnosis.  There is no information available on number of injections, duration of the study, primary or secondary end points.  They are recruiting in London, England.  Contact information is:  Ms Rhanya Chaabane, Tel: 02071888472 Ext: 81932,
rhanya.chaabane@gstt.nhs.uk.

Note: This trial is registered with the United Kingdom's clinical trial registry which contains a lot less information than the United States clinical trial registry.  It is also registered with the European Union clinical trial registry, but they don't publish records for phase-I trials at all.  Therefore, I have a lot less information about this trial than other trials, which is why they are not getting a blog posting of their own.

Trial web site: http://www.multipeptide.co.uk/
Magazine article: http://www.multipeptide.co.uk/pdf/jdrf_article_on_multipeptide.pdf
Clinicial Trial Record: http://public.ukcrn.org.uk/Search/StudyDetail.aspx?StudyID=19114


Stop Following Gevokizumab (Xoma 052)

I've decided to stop following the drug Gevokizumab (which started it's research life as Xoma 052). You can see my previous coverage here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Xoma%20052

The last news I had related to this drug in type-1 diabetes was that it started a Phase-II clinical trial in 2009.  The clinical trial record was updated to "Completed" in 2014, but there is no listing for published results.  I have searched for any results, but can find none, so I'm going to assume that the phase-II trial was a failure.  (It was run by a commercial company, so there is no reason for them to publish the results, if the trial failed.)

Since that time, Xoma, the company developing Gevokizumab, has published clinical trial results for both type-2 diabetes and Behçet's disease uveitis (both failed their primary end point).

Based on all this, I'm going to remove Gevokizumab (Xoma 052) from the list of possible cures of type-1 diabetes that I follow.

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.

JDRF Funding for a Cure 2015

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

Let me give you the punch line up front: 69% of the treatments currently in human trials have been funded by JDRF. (And the number is 77% 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 and helps to fund ITN and several other organizations, so I include research done by these other groups as well, as being indirectly JDRF funded.

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 third 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 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 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 
• Gleevec by Gitelman at UCSF 
• Oral Insulin (Preventative) 
• Rituximab by Pescovitz at Indiana University 
• Stem Cell Educator by Zhao (Established) 
• Teplizumab (AbATE study team) 
• Teplizumab by Herold/Skyler/Rafkin (Preventative)
• 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 
• Atorvastatin (Lipitor) by Willi at Children's Hospital of Philadelphia 
• BCG by Faustman at MGH (Established) 
• Brod at University of Texas-Health Science Center 
• Vitamin D by Stephens at Nationwide Children's Hospital (Prevention)

Cures in Phase-I Human Trials
Summary: there are 20 trials in phase-I, and 12 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) 
• IBC-VS01 by Orban at Joslin Diabetes Center 
• Leptin by Garg at University of Texas 
• Nasal insulin by Harrison at Melbourne Health (Prevention)
• Smart Insulin (MK-2640) by Merck (Established) 
• 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) 
• Etanercept (ENBREL) by Quattrin at University at Buffalo School of Medicine
• 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 
• The Sydney Project, Encapsulated Stem Cells (Established) 

Summary of all Trials
42 in total
29 funded by JDRF
So 69% of the human trials currently underway are funded (either directly or indirectly) by JDRF. Everyone who donates to JDRF should be proud of this huge impact; and everyone who works for JDRF or volunteers for it, should be doubly proud.

Just Looking at Trials on Established Type-1 Diabetics
13 of these treatments (31%) are being tested on established type-1 diabetics.
Of these, 8 are funded by JDRF
So 62% of the trials recruiting established type-1 diabetics are funded by JDRF.

Compared to Last Year
In 2014 there were 40 treatments in clinical trials, in 2015 there are 42 (growth of 5%)
In 2014 there were no treatments in Phase-III trials, in 2015 there are none (no change).
In 2014 there were 21 treatments in Phase-II trials, in 2015 there are 22 (growth of 5%).
In 2014 there were 19 treatments in Phase-I trials, in 2015 there are 20 (growth of 5%).

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.

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

• http://cureresearch4type1diabetes.blogspot.com/2014/09/jdrf-funding-for-cure-2014.html
• http://cureresearch4type1diabetes.blogspot.com/2013/10/jdrf-funding-for-cure-2013.html
• http://cureresearch4type1diabetes.blogspot.com/2012/09/jdrf-funding-for-cure-2012.html
• http://cureresearch4type1diabetes.blogspot.com/2011/10/jdrf-funding-research-for-cure-2011.html
• http://cureresearch4type1diabetes.blogspot.com/2010/09/jdrf-funding-research-for-cure-2010.html
• http://cureresearch4type1diabetes.blogspot.com/2009/09/jdrf-funding-research-for-cure.html
• http://cureresearch4type1diabetes.blogspot.com/2008/10/jdrf-funding-of-cure-research-phases-ii.html

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.

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.

Seasonal Flu Vaccine and Type-1 Diabetes

Every now and then I get asked about any safety issues for a flu vaccination for someone who has type-1 diabetes.  So I researched that question, and below is my summary of research to date.  Note that this summary focuses on flu vaccines only;  I have separate summaries for childhood vaccinations and also for HPV vaccinations.

I looked for all clinical trials where they gave flu vaccine to type-1 diabetics, specifically.  I did not think there would be any such studies, because recruiting from such a limited population would be tough.  But I was wrong.  There were several, but I only had time to look at the first 8 (listed below); some studies covered more than one area:

• Two studies focused on safety, and these found no added risk to type-1 diabetics.
• Four studies focused on effectiveness, and three of these found no differences in effectiveness between type-1 diabetics and the general population.  One study found that flu vaccines were less effective for type-1 diabetics as compared to the general population.
• Three studies focus on flu vaccines affecting the immune system in a way which would contribute to type-1 diabetes, and these found that it did not.

Rather than summarize each study, I'm letting each study "speak for itself" by quoting the abstract from each one.  You can click on the abstract to see the exact study design: most were intervention studies with control groups; one was a population registry study.

http://www.ncbi.nlm.nih.gov/pubmed/21916971

One injection of 2009 pandemic influenza A(H1N1) MF59-adjuvanted vaccine is immunogenic and safe in young patients with Type 1 diabetes who are at increased risk of influenza morbidities. Pandemic vaccine can be safely co-administered with seasonal influenza vaccine.

http://www.ncbi.nlm.nih.gov/pubmed/19607951

The results indicate that in older children and young adults with type I diabetes influenza vaccination with a virosomal or a standard subunit vaccine is safe and adequately immunogenic against the three influenza vaccine strains. In addition, the virosomal vaccine may show better long-lasting immune response than the standard subunit vaccine, especially in subjects without pre-existing antibodies to influenza strains.

http://www.ncbi.nlm.nih.gov/pubmed/2074915

From these results it is concluded that IAA [an autoantibody linked to type-1 diabetes] formation is not a direct sequela of viral infection or vaccination.

http://www.ncbi.nlm.nih.gov/pubmed/19459478

Use of Pneumo 23 vaccine or its combination with Grippol vaccine in patients with DM1 did not result in increase of levels of autoantibodies to n-DNA, d-DNA and pancreatic tissue, was not able to initiate or lead to disease progression as well as positively influenced on the immune response with tendency to normalization of the several arms of the immune system and, at the same time, did not result in activation of autoimmune process.

http://www.ncbi.nlm.nih.gov/pubmed/2789342

No significant difference was found between diabetic patients and control subjects with respect to antibody response after vaccination. 

http://www.ncbi.nlm.nih.gov/pubmed/9607024

The influenza-specific antibody response in both serum and oral fluid were similar for both groups, and also showing a kinetic profile in accordance with our earlier data for healthy adults. Our study did not detect a difference in the humoral immune response between juvenile diabetics and healthy controls.

http://www.ncbi.nlm.nih.gov/pubmed/21994316

Risks for Guillain-Barré syndrome, multiple sclerosis, type 1 diabetes, and rheumatoid arthritis remained unchanged.

http://www.ncbi.nlm.nih.gov/pubmed/3678660

In Type 1 (insulin-dependent) diabetic patients the incidence of non-responders to two vaccine components was significantly increased

Summary
Taken together, these studies show that flu vaccines are safe for type-1 diabetics, do not worsen the immunology behind type-1 diabetes, and are effective for type-1 diabetics. One one study found that flu vaccines were less effective for type-1 diabetics than for the general population, but less effective does not mean "not effective"!

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.

Summary of EASD 2015

EASD is the European Association for the Study of Diabetes.  Their conference is the largest diabetes research gathering in Europe.  I did not attend, but reviewed all the abstracts, posters, and 100s of tweets sent with the EASD2015 hashtag.  This posting is my summary.

Unfortunately, as with ADA 2015 earlier this year, there was not much research aimed at a cure which had reached human trials.  I've divided this posting into four areas: news on human trials aimed at a cure, artificial pancreas research, high buzz research, and other research I found interesting.  But there was only one abstract dealing with a cure in human trials.  Disappointing.

Research In Human Trials Aimed At A Cure

Proinsulin peptide immunotherapy in type 1 diabetes: safety data of a first in new-onset type 1 diabetes phase 1b trial || Abstract #503
http://www.easdvirtualmeeting.org/resources/proinsulin-peptide-immunotherapy-in-type-1-diabetes-safety-data-of-a-first-in-new-onset-type-1-diabetes-phase-1b-trial--2
These researchers are testing a type-1 diabetes vaccine made from part of an insulin molecule.  They are testing it for safety in newly diagnosed type-1 diabetics.
The poster is not on line, but you can see the abstract.  It appears that the study was strictly safety-only, and there were no safety issues, but no data on effectiveness, either.

Artificial Pancreas Research

There was a lot of AP research.

This was a presentation by the Cambridge group:
http://www.easdvirtualmeeting.org/resources/twelve-week-unsupervised-day-and-night-closed-loop-insulin-delivery-during-free-daily-living-in-adults-with-type-1-diabetes-a-multicentre-randomised-cross-over-study--3
33 adults used an AP for 12 weeks "free range".  Trial was open label, cross-over design.  (Meaning that all patients were both treatment group and control group at different times.)  AP did not handle meals.  AP did better than non-AP in terms of average BG, and no worse for lows.  AP also did better on A1c.  This research was published in the New England Journal of Medicine:
http://www.nejm.org/doi/full/10.1056/NEJMoa1509351
and is also discussed here:
http://www.clinicalendocrinologynews.com/specialty-focus/diabetes/single-article-page/artificial-beta-cell-insulin-systems-post-more-positive-data/8e1e8f69192b2d3f1dc40f418cffb9a6.html
and here:
http://www.medpagetoday.com/MeetingCoverage/EASD/53621

This was a presentation by groups in France and Italy using the University of Virgina AP:
http://www.easdvirtualmeeting.org/resources/hba1c-improvement-with-less-hypoglycaemia-in-patients-with-type-1-diabetes-wearing-an-artificial-pancreas-for-two-months-from-dinner-to-breakfast
35 adults used an AP overnight for two months. Trial was cross-over design.  AP did better than non-AP in terms of time in target, with less time in both high and low BG.
One patient dropped out of this study because he was not able to trust the device enough to participate in the study.  This patient was a professor of mathematics.  (This got a laugh during the presentation.)
These researchers are now testing 24 hour use of the device.

This presentation was by Steven Russell on the Bionic AP (same project as Dr. Damiano works on):
http://www.easdvirtualmeeting.org/resources/the-bionic-pancreas-when-will-the-dream-come-true
This presentation included previous data from adults and camp kids, but also new (to me) data from younger children (6-11 years old).  This was also at camp, and was 5 days on, 5 days off (cross-over design).  The BG improvements seen in these younger kids was better than seen in adults or in camp kids.  In my opinion, the improvements seen in these kids were striking.

He then presented data from a "free range" trial of 40 adults for 11 days on, and 11 days off (cross-over) study.  This data was also very good.  The whole presentation was well done, and well worth viewing, but if you just want some quick data: fast forward to slide 25 (usual care) and then compare it to 26 (AP); this is for one selected patient, but you can see the huge improvement.

He then presented data from a comparison of glucagon vs. no glucagon study.

Finally he presented their target (hoped for) timeline:

• Transitional Studies: 2013 - 2016
• Production of a fully integrated device (prototype already made via private donations).
• Bridging Studies: starting in 2016
• Pivotal Studies: 2017 - 2018
• Review by FDA: 2018
• Commercial availability: late 2018 or early 2019

Dr. Russell said that the FDA had indicated that this device and long term glucagon use, could be approved based on a single pivotal trial of 450 patients for 6 months, with a 6 month extension for 100 of the patients.  (And this length and size is due to the needs of the glucagon approval.)

Also, Tidepool is collaborating with this research team in creating the user interface for their AP.

High Buzz Research

The research which generated the most buzz, by far, was the results of the EMPA-REG study.
However, this was a huge study of a SGLT2 drug in type-2 diabetes, so I won't comment.

There were also a lot of "Insulin vs. Insulin" and "New Insulin" papers and posters.  These are studies which show that one type of insulin is better than another, or that a new type of insulin is safe and effective.  I didn't count, but suspect there were over 20 of them, but this kind of research does not excite me.  There was some early work on a weekly shot basal insulin, and that is interesting to me. The research was on people, too.  But it is still years off, I think.

Glucagon nasal powder: an effective alternative to intramuscular glucagon in youth with type 1 diabetes (Abstract #42) generated some buzz:
http://www.easdvirtualmeeting.org/resources/glucagon-nasal-powder-an-effective-alternative-to-intramuscular-glucagon-in-youth-with-type-1-diabetes--2
You can watch the 15 minute presentation or read the abstract, at this web page.
Slide #5 shows clearly that glucagon nasal powder is similar to glucagon injection.
This tweet contains a one chart summary: https://twitter.com/jgryan0/status/643779712385478656
Patients in this study were between 4 and 17 years old; a previous study had focused on adults.
The nasal formulation was much easier to use, and (of course) no needle was needed.  Also the same nasal dose can be used for youth of all ages, so no more "half shots" for younger/smaller kids.
One patient sneezed immediately after getting the nasal glucagon, and this patient's BG levels did not rise, but the researcher wasn't worried because glucagon is usually given to unconscious people, who don't sneeze.  The company involved (Locemia Solutions) is "in discussions with regulatory agencies".

There was a phone app (I think called "gocarb") where you took a picture of a plate of food, and it estimated carbs.  Here are some of the tweets for that:
https://twitter.com/sugartweaks/status/643400361588465664?ref_src=twsrc%5Etfw
I'm a little dubious about this whole idea, but it did generate a lot of positive tweets.

Dexcom's G5 will soon be available in Europe:
https://twitter.com/danielvegh/status/643770125095706624

The Google/Dexcom tiny BG sensor also generated some buzz:
https://twitter.com/diaTribeNews/status/643339894522142720?utm_source=fb&utm_medium=fb&utm_campaign=sciencehorse&utm_content=643759843656884224


Other Research I Found Interesting

The talk by Andrew Hattersly:
http://www.easdvirtualmeeting.org/resources/insights-into-the-beta-cell-from-patients-with-monogenic-diabetes
This is a one hour talk given by Dr. Hattersly, who basically discovered monogenic diabetes (often called MODY).  I really enjoyed it, even if I did not understand all of the science.  The talk is good because it shows how different scientific work comes together to make important discoveries, and how science is a team effort, and patients are involved.  Monogenic diabetes  is caused by a single genetic mutation.  There are several different types of monogenic diabetes , each involves the mutation of a different single gene.  This is quite different than classic type-1 diabetes, where there are many genetic features, some of which make type-1 more likely, some less likely, plus environment triggers, all of which come together to cause type-1 diabetes.  Monogenetic is binary: you have the gene, you get the disease.

The key points from this talk are two fold:

1. Anyone diagnosed with type-1 diabetes when they are under six months of age, actually has neonatal diabetes (one form of monogenic diabetes ).  Neonatal diabetes can be treated with insulin, but can also be treated with a much cheaper pill (no shots!)  If you, or someone  you know, was diagnosed when less than six months old, and uses insulin, you (or they) may want to talk to your doctor about trying to switch to the pill.  More information: http://www.diabetesgenes.org/content/neonatal-diabetes
2. Dr. Hattersly estimates that between 1% and 3% of the people diagnosed with type-1 diabetes actually have some form of monogenitic diabetes. Except for neonatals, these people generally must be treated with insulin, just like type-1s, but it's still valuable knowledge.  He has an experimental web page to calculate a person's chance of having monogenic type-1 diabetes: http://www.diabetesgenes.org/content/mody-probability-calculator

Autoimmune diseases in children and adults with type 1 diabetes from the type 1 diabetes exchange clinic registry || Abstract #499
http://www.easdvirtualmeeting.org/resources/autoimmune-diseases-in-children-and-adults-with-type-1-diabetes-from-the-type-1-diabetes-exchange-clinic-registry--2
This link has an abstract, the poster, and a 5 minute discussion by the author.
The Type 1 Diabetes Exchange is a huge project, funded by the Helmsly trust, to gather all kinds of data on over 25k people who have type-1 diabetes.    Some findings:
The #1 additional autoimmune disease found in type-1s is thyroid disease at 19%.
Celiac's is #2 at 6%.


Sustained glycemic control and less nocturnal hypoglycemia with new insulin glargine 300 U/ml versus glargine 100 U/ml over 1 year in Japanese people with type 1 diabetes mellitus (EDITION JP 1) || Abstract #4http://www.easdvirtualmeeting.org/resources/sustained-glycaemic-control-and-less-nocturnal-hypoglycaemia-with-new-insulin-glargine-300-u-ml-versus-glargine-100-u-ml-over-1-year-in-japanese-people-with-type-1-diabetes-mellitus-edition-jp-1--2
ADA 2015 had at least one paper (which I found interesting) suggesting that higher density insulins were better for type-2 diabetics.  Some extremely obese type-1 diabetics need to refill their pump every day with standard u100 insulin, but only every other day with u300 insulin.  This is a money and convenience issue.  But additionally, there was evidence that higher density insulins were more effective; that fewer units were needed for the same carb or basal situations.  This study found that type-1s used more insulin, but had lower nocturnal numbers and at the same time, fewer lows.  That's still a good outcome.

I found the comparison to u100 to higher density insulins interesting, especially if we get sets that can last longer than 3 days, the pressure for high density will become stronger.

Joshua Levy
http://cureresearch4type1diabetes.blogspot.com public
joshualevy 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.

AAT Completes a Phase-I Trial (No Strong Results)

AAT is an anti-inflammatory / immunomodulatory drug, which the body makes naturally, and which is already FDA approved for people who have a rare condition where they don't make enough of it on their own. Using AAT to treat type-1 diabetes is based on the idea that one of AAT's effects (lowering inflammation, immune modulation, or wound healing) can cure/prevent/treat the disease.

Kamada (makers of one form of AAT) recently published the results of a Phase-I trial in honeymoon type-1 diabetics.  There are several AAT clinical trials going on, and I've reported on different results before:
http://cureresearch4type1diabetes.blogspot.com/search/label/AAT

AAT Completes a Phase-I Trial (But No Strong Results)

This study was open label, with no control group.  A total of 24 people were divided into three groups and each group got a different dose [d1].  Primary end points were safety related, but effectiveness was measured in secondary end points.  The study lasted 37 weeks.  The patients got a total of 18 doses of AAT, spread out over the first 28 weeks of the trial.

The results were:

• No serious adverse events occurred, and non-serious adverse events were not dose dependant.
• Average hemoglobin A1c decreased from 8.4% to 7.1% [my rounding]. 
• C-peptide levels dropped during the study, but the researchers felt that they dropped less than seen in untreated people from other studies.  At the end of the study, 18 subjects (75%) had a peak C-peptide ≥0.2 pmol/mL. 
• At the end of the study 1/3 of the subjects met the definition of "possible responder" meaning their C-peptide numbers had gone down 7.5% or less.

Opinions of Results

First, no serious adverse events is a good safety result, and having non-serious adverse events be non-dose dependent is also a good safety result.  If there were safety issues, they would likely get stronger as the dose gets higher, since that did not happen, it is likely that these adverse events were not related to the treatment.   So it looks like it passed the safety part of the trial.

Because this study was done on youth between 10 and 18 years old, showing a good safety profile is particularly important.  It is likely to open up future trials to youth.  Recruiting youth speeds the clinical trial process (especially in the honeymoon phase) because type-1 is so often first diagnosed in children.  The safety profile might also lower barriers to "off label" use of this drug [d2]. 

Now an optimist would say "phase-I tests safety and safety is OK, so trial is a success". However, they did measure effectiveness also, and so I do think it is important to look at the effectiveness numbers that we have.  I have noticed that if the phase-I is not effective, it makes it less likely that the phase-II will be.  So with that in mind:

The most important thing to remember is that this study did not have a control group, and that makes interpreting the results difficult.  The A1c group, the C-peptide group, and the "responder" group all have the same fundamental difficulty: we know what happened to the treated people, but there is no untreated group to directly compare them to.  Therefore the researchers compare these people with untreated people from other studies; and I'm doing the same.   

I think that the drop in A1c levels was meaningless.  This was a honeymoon trial; people were recruited within 6 months of diagnosis.  That first A1c number covers either the early months of type-1 diabetes self treatment or the weeks just before diagnosis (or some of each).  These are both times of high A1c numbers.  Conversely, the second A1c number covers a time when the patient has between 6 and 12 months of experience with type-1, and is therefore better at treating their type-1. So of course the A1c numbers are better.

The researchers compare these A1c numbers to average A1c numbers in adults, and note that the first is above average while the second is below.  However, for the reasons described above, I don't think this is a case where comparing to average is an appropriate thing to do.  

For the C-peptide data, I think the data is hard to interpret, but disappointing.  The researchers summarized their findings this way:

subjects treated with AAT showed less of a decline in C-peptide levels as compared with historical controls.  However, in the absence of a randomized control group, these findings should not be interpreted as showing a beneficial effect on beta cell preservation
and glycemic control.

For me "less of a decline" is the very smallest sign of success a researcher can talk about.  I'd put these results below results from TOL-3021 and Alefacept  (both which held C-peptides constant), and maybe even Teplizumab (which held C-peptides constant in some people).

Each person has to decide for themselves which results excite them, and which don't.  For my part, in honeymoon trials, results where the C-peptide numbers go up (after a year) excite me.  Results where they stay constant are unexciting.  And, results where they go down are disappointing.  Here the average went down.

People in this study will be offered a chance to participate in a long term (3 year) follow up study. Those who still generate C-peptides [d3] will be kept on their current dose of AAT.  Those who don't (or who don't want to continue, will not get AAT, but will be followed as a comparison group.

Overall Status of AAT As A Cure For Type-1

AAT is unusual, in that there are two different types of information on it.  There are results of previous clinical trials.  But there are also anecdotal reports from the popular press.  The anecdotal reports are far more positive.   Unfortunately, these phase-I reports are clearly in line with the previous clinical trial results.  They are lackluster and will not lead to a cure without a large improvement in effectiveness.

The good news is that there are two phase-II clinical trials of AAT already underway, so there is nothing to do but wait.  Especially since one of those phase-II trials is being done by the same company as did this trial: they have incorporated what was learned from the older trial into the design of the newer trial.  If there are good results from the phase-II trials, then AAT is in good shape.   Mediocre results in phase-I mean nothing if the phase-II results are good.  If those results are as good as the anecdotal results, then AAT is in great shape.  But if those phase-II results are similar to these phase-I results, then that would be bad news for AAT.

Opinionated Discussion of Footnote 30

Because this study did not have a control group of it's own, the researchers used control group data from other studies.  In particular, some control group data from the phase-II trial of DiaPep 277, and this reference was provided in footnote 30.   In my opinion, using this data raises a red flag.  One of DiaPep's phase-III trials was canceled because of serious scientific misconduct [d4].  The article reporting the results of the other phase-III trial was retracted because the same misconduct was found in that study as well. To my knowledge, no misconduct has been found in the phase-II trial, but none was particularly looked for, either.  And there are authors in common between the retracted phase-III paper, and the cited phase-II paper [d5]. Finally, the manipulation that was done in the phase-III paper changed both the treated group and the control group [d6].  So if that same manipulation was done to the phase-II trial, (that is a big "if" of course) then it would effect the exact data that these AAT researchers are using.

For all these reasons, I think using data from the DiaPep 277 phase-II study is a mistake.  The AAT researchers were using control group data.  Lots of studies have control groups.  Why use potentially tainted data, when untainted data is available?

Thanks

I want to specifically thank the author of this paper who sent me a copy of the full paper, so I could comment on all of the paper, and not just the abstract.

More Discussion

[d1] The researchers listed this trial as "Phase-I/II".  Generally I consider phase-I to be less than 20 people, and phase-II to be larger than that, but I also expect a Phase-II to have a control group, which this did not.  So based on the whole trial, I consider this a phase-I trial.

[d2] In the USA once a drug or device is approved, a doctor can prescribe it in situations different than it was originally approved for.  As an example, a doctor may prescribe it for a different disease, at a different dose, or for a different type of person than it has been approved for.  In the world of type-1 treatments, drugs or devices that have been approved for use on adults are often prescribed for children.  This is a classic "off label" use.  Off label use is based on the professional opinion of a doctor, and consent of the patient.  Therefore safety data (such as from this study) can make doctors more willing to prescribe "off label", and patients more interested in trying it.

[d3] Specifically, patients who have C-peptide levels of ≥ 0.2nmol/L will be able to continue their AAT regimen.  Note also that I refer to the other group as a "comparison" group and not a "control" group.  These two groups start off different, so I don't consider one to be a good control for the other.

[d4] Hyperion used the term "serious misconduct" in describing the situation, and Globe News used the term "fraud".

[d5] I want to stress that there were authors who only worked on the phase-II paper, and there were authors who only worked on the phase-III paper.  And, there were authors who worked on both papers.  To my knowledge, there has never been a public naming of who was involved in the misconduct, so there is no way to know if one of the authors was involved or if it was someone else in the organization, or even how many people were involved.

[d6] A more complete discussion of the misconduct alleged in this case is in my previous blog posting:
http://cureresearch4type1diabetes.blogspot.com/2014/09/diapep277-development-canceled-due-to.html

References

Abstract: http://onlinelibrary.wiley.com/doi/10.1111/pedi.12283/abstract
Press Release: http://www.businesswire.com/news/home/20150706005216/en/Kamada-Announces-Publication-Pediatric-Diabetes#.VcY2xPlVhBc
Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT01304537
Poster: http://www.kamada.com/files/files/Prduct%20Development/Diabetes_print%20Jan13.pdf
Follow On Study Clinical Trial Record https://clinicaltrials.gov/ct2/show/NCT01661192

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.

Background Information: "Adverse Events" In Clinical Trials

This blog posting applies to all clinical trials, not just those for type-1 diabetes.

I try to avoid using technical jargon when I describe clinical trials.  I think one of the values of this blog is that I turn technical jargon in to plain English.  (I sometimes joke about providing "researcher to patient simultaneous translation", but it's not really a joke.  It's important.)  However, one technical term that I do use is "adverse event".  "Adverse event" generally means "bad side effect".  Serious adverse event generally means "really bad side effect".  But the truth is more complex than this simplified version, and so I thought I would make a post describing exactly what "adverse event" and "serious adverse event" means, because these terms are defined by the US FDA, and their meaning is the same no matter which clinical trial I'm discussing.

The Basics

The basic definition of "adverse event" and "serious adverse event" comes from the US FDA:
http://www.fda.gov/Safety/MedWatch/HowToReport/ucm053087.htm
for lots more details:
http://www.fda.gov/downloads/Drugs/Guidances/ucm073087.pdf

• An "adverse event" is any bad effect seen in the study.  The FDA uses the term "undesirable experience".  It does not have to be caused by the treatment!
• A "serious adverse event" is an adverse event that causes death, hospitalization, persistent or significant disability, or a birth defect.  Or one which requires immediate medical attention to prevent one of these outcomes.

For example, a mild allergic reaction would usually be considered an "adverse event", but if the patient had trouble breathing, that would be a "serious adverse event".

The First Complexity: How Bad Is Serious?

No matter how many rules the FDA makes, and how many documents it publishes, there will always be room for researchers to interpret a specific events as serious or not.  Therefore, there will always be controversies about it.

For example, in one Chronic Fatigue Study there was controversy because several adverse events required patients to go to a clinic (but not a hospital).  Now hospitalization clearly means serious, but the company producing the drug felt that going to a clinic was not a sign of a serious adverse event. When the FDA reviewed the study, they disagreed, and the the larger number of serious adverse events the FDA counted were part of the reason the drug was not approved.

The Second Complexity: Treatment Related Or Not?

In general, researchers are required to track all adverse events, no matter what their cause. The FDA terminology is "associated with" not "caused by". After all, these are experimental treatments and some of the bad side effects might be unexpected. I've seen a trial for an immune system drug, which listed one serious adverse event: a broken arm. Now, I don't think that broken arm had anything to do with the immune treatment being tested.  But it is still a serious adverse event, and must be reported.
A more complex situation is adverse events associated with the disease being treated.  For example, if you are testing a drug for depression, and someone in the study commits suicide, that is clearly a serious adverse event, but is it treatment related?  How would anyone ever know?

This whole area is usually resolved by comparing adverse event rates between the control group and the treated group.  If there are statistically significantly more adverse events in the treated group as compared to the control group, that is the important result.  Arguing that some of these adverse events are not "treatment related" much less important. More adverse events is bad, no matter if the researchers think they are not related to treatment.  But what about those phase-I trials that don't have control groups?  For those trials, arguing about "treatment related" can be important.

The Third Complexity:  Who Decides?

Someone goes through every event and decides if it is serious or not.  The same is true for "treatment related" if that is reported separately. Obviously, this is a human activity and the results will be imperfect, but the exact procedure used can minimize (or maximize) risk of bias.  The two things to look for are blinding and reviewers.

The review can be done "blind" or not "blind".   The reviewer looks at the event, and maybe some data about the person who had the event, but does not know if the person is in the control group or the treated group (or what dose the person got, if multiple doses were tested).  But if the reviewer knows that the event occurred in the control group or the treated group, the risk of bias is more pronounced.  If the study doesn't have a control group, then this review will never be blind.

The reviewing is usually done by the same researchers running the trial. However, it can be done by a different group of doctors, recruited especially for that purpose.  Having a different group lowers the risk of bias, and this is done for some particularly controversial or emotional trials.

Some Discussion and Opinions

Overall, I think we are lucky in the world of type-1 diabetes research, in that the reporting of adverse events is generally not complex or controversial.  Type-1 diabetics are generally pretty healthy, and also the bad complications of type-1 diabetes are generally well understood.  Therefore, there is consensus as to the types of adverse events that are likely related to treatment, and those that are not.

Especially in larger clinical trials, serious adverse events will happen.  So the important thing to look at is: Were there more serious adverse events in the treated group than in the control group?  Also, if multiple different doses were given to different groups of people, do the higher dosed groups see more serious adverse events, or are they randomly spread throughout all the dosing groups?

Since all adverse events must be reported, it is important to consider the impact of different adverse events as compared to the disease being treated.  For example, rashes or mild fevers are common adverse events (not serious ones). Compared to curing type-1 diabetes, these might be well worth it.  On the other hand, in a drug which merely treats type-1, the very same adverse event might cause you to use a different drug.

Because the long term outcomes of type-1 diabetes is relatively well known, it's easy for patients to "trade off" the adverse events seen in testing a cure, to the long term complications of having type-1 diabetes.

One problem in the whole approval process is the issue of very rare side effects, especially those which happen rarely in healthy, untreated people. Take the following situation, you treat 300 basically healthy, basically young, people with a drug. One of them has a stroke. That's a serious side effect. But it is something that happens -- although very rarely -- in young people who are not taking the drug. With 300 people you may not have the statistical power to know if it is a statistically significant event. Are you going to delay availability and require a larger (and very expensive) study just to eliminate the statistical chance that the drug causes stroke? Or maybe approve the drug, but require a strong (ie. "black box") warning about stroke? Or just decide that it was random bad luck, and approve the drug?
(The situation is much worse with diseases like type-2 diabetes.  Was that stroke caused by type-2 diabetes, or the drug given to treat the type-2 diabetes?)

In a sense, the FDA cannot win in these cases, because no matter which outcome they choose, some people will want the other one.  So if the drug is delayed, some patients (and the company involved) will scream loudly about delaying needed treatments and creating unnecessary hurdles to drug approval.  On the other hand, if the drug is approved, another group of patients (and consumer advocates) will yell about approving dangerous drugs so big pharma can profit.  If the drug is given to 10,000 and one of them has a stroke (by chance? or because of the drug?) then recriminations will be deafening.


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.

Research In The News (August)

This blog posting contains bits and pieces of news on type-1 diabetes research aimed at a cure.

The Phase-II Trial of Secukinumab Was Terminated

The phase-II clinical trial of Secukinumab was canceled in June 2014. I have not seen any public notification about why it was canceled. Apparently five people were dosed before it stopped, but I have no idea if any results will be published or not.  This trial was being run by Novartis.

You can read my previous blogging on this trial here:
http://cureresearch4type1diabetes.blogspot.com/2014/05/secukinumab-and-ustekinumab-each-start.html

Reporting: http://webcache.googleusercontent.com/search?q=cache:-Iu_s9VcSmwJ:adisinsight.springer.com/drugs/800023920+&cd=1&hl=en&ct=clnk&gl=us
Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02044848


Phase-II Trial of BCG By Faustman Starts Recruiting

I made a big announcement when Dr. Faustman announced she was ready to start her phase-II trial. However it took over a year to actually start recruiting patients.  The blog I wrote previously is still accurate (except as described below), so If you want to know what is going on with BCG, I'd start out by reading my previous blog:
http://cureresearch4type1diabetes.blogspot.com/2014/04/dr-faustman-starts-phase-ii-trial-for.html
and then consider the following updates in the last year:

First the good news: it will include 150 patients, rather than 120 as before.

Second, the bad news: the delay means the study will complete in 2023 rather than 2022 as before (which means publication in 2024 is a reasonable goal).

Third, a change in primary outcome.  The study as I read it now, is going to have A1c measurement as it's primary end point, and C-peptide measurement as a secondary end point.  Previously, I had thought that both would be primary end points, but I might have just misread the clinical trial registration.

However, no matter which is primary and which is secondary, the important end point is the C-peptide numbers, not the A1c numbers.  For cure research, C-peptide is a much better measure of success than A1c.  C-peptide is what the FDA requires for cures, and that is what measures how much insulin your body is creating itself. A1c, on the other hand, is a good measure for type-1 treatments.  So in this case, in 2024, when we are looking at the results, it will be the C-peptide results that matter.

I don't see that there are any other major changes from a year ago: no change to dosing regimen and no change to duration.

Press Release: http://www.eurekalert.org/pub_releases/2015-06/mgh-mgh060315.phpClinical Trials Record: http://clinicaltrials.gov/ct2/show/NCT02081326

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.

Artificial Pancreas Updates From ADA (July 2015)

In my opinion, artificial pancreas (AP) technology was the single most important technology of the American Diabetes Association Scientific Sessions this year.  There were many papers, posters, and presentations on artificial pancreases and related technologies (such as continuous glucose monitoring, stable glucagon, etc.)  Nothing generated more Twitter buzz.

This blog posting attempts to summarize a little of the research presented.  There was way too much for me to cover it all, and so this posting gives light coverage to the most important news.

My overall summary is that we are no longer talking about if there will be an AP.  The question is: when there will be an AP, and how many APs, and how many different types of technology they will use.  I continue to be heartened by:
(a) the progress made by AP research projects over the last few months (and years)
(b) the large number of new companies entering the field
(c) the product roadmap announced by Medtronic as they move their existing partial AP to a full AP.

The AP world is more and more driven by commercial considerations, rather than research considerations, and that is a strong signal that we are close to general availability.  (Close meaning years, but not too many of them.)

This tweet summarizes my thoughts, as well:

“Closing the loop is no longer a mystery; it’s not a puzzle. We just have to do it.” 

https://twitter.com/eliotmbrenner/status/607536971192377344

Second Bi-Hormonal Artificial Pancreas In Development

I recently found out about a second bihormonal AP  (in addition to Dr.  Ed Damiano's).  These researchers are in The Netherlands, and you can read more about it here:

http://www.inredadiabetic.nl/diabetes-product-ontwikkeling/
http://www.inredadiabetic.nl/us/history/
http://www.inredadiabetic.nl/news/

It's a little hard for me to figure out exactly where they are, and I have not found any articles in scientific journals.  However, it appears that earlier this year they ran a two day test on one person, and got quite good results.  The average BG was 125.  Based on that they are hoping to run two clinical trials (called APPEL 4 and APPEL 5) later this year.  They hope those trials will used as the basis for European "CE" approval.

Maybe a Third?

They haven't started recruiting yet, but this looks like a phase-II trial for yet a third bi-hormonal artificial pancreas.  I'll blog more fully if they start recruiting:

https://clinicaltrials.gov/ct2/show/NCT02379299

Back To Ed Damiano's Bi-Hormonal Artificial Pancreas

Not from ADA, but from another conference, comes this summary of Ed Damino's current status:
http://www.medpagetoday.com/MeetingCoverage/AACE/51551?xid=nl_mpt_DHE_2015-05-16&eun=g118127d0r

But if you want a summary in 140 characters, here it is, from
https://twitter.com/DiabetesMine/status/607298177952321537:
Damiano says #BionicPancreas showing ave BGs of 135-142, which would equate to 6.5% A1C.
[What's not to like!]

Plus there was this good news tweet:
From https://twitter.com/InsulinNation/status/607300794875002882:
Ed Damiano says there is room temperature stable glucagon that stays good for up to a year. Needs FDA approval.

Medtronic's 670G

The Medtronic 670G, as announced, will be an "all but meals" style, single hormone artificial pancreas, available in the United States in April 2017.  As far as I know it is the most powerful AP with a clear commercial delivery date.  For comparison, the 640G is already available in Europe, but does not prevent "highs," only "lows".

diaTribe interviewed a patient who has used the 670G as part of a clinical trial:
http://diatribe.org/medtronic-minimed-670g-hybrid-closed-loop-exclusive-interview-17-year-old-trial-participant

This is Medtronic's press release summary of results from a 640G study, a 670G study, and some other research they presented at ADA:
http://finance.yahoo.com/news/medtronic-accelerates-path-artificial-pancreas-140201655.html
The current plan is for the 640G to be available next year, and the 670G the year after.

This news resulted in the following tweets (and many more, of course):
https://twitter.com/DiabetesMine/status/607197166193508353
https://twitter.com/DiabetesMine/status/607198339600392192

More General AP News

The following, more cautionary tweets report on other aspects of AP research:

From https://twitter.com/InsulinNation/status/607284169622880256:
During artificial pancreas study, the AP couldn't be used 1 in 3 nights because of tech issues (sensors) or family/health issues.[But I don't know which AP this tweet is about!]

From https://twitter.com/DiabetesMine/status/607284048931770368:
CDE Laurel Messer: Still enough tech issues exist with CGM sensors to impact hoe [sic, should be "how"] closed loop is used in kids and young adults.
From https://twitter.com/InsulinNation/status/607278840193400832:
Predictive pump technology significantly reduced nighttime lows in kids in almost 1000 night study. [But again: I don't know what AP this refers to!]

The following link goes to a summary of one of the ADA sessions:
http://www.saluteh24.com/il_weblog_di_antonio/2015/06/artificial-pancreas-moving-toward-pediatric-use-2015ada-meeting-in-boston.html

Personal testimonial (with graph) of how well an AP works, but I don't know which one!  Anyone recognize the screen?
https://twitter.com/DiabeticSisters/status/607709090278699008

Bigfoot Explodes Big  (In a Good Way!)

Bigfoot is a one year old company.   They had a very successful ADA and generated a lot of "buzz", which this tweet tries to summarize.
From https://twitter.com/diaTribeNews/status/604309757093011456:
@BigfootBiomed acquires Asante pumps! Goal to enter pivotal trial of full #artificialpancreas system late 2016

A "pivotal" trial is industry-speak for a phase-III clinical trial.  What they are saying is that they hope to start phase-III trials of an AP next year.  That would put them shoulder to shoulder with Medtronic and front running bihormonal research projects.  Even if they are overly optimistic, and they actually start those tests in 2017, they are still not that far away from a commercial AP.

But even more promising (to me) is that Bigfoot feels like a tech start up, not a medical device company. It feels like Silicon Valley rather than Washington D.C.  I can't tell if that's a marketing strategy or the truth, but if you look at the founders, look at the tactics (reuse the failed carcass of another project), and the strategy: it really does look like the way things happen "out here".

When a company like that can successfully create an AP, it means that APs are technology gizmos, and not medical devices, and technology products can improve much more quickly than medical products.  I'm sure the FDA will have something to say about it, but even if Bigfoot is just a 20% step in the direction of Silicon Valley, that's going to "light a fire underneath" some medical device companies.

The following link goes to one diaTribe story, but that story has links to other stories, and you can get the whole saga of how big they've grown, how quickly, and how important that might be:
http://diatribe.org/bigfoot-biomedical-acquires-asante-snap-pump-technology

TypeZero: Yet Another New Company Focused On A Single Hormone AP 

And if that were not enough, TypeZero Technologies is yet another new company trying to create a single hormone AP "from scratch".  DiabetesMine has a summary article:
http://www.healthline.com/diabetesmine/typezero-tech-closed-loop-commercialization

This is based on AP research done at the University of Virginia which I have reported on before.

Comparison

There was some debate at ADA about which was better: single hormone artificial pancreases, or bihormonal artificial pancreases.  My first reaction to this debate was this: who cares?  Either one is so much better than what we have now, let the people who like insulin only APs develop those, and let the people who like insulin and glucagon APs develop those, and let the market decide, or maybe let the market decide that there is room for more than one AP technology.  I mean some people have cable while others have satellite, why not the same with APs?  Have we learned nothing from the death of communism?  Let the market decide, as fed by the strongest proponents of each system.

My second reaction to this debate was that it can never be resolved by research. The data we have now is pretty clear: single hormone APs result in average BG numbers about 10 points higher than dual hormone APs  (for example mid 130s vs mid 140s).  However, dual hormone APs are more complex to manufacture, more complex to operate, and involve the tiny risk of long term, very low dose glucagon (and that risk is unknown, and will remain unknown for years).  So some people are going to say dual hormone is 10 points better than single hormone, end of story.  But others will say, mucking about with refilling two reservoirs is just not worth 10 points.  And neither of these opinions is right or wrong, they are just different.  And always will be.

However, even if research cannot answer a question, it can still inform the discussion, and there have been some papers directly comparing the two systems. The following tweet is one summary, but the links to the abstracts below contain more data.

From https://twitter.com/sarhoward/status/608301471529107457:
Haidar: Both single and dual hormone artificial pancreases better than pump for BG control at night, dual better for reducing hypos

http://www.thelancet.com/journals/landia/article/PIIS2213-8587(15)00141-2/abstract
http://www.thelancet.com/journals/landia/article/PIIS2213-8587(14)70226-8/abstract


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.