Stem Cell Educator Starts Two Phase-II Trials

The Stem Cell Educator (SCE) is an attempt to cure established type-1 diabetes by exposing a patient's immune cells to umbilical stem cells, and then returning the cells back to the patient.  Each person had a blood draw, and then a particular kind of immune cell was separated from the blood and specially processed.  The processing phase uses umbilical cord stem cells previously donated by a third party.  The patient's own "educated" immune cells were then returned to the patient.  The stem cells did not go into the person; they were only used for the external processing.

In the last six months, two new studies have started, which I blog on below.  The first is in New Jersey and the second Beijing.

The New Jersey Clinical Trial (NCT02624804)

This study will enroll 10 people.  Everyone will be treated (no control group, no blinding).
The end points are mostly safety related, but there will be some efficiency related end points as well.  There is no mention of collecting efficiency data (such as C-peptide numbers, A1c data, blood glucose, insulin usage, etc.)

This study has started recruiting.  There was hope it would start in mid 2017, but the study needed some lab infrastructure which the medical center did not have at that time, hence the delay while the new labs were set up.

Recruiting at one site: Hackensack University Medical Center
    Hackensack, New Jersey, United States, 07601
    Contact: Mariefel Vendivil    551-996-5828    Mariefel.Vendivil@HackensackMeridian.org 
    Contact: Andrea Ortega    551-996-3923    Andre.Ortega@HackensackMeridian.org 

Clinical Trial Records: https://clinicaltrials.gov/ct2/show/NCT02624804
But note that this clinical trial record is out of date.  The study has not yet started recruiting, no efficiency end points are listed, and the completion dates are too short.

The Beijing Clinical Trial (NCT03390231)

This study will enroll 100 people.  Everyone will be treated (no control group, no blinding).
The primary end point will measure specific immune cells (which are involved in type-1 diabetes) one month after treatment.  Secondary end points will cover insulin sensitivity after a month, and A1c, blood glucose, and c-peptide measurements after three months.

They started in Nov-2017, and hope to finish in either July-2018 or Dec-2020 (see discussion below).

Recruiting at one site: Department of Endocrinology, Chinese PLA General Hospital
    Beijing, China, 100853
    Contact: Yu Cheng, MD,PhD    86 10 55499301    chengyu_301@163.com 
    Contact: Yiming Mu, MD,PhD    86 10 55499301    muyiming@301hospital.com.cn 

Clinical Trial Records: https://clinicaltrials.gov/ct2/show/NCT03390231

Discussion

Differing Results: This treatment has been previously tested twice before.  One of these clinical trials had strong results, but the other one had very weak results.  I've blogged on these in the past:
http://cureresearch4type1diabetes.blogspot.com/search/label/Stem%20Cell%20Educator

The researchers believe they understand why the two trials had different results, and are hoping to apply this knowledge to the current two trials, in order to get better results.

Date confusion: The FDA's clinical trial registration page requires researchers to list three dates for a clinical trial: start date, primary completion, and study completion.  (Once the trial starts, the first is known, while the second two are estimated.)  The primary completion date is when the last data for the primary outcome will be gathered.  The study completion date is when the last data for the study will be gathered.

For the Beijing study, the primary completion date is May-2018 and the study completion date is Dec-2020.  However, the primary end point is a month after treatment, while the secondary end points are either one or three months after treatment.  So that means the study completion date should be two months after the primary completion date, not 2 1/2 years!  My guess is that there are some two year end points as well, which are not listed in the clinical trial registry.   (The New Jersey trial also has two year end points which are not listed in the registry database.)

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 Feburary)

These two news updates are both interesting, and each probably deserves it's own blog entry.  However, since I'm backlogged, I'm putting them together in one posting (together with a Zhao update).  Even after this posting, I'm still a month or more behind.

Results from a Polish Trial of Polyclonal Tregs

What is being tested?  I call this technique "Polyclonal Tregs", but I'm not sure if it has a more official name.  Basically, the researchers remove one specific type of T regulator cell (called a "CD3(+)CD4(+)CD25(high)CD127(-)" T regulator) from a person with type-1 diabetes.  They use these cells to grow a lot more of these cells outside of the body, and then put them back in the body.  Since regulatory T cells naturally regulate the body's immune system, the hope is that they will prevent the autoimmune attack which causes type-1 diabetes.  Previous research in both animals and people has supported the idea that increasing regulator T cells may be a path to a cure.  

The Polish group tested this technique on 10 recently diagnosed (within 2 months) type-1 patients and compared them to 10 patients who did not get the treatment.  4 people got a lower dose (10 × 10^6 Tregs/kg) and 6 people got a high dose (twice as much).  In my opinion, they packed a lot of research into a small trial.  However there were no differences between the lower dose group and the higher dose group.  

Because it was an early trial, safety was an important consideration, and there were no safety related issues.  So that was good.  The publication had effectiveness data from a short (four month) follow up.  Basically:

• The treated patients generated about 50% more C-peptide than untreated.
• The treated patients used about half the injected insulin as untreated.
• A1c levels were about the same.

You can see that here:
http://care.diabetesjournals.org/content/35/9/1817/F1.large.jpg
Remember: grey bars are untreated and white bars are treated.

But remember, these people were within 2 months of diagnosis, and even at the end of the data presented here, were within 7 months of diagnosis, so well within the common honeymoon timeframe.  So I think longer follow on is critical to understanding how important these results are.  If these patients are still using half the insulin that untreated patients are using after 2 years, that would be wonderful.

The good news right now is that they already have one year follow up data, and expect to get it published later in 2013.  Beyond that, they have some improvements to the protocol, and hope to start a follow on trial with an updated protocol soon.  

The Other Polyclonal Treg Study ...

This is not the only study using this "Polyclonal Treg" method.  About two years ago a very similar study started in San Francisco.  Dr. Gitelman is running it, and results are expected in 2016.   I've blogged in the past about this trial here:
http://cureresearch4type1diabetes.blogspot.com/2011/01/possible-cures-for-type-1-in-news-jan.html

This trial has now enrolled its first two groups (out of four total).  I'm told all subjects are doing well with stable pancreas function. The researchers are currently in the middle of the 3rd group, and they anticipate completing the full study enrollment this year.  Each group gets 8 times as large a dose as the previous group so the last group will get about 500 times as much as the first.

... and the Ethics of Experimenting on Children

There is an obvious question here: If both studies started at about the same time, why does one have results 4 years sooner than the other?  I think there are two answers to this question.  The first is pretty simple: the Polish researchers published data covering 4 months after treatment.  The American researchers are gathering data for years.  But that only explains about 20 months of difference.

The second reason might be more important: The American researchers are only enrolling adults, people over 18 years old.  The Polish researchers enrolled children, 5-18 years old.  Obviously, when you are looking for recently diagnosed type-1 diabetics, there are a lot more to be found in the 5-18 year range than the 18+ year range.  By limiting recruitment to adults, the Americans have a much smaller pool of people, and it will therefore take them much longer to fully populate their trial.

But why are the American researchers only enrolling adults?  That answer is a combination of ethics and previous experience.  There is a general ethical principal (enshrined in various FDA rules, and international guidelines) that research should be done on adults first, before it is done on children, if that is feasible.  That makes a lot of sense, of course, but here we see the impact.  For a disease like type-1 diabetes, it is possible to recruit recently diagnosed adults, but it is far harder and slower.  So if we insist that the first bunch of patients are adults, it serves to slow down research disproportionately.

The Polish group had previously run a similar clinical trial in adults with a different disease (graft vs. host disease).  Now measuring safety in adults with one disease is not exactly the same as measuring safety in adults with a different disease, but it is similar.  Therefore, they could recruit children based on the safety profile with adults in the previous study.  Also, they could test different doses more quickly, again based on the previous experience.

Abstract: http://www.ncbi.nlm.nih.gov/pubmed/22723342
Full paper: http://care.diabetesjournals.org/content/35/9/1817.long (Thanks to ADA's DiabetesCare.)

Clinical trial record for the American study: http://clinicaltrials.gov/show/nct01210664

More Details on This Treatment

One way to view the immune system is a balancing act.  We want aggressive immune cells to attack foreign cells, but overly aggressive cells might attack our own beta cells and cause type-1 diabetes.  So we also want regulatory immune cells to keep the aggressive cells in line.  But we don't want those cells too strong, because then they would prevent an attack on the foreign cells.  In this view, type-1 diabetes can be seen as a too aggressive immune system, and therefor boosting the regulatory side might be a cure.

The regulatory cells which are been grown out (or "amplified" might be a better word) are general purpose regulatory cells.  That's a good place to start, but it would be even better if the researchers could multiply a regulatory cell that specifically targeted autoimmune cells (the "bad" cells that are attacking the wrong target).  Unfortunately, the technology is not there yet, although people are working on it.  But in any case, we need to start somewhere.

Below is a link to a study that suggests that newly diagnosed type-1 diabetic children have lower levels of these T regulator cells, than children who do not have type-1 diabetes.  (Although it was a small group.)  http://www.ncbi.nlm.nih.gov/pubmed/19454187

A Note About "Remission"

Some type-1 researchers use the term "remission".  Specifically, they use it to mean "Uses less than 1/2 a unit of insulin per kg of body weight per day".   Don't be confused.  Non-researchers think of "remission" as meaning "doesn't use insulin", but that is NOT how researchers use the term.   If your child weighs 40 kg (about 88 pounds), and uses 20 units of insulin, or less, then they are "in remission", and this does happen to some people during the honeymoon.


Perle Bioscience Starts two Phase-III Clinical Trials of Cyclosporine and Lansoprazole ("Prevacid")

Dr. Claresa Levetan at Perl Bioscience has filed the paperwork to start two very interesting studies.   Both studies are looking at a combination of Cyclosporine and Lansoprazole (commonly known as "Prevacid") as a cure for type-1 diabetes.  The two studies are identical, but one recruits honeymooners and the other established type-1 diabetics.  These are combo clinical trials exactly like many people have been hoping for, for years:  Cyclosporine is known to stop the autoimmune attack and Lansoprazole is known to encourage the natural regrowth of pancreatic beta cells.  Both are approved drugs (for other diseases).  Lansoprazole (as "Prevacid") is over the counter, so has a very good safety profile.  Cyclosporine has a more complex safety profile.  I'm sure if this study pans out, the relative safety of Cyclosporine is going to be an important topic of discussion.

Both studies are expected to enroll 200 people (half getting the treatment and half getting placebo).  They plan to start in September 2013 and end by March 2014 (so very quick).   There will be four groups: one group getting both drugs, one just getting Cyclosporine, one just getting Lansoprazole, and one getting neither.  This is good experimental design for a two drug combination. They will measure C-peptide in response to eating, A1c, and insulin usage.

Note on phases: The researchers running this trial have described it as a "phase-III trial", however I consider it a phase-II trial.  Why the difference?  For me, size is the most important issue.  At 200 people, it is right on the border between what I consider phase-II and phase-III for clinical trials aimed at curing type-1 diabetes.  (For comparison, all eight recent phase-III trials have involved 300 people.  That seems to be the magic number for FDA approval as a pivotal trial in type-1 diabetes.)  Also, this combination of drugs has never (to my knowledge) been tested on type-1 diabetics before.  Since both drugs are approved for other things, I'm willing to call it phase-II (rather than phase-I), but with zero experience with the combination, I'm not willing to call it a phase-III.

Of course, the important question is not what I consider the trial, or even what the researchers consider the trial, the real question is how will the FDA consider the trial?  That remains to be seen, but remember: since both drugs are already approved for other uses, your doctor can prescribe this combination right now.  It would be an off label use.

The researcher working on this, Dr. Claresa Levetan, previously worked on CureDM, and sold that to Sanofi-Aventis two years ago.  My understanding is that they are developing the CureDM technology (a peptide which stimulates beta cell development) for the type-2 market.

Wikipedia on Lansoprazole: http://en.wikipedia.org/wiki/Lansoprazole
Wikipedia on Cyclosporine: http://en.wikipedia.org/wiki/Cyclosporine
Clinical Trial Record (Honeymoon): http://www.clinicaltrials.gov/ct2/show/NCT01762644
Clinical Trial Record (Established): http://www.clinicaltrials.gov/ct2/show/NCT01762657

More Background on
http://www.ncbi.nlm.nih.gov/pubmed?term=3125434

Zhao Updates from Spain 

Previous blogging on Zhao's "Stem Educator" is here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Zhao

These two links go to Spanish language news reports on people getting treated with the Stem Educator in Spain.  I found that using Chrome to translate them into English worked pretty well for me:
http://www.rtpa.es/ciencia:El-HUCA-busca-financiacion-para-un-proyecto-pionero-en-el-tratamiento-de-la-diabetes_111357993752.html
http://diabetesmadrid.org/2012/12/05/el-huca-lidera-la-lucha-contra-la-diabetes/

The basic summary is that the clinical trial in Spain has started.  Two patients had their first session of stem cell educator therapy in December 2012.  The plan is to treat a total of 30 people.  (Not sure how many are placebo and how many will get the real treatment.)  The two treated so far have had type-1 for over 10 years.  This trial is expected to end in September 2014, but we will not know with certainty until it is fully enrolled.

JDCA State of the Cure 2012


The JDCA (Juvenile Diabetes Cure Alliance) is trying to focus more research dollars into cure research (as opposed to treatment research, cause research, etc.)  They publish research papers, which are often quite interesting.  They use my blog as a source, and we sometimes discuss various research issues.

The article below is their year end summary, and well worth a read.  Although I certainly don't agree with everything in it, it is a rich source of information.  (I especially object to their not including Dr. Zhao's research as a possible cure, and JDCA did cover Zhao in a report after this one.)

http://www.thejdca.org/wp-content/uploads/2012/11/State-of-the-Cure-report.pdf

A Final Note

In the past, I have included a specific "thank you" when people reviewed a blog posting, provided information for it, or pointed out the news to me (when only one person did so).  Unfortunately, keeping track of who helped with what, and also making sure it was OK to thank them by name, has become too much of a burden.
So I'm going to stop doing that.

I'm very sorry I will not be able to thank people individually for their help in writing this blog.  But I do want to thank:

• My wife, who improves my English, and puts up with the hours I spend yelling at the computer when I should be talking with her.
• All the researchers who have answered my questions and provided extra information.
• Everyone who emails me when they see news that I should cover.

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/

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

Summary of Three Months of New Trials

This is a quick summary of all of the new clinical trials into type-1 that started between July 1st and October 1st, 2012.  These are trials which were entered for the first time during these three months.  I got this list from the FDA's clinical trial database, which is on line here:
www.clinicaltrials.com

37 New clinical trials in total
-- ----------------------------
14 Delivery / New Insulins / New Test Kits
06 Long Term Side Effects
03 Artificial Pancreas
03 CGM
01 AAT
01 Psychological
08 Other (1 of these was a Vitamin-D trial)

My only comment is that only one of these (the AAT one) might lead to a cure.  That's not a lot.

What's Up with AAT (alpha-1 antitrypsin)?

The new AAT study reminded me that there are now a total of five AAT studies ongoing, and that's enough to have a summary of AAT research, so here it is.

I've blogged on AAT before, here:
http://cureresearch4type1diabetes.blogspot.com/search/label/AAT
and some background on AAT is here:
http://cureresearch4type1diabetes.blogspot.com/p/drugs-and-treatments-in-clinical-trials.html


Study Number  Phase Size Sponsor   Duration  Completion Date
NCT01304537     I    24  Kamada    1 year    November 2012
NCT01319331     I    15  Omni Bio  2 years   September 2013
NCT01183468    II    16  NIAID     2 years   November 2014
NCT01183455    II    66  NIAID     2 years   November 2014
NCT01661192    II    24  Kamada    3 years   December 2016

Initially, that looks pretty good.  Unfortunately, one of these trials (the second one, by Omni Bio) released some early data, and this data was only slightly positive.  The treatment showed no benefit to people with established type-1, and relatively small improvements to people who took it soon after diagnosis.  No specific numbers were published, which I consider to be a bad sign.  The first complete study (Kamada's) should be done very soon, and that should give us a much better "feel" for the level of success.  By 2015 we should have results on four studies, which should be definitive.
Another Trial for Zhao's Cell Educator (if they raise money)

I've previously blogged on Zhao's work here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Zhao

It looks like researchers in New Zealand are raising money specifically to replicate Dr. Zhao's work.

Here is their description of what they want to do:

In the first trial we would infuse activated stem cells back into the patient and measure their ability to switch the behaviour of aggressive T lymphocytes to ‘peaceful’ T regulator cells. Trials like this are occurring internationally but without the activation step, and results are not yet clear. The second trial will be similar to the Chicago study [Zhao's trial, which was actually done in China]. The stem cells from each person will be used in the laboratory to ‘condition’ their white blood cells in the laboratory, before re-infusing the white blood cells.

I don't usually put information about donating money in my blog posts, but I've gotten several requests for information on how to help fund Zhao.  I don't know how an individual can do that effectively, but the researchers in New Zealand have these instructions:

If you would like to make a donation towards this cause, then the Spinal Cord Society NZ website www.scsnz.org.nz provides a means for you to do that. An email plus a donation will ensure that your contribution goes only towards the joint SCSNZ-Diabetes research work.

Please remember: I know nothing about these guys or this organization.  I am not endorsing them!

News: http://www.scsnz.org.nz/assets/Uploads/diabetes-winter-2012-focus-2.pdf
News: http://www.stuff.co.nz/national/health/7914909/Stem-cell-study-holds-diabetes-cure-promise

I want to especially thank Brian Braxton for the information and sources he provided, and everyone else (there were several) who pointed this news out to me.

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/

Zhao Starts Phase-II Clinical Trial of "Stem Cell Educator"

Zhao Upgrades His Clinical Trial to Phase-II

I've previously blogged on Zhao's work here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Zhao

He published his phase-I results in January 2012, and in July, he changed the basic nature of his clinical trial record from phase-I/II to phase-II.  Change a trial from I/II to II is uncommon, but it does happen. (The more common thing is to create a new clinical trial for the phase-II study.)  But the whole point of a I/II trial is that it can turn into a II if things go well.  In January, Dr. Zhao published data on 12 treated patients and 3 placebo patients, but the clinical trial record was for 100 people, so the remaining 80+ people (I assume) will be his phase-II trial.

Notice that it took him only 6 months to "turn around" from publishing his phase-I study to starting the phase-II study.  That's quicker than most research I follow.

The trial record was also updated in Augest and October, so if you group together all the changes made, here is a summary of the changes:

• Phase goes from 1 to 2.
• A second trial site has been added.  In addition to China, patients in Spain can enroll at Hospital Universitario Central de Asturias.
• Purpose goes from "Safety/Efficacy" to "Efficacy" Study.
• The study was expected to complete in 2012 now is expected to complete in September 2014.
• Sponsor goes from University of Illinois to Tianhe Stem Cell Biotechnologies (Zhao's company).
• Trial design went from single blind to open label, and 
• There is no mention of a placebo or control group.

Also, Tianhe (Zhao's company) has also started a separate clinical trial aimed at using this same technology to cure/treat Alopecia Areata, which is another autoimmune disease involving T-cells. The trial is being run in China.

Finally, another researcher (Dr. Mark Atkinson) has been funded by JDRF for a year to test Dr. Zhao's Cell Educator "ex vivo" (not in living organisms, but in tissue samples or similar). The goal is to independently verify parts of Dr. Zhao's results.  You can read details here:

JDRF "lay abstract": http://onlineapps.jdfcure.org/AbstractReport.cfm?grant_id=38534&abs_type=LAY

Discussion

From my point of view, there is both good and bad news here.  Going from single blind to open label is a step backwards, in my mind.  Not having a placebo group is also going the wrong direction.   On the other hand, another site, more people, and an end point in the near future are all good things.

Corporate web site: http://www.tianhecell.com/
Clinical Trial Record: http://www.clinicaltrials.gov/ct2/show/NCT01350219

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/

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

Status of DiaPep277

The good news: DiaPep277 has finished one successful phase-III clinical trial, and is expected to finish enrollment of the second (and last) one in the next few weeks.  Once that second one is fully enrolled, there is a two year wait for it to complete, and then (if it is also successful) another year or two for marketing approval, and then (with a lot of luck and good results) DiaPep277 will be generally available in the US.  The EU timeline would be similar.

The bad news: The results from their first phase-III clinical trial are no where near a cure.  The results so far have been a statistically significant, longer and stronger honeymoon phase. Something like 25% more insulin production in the year after diagnosis.

Discussion: So, if we assume that DiaPep is successful from here on, and gets approved,  and works as well in actual use, as it worked in this first phase-III trial, how good is that news?

If you are a glass is half full kind of guy, then you can say things like this: DiaPep is the first treatment that actually changes the path of type-1 diabetes.  In addition to lengthening and straightening the honeymoon period, it may result in fewer lows and fewer highs, which means fewer long term complications of the disease.  Plus, future research may well make it better than it is now.

If you are a glass is half empty kind of guy, then you can say things like this: DiaPep's impact is only for a year in the honeymoon phase, and it's not even clear that it's good effect will have any impact at all in the long term complications of the disease.

But in any case, I think we are still 4+ years away from general availability.

Zhao in Spain

Drs. Delgado and Otero at Hospital Universitario Central de Asturias (in Spain) are going to start a clinical trial of the Zhao research. (Previous blogging here: http://cureresearch4type1diabetes.blogspot.com/search/label/Zhao)  They expect to treat 30 people, and to start in the fall.  


News: http://www.hayalternativas.org/noticias/?p=1015 (in Spanish)

Non-Cure Trial to Reduce Hypoglycaemia

I thought this study was interesting, even if it is not aimed at curing type-1 diabetes.  The goal here is preserve alpha cell function.  Alpha cells are cells in the pancreas that generate various hormones, but not insulin.  Almost all of the current research on type-1 diabetes is focused on beta cells (which generate insulin), but type-1 also effects alpha cells.  So this research is aimed at trying to preserve the body's natural glucagon response to low blood sugar events.

The news here is that this trial completed enrollment on 7-March-2012, and since it takes 3 months to gather the data, they should have it all by now.  So we just need to wait for them to publish the results.

Clinical Trial: http://www.clinicaltrials.gov/ct2/show/NCT01272583

Great Blog (by Riva) on Meter Accuracy

This is a great posting on meter accuracy:
http://www.huffingtonpost.com/riva-greenberg/glucose-meters_b_1624263.html

Compares different meters to each other.  Compares the same meter used at different times.  Compares household meters to blood lab readings.  What more could you want?

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/

More Information on Zhao's Stem Cell Educator

Zhao's Stem Cell Educator phase-I trial, which I blogged about here:
http://cureresearch4type1diabetes.blogspot.com/2012/01/zhao-et-al-tianhe-publish-successful.html
has generated a lot of interest, so I've done some extra research on it, and this blog contains what I've learned.

Good News First

The best news that I gathered about this work, is that the published paper is not the final report on a 15 person clinical trial.  Is is the initial report on the first 15 people treated in a clinical trial which is on-going and continuing to enroll more people.  This is great news, for two reasons.  First, because it means that they are continuing to follow those 15 people.  With a little luck we can look forward to follow up reports describing what happens to these people in another year, two more years, and so on. Also (again, with some luck) we can expect reports on 50 people, 80 people, maybe even more people.  All this data is already being gathered as part of the current clinical trial.

The next good news is that the researchers very much want to start a clinical trial in the US.  That will take some time, due to regulatory approvals.   If they do start a trial in the US, it is likely to be similar to the one in China [d1].

Several people have asked me how this treatment works, and this is how it was explained to me:
First, there are proteins which train the body's immune system not to attack itself [d2].  These proteins are found on stem cells, so exposing immune system cells to the stem cells has the effect of training the immune cells not to self attack.  Second, these researchers believe that there are cells in the pancreas which are ready to become beta cells[d3], and also that there are stem cells circulating in the blood stream [d4] which can turn into beta cells.  They don't know which of these two routes are creating the new beta cells, but they believe some combination of them is creating enough beta cells to cause the large decrease in injected insulin and increase in C-peptide.

One question that I had was basically this: "Do you really think that the body can regrow so many beta cells that it can generate 25 to 38% of it's own insulin in just a few weeks?  No one else has seen anything like that when using other techniques to stop the autoimmune attack."  The answer was that was exactly what they thought was happening.  First, it was the theory that explained the results the best, and second, it was what they saw in their animal studies, so they were not surprised to see it in people.  We can only hope this is correct.  Future trials will tell.

I did ask if there was anything special about stem cells from the umbilical cord, which made that particular type of stem cell important to the research.  The response was no.  They expected that many types of stem cells would work, but they choose to use umbilical cord cells because they were convenient to use and  easy to get, as compared to other types of stem cells.

The researchers have professional connections to researchers in Amman, Jordan and Hue, Viet Nam, and that is why they might start clinical trials in those places.  Because there will be fewer regulatory hurdles, those studies could start more quickly than the one in the USA.  My feeling was that if they did studies in those place, the studies would be similar to the Chinese one, but they would try to improve ("optimize") the procedure.

Finally, I want to say that I have heard from several different sources (all private communications) that the researchers are in touch JDRF to discuss the funding of future studies.   They may well be in contact with other organizations, I hope that they are, but I've gotten specific information about JDRF.

Not-So-Good News Second

It does not look like this is the kind of treatment that the FDA is likely to allow under the "surgical exception" that I discussed in the previous discussion of this research.  So therefore, it is likely that a full FDA approval cycle will be needed, so about 4 clinical trials (and I'm not sure if this first one would count [d1]).

I do not think that any of the patients were ever free of injected insulin.  So I don't think they cured anyone, even temporarily.  On the other hand, I got the feeling everyone was helped to some degree.  In some research, there are some people where it just doesn't work.  Those people are sometimes called 'non-responders" and I think there were few to none "non-responders" in this trial.

More Reading

The research below was all done in mice so I have not read it in detail, but it is listed, for people who want a lot more details.

http://www.omicsonline.org/2161-1025/2161-1025-1-104e.pdf (2011)
http://www.sciencedirect.com/science/article/pii/S1568997210001795 (Cord Blood Background 2010)
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0004226 (Mice Cure 2009)
http://www.springerlink.com/content/0640621007560k70/ (2009?)
http://www.sciencedirect.com/science/article/pii/S0006291X07012715 (Beta Cells from Blood 2007)
http://www.sciencedirect.com/science/article/pii/S0165247806002379  (2007)
http://www.sciencedirect.com/science/article/pii/S0014482706001558 (Why Stem Cells 2006)

Discussion and References

[d1] Unfortunately, the FDA doesn't give much weight to data from foreign trials, so things learned in other countries need to be relearned in the US, so the FDA will fully consider it.  I'm quite worried that even once the study starts in the US, they might be limited to a very small phase-I study, because the FDA will not consider the Chinese study as proof of safety, even it if involves more people than an American phase-I study.

One of the researchers involved told me a story -- equal parts funny and shocking -- about trying to get approval for a medical device that had been tested in Australia.   The FDA would not accept data from Australia.   They wanted studies re-done in the US, so they could review that data, as though Australia was some corruption ridden, third world country, without a quality regulatory system!

[d2] Although I'm not sure exactly which proteins they are referring to, the general idea that a protein could re-educate the immune system is not controversial.  Drugs like DiaPep277 and other antigen specific treatments are based on this idea.   Haller's work in Florida is based on similar ideas, although his effectiveness was no where near what Zhao and crew see.

[d3] Although this idea was controversial a few years ago, I think that consensus is shifting.  There is now some research that shows that stem cells already in the pancreas may be able to grow into beta cells.  Even stronger was a paper published last year (sorry don't have the reference handy) which showed very specifically that in mice, alpha cells in the pancreas could turn into beta cells that produced insulin in response to sugar. Plus there is the Joslin "Medalist" study (more than one) and  Dr. Faustman's paper just published last week which adds support to this same idea.

[d4] This was based on their own previous work in mice.  But I know that other researchers have been looking into this area.  Although the research in mice is not conclusive, there is some supporting evidence for this, in addition to the Zhao group.


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/

Background on Four Types of Stem Cell Research

This blog post contains general background information on four types of stem cell research.  I'm writing it because the term "stem cells" is used to describe several different lines of research, and it is important not to mix them up.  Good news from one type of "stem cell" research should never be used to suggest that a different type of "stem cell" research is going to be successful.

Quick Summary
Here is a very quick summary of four types of stem cell research:
1. "Burt"  Reboots the body's immune system to stop the autoimmune attack.  First, the patient is given very powerful drugs to shut down their immune system, then they are given drugs which causes the body to mobilize it's own adult stem cells to rebuild the immune system, without the autoimmune flaw.  Has resulted in the best cure results of any research to date, but is also the most dangerous.
2. "Zhao"  Patient's immune cells are removed and stem cells from the umbilical cord used to help retrain them   to stop the autoimmune attack.  The immune cells (without the stem cells) are then put back in the patient.  Good results and appears to be much safer than Burt.
3. Several companies (example: Viacycte) are attempting to grow new beta cells from stem cells.  They are taking undifferentiated stem cells and trying to find the recipe to cause those stem cells to differentiate into beta cells.  None of this work is in human trials right now.
4. Many stem cell clinics (example: Xcell) will infuse bone marrow stem cells in the hopes that this will cause the patient to regrow beta cells and improve their type-1 diabetes.  Although many clinics will provide this service, I have never seen a peer reviewed study showing that it improves type-1 diabetes.

How They Are Different

Burt
Burt's research does not use external stem cells.   Rather, the patient is given a drug which "mobilizes" their own internal stem cells.  People have several different forms of adult stem cells in their body.  Part of Burt's protocol is to give the patient a drug which is well known to cause them to generate more of their own bone marrow stem cells, and cause these cells to be released into the blood stream.

Zhao
Zhao's research is very different from the rest, because he is not trying to grow beta cells from the stem cells.  Instead, he is using them to train the immune cells not to attack beta cells.  (This is sometimes called "curing autoimmunity".)

You may ask, "why should stem cells cure autoimmunity?"  It's a very good question, and I don't know the answer.  But I'm not an immunologist, and for me it is far more important that a treatment work, than that I understand how it works.  Many treatments are used for years before we understand exactly why they work.  (Aspirin is a 100+ year old example.)

Beta Cells from Stem Cells
There are several companies working on ways to differentiate beta cells from stem cells.  Generally, they differ from each other two ways.  First, in the kinds of stem cells they start with (embryonic from an embryo, embryonic from cord blood, or different types of adult cells or adult stem cells that have been treated in some way to make them undifferentiated).  Second, in the recipe they use to transform these undifferentiated stem cells into beta cells.

Stem Cell Clinics
These guys harvest bone marrow stem cells from a person, and then put them back into that person or a different person.  They differ in exactly how they put the stem cells back in (in the blood or directly in the organ that needs them), and also in what processing or separation is done to the bone marrow cells before being put back.

My opinion of the stem cell clinics is very low.  They are a cash up front business without evidence that they help anyone.  For example, to approve a new drug, the US FDA requires four clinical studies to show that it works and is safe.  Currently, there is not one stem cell clinic, that has published even one peer reviewed study (that I have found), that shows that it works.

Most of these clinics are in third world countries, but there was one, called Xcell in Germany.  Years ago, Xcell said that they were running two studies to show that their treatment would help type-1 and type-2 diabetics, respectively.  Neither of these studies were ever published in a peer reviewed journal, and last year the German government shut down Xcell after an 18 month old baby died of complications from a stem cell treatment at the clinic.  (And this after a 10 year old boy almost died after the same procedure!)

I often see these clinics cite Burt's work as peer-reviewed, scientific research that suggests their clinics are on the right track. But this work is wildly different from the work done at these clinics and the success of one does not support the treatment of the other.  As an example: Burt uses three drugs in his trial.  These clinics sometimes use one of those drugs, and sometimes none at all.  They never use all three of them, and never get close to the same procedures that Burt uses.  My guess is that you will see these guys citing Zhao's work soon as well, even though Zhao is using a totally different type of stem cells and not even putting in the patient.


Other Terms to Understand

Adult vs. Embryonic
These are the two types of stem cells that we have heard about for the longest, and the loudest.  Much of the arguments about stem cells (especially in the US) are phrased in terms of Adult vs. Embryonic.  However, I have come to believe that, while this difference is critical religiously, politically, and socially, that it is not important in terms of research aimed at curing type-1 diabetes.

The confusion comes from the fact that in the early days of stem cell research, embryonic stem cells were the only undifferentiated stem cells known.  So when people talked about the power of embryonic stem cells, they were often talking about the power of undifferentiated cells.  However, now we can get several different types of undifferentiated stem cells from adult sources, and from different embryonic sources.

Differentiated vs. Undifferentiated
A better way to talk about stem cells, is undifferentiated (and if so, what is their source) vs. differentiated (and if so, how were they differentiated). Differentiated stem cells are those which have already specialized into a specific type of cell. For example, a beta cell. Undifferentiated stem cells have the potential to do this, but have not yet done it. With the current research results, it appears that undifferentiated are not useful for growing beta cells in the simple minded way used by the current clinics. However, both Burt and Zhao have had success using them in other ways, and undifferentiated stem cells have not yet been tested (in people) as a source for growing beta cells.
A lot of the recent news in stem cell research is reporting on different ways to create different types of undifferentiated adult stem cells.  These different type stem cells might have different properties and be good or bad at different things, but we really don't know yet.

Another type of research news that we have gotten recently, but is not as common, is success in turning different types of undifferentiated stem cells into beta cells.  It is especially important to turn them into beta cells that generate insulin when presented with sugars.  The has been some success at this, but none of it has progressed into human trials (that I know of) as yet.  Even if they did, we would still need to either encapsulate them or cure the autoimmunity before they would be a cure for type-1.

Self vs. Others
Any kind of stem cells can be gotten from the person being treated (self) or from someone else (others).  This is true for both embryonic stem cells, and adult stem cells.   You can get embryonic stem cells (for example, from the cord blood) and use them on the person you got them from.  Or you can get adult stem cells from that same person.   Self stem cells are going to have fewer immune issues than those from others.

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/

Zhao et al (Tianhe) Publish Successful Phase-I Results (in non-honeymoon diabetics)

In my opinion, this is big news.
It's the result of a phase-I study, published in BioMed Central's Medicine Journal (which is peer reviewed) by a group of researchers working at the University of Illinois at Chicago and in China.

What Did These Guys Do?

This trial was done on people with established type-1 diabetes.  Each person had a blood draw, and then a particular kind of immune cell was separated from the blood and specially processed.  The processing phase used umbilical cord stem cells, but not the patient's own umbilical cord.  (This was generic umbilical cord stem cells, not from the exact person being treated.)  The immune cells were then put back in the person.  The stem cells did not go into the person; they were only used for the external processing.

The goal was to teach the body's immune system to stop attacking beta cells.  The researchers refer to this as "education", and refer to the processing device used as an "Stem Cell Educator".

The treatment was done once and I think it took about 10 hours.  Patients were in the hospital for 2 days, but it's not clear to me if that was due to an over abundance of caution (this was a phase-I study, after all), or if it was really needed.  This trial was done at the General Hospital of Jinan Military Command (Jinan, Shandong, China).  The lead author of the paper is Yong Zhao, is an Assistant Professor at the University of Illinois at Chicago.

The patients averaged about 29 years old, and had had type-1 for an average of about 8.5 years.  Patients were followed for a total of 40 weeks, but most of the results data was gathered at 4, 12, and 24 weeks after the procedure.

The researchers divided their patients into three groups.  Group A (6 people) had some insulin production before treatment. Group B (6 people) had no measurable insulin production before treatment, and Group C (3 people) also had some insulin production  before treatment, but they got a "sham" (or placebo) treatment. 


What Results Did They Get?

There were no significant safety issues during the trial.

Average Daily Insulin Usage:
Group A's insulin requirement was down 38% at 12 weeks (from about 36 to 22 units/day).
Group B's insulin requirement was down 25% at 12 weeks (from about 48 to 36 units/day).
Group C's insulin requirements didn't change.

Note: earlier version of this blog had a typo in Group B's starting insulin units/day.  Fixed here.

Average A1C levels:
Group A started at 8.73 and dropped to 7.67 at 4 weeks and to 6.82 at 12 weeks (almost 2 points overall).
Group B started at 12.2 and dropped to about 10.5 at 12 weeks.
Group C started at 9 and was at 8.7 at 12 weeks.
Note: I consider a drop of 1 to be important, although some researchers consider even a drop of 0.5 as important.  Here we have drops of over 1.9 and 1.7.

Fasting C-peptide (ie. Body's ability to generate "basal" insulin at background levels)
All these numbers are average ng/ml, and are very approximate based on graphs in the paper.
Group A: Starts at about 0.35 and ends at about 0.8 at 24 weeks.
Group B: Starts at about 0 and ends at about 0.5 at 25 weeks.
Group C: Stays at about 0.4 at 4, 12, and 24 weeks.
Note: Non type-1 diabetics generally have a fasting C-peptide level between about 0.5 and 2.0.  The paper's authors felt that 0.6 was the lower bound of normal C-peptide in the population being studied.  So it is possible that Group A has moved into the bottom of the normal (for non-type-1 diabetics) range.

OGTT C-peptide (ie. Body's ability to generate "bolus" insulin in response to food)
All these numbers are average ng/ml, and are very approximate based on graphs in the paper.
Group A: Starts out generating 1 after a meal, at 4 weeks generates about 1.6, and at 12 weeks about 1.7.
Group B: Starts out generating about 0 after a meal, at 4 weeks generates about .05, at 12 weeks about 0.35, and at 40 weeks about 0.6.
Note: I don't know what "normal" is for this test, so can not compare either group to non type-1 diabetics.

The paper also contains data on immune system changes which the researchers felt showed significant improvement in autoimmunity.    I can not evaluate those results.

Also interesting, the researchers are very specific in saying that they think this study shows that beta cells do regrow, in people, if the immune system stops attacking them:

Notably, our clinical data provide powerful evidence that reversal of autoimmunity leads to regeneration of islet β cells and improvement of metabolic control in long-standing T1D subjects.

My take on all this data is that there is no question that the body is generating more of it's own insulin after this treatment than before.  And that happens in people who have had diabetes for a long time, and who are not generating any of their own insulin before treatment.  That's huge.  The results are large enough so that type-1 diabetics would see the improvement in their insulin usage and A1C numbers.

Discussion

Obviously, there is a lot of issues to discuss here:

Possible Conflict of Interest

I hate to start off with discussion of a conflict of interest, but in this case, the situation makes me nervous, so I'm discussing it first.  In the paper's pre-publication version, it says:

Competing interests 

The authors declare that they have no competing interests.

However, the unique and specialized equipment that they used in their clinical trial was manufactured by Tianhe Stem Cells Biotechnology.  This equipment was central to the clinical trial.  However, that company is connected to three of the authors (including both first and last authors).  Here is a quote from the University of Illinois web page:

Tianhe is a stem cell biotechnology company commercializing the inventions emanating from the labs of Drs. Zhao, Mazzone and Holterman within the Departments of Medicine and Surgery at the University of Illinois at Chicago. With operations in both Illinois and overseas, the Company is pursuing the application of stem cells for the treatment of autoimmune diseases.  Tianhe is initially pursuing the treatment of Type 1 diabetes through a clinical system which extracts the patient own stem cells and utilizes them to re-educate the patient’s faulty immune cells to prevent future immune response to the patient’s own insulin producing cell.    [from http://otm.illinois.edu/sites/all/files/files/otm-annual-reportseptember-1final.pdf]

Obviously, I don't know the exact financial details involving the University, Tianhe, and the three researchers, but I would like to see more details before I accepted the claim that the authors had no competing interests!  It certainly sounds like the researchers are testing equipment that they will make money off of, if it works.  On the other hand, if this relationship gets this research to market quicker, and the research helps people with type-1 diabetes, then I'm all in favor of it. :-)

Missing Data

There are a couple of obviously missing data points.  For example, Group A's 40 week post-meal C-peptide numbers are not reported.  And 40 week fasting C-peptide data is not reported for any group.  The trial design only collected insulin use and A1C data at 12 weeks, which is too bad.  I would have like to see it at 24 or even 40 weeks as well.

There are also a few other odditites.  For example: in Groups A and B (treated), about 2/3 of the patients are women, but Group C (placebo) is all male.  Also, the Group B A1C before treatment averaged 12.2, which is a lot higher than you would see in the US (I hope!)

None of this is particularly unusual for a phase-I trial; and none of it makes me nervous about the results.  It just makes me want to see data from a larger phase-II study.

Next Steps To Market

Getting a cure to market requires three things:
1. Scientific success.
2. Engineering and corporate success.
3. Regulatory approval.

This study is a solid, successful phase-I clinical trial.  No doubt (in my mind) about that.
Plus, it is the first time this has been used in people, as far as I know, and there are obvious ways to improve it.  More blood could be put through the machine.  The blood could spend more time in the machine.  It could be used repeatedly, etc.  The classic goal of a phase-II trial is to figure out the best dosing, and I think these guys are well positioned to do that.

There is a clear engineering path to market.  The "Educator" equipment is produced by Tianhe corporation, and I would expect that once the equipment is for sale, many doctors would be able to use it.  It sounds to me like there is a clear way to make money off this, and so I would expect that (if it works scientifically) Tianhe will have no problems getting funding and getting the corporate structure required to build a business around using their equipment to treat/cure type-1 diabetes.

As for regulatory approval, I think there are two paths forward.  The normal path to approval is a phase-II trial, and then two phase-III trials.  The already completed phase-I trial took about a year, I would expect the phase-II to be about that long, maybe a little longer, and phase-III to be still longer.  However, if they are successful and well funded, these guys could get to market in less than 10 years.  Of course, the next question is, what will they make it to market with?  Will the thing available be a treatment?  A cure?  A temporary cure?  Fewer long term complications?

There is a second, much faster, path to approval, called the "surgical procedure exemption".  I do not know all the details, but the FDA does not require that surgical procedures be proven "safe and effective" before a surgeon uses them.  Under this exception the FDA does allow some treatments to be sold without full approval, if those treatments involve taking something out of the body, processing it in some simple ways, and then putting it back in.  I don't know if this "educator" process would qualify or not.

I know some people are nervous about research done in China, and especially at a Chinese military hospital.  I think this is my first detailed blog post on research done in China.  I do want to point out that this trial has ethical approval from the review board at the University of Illinois at Chicago, and that it looks to me like the researchers followed US FDA standards in the trial, and international standards where applicable.  I don't have detailed knowledge of FDA requirements, but it does look to me like, even at this early stage, these guys are working to eventual US FDA approval.

News Coverage: http://www.medscape.com/viewarticle/756691?src=emailthis
Clinical Trials Record: http://clinicaltrials.gov/ct2/show/NCT01350219
Full Paper: http://www.biomedcentral.com/content/pdf/1741-7015-10-3.pdf

Some general information on C-peptide values:
http://www.diabeteshealth.com/read/2000/09/01/2020/interpreting-your-c-peptide-values/

A Personal Note
2011 was an awful year for following clinical trials aimed a curing type-1 diabetes.  We lost three phase-III clinical trials, and started zero new ones.  In phase-I and phase-II trials, the successes seemed small; the failures, great.   These results are a wonderful way to start 2012.

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.
Blog: http://cureresearch4type1diabetes.blogspot.com/