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

T-Rex is a phase-II study of polyclonal T Regulator ("T-Reg") cells.  It is a follow on study to work done at UCSF and in Poland which I've blogged about in the past:
http://cureresearch4type1diabetes.blogspot.com/search/label/Polyclonal%20Tregs

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

The Study

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

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

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

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

Fargo, North Dakota, United States, 58122
    Contact: Kathryn McEvoy    701-234-3722    kathryn.mcevoy@sanfordhealth.org
    Contact: Vicki Oberg    701-234-6722    vicki.oberg@sanfordhealth.org
Sioux Falls, South Dakota, United States, 57104
    Contact: Lynn M Bartholow, BA    800-305-5059    Lynn.bartholow@sanfordhealth.org
    Contact: Alycia Brantz    605-328-1369    Alycia.Brantz@sanfordhealth.org

Discussion

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

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

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

The Company's web site: http://www.caladrius.com/product-candidates/clbs03/
More: https://www.sanfordhealth.org/promo/the-sanford-project
http://www.prweb.com/releases/2016/04/prweb13308934.htm
http://bismarcktribune.com/lifestyles/health-med-fit/year-old-west-fargo-girl-among-handful-of-kids-in/article_f098e85f-a3b7-5ad0-83a9-0f949147a04c.html
Newspaper Article: http://www.grandforksherald.com/accent/health/4037848-grand-forks-student-participates-groundbreaking-t-rex-diabetes-study
Clinical Trial Registery: https://clinicaltrials.gov/ct2/show/NCT02691247

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

Joshua Levy 
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.

Possible Cures for Type-1 in the News (early Aug-2012)

Prologue: Why Completing Enrollment is an Important Milestone for Clinical Trials

For two reasons.  First, because at that point it is possible to predict when the researchers will eventually finish collecting data.  The experimental design will say how long data will be collected for each person, so you can just add that duration to the date they finished enrollment, and that tells you when the final data will be collected.  Second, because much of the uncertainty that surrounds clinical trials involves recruiting participants, it is often unclear how hard it will be to get people, and long it will take.   But at this point, all that cunertainty is behind the researchers.  Once enrollment is complete, it is just gathering data, then analyzing data, and then publishing the data.  Researchers have a lot more control over those later stages, than over recruiting people in the first place.

Put another way, a clinical trial is made up of five tasks:
1. Do research to figure out what clinical trial should be done.  During this phase, the researchers are at the mercy of the science.  If they science doesn't pan out, then the experiment never gets done.
2. Get FDA approval for the clinical trial.  During this phase, the researchers are at the mercy of the FDA (or similar regulatory agency).  If they don't get approval, the experiment never gets done.
3. Recruiting patients.  During this phase, the researchers are at the mercy of the patients (or their parents).  If they can't get enough people to enroll, the experiment fails.
4.  Gathering the data.  During this phase, the researchers pretty much control their own destiny, unless a huge number of people drop out, or there is some unexpected safety issue.
5. Writing and publishing the results.  During this phase, the researchers are subject to editors and peer review (to some degree).  However, there are so many journals and web sites, that the researchers have many choices; they can even self publish, if all else fails.  They are not at the mercy of any one person or committee.

Completing enrollment is the end of phase 3 / start of phase 4, and you can see that researchers have a lot more control of their own destiny in phases 4 and 5, then in 1, 2, or 3.  

"REPAIR-T1D" (Lansoprazole and Sitagliptin) phase-II Study Completes Enrollment

This study finished enrolling in May 2012 and they plan to gather data for two years, so we should have results soon after May 2014.  This trail gives two currently approved drugs (Januvia and Prevacid) to type-1 diabetics within six months of diagnosis.  The hope is that it will restore or at least preserve beta cell function.

Press Release: http://www.newswise.com/articles/the-sanford-project-reaches-milestone-in-quest-to-cure-type-1-diabetes
Clinical trial record: http://www.clinicaltrials.gov/ct2/show/NCT01155284

GCSF/Neulasta phase-II Study Completes Enrollment

Previous blogging here: http://cureresearch4type1diabetes.blogspot.com/search/label/Haller

This study finished enrolling in March 2012, and they plan to gather data for two years, so we should have results soon after March 2014.  (Their clinical trial record says December 2014.) GCSF, also known as Neulasta or Pegfilgrastim, causes the body to generate it's own stem cells from bone marrow. These might rebalence the immune system or they might retrain it, but in any case, the hope is they will help cure type-1.

Burt's trial (the most successful so far) uses GCSF, ATG, and CZ. CZ is, by far, the most toxic of the three, so this trial can be viewed as "Burt ultra-lite". GCSF and ATG together would be "Burt lite" and there is a trial for that also ongoing.
Clinical Trial Record:   http://www.clinicaltrials.gov/ct2/show/NCT00662519

Thymoglobulin (ATG) Phase-II Study Completes Enrollment

Please read about Thymoglobulin (ATG) here: http://cureresearch4type1diabetes.blogspot.com/p/drugs-and-treatments-in-clinical-trials.html (scroll down the page until you see the section on ATG)

This phase-II study of ATG has completed enrollment.   It took them about 2 years longer than expected, so that's not good, but we can expect data collection to be complete in 2 years, and hopefully results will be published soon there after.  The ATG link about has complete information on why the researchers hope ATG might cure type-1 diabetes or be part of a cure.

Clinical Trial Record:  http://www.clinicaltrials.gov/ct2/show/NCT00515099
Previous blogging here: http://cureresearch4type1diabetes.blogspot.com/search/label/Gitelman

Combo (Diamyd, Lansoprazole and Sitagliptin) Trial Fails

This trial has a long and not so good history, which you can read in my previous blogging here: http://cureresearch4type1diabetes.blogspot.com/search/label/Combo

This Phase II study combined regenerative agents (lansoprazole and sitagliptin) and also Diamyd. The regenerative agents are both marketed drugs in the US. Diamyd is a vaccine like drug which trains the body's autoimmune system not to attack it's own cells.

This study's clinical trial record updated to show that it was terminated on 20 March 2012, although I think it had actually ended earlier.  Dr. Harlan, who started this study, had left the NIH, and the phase-III studies of Diamyd alone had failed or been canceled, so they decided not to pursue it.  

Obviously, it's too bad that it was canceled.  This was the first study that I knew of that attempted to combine a drug to stop the autoimmune attack and drugs to encourage the regrowth of beta cells.      I think that combining treatments like that is still a good thing to try, even if this specific combination did not work out.

Clinical Trial Record:  http://www.clinicaltrials.gov/ct2/show/NCT00837759

More Stable Glucagon

This is only vaguely related to a cure, but I thought I'd mention it.  Xeris is trying to create a form of glucagon which can be stored at room temperature for long periods of time.  From a cure point of view this is useful for an artificial pancreas (if you consider that a cure).  Simple APs are based on insulin alone.  However, there are more complex APs, which are based on insulin and glucagon.  Having a glucagon which was approved to sit in the pump for days, maybe weeks, would be important to these "bihormonal" APs.

As a nice side effect, it would mean that emergency glucagon needles could be preloaded, just like insulin pens, which would make them much easier to actually use in an emergency.  It also would make mini-glucagon doses much easier to administer, for those who use them.

You can think of an insulin only AP sort of like a car with a break but no accelerator.  The engine "revs high" and you run along.  You use the break to slow up.  A bihormonal AP (insulin and glucagon) is more like a car with a break and an accelerator.  More control.  The analogy is not perfect, but that's the basic idea.

Press Release: http://www.marketwatch.com/story/xeris-pharmaceuticals-awarded-phase-i-ii-nih-sbir-fast-track-grant-to-advance-stable-non-aqueous-glucagon-for-bi-hormonal-artificial-pancreas-2012-07-31

Why Pharma/Med Device Co's Apply for Approval in Europe FIRST

If you haven't read this blog posting by Scott Strumello, you should!  It compares the approval process for medical devices in the EU to the same process in the US:
http://blog.sstrumello.com/2012/08/why-pharmamed-device-cos-apply-for.html

Next Up: Results from Dr. Faustman's Phase-I BCG Trial

She published in PLoS last week, so I hope to blog about it in a week or two.

Joshua Levy
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My blog contains a more complete non-conflict of interest statement.
Clinical Trials Blog: http://cureresearch4type1diabetes.blogspot.com
Cured in Mice Blog: http://t1dcuredinmice.blogspot.com/

Update on Gitelman's ATG Phase-II Clinical Trial

Dr. Gitelman at UCSF has started a Phase-II human trial aimed at using ATG to cure (or lessen) type-1 diabetes. The goal of this study is to preserve remaining beta cells for people within 100 days from diagnosis. This study started in August 2007, and is expected to run until June 2011. So far it has enrolled 11 out of an expected 66 patients. It's a four day treatment (in hospital), and 12 follow up visits over a 2 year period. They are recruiting at a total of 9 sites (growing to 13), which are listed in the clinical trial page linked below.

Here is a quick summary of how they hope ATG (Thymoglobulin) will work:

Type 1 diabetes is caused by destruction of insulin-producing beta cells by T cells, part of the immune system. Thymoglobulin is a mixture of different antibodies that target T cells. This mixture includes the anti-CD3 antibody (and anti-CD3 treatments are in Phase-III trials already, having completed successful Phase-I and II trials). The researchers hope that this multi-faceted approach will be even more successful and have a longer lasting effect than with anti-CD3 alone, and may treat diabetes by several mechanisms. First, it lowers the number of T cells, so there are fewer to attack the beta cells. It also seems to alter the T cells remaining behind, rendering them less likely to be destructive. Following this depletion, the T cells that grow back in the following weeks may be reset and have a healthier balance (meaning that a special type of T cells, called regulatory T cells, will help keep the destructive T cells in check).

Using ATG to cure type-1 diabetes is an idea that flows from two sources. The first source is a line of clinical trials aimed directly at curing type-1 with ATG. Eisenbarth's work of long ago, a Phase-I trial done in Europe, etc. But it also has another source, which is Burt's Brazilian research as described below.

Discussion: How to Follow Up Burt?

One of the questions that I'm occasionally asked is this: when will there be a follow up to Burt's Brazilian research? When will there be a Burt, phase-II? This is a natural question, because Burt has -- by far -- the best results of any one. Many patients on that trial went years without using external insulin. No other study comes close. So an obvious question is: how do you move forward with that research.

Burt's research is the opposite of most. Most researchers use the smallest possible doses during phase-I. Phase-I is targeted at safety, so they use small doses to assure safety even at the expense of effectiveness. So for most studies, for phase-II studies, they move forward by raising the dose to try to make a safe treatment a more effective one. But Burt's research is the opposite. The effectiveness is the strongest yet, but there are real questions about safety. So you would NOT follow it up by raising the doses!

One way to follow up Burt's relative success, is by turning down the dose. Trade off a little effectiveness for added safety. Oversimplified a little: Burt's research involves using three drugs (ATG, GCSF, and cyclophosphamide), and reinjecting the patient's own precursor bone marrow cells (previously removed). Dosing with just ATG can be viewed as a "kinder, gentler" Burt. Especially since the cyclophosphamide is the most risky drug of the bunch. (I'll be posting on two GCSF clinical trials in the coming weeks.)

Since I'm a software engineer, I'll use a software analogy: Burt is doing a "hard reboot", Gitelman is trying for a "soft reboot".

Notes

One of the complexities of following the research, is that ATG is referred to by many different names by different groups. For example: Thymoglobulin, rATG, hATG, ATGAM, antithymocyte globulin, etc.

The cells that Burt is removing and then reinjecting are sometimes called "precursor bone marrow cells" and other times "adult stem cells".

The lead investigator for this clinical trial is Dr. Gitelman at UCSF. For those of you at Bearskin Meadows: yes, this is the same "Dr. Steve" who is often up there. I'm indebted to Dr. Gitelman for his insights into Burt's research and how it relates to other research, including his own. All mistakes, opinions, and oversimplifications are my own.

Patient oriented information on this trial:
http://www.type1diabetestrial.org

Previous Blog postings on this
http://cureresearch4type1diabetes.blogspot.com/search/label/ATG (blog on ATG)
http://cureresearch4type1diabetes.blogspot.com/search/label/Burt (blog on Burt)
http://cureresearch4type1diabetes.blogspot.com/search/label/Gitelman (blog on Gitelman)

Web pages (but these need updating):
http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials#ThymoglobulinalsoknownasATGbyGitelman (Gitelman)
http://joshualevy.pbworks.com/DiabetesCureReadyForHumanTrials#ATGandothersbyBurtatUniversityofSaoPaulo (Burt)

Clinical Trial records for this study:
http://www.clinicaltrials.gov/ct2/show/NCT00515099 (Phase-II ATG)
http://www.clinicaltrials.gov/ct2/show/NCT00190502 (Phase-I ATG)
http://www.clinicaltrials.gov/ct/show/NCT00315133 (Burt)

Joshua Levy

Best News of 2008 in Clinical Trials to Cure Type-1 Diabetes

Here is my list of Best News of 2008 in Clinical Trials to Cure Type-1 Diabetes. I've based this list on these simple rules:

1. The best news is a cure, or a measurable improvement in BG, A1C, or insulin used.
2. The bigger the drop (in BG, A1C, or insulin used) and the more people helped, the better.
3. Results for non-honeymoon diabetics are better than the same results for honeymooners.
4. Results from later phase trials are better than results from earlier phase trials.

So with that in mind, here are five "best news" and a few special mentions. Note that I have not parked one "best" another "second best" etc. They are all really good news in different ways:

The "Big 5"

LCT finishes a phase-I trial, and shows some results
This news had it all: shows improvements for type-1 diabetics, works for people who have had diabetes for a long time, and marks the end of a clinical trial, with data we can see. Insulin usage dropped 24%, and almost everyone's A1C number went down. One person was cured (used no insulin at all) for a period of months.
Hope for next year: The start of a bigger trial and to see longer term data from this trial. Publication in a peer reviewed journal would be nice, too!

More data here: http://cureresearch4type1diabetes.blogspot.com/search/label/LCT
and here: http://joshualevy.pbwiki.com/DiabetesCureReadyForHumanTrials#LivingCellTechnologiesDiabecell

Burt Publishes 3+ year follow up data for their phase-I trials
This is the most amazing results seen yet: more than half of the patients where completely and permanently cured (low BG, A1C, and no more insulin needed). Some for over 3 years! Safety concerns linger, and it was honeymoon only.
Hope for next year: Start a phase-II trial for this, or better understand the safety issues.

More data is here: http://cureresearch4type1diabetes.blogspot.com/search/label/Burt
and here: http://joshualevy.pbwiki.com/DiabetesCureReadyForHumanTrials#UniversityofSaoPauloBurt

Diamyd starts two large phase-III trials
These guys are the closest to mass marketing a type-1 cure for some people. Their treatment shows improvements (lower BG, A1C and insulin usage) for many people, and might cure some people. It has only been tested on honeymooners, but once it is approved for general use, anyone will be able to try it. Their phase-II trails suggested that Diamyd use doubled the amount of surviving insulin producing beta cells. This means they require less insulin, and are very likely to have far fewer complicatoins in later life.
Hope for next year: See some intermediate results from this phase-III trial, or test it on non-honeymooners, or both!

More data is here: http://joshualevy.pbwiki.com/DiabetesCureReadyForHumanTrials#DiamydDiamydTorGAD65
and here: http://diamyd.blogspot.com/

ToleRx starts a phase-III trial
These guys are also making steady progress on a treatment that may cure some people and improve the health of many more. It has been shown to lower BG, A1C, and insulin requirements, but has only been tested on honeymooners. People treated in phase-II trails required significantly less insulin even after 18 months, compared with untreated people. (Although they did not have a big milestone this year, MicroGenics is testing a similar CD3 based cure, and is only a half step behind ToleRx.)
Hope for next year: Maybe finish this phase-III trial, or test it on non-honeymooners, or both!

More data is here: http://cureresearch4type1diabetes.blogspot.com/search/label/tolerx
and here: http://joshualevy.pbwiki.com/DiabetesCureReadyForHumanTrials#TolerrxTRX4orChAglyCD3

Gitelman and Osiris both started phase-II trails.
These are different immunology based cures, which are both at very similar point in their development. They are both being tested on honeymoon diabetics. Gitelman's research is based on previous phase-I research aimed a curing type-1 diabetes. The Osiris treatment has been tested in the past on several other immunological diseases, but this is the first time it has been tested as a cure for type-1 diabetes.
Hope for next year: probably nothing, but in 2010 good results from both!

More data is here: http://cureresearch4type1diabetes.blogspot.com/search/label/Gitelman http://cureresearch4type1diabetes.blogspot.com/search/label/Osiris
and here: http://joshualevy.pbwiki.com/DiabetesCureReadyForHumanTrials#NIAID/ITNGitelmanThymoglobulin/ATG http://joshualevy.pbwiki.com/DiabetesCureReadyForHumanTrials#OsirisTherapeuticsPROCHYMAL

More Generally

While the above paragraphs describe some specific research milestones of 2008, there are also more general good news out there. For example, I've been covering human trials aimed at curing type-1 diabetes for several years now, and every year I do it, there are more and more trials to keep track of. This year, for example, is the first year that there has been more than 1 phase-III clinical trial active. There were three of them at the end of the year. Will they all pan out? Probably not, but more trials means a bigger chance of one success. And we only need one success.

I'm also very intrigued by the new findings this year, about the importance of inflammation as a possible causative factor in type-1 diabetes. Although none of this research has yet led to clinical trials, it is clearly something new and different. As it is only a year old as a research direction, there is still lots of time for it to grow into something useful. Watch these guys:
http://joshualevy.pbwiki.com/DiabetesCureReadyForHumanTrials#HarvardKoulmandaandStromAAT

New to Me: Phase-I Clinical Trial of Polyclonal Anti-T-Cell (ATG)

This clinical trial treats honeymoon diabetes (during first 6 weeks) with ATG. The hope is for some beta cell preservation. This is a prelude to Gitelman's phase-II ATG trial, described here: http://joshualevy.pbwiki.com/DiabetesCureReadyForHumanTrials#NIAID/ITNGitelmanThymoglobulin/ATG, except that this trial is still ongoing. However, they have published interrum results (on their first 17 patients) here: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1783538

My eyeballing of the interrum results looks like the ATG group used about 60% as much insulin as the untreated group after about 12 months, and this seemed pretty stable. It did not look to me like the effect was "wearing off". This was good enough to motivate a follow-on, phase-II clinical trial, which is currently underway. I'm also very interested in what happens to these 17 patients after 2 years, 3 years etc. If the lower insulin requirement gradually goes away, that's too bad. If it stays stable, then that is very promising. If it gets even better slowly over time, that suggests that the body is growing new beta cells, and would be good news both for ATG treatments and for many others.

US Government Clinical Trial Record: http://clinicaltrials.gov/ct2/show/NCT00190502

Estimated Enrollment:	28
Study Start Date:	November 2000
Estimated Study Completion Date:	December 2007

This work was sponsored by the Ministry of Health, Czech Republic, and is being done in Prague.