Wednesday, June 22, 2016

Summary of ADA 2016

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

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

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

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

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

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

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


Reports From Clinical Trials Aimed At Curing Type-1 Diabetes 

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

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


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

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

5-IT-SY03 - What Is the Future of Immunotherapy for Type 1 Diabetes?
This session contained about 5 talks which focused on using immunology to cure type-1 diabetes. Unfortunately, there were no abstracts for the talks, and no information about them at all.  So my only knowledge is a few tweets and web articles.
  1. Here is the official ADA preview of the session:
    http://www.diabetesdispatchextra.org/new-trials-testing-immunotherapy-for-type-1-diabetes/
  2. There was general optimism about IL-2 (which I just recently blogged about).
    https://twitter.com/em_saidwhat/status/742120883129593857
  3. There was pessimism about antigen-based therapies (ie. blocking the immune system's reaction to a specific target):  "Antigen-based new onset and Immunomodulatory onset studies have really not showed any positive substantial results.  --Jay Skyler MD"
    https://twitter.com/Diabetesdad/status/742109575868882944
Safety and Tolerability Results from a Phase-I study of Phizer's PF-06342674
PF-06342674 is a antibody that blocks a part of the immune system (IL-7 binding). This trial is testing physical properties of the treatment (how much ends up in the body, how quickly the body sheds it, any adverse effects, etc.) This is called "safety and tolerability". This trial is not in any way testing that PF-06342674 will treat or cure type-1 diabetes, but based on what is learned here, future studies could test this as either a treatment or a cure.

Optimistic Overview of Transplanting Pig Islet Cells Into People
http://www.ajmc.com/conferences/ada2016/islet-cell-transplantation-addressing-the-underlying-defect-in-type-1-diabetes
My comments: LCT is the company farthest along in transplanting pig islet cells.  They have done several phase-I and phase-II clinical trials, but the results have not led to a cure as yet.  As for islets from stem cells, Viacyte has started a phase-I trial.  Neither LCT nor Viacyte announced new data at ADA 2016 (that I know of).

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

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

Transplants  (But Still Need Lifetime Immunospressive Drugs)
http://www.abstractsonline.com/pp8/#!/4008/presentation/44271
My comments: one patient, but successful.

Tidepool
873-P / 873 - Pilot Study of Tidepool’s Blip Application for Data Visualization in Type 1 Diabetes (T1D)
http://www.abstractsonline.com/pp8/#!/4008/presentation/39609

AP Papers, Posters, Tweets, etc.

What do people think an AP is?  (It turns out to be totally different than what I think it is.)
http://www.abstractsonline.com/pp8/#!/4008/presentation/39746

More commerical AP links:



DiabetesMine @DiabetesMine
In designing AP pivotal trials, discussion is to make them 6-12 months to pursuade payers. Beyond FDA's 3-month requirement. #2016ADA
https://twitter.com/DiabetesMine/status/742167089453006848
My comment on this last tweet: The FDA has made it clear that they will approve APs based on 3 month clinical trials.  (I think this even covers bihormonal APs, which would include approving a lifetime of Glucagon micro doses with only 3 months of testing.)  However insurance companies may not pay for APs based on 3 months of data.  They might argue for more data to show it really is better.  Therefore there is pressure to run longer phase-III trials, so that one trial can lead to both FDA approval and insurance company payment.  But that would delay initial FDA approval while the longer trials completed.  There was a similar issue in CGMs.  They were approved by the FDA, but some insurance companies would not reimburse until the JDRF funded a longer study that showed benefits that the insurance companies could accept.


More "we are not waiting" (Homebrew AP) links:
While using #OpenAPS: self-reported outcome measures showed median HbA1c dropped from 7.1% (SD 0.8%) to 6.2% (SD 0.5%). #2016ADAWhile using #OpenAPS: self-reported outcome measures showed median HbA1c dropped from 7.1% (SD 0.8%) to 6.2% (SD 0.5%). #2016ADA
https://twitter.com/danamlewis/status/741671445911248896
#OpenAPS self-reported outcome measures showed median percent time in range (80-180 mg/dL) increased 58% (SD 14%) to 81% (SD 8%). #2016ADA
https://openaps.org/2016/06/11/real-world-use-of-open-source-artificial-pancreas-systems-poster-presented-at-american-diabetes-association-scientific-sessions/
Of note: user growth of #OpenAPS is doubling every 3 months, even though users must self-build these AP systems. #2016ADA
https://twitter.com/danamlewis/status/741671296245862401
My comment: that is a growth curve that any high-tech start up would be proud of.

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

Easing the Child to Young Adult Transition
Two good tweets from Dan Browne:
Monaghan: for young adults, shared responsibility w/ parents for t1d care correlates with worse hbA1C. #2016ADA @collegediabetes
https://twitter.com/nakedsucrose/status/742719716632862721
#2016ADA Monaghan: protective factors for YA A1C: pers. responsibility, contact w providers, fear of hyperglyc. #2016ADA @collegediabetes
https://twitter.com/nakedsucrose/status/742719143649017856
My comment: what this seems to say is that giving young adults personal responsibility for their BG is a better strategy than shared responsibility.  I don't think that is conventional wisdom, however.  I do think this talk will be available on line in the future, and will be worth viewing when it is.

Systematic Population Screening, Using Biomarkers and Genetic Testing, Identifies 2.5% of the U.K. Pediatric Diabetes Population With Monogenic Diabetes.
http://www.ncbi.nlm.nih.gov/pubmed/27271189
via Eleen Ullman's tweet:
https://twitter.com/CureT1Diabetes/status/741676639096963073

CGMs Beat Diabetic Alert Dogs 
Basically, CGMs detected lows earlier than dogs, and dogs often alerted when there was not a low situation.  You can read more in this news article:
http://www.healio.com/endocrinology/diabetes/news/online/%7B7577bf07-3df7-4937-82fd-7bf741697f60%7D/service-dogs-can-detect-hypoglycemia-alert-companion
http://www.medpagetoday.com/clinical-context/Diabetes/58474
And three tweets on that talk:
https://twitter.com/dcarbohydrated/status/741645653969928192
https://twitter.com/KellyRawlings/status/741644965407789056
https://twitter.com/sstrumello/status/741649562847305728

Causes of Death for People With Type-1
http://www.abstractsonline.com/pp8/#!/4008/presentation/40218
1473-P / 1473 - Causes of Death in the First 100 Type 1 Diabetes (T1D) Donors in the Network for Pancreatic Organ Donors with Diabetes (nPOD)
My comment: the link above goes to an abstract.  It is tough to read but important.  Deaths directly caused by type-1 were very common.  So was suicide and drug use.  This is very cautionary data which should not be ignored.

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


Dosing For Protein
Pratik Choudhary tweeted:
#2016ADA - preliminary results show 60 gms protein require 25% more insulin - practically - % increase of bolus with increased fat or prot
https://twitter.com/drpratikc/status/741760675622621184

Nasal Glucagon
https://twitter.com/SEDiabetes/status/742732325914562561

Type-1 Diabetes and Autism
http://www.abstractsonline.com/pp8/#!/4008/presentation/40873
http://www.abstractsonline.com/pp8/#!/4008/presentation/40901

Type-1 Diabetes and Sleep Apnea
http://www.abstractsonline.com/pp8/#!/4008/presentation/39594

Metformin (there was far more than this)
https://twitter.com/Doctor_Deena/status/741377801996009472
http://www.abstractsonline.com/pp8/#!/4008/presentation/39832

Type-2 
Shaming Is Common:
https://twitter.com/janespeight/status/742360128716984320
LEADER data:
https://twitter.com/kellyclose/status/742476794352144384
http://www.nejm.org/doi/full/10.1056/NEJMoa1603827#.V18nymZf1mY.twitter
My comments: If you have type-2, you may want to discuss this with your doctor.  (And even if you don't, your doctor may want to discuss it with you. :-)
EMPA-REG data:
https://twitter.com/RpratleyMD/status/742711726978699266
Position paper on terminology for "Diabetes"
https://static.diabetesaustralia.com.au/s/fileassets/diabetes-australia/9864613f-6bc0-4773-9337-751e953777cd.pdf
My comments: This statement misses what I consider the two most important rules:
Differentiate between type-1 and type-2 diabetes! (when appropriate)
Do not say "diabetes" when you mean "type-2 diabetes" or when you mean "type-1 diabetes".


More Interesting Tweets:

Doctor Deena @Doctor_Deena
Amazing #technology for #diabetes-- a skin patch using wavelengths to deliver #insulin into skin pores. #2016ada
https://twitter.com/Doctor_Deena/status/741745686526361600

Mark Harmel MPH, CDE @MarkHarmel
Results of DiaMonD study (CGM in MDI users) impressive. #2016ADA Fewer highs, lows and reduced variability. + Lower A1C by 0.9% at 24 weeks
https://twitter.com/MarkHarmel/status/742120533848936449
My comment: MDI is multiple daily injections.  What this study is showing is that even people who are not using a pump will benefit from using a CGM.  While I suspect this is true, I'm not sure it is useful, because I suspect these people don't want or cannot use a CGM for the same reason they don't want or cannot use a pump: they don't want an attachment or can not afford it.  Telling non-users "it is good for you" will not make them users: they know it is good for them.  They have other reasons for not using it.

Dr.Harsha Doddihal @Harshadod
Consuming #proteins followed by carbs could be beneficial in #glycemic control! Poster 62-LB
https://twitter.com/Harshadod/status/742123177766223872
My comment: is this news?  I always thought eating carbs after non-carbs led to smaller post meal BG spikes.


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, June 5, 2016

Metformin Starts a Large Trial To Prevent Type-1 Diabetes

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

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

Why Metformin As Preventative?

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

The Accelerator Hypothesis

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

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

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

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

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

Discussion

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

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

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

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

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

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

Trial Structure

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

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

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

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

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

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

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

The trial is being funded by JDRF.

Extra Discussion

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

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

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

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

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

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

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

References and Sources

[r1] Trial Website: http://adaptdiabetes.org/
[r2] News Article: http://www.techtimes.com/articles/151904/20160420/new-trial-aims-to-prevent-type-1-diabetes-in-children.htm
[r3] Press Release: http://medicine.exeter.ac.uk/news/title_506628_en.html

[r4] EU Clinical Trial Registry:
https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-000748-41/GB
https://www.clinicaltrialsregister.eu/ctr-search/search?query=2015-000748-41
EudraCT Number: 2015-000748-41  (this is a European clinical trial registry number)
[r5] UK Clinical Trial Registry: https://www.ukctg.nihr.ac.uk/trials/trial-details/trial-details?trialId=34351
The UK trial registry lists this trial ID as 20540, but the query above uses 34351, and I don't know which one is correct.

[r6] Here is the original paper on the theory, from 2001:
http://download.springer.com/static/pdf/213/art%253A10.1007%252Fs001250100548.pdf?originUrl=http%3A%2F%2Flink.springer.com%2Farticle%2F10.1007%2Fs001250100548&token2=exp=1462141633~acl=%2Fstatic%2Fpdf%2F213%2Fart%25253A10.1007%25252Fs001250100548.pdf%3ForiginUrl%3Dhttp%253A%252F%252Flink.springer.com%252Farticle%252F10.1007%252Fs001250100548*~hmac=2a7ec6140ae9ef099ca55256b1e12795f78cb39c2aa342820a7705fb547a038d

[r7] Much more detail on the Accelerator Hypothesis of type-1 diabetes in included the following 2009 review article, written by the same researcher who is running this trial:
http://www.nature.com/ijo/journal/v33/n7/full/ijo200997a.html

[r8] http://www.diapedia.org/type-1-diabetes-mellitus/21040851194/accelerator-hypothesis

[r9] http://link.springer.com/article/10.1007/s00125-007-0726-9/fulltext.html

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 19, 2016

Research In The News (May)

This blog posting covers a couple of different topics, but starting with a piece of bad news:

Perle Biosciences Ends A Phase-II Trial of a Combination Cure

In November 2015 I blogged on a clinical trial by Perle Biosciences testing a combination of Cyclosporine and Omeprazole.  You can read the details here:
http://cureresearch4type1diabetes.blogspot.com/2015/11/perle-biosciences-starts-phase-ii-trial.html
Unfortunately,  that trial was listed as "Prematurely Ended", but I'm not sure exactly when.  There hasn't been an official press release on the trial, but JDCA quoted Perle Biosciences's president as saying the trial was stopped because "Enrollment was disappointing in Europe and we are planning to move all studies to the U.S."

Of course, I'm hopeful that they do start a trial in the US, and soon.  They are working with a combination of drugs: one of which stops the autoimmune attack and the other regrows beta cells. Both are already approved in the US (one is over the counter).  So you can see why this is an exciting treatment.

Unfortunately, this is not the first time Perle has had problems starting a study.  Prior to starting this European study, Perle filed paperwork to start two studies in the US.  This paperwork languished for over two years and the American studies never did start.   A parallel effort in Europe did led to this study, which has now been ended.

JDCA Coverage: http://thejdca.org/practical-cure-project-update-perle-bioscience-drug-combination-human-trial-ends-prematurely

Not In Human Trials: Stem Cells From Self

Researchers were able to create beta cells from stem cells, the stem cells having been created from skin cells of people with type-1 diabetes.  This might be important for a couple of reasons.  First, these cells could be used to test new drugs.  Many people have noticed (especially in the world of type-1 diabetes) that treatments which work on mice often don't work on people.  This is a way to test treatments on beta cells similar to a type-1 diabetic's actual beta cells.  Second, these cells could be used in transplants.  But remember, that only solves half the transplant problem.  Transplanted beta cells have two problems: the body's good immune system is trying to kill them because they are foreign and the body's bad immune system is trying to kill them because they are beta cells.  Since these cells are from the patient's own body, they will not have the first problem, but might still have the second problem.

To the best of my memory, previous reports of making beta cells from stem cells always involved the use of 3rd party stem cells (ie. the stem cells did not originate from the person who would eventually get the beta cells).  So this is a step forward in that regard.

This is animal research only right now, but could get into human trials in 3-5 years, which would then take an additional 10-15 years to become generally available.  That is, assuming it is successful.

Press Release: https://www.sciencedaily.com/releases/2016/05/160510132809.htm
Paper: http://www.nature.com/ncomms/2016/160510/ncomms11463/full/ncomms11463.html


Stepping Back from Artificial Pancreas Coverage

I've decided to scale back my coverage of artificial pancreas research.  This is for two reasons:
  1. Because limited functionality Artificial Pancreas devices are already available from Medtronic now in Europe (the 640G) and in the United States (the 530G), and because an all-but-meal Artificial Pancreas device (the 670G) is planned for release in both places in the next few years, there is a lot of "regular" news coverage on Artificial Pancreas developments.  I do not think I'm adding a lot of value to Artificial Pancreas research reporting.  To be blunt: DiabetesMine, diaTribe, ASweetLife, and similar web sites are doing such a good job publicising AP progress, I don't feel like I'm needed in that area.
  2. Because there is so much progress being made, on so many different Artificial Pancreas fronts, the avalanche of information is overwhelming me.  I just can't keep up.
Obviously, these are both good reasons to stop coverage.  I'm absolutely confident that a full Artificial Pancreas will be available in the United States in a few years, and I'd rather spend my time following research that is less certain, and harder to interpret.

If you are desperately in need of an AP update, read these:


My Internet World

I use Blogger, LinkedIn, Facebook, and Twitter, but I divide up my internet world like this: The blog is very specifically focused on clinical trials aimed at curing type-1 diabetes. If that is what you care about, then either follow the blog or sign up for mail notifications when a new entry is posted. (There is a field in the upper right hand corner of the blog for that.)  My twitter covers type-1 diabetes more broadly and also some non-diabetes issues which are important to me.  It is more than half type-1 and less than half other issues.   I try to keep LinkedIn very strictly for work related stuff, and Facebook for family and friends.  So if you are linked with me either on LinkedIn or Facebook, but only care about diabetes news, then you'd probably do better to either sign up for emails from my blog or link with me on Twitter.

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, May 1, 2016

General Update on IL-2 Research

This is a long blog posting, because I'm attempting to summarize all the current research which attempts to cure type-1 diabetes using Interleukin-2 (IL-2).

IL-2 is a protein that the body's immune system uses for communications.  It is part of the system that helps the immune system identify the body's own cells from foreign cells.  Since the root cause of type-1 diabetes is a failure in this process, IL-2 is a possible cure.  Several different groups are testing it (or have tested it).  More information is on Wikipedia:
http://en.wikipedia.org/wiki/Interleukin_2

Of course, IL-2 cures type-1 diabetes in NOD mice:
http://jem.rupress.org/content/207/9/1871.short

Overview Of IL-2 Research

Many of these clinical trials have similar names and some of them are being run by the same researchers in the same organization.  So in the list below, I've included their FDA registration number (starting with NCT), to help me keep track of which trial is which.

Three studies have been completed:
  • DF-IL2 (NCT01353833)
  • DILT1D (NCT01827735)
  • Combo (NCT00525889)
And three more are recruiting now:
  • DFIL2-Child (NCT01862120)
  • DILfrequency (NCT02265809)
  • DIABIL-2 (NCT02411253)
Completed Clinical Trials

DF-IL2 (NCT01353833)

This was a "mechanistic" trial, meaning that it's goal was to show that IL-2 would increase the number and activity of good immune cells (T-reg cells).  T-reg cells regulate the immune system so that it does not self attack, and many researchers believe that getting the body to generate more T-reg cells, and making them more active, is a key to stopping the autoimmune attack.  This trial involved 25 people within two years of diagnosis.  They were divided into four groups: three getting different IL-2 doses, and a placebo group.

This first trial was successful because the researchers saw changes in the T-reg cells.  However, they did not measure C-peptide, A1c, insulin usage or any other "patient impacting" parameters, so we don't know if the T-reg changes that they saw actually resulted more natural insulin, better A1c number, etc.

This same group of researchers has started a follow on trial, called DFIL2-Child (NCT01862120) and described later.


DILT1D (NCT01827735)

This trial completed in May 2014, but results have not been published.  However, the researchers involved have started a follow on trial, called DILfrequency (NCT02265809) which is described later.  This trial included 40 people, within 2 years of diagnosis.  It was not blinded, and had no control group.


Combo (NCT00525889)

This trial combined two treatments: Rapamycin and IL-2.  Rapamycin suppresses the immune system.  It enrolled 9 patients with no control group.  These people had been diagnosed less than 4 years ago, but more than 3 months ago.

This trial was not successful (in terms of moving us towards a cure).  Although it did result in more regulatory T cells, yet C-peptide numbers (a measure of the body's ability to create it's own insulin) dropped at the same time.  

(Thanks to the ADA for making this paper freely available.)

Clinical Trials Currently Underway

DFIL2-Child (NCT01862120

This is a 24 person phase-II study, where different groups will get three different doses of IL-2, and a fourth group will get placebo.  The primary end point is a CD4 measurement 22 days after dosing. The secondary measures are more clinically useful: C-peptide numbers (which show insulin production) and A1c number.  They are also measuring changes in T-regs, to give insight into the mechanism of how IL-2 works.  The study will gather data for each participant for about 15 months.  This trial started in June 2013.  Since they completed enrollment in April-2016, they should finish collecting data by mid-2017

This trial in France and is open to children aged 7 to 14, who are in the honeymoon phase (treated with insulin for less than 3 months). Here is the contact information for this trial:
David Klatzmann, MD, PhD   Phone: +33(0) 1 42 17 74 61   Email: David.klatzmann@upmc.fr

This study is recruiting at many different hospitals:
Service d'Endocrinologie Pédiatrique -- Le Kremlin Bicetre, France, 94275
Service de Pédiatrie - CHU de Nîmes -- Nimes, France, 30029 cedex 9
CIC pédiatrique - CHU de Necker -- Paris, France, 75015
Service d'endocrinologie pédiatrique - CHU de Necker  -- Paris, France, 75015
CIC 9202 CHU Rober Débré -- Paris, France, 75019
Service d'endocrinologie Diabétologie pédiatrique CHU Robert Débré -- Paris, France, 75019

Clinical Trial Registry: https://clinicaltrials.gov/ct2/show/NCT01862120


The DILfrequency Trial (NCT02265809)

This study is testing Aldesleukin (also called Proleukin or IL-2), and uses "adaptive design". Basically, they give the early participants many small doses of the drug they are testing, and based on how and when they react to those doses, the later people in the trial get "better" doses.  (The engineering term for this is "fast feedback loop" and the software term is "agile development".)

This trial is for adults (18-70) who are within 5 years of diagnosis, so not just honeymooners.

If you really want to keep up with these researchers, they are all over twitter and facebook:
https://twitter.com/t1diabetestrial
https://www.facebook.com/ClinicalTrialsType1Diabetes

Update

Since January, this study is enrolling the last group of patients needed for completion.  There is no control group so everyone is getting the drug.  One patient has completed all follow up visits.  But the big news from my point of view, is that they are well past their "learning" phase, and are now testing doses based on the data from the earlier phases.

Once they have recruited all their patients, it will take them less than 4 months to collect their data. They hope to finish by October 2016.

I'm wondering if this clinical trial represents the future of clinical trials in an internet world.  Take a look at their list of URLs:

Web Page: http://www.clinical-trials-type1-diabetes.com/
Facebook: https://www.facebook.com/ClinicalTrialsType1Diabetes
Twitter: https://twitter.com/t1diabetestrial
Pinterest: https://www.pinterest.com/t1diabetestrial/
Clinical Trial Registery: https://clinicaltrials.gov/ct2/show/NCT02265809

Pretty soon, they will need a web page to keep track of their web pages.   From my point of view, all this information gives me a great view into the process of running the clinical trial.  Especially, it tells me when various internal milestones were reached.   Usually, I don't have any knowledge of those milestones, so it is great to see them.

DIABIL-2 (NCT02411253)

This trial is being run by the same researcher (Dr. David Klatzmann) who is running the DFIL2-Child study discussed above.  This trial is much larger (185 person), and is open to honeymooners (ie. within 2 months of diagnosis) between 12 and 35 years old.  It started in March 2015 and plans to finish in June 2018.

This trial is already recruiting in Germany, and many places in France.  It is planning to add Belgium, The Netherlands, Sweden, and Switzerland, too.

Service d'endocrinologie, diabétologie, maladies métaboliques, et nutrition, CHU de Bordeaux, Hôpital Haut Levêque Recruiting
Pessac, Aquitaine, France, 33604
Contact: Vincent RIGALLEAU, Pr.    06 63 24 45 51    vincent.rigalleau@chu-bordeaux.fr
Service d' Endocrinologie HOPITAL CAVALE BLANCHE Recruiting
Brest, Brittany, France, 29609
Contact: Emmanuel SONNET, Pr    02 98 34 71 19    emmanuel.sonnet@chu-brest.fr
Service de Pédiatrie, HOPITAL MORVAN Recruiting
Brest, Brittany, France, 29609
Contact: Chantal METZ, MD    00 33 2 29 02 00 04    chantal.metz@chu-brest.fr
Médecine pédiatrique, CHU Jean Minjoz Recruiting
Besançon, Franche-Compté, France, 59037
Contact: Anne-Marie Bertrand, Dr.    03 81 21 81 34    bertrand.anne-marie@wanadoo.fr
Service Diabétologie -Endocrinologie, CHU Jean Minjoz Recruiting
Besançon, Franche-Comté, France, 59037
Contact: Sophie Borot, Dr.    06 89 16 22 46    sophie.borot@gmail.com
Endocrinologie gynécologie diabétologie pédiatriques, Hôpital Universitaire Necker Enfants Malades. Recruiting
Paris, Ile De France, France, 75015
Contact: Michel Polak, Pr    +33 (0)1 44 49 48 02    michel.polak@nck.aphp.fr
Institut E3M, Hôpital Pitié-Salpêtrière Recruiting
Paris, Ile-de France, France, 75013
Contact: Agnés Hartemann, Pr.    01 42 17 81 18 ext 80 70    agnes.hartemann@psl.aphp.fr
Service d'Endocrinologie Pédiatrique, Hôpital d'enfants Robert Debré Recruiting
Paris, Ile-de France, France, 75019
Contact: Jean-Claude CAREL, Pr    01 40 03 53 03    jean-claude.carel@inserm.fr
Service Pédiatrie - Pôle femmes enfants, CHU de Nîmes, Hôpital Universitaire Carémeau Recruiting
Nïmes, Languedoc-Roussillon, France, 30029 Cédex 9
Contact: Tu Anh TRAN, Pr.    04 66 68 32 84 ext 32 85    tu.anh.tran@chu-nimes.fr
CHRU de Lille, Hôpital Claude Huriez Service d'endocrinologie Recruiting
Lille, Nord-Pas-de-Calais, France, 59037
Contact: Pierre FONTAINE    03 20 44 45 13    pierre.fontaine@chru-lille.fr
Service d'endocrinologie-diabétologie gynécologie pédiatriques, CHRU de Lille, Hôpital Jeanne de Flandre, Recruiting
Lille, Nord-Pas-de-Calais, France, 59037
Contact: Jacques WEILL, Pr.    03 20 44 46 95    Jacques.WEILL@CHRU-LILLE.FR
Institute of Diabetes Research, Helmholtz Zentrum München Recruiting
München, Bayern, Germany, D 80804
Contact: Annette G ZIEGLER, Pr    00 49 089 3187 2896    anette-g.ziegler@helmholtz-muenchen.de

General Discussion of IL-2 As A Cure For Type-1 Diabetes

Unfortunately, IL-2 does not have a strong history of success in previous trials aimed at type-1 diabetes.  If you look at the three completed trials: two saw some changes to T-regs, but not to "patient visible" results like C-peptides, A1C numbers, or insulin use; the other has not been published.

Of the trials currently underway, two are aimed at honeymooners, and one at long term type-1 diabetics, and all will have results in the next two years.  The trials currently underway are all gathering C-peptide data, which I consider the most important measure of progress in curing type-1 diabetes.  And they are also gathering information on A1c and insulin usage, plus various data which should show what is happening "inside" the immune system.  So I'm optimistic that with that data, it will be clear if IL-2 is worth further research or not.  Of course, when the results are reported, I'll be focusing on the results which directly impact people with type-1 diabetes: C-peptide, A1c, and insulin usage.

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

Saturday, April 23, 2016

Gluten Free Diets To Prevent or Cure Type-1 Diabetes

One of my policies in blogging has been that I don't "play favorites".  I don't blog on something because I think it is a good idea, nor do I refuse to blog on something because I think it is a bad idea. I try to blog on all clinical trials which are aimed at curing type-1 diabetes no matter if I personally think they will be successful or not.  That is why I'm writing this blog on various researchers trying to cure type-1 diabetes with a gluten free diet.

Introduction

There is general consensus that celiac disease and type-1 diabetes are related conditions, in that people having one are noticeably more likely to get the other.  Many researchers think that both are autoimmune diseases and that they share some genetic susceptibility, so that that someone genetically more likely to get one is also more likely to get the other.

The standard treatment for celiac disease is a gluten free diet.  Since many of the bad effects of celiac disease are triggered by gluten in the diet, reducing or eliminating gluten can dramatically reduce symptoms.

Therefore, some researchers have looked at the possibility that a gluten free diet might help type-1 diabetics as well.  The rest of this blog discusses this research, divided into two sections: Completed Studies (everything until about 2012) and Underway Studies (basically 2013 - on).

My discussion is at the end.

Completed Studies

From 1999: Gluten-free diet prevents diabetes in NOD mice.

NOD mice (the standard animal model of type-1 diabetes) were given either gluten-free or normal diets.  The diabetes rate in the normal diet was about four times higher than in the gluten-free mice, and the if they did get diabetes, the gluten-free mice got it later in life.  Both effects were statistically significant.

Abstract: http://www.ncbi.nlm.nih.gov/pubmed/10585617

From 2011: Gluten Free First Year Does Not Prevent Type-1 Diabetes

This study involved 150 babies.  Half started eating gluten normally (at 6 months).  The other half delayed gluten until 12 months.  All of the babies had a family history of type-1 diabetes and a genotype (called HLA) which raised their chances of getting type-1 diabetes.

These children had their autoantibodies measured at 3 years and their type-1 diabetes status measured at 10 years.  The results were the same in both groups, so a gluten free first year did not prevent or delay either autoantibodies or actual onset of type-1.

Abstract: https://www.ncbi.nlm.nih.gov/pubmed/21515839
Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT01115621

From 2012: Remission without insulin therapy on gluten-free diet in a 6-year old boy with type 1 diabetes mellitus.

This is a single case study (not a clinical trial), but it generated the interest in gluten free diets reflected in the clinical trials currently underway.  These doctors reported on the case of one newly diagnosed type-1 diabetic who immediately went on a gluten free diet, and did not need to inject insulin after that.  This patient was followed for 20 months, and did not need to use insulin during that time.  The doctors in this case were of the opinion that the gluten free diet had extended the length and strength of his honeymoon remission.  The patient was a 5 year old boy, and tested positive for the GAD autoantibody.

Abstract: http://www.ncbi.nlm.nih.gov/pubmed/22729336

Underway Studies

Gluten Free Diet Starts a Phase-I Honeymoon Trial

This trial will enroll 20 people between 2 and 18 years old within 3 months of diagnosis.  All will eat a gluten free diet; there is no control group. C-peptides and insulin usage will be measured after 1 year to see if a gluten free diet results in slower or less loss of beta cells or less need for injected insulin.

This study is being run by Jannet Svensson, PhD at the Copenhagen University Hospital in Herlev, but is already fully enrolled.  She was one of the authors of the case study listed above.  This study started in March 2012 and has already finished.  It has been submitted for publication, but I have no news yet on when it will be published.

Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02284815

Gluten Free Diet Starts a Phase-II Prevention Trial

This trial will enroll 60 people between 2 and 50 years old who have one or more autoantibodies, but are not showing other symptoms of type-1 diabetes.  Half will eat a gluten free diet and half will eat a normal diet, while both groups will get Vitamin D, Omega 3 fatty acids, and probiotics. C-peptides will be measured throughout the trial to see if a gluten free diet results in slower or less loss of beta cells.

If you are interested in enrolling, you can contact  Dr. Helena Elding Larsson at Lund University, Department of Clinical Sciences Malmö, Sweden, 20502

Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02605148

Gluten Free Diet Starts a Phase-II Honeymoon Trial

This trial will enroll 60 people between 1 and 17 years old within 4 months of diagnosis.  Half will eat a gluten free diet and half will eat a normal diet. C-peptides will be measured after 1 year to see if a gluten free diet results in slower or less loss of beta cells.

The trial started in March 2015 and should end in March 2017 (meaning they should be finished with enrollment right about now: March 2016).  If you are interested in this study you can contact  Dr. Eba Hathout at Loma Linda University, California.

Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02605564

Discussion


Somehow I think that if gluten free diets could prevent or cure type-1 diabetes, someone would have noticed before now.  There are human populations, such as Inuit (Eskimos) and Masai, who have naturally gluten free diets.  If this theory were correct, these populations would have low or nonexistent rates of type-1 diabetes, and that would have been noticed by now.  Also, in the early 1900s (prior to the discovery of insulin) one of the common type-1 life prolonging diets was essentially gluten free, but it did not cure type-1 diabetes, either.

My basic summary is that right now, if you look at clinical trials (and ignore case studies and animal research), there is one published study, and it was unsuccessful.  In the next few months we will get one more, and two additional results in the next two years or so.  That will be a total of four studies, and should be enough to answer the question (or at least show a strong trend).

Obviously, the optimism about gluten free diets is generated from the case study.  It does appear that the child had type-1 diabetes (and was not a misdiagnosis).  I say that because they detected GAD antibodies, a marker for type-1 diabetes, and also because the researchers involved were (and are) heavily involved in type-1 research.  I just don't see them making a misdiagnosis error.  Going insulin free for 20 months after diagnosis is certainly very unusual.  Going insulin free for a short period of time after diagnosis does happen.  And we do not know how long the longest honeymoon period is. However, even taken together, 20 months insulin free is highly unusual.  Of course, the gluten free diet could just be random chance.  (That is, not causation, not correlation, but just lucky chance.)  But it is exactly the kind of coincidence that should be followed up on, and these four studies are a strong follow up.

One final point I want to make: often times I hear proponents of alternate medicine complain that their theories are ignored by mainstream medicine. Specifically they say that drug based treatments are pushed in preference to diet based treatments, so that drug companies profit.  The research described here is a strong counter example.  Given a single case study showing a diet based therapy might work, mainstream researchers have launched three clinical trials in an attempt reproduce the result.  The results will speak for themselves.

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

Tuesday, March 29, 2016

Research In The News (March)

Here are a few updates related to possible cures for type-1 diabetes being tested in people:

Grifols Therapeutics Completes Recruiting on a Phase-II Trial of AAT

In February 2016, Grifols completed recruiting people for their phase-II trial of AAT (Alpha-1 Antitrypsin).  This is a 76 person study with two different dose treatment groups and a placebo group. Assuming the study progresses normally, they will finish collecting data in February of 2018 and publish the year after that.

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.  My previous blogging on AAT is here:
http://cureresearch4type1diabetes.blogspot.com/search/label/AAT

Discussion: My summary of AAT's status is this: after several phase-I studies which did not give a strong signal of success, we now have two phase-II studies (the other is Kamada's involving about 60 people) and these will finish collecting data in 2016 and 2018, respectively.   When those two trials are published, we should have a clear success/failure signal.

Previous blogging on AAT: http://cureresearch4type1diabetes.blogspot.com/search/label/AAT
Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02093221

Combo of Diamyd and Vitamin D Starts a Phase-II Prevention Trial

This is a classic prevention trial.  The researchers will enroll 80 children (between 4 and 18) who are positive for two autoantibodies (GAD and any one other), but not yet showing any symptoms of type-1 diabetes.  These people will be followed for 5 years to see how many are diagnosed in that time. This study started in March 2015 and is expected to finish in March 2022.  Half the children will be given Diamyd and Vitamin D, the other half, just Vitamin D.

Diamyd is similar to GAD, which is the target of the most common autoantibody seen in type-1 diabetes.  The hope is that Diamyd will train the immune system not to autoattack.

This study is enrolling "by invitation only", so if you are interested in enrolling, you can contact Dr. Helena Elding Larsson at Lund University, Clinical Research Center, Pediatric Endocrinology, Jan Waldenströms gata 35, 60:11 Malmö, Sweden, 20502

Discussion: Diamyd was unsuccessful at curing honeymoon type-1 diabetes in a large phase-III clinical trial and also unsuccessful in curing adult onset type-1 diabetes, but their earlier, smaller phase-II trial showed better results, so this study is testing it as a preventative. According to TrialNet research, essentially all of the people in this trial will eventually be diagnosed with type-1, but not within 5 years.  It will be interesting to try to match up the numbers from this study and TrialNet.

Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02387164

Combo of Diamyd, Vitamin D, and Etanercept Starts a Phase-II Trial

This trial will test a combination of Diamyd, Vitamin D, and Etanercept as a cure for type-1 diabetes.
The trial will enroll 20 honeymooning children (ages 8 to 18), all of whom will get the treatment. There will be no control group.  People will be followed for 2 1/2 years, checking for C-peptide (natural insulin generation), A1c, and insulin, plus a bunch of safety measures and immunological measures.  This trial is expected to finish in November-2018, but that will only happen if they are fully enrolled by May-2016, which is coming up quickly!

The hope for this trial is that Diamyd will stop or lower the autoimmune attack, Etanercept will lower inflammation and stop the immediate loss of beta cells, and Vitamin D will do some unspecified good (based on the fact that countries closer to the equator have more sunlight so more Vitamin D and less type-1 diabetes).

They are recruiting people all over Sweden:
Eskilstuna Hospital -- Eskilstuna, Sweden -- Contact: Ulf Söderström, MD      
Helsingborg Hospital -- Helsingborg, Sweden -- Contact: Anna-Karin Albin, MD      
Linköping University Hospital -- Linköping, Sweden -- Contact: Johnny Ludvigsson, MD      
Lund University Hospital -- Lund, Sweden -- Contact: Annelie Carlsson, MD      
Skåne University Hospital, UMAS -- Malmö, Sweden -- Contact: Tore Vigård, MD      
Sachsska, Södersjukhuset -- Stockholm, Sweden -- Contact: Björn Rathsman, MD      
Uddevalla Hospital -- Uddevalla, Sweden -- Contact: Ragnar Hanås, MD      
Västerås Hospital -- Västerås, Sweden -- Contact: Carl-Göran Arvidsson, MD      
Örebro University Hospital -- Örebro, Sweden -- Contact: Stefan Särblad, MD

Discussion: Diamyd has been tested in much larger trials, and has not been found effective.  Vitamin D has not yet been tested in an intervention trial (and the news is mixed from population studies), but Etanercept did have one successful phase-I trial, but it did not (by itself) rise to the level of a cure. I've blogged about all these separate treatments, but this is the first study I know of which combines them:
http://cureresearch4type1diabetes.blogspot.com/search/label/Diamyd
http://cureresearch4type1diabetes.blogspot.com/search/label/Vitamin%20D
http://cureresearch4type1diabetes.blogspot.com/search/label/Etanercept

Don't mix this research up with the DIABGAD trial (also done by Dr. Johnny Ludvigsson), which combined Diamyd, Vitamin D, and Ibuprofen.  Although the two projects are similar in that they are both Diamyd plus Vitamin D and an anti-inflammatory.  Ibuprofen and Etanercept are both anti-inflammatories, although they use different mechanisms: Ibuprofen is a COX inhibitor, while Etanercept is an TNF inhibitor.

Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02464033

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, March 20, 2016

LCT Update


LCT gave a presentation in late 2015 with an update on their "Diabecell" encapsulated cell technology. They have been testing this in people for more than 10 years, and you can see my previous blogging on them here:
http://cureresearch4type1diabetes.blogspot.com/search/label/LCT
The following blog posting covers LCT's history up until about 2008:
http://cureresearch4type1diabetes.blogspot.com/2008/12/lcts-research.html

LCT uses pig beta cells encapsulated in a proprietary coating, so patients do not need a lifetime of anti rejection drugs.

The new information is from eight patients in a phase-II trial who were followed for about 2.5 years. The trial was done in Argentina.  All the patients got two transplants.  The first group got a medium dose, and the second group got twice as much.  The results are still being analyzed, but the basic results seem to be:
  • A1c before the transplant was between 8.5 and 9.5, and afterwards was around 7.5 (for the lower dose group) and 6.5 (for the high dose group).
  • At the same time, insulin dose dropped about 10% in the lower dose group, and 25% in the higher dose group.
  • They presented data on fewer "unaware lows" and estimates of how much insulin the transplanted beta cells were generating.  
Discussion

I think that these are some of the best results I've seen for encapsulated beta cells, but it is still hard for me to get excited about them.  Earlier on, I was hopeful that they could just transplant more cells and get better results, but that does not appear to be happening.  Specifically:
  • A phase-I trial reported in 2008 that overall insulin usage dropped 24%, and reported two patients went insulin free, one for weeks and the other for months.
  • A phase-II trial reported in 2010 that overall insulin usage dropped 30%, but no reports of people going insulin free.
  • A phase-II trial reported in 2013 that overall insulin usage dropped 20%, and no reports of going insulin free.
  • A phase-II trial reported in 2015 that overall insulin usage dropped 10% and 25% (in different groups), and no reports of going insulin free.
I find this lack of progress to be disheartening.  It does not feel like they have "cracked the code" to an encapsulated beta cell cure.  At least not so far.

It will be interesting to see how LCT's Diabecell results compare to Viacyte's VC-01 results.  Both companies are working on encapsulated beta cell cures, so a head-to-head comparison makes sense when Viacyte's phase-I (40 person) results come out in 2017.  Hopefully LCT will have results from a similar number of people by then as well.  

Press release and presentation: http://www.asx.com.au/asxpdf/20151116/pdf/433073gv8cc3wx.pdf
This presentation contains a lot of data from several different clinical trials and case studies.
Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT01739829

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.