Saturday, December 20, 2014

Phase-II Results from Rebooting The Immune System To Cure Type-1


First, a discussion about naming.  In the past, I've referred to this treatment as the "Burt" treatment, because that was the senior (last listed) author of the first paper I saw on it, and because I didn't have a better name for it.  I haven't seen Dr. Burt's name on clinical trial for this treatment in many years, so it's no longer an appropriate name.  But I don't have a better name.  In any case, you can read my previous blogging about this treatment under the label "Burt" on my blog:
http://cureresearch4type1diabetes.blogspot.com/search/label/Burt

Second, a little background. The original clinical trial of this treatment, in Brazil, was one of the very few clinical trials which actually cured people of type-1 diabetes. I know that is a provocative statement, so let me be clear: Some of the people treated in this trial did not need to use external insulin (yet still had reasonable A1C numbers while eating normal diets) for as long as the study ran. Some of these people were followed for years. This was not just a "couple of weeks" or even a "couple of months" event.

Third, some important safety issues. Basically, the treatment is to "reboot" the immune system, hobbling the immune system, and then treating it so that when it comes back, it does not attack the body's own beta cells. There are two serious safety issues here: first, during the time the immune system is down, the patient must stay in an isolation ward in a hospital, and is subject to opportunistic infections, which can cause death. Second, the act of shutting down the immune system is a big deal, and might cause problems "down the road". Cancerous tumors are a particular worry. Neither of these risks is completely unknown. Very similar immune system "reboots" are used today to treat cancer, and some other autoimmune diseases and their safety is understood. Never the less, the level of risk is higher than other possible cures for type-1 diabetes.

The Studies

This paper is not reporting on the results of one study.  Rather, it was reporting on a pool of patients enrolled at three different sites, one in Poland and two in China.  There were a total of 65 people included (24 in Poland, and 13 and 28 in China).  All studies enrolled people as young as 12, while the Polish study limited recruitment to the first 6 weeks after diagnosis, the Chinese studies accepted people for a year after diagnosis, but these are all honeymoon diabetics.  There were a few other differences in experimental procedures, as well.

The Results

The following points are all quotes from the abstract:
  • A total of 59% of individuals with T1D achieved insulin independence within the first 6 months
  • 32% remained insulin independent at the last time point of their follow-up
  • All treated subjects showed a decrease in HbA1c levels and an increase in C-peptide levels compared with pretreatment.
The authors' summary of their own results (also quoted from the abstract) is:
  1. That remission of T1D is possible by combining [bone marrow stem cells] transplantation and immunosuppression; 
  2. That [their procedure] represents an effective treatment for selected individuals with T1D; and,
  3. That safer ... therapeutic options [based on bone marrow stem cells] are required.
And I think that's an excellent summary.

Here are some other points that I'd like to make:
  • Of the 65 people reported on, one died of sepsis; obviously, this is the worst adverse effect possible.
  • 34 people experienced adverse effects (65 events in total).  There was no published data on severity of these events.   As an example, the most common adverse event was fever, but there are no notes on how serious or threatening the fever was.  Alopecia was the second most common adverse effect.
  • The earlier in the honeymoon period that a person was treated, the more successful the treatment.
Discussion

There are lots of interesting discussion points in here, and I don't have time or space to go into all of them, but here are a couple:

The researchers believe that a specific type of immune cell, called a CD34+, is critical to success of this technique. Remember that the immune system has many different types of cells, which are often named based on proteins on their outside coating which have these "CD" numbers.  CD34+ is not a cell I have seen specifically "called out" in previous research done in people.  However CD34+ cells are found in umbilical cord blood, which has been used in human research, as well as in bone marrow (as in this trial).

The researchers did measure the long term health of the immune system after treatment, and their summary was "Immune system recovery was rapid and complete".  So they found no evidence of long term weakness in the immune system after this treatment.

What is the future direction of this work?  The researchers discuss two paths for future development of a safer cure based on this work.  The first path is to improve the treatment, by using less immunosuppression at the start, and stronger drugs to prevent infections during treatment.  There are many different immunosuppressive drugs in use, and it may be that a safer drug (or drug combination) can be used in the future.  Similarly, there are many drugs designed to prevent infection by bacteria, viruses, etc.  and it may be that there is a better combination of these drugs available. The second path, is to make the treatment more effective, possibly by increasing the number of CD34+ cells infused back into the patient.

Is this treatment a cure?  That depends on your view of safety.  With a death rate of 1 in 65, I think few people would consider this a cure.  However, if you assume that someone with type-1 diabetes lives (on average) 5 years less than someone without, then in an actuarial (purely mathematical) sense, this treatment does extend average life. This is comparing shaving a few years off of many people's lives vs. cutting a few lives very short.  While this might be a mathematically viable comparison, I don't think it's how most people really think, and certainly not in making decisions about their children.  But of course, research is fueled by hope for the future: what it will grow into, not limited to what it is right now.

Previous Blogging: http://cureresearch4type1diabetes.blogspot.com/search/label/Burt
Abstract: http://diabetes.diabetesjournals.org/content/63/9/3041?etoc

I want to thank the authors of the paper, who provided me with a copy so that I could blog on it.
Normally, this paper is behind a pay wall.

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.

Saturday, November 29, 2014

Will That Clinic Cure You (Or Your Kid)?

One thing that I am thankful for, is the relative lack of quacks and charlatans in the world of type-1 diabetes.  Sure, we have a few researchers who say "cured in 5 years", and a plague of reporters and bloggers always looking forward to amplify whatever fool thing they say.  But that is very different from the outright fraudsters who are attracted to some other diseases.  We get fewer of those.  This posting describes how to look at doctors and clinics which claim to cure/treat type-1 diabetes and decide for yourself if they are worth your money, time and energy. Although it is targeted specifically at far away clinics (especially stem cell clinics). Most of what I write here will apply very well to other treatments "too good to be true".

Far Away Clinic X Says They Can Cure Type-1 Diabetes! 
Have You Heard Of Them?

Every now and then I get a question about some clinic or doctor who claims to be able to cure type-1 diabetes.  When I get these emails, if I have time, I look into the clinic or doctor.  They are mostly the same, they take stem cells from a person's bone marrow, and then reinject them back into the person.  Although some of them inject other stuff.

The rest of this blog contains four different ways to evaluate a clinic or doctor who claims to cure type-1 diabetes:
  1. Five questions to ask.
  2. Common excuses for not having data.
  3. Danger signs.
  4. How much evidence of safety and effectiveness do they have, and how much do you need?
Five Questions To Ask

Actually, before asking any questions, search the web.  What do the patients say about the clinic? Especially, what do the people who were cured of type-1 diabetes say about the clinic?  Obviously, any clinic that can cure type-1 diabetes is going to have scores of happy customers posting to every internet forum you can imagine.  (Not just one or two, but swarms of them.)  So start by reading posting on the various type-1 forums.  How many of their customers have posted happy results on www.childrenwithdiabetes.com?  How about tudiabetes.org?

I don't know about you, but if my daughter was cured, you couldn't stop me from posting everywhere about it!  I would go out of my way to help by talking to reporters, potential patients, venture capitalists, anyone…..  Nothing would make me happier than to make the discoverer of a cure for type-1 diabetes rich.

Clearly, it is easy to post fake reviews and postings in the web, so happy customer testimonials need to be researched.  (Do they reply to email?  Did they post somewhere besides the clinics' own web page?  Did they post on type-1 forums prior to their cure?)  But if you find nothing, then they obviously haven't cured anyone, or very few people.  

After that, here are the five questions that I would ask of any person or any clinic who says they can cure type-1 diabetes:
  1. Where is your data?  I'll describe how to use this data in the next section.  But if you ask this question, and get excuses rather than data, then it's clear they have nothing.  Remember, everyone who does not have data, will certainly have excuses.   Whatever the excuses, ignore them, but do look at the data they provide.  
  2. Who have you cured?  This is pretty obvious, but in the cases I've seen, the person or clinic has claimed to be able to cure people for a long time, yet doesn't have a bunch of cured people available.  In one case, the guy claimed to have cured over 10,000 people in the last 20 years, yet not one of them had ever posted to a forum or spoken to a reporter.  In another case, a clinic claimed to have used their cure for 15 years, yet again: no forum posts, no interviews with the media, no discussions with potential new patients, no one available. 
  3. What insurance do you take? / What country's medical plans send their type-1 patients to you to be cured?  This might strike you as silly questions, since none of these guys are ever covered by insurance.  But think about it: your insurance company spends thousands of dollars every year treating your type-1 diabetes.  They are going to continue to spend that money for years, maybe decades.  If someone could cure type-1 diabetes, even for $20,000, your insurance company would be overjoyed to pay for it.  Indeed, they would likely force you to go get cured, so they could avoid paying out all the money they do now.  So this is a serious question. Taking it a step further, there are many European countries which have "single payer", or have some form of public health insurance.  In those countries, the minute someone is diagnosed with type-1, the  public health insurance knows they are going to have to pay over $100,000 over that person's life.  In those countries, they would save vast amounts of money by chartering a jet, and shipping all their type-1 patients to this clinic to be cured.  Even if the country were in Scandinavia, and the clinic in Mexico.  So why don't they?
  4. How many type-1 diabetics work for you?  They're all cured, right?  Many people with type-1 diabetes end up working in clinics for people with type-1 diabetes.  So an obvious question is, do you employ any type-1 diabetics, and have you cured them?  After all, type-1 diabetics would flock to employment at a clinic that really could cure type-1 diabetes, both to cure themselves and to cure others. 
  5. What did you do before?  In a certain sense, I don't care what someone did before they cured type-1 diabetes.  If their previous job was sitting under a bridge and eating goats, that's fine with me, as long as they have peer-reviewed data showing that they cured type-1 diabetes. However, in cases where they don't have data, or it is not peer reviewed, then I think it is worthwhile to look into what they have done before.  For example, what if a guy's previous job was "the founder of the 'Essene Order of Light', an offshoot of a New Age religion based upon modern interpretations of the Essenes, an ancient Jewish sect?" (This quote comes from the man's self bio.)  Does that make you nervous? Should it?  And don't laugh about this example, it is a real guy, Dr. Gabriel Cousens, who really claims to be able to cure type-1 diabetes.  
Common Excuses For Not Having Data

Remember, when you ask for data, and the clinic gives you excuses for not having data, my advice is not to consider if the excuses are good or not, because it just doesn't matter.  If they don't have the data, then they don't have the data.  Having an excuse is never a replacement for missing information. But with that in mind, the following excuses are common:

Privacy is a common excuse which you should ignore, for two separate reasons: first of all, you don't want to know people's names, you want to know how they did, so you are not asking for personally identifying information; second, if this clinic has cured people, those people should be overjoyed and excited about others being told about their successes.  Think about it: if a clinic cured your child, and the clinic asked if they could write up your experience as a case study, and even have you talk to future patients, you would say "yes" in a heartbeat, right?  You would want to tell others about this cure.

Another excuse, is that "no one will publish my results showing a cure".  If you get that, say, "No problem!  I'll take a look at your manuscript, I don't care if it is published or not!"  And see what happens.  Obviously, a peer reviewed article would be better, but if they don't have a manuscript, they never even tried to get it published.

A third excuse is "no one will pay for a study to show my treatment works!".  Tell them, that's fine, but you'd still like a summary of how many of their patients were cured, and for how long. No complex study, just the basic data.  And if they don't keep that, what does that say about their follow up with their existing customers?

Danger Signs

In general, I focus on peer-reviewed evidence of effectiveness and safety; the kind that comes from clinical studies.  However, when looking at treatments for my daughter, I don't ignore danger signs associated with fraud.

No matter how much or how little data a clinic has to support their cure, these signs can provide a separate warning that you are getting into trouble.  None of these prove that the clinic or doctor in question is a quack, but I've found that they are suggestive that the treatment is shaky:
  1. Do they use the same treatment to treat different diseases?  Many of these clinics (especially the stem cell clinics) treat all diseases the same.  In some cases the treatment is absolutely identical, treating lung cancer, the exact same way as heart attacks, as type-1 diabetes, as eye problems, etc.  In other cases, the treatment is identical, except that the injection is in a different place. Ask yourself: does that make sense?  Cancers are a large group of related diseases, and they are treated very differently.  So does it make sense for these guys not only to treat all cancers the same, but heart attacks and autoimmune diseases, as well?  For me, it does not.
  2. Any clinic run by, or associated with, any doctor who has lost his license somewhere else.  (If they can cure type-1 diabetes, there is no reason for them to associate with anyone even slightly "shady".) 
  3. Associating their treatment with other, different treatments that are in the news. 
  4. Associating their research with reputable organizations (often Universities), which are actually doing different research.  
For points 3 and 4: Some of the more sophisticated clinics have links on their web pages to studies that supposedly support their ability to cure people. When I have tracked down these studies, I often find that they share only a buzzword or two with whatever the clinic is doing.  So if their marketing literature uses the term "stem cells" then they will have a link to some academic research, which also uses the same term, but otherwise is completely different from what they are doing.

How much evidence of safety and effectiveness do they have, and how much do you need?

The critical question, that you need to answer before you think about a specific clinic or treatment, is how much evidence do you need?  Not just for that one clinic or that one treatment, but for all of them.  For example, the FDA generally requires four clinical trials before they will approve a new treatment.  But that's them, and you are free to choose a different level of evidence, if you want. Maybe you are OK with only two clinical trials?  Or three?  Maybe you want four clinical trials, and two years worth of real world experience, before you will use a new treatment.  These are all reasonable answers to the question.  There is no one universal answer.

Once you have your answer, and you've considered it calmly, and grown comfortable with it.  Then, you need to apply it to these clinics.  In my experience, they have almost no strong evidence that their treatments work.  So even if you have quite low standards (just two peer reviewed papers showing results, for example), they usually can not even make that low bar.  Even if your requirement is "they don't need any published papers at all, I just want to talk to five people who they have cured, one of who I find myself", my guess is that you will not be able to find them.

My experience has been that these clinics are very strong in providing reasons why they have never published papers, why they don't even have the (unpublished) data you want.  Very strong in describing why the FDA, the AMA, the ADA, and everyone else is against them.  But they are very weak in terms of data to support you giving them thousands (sometimes tens of thousands) of dollars. At the end of the day, these kinds of excuses don't even start to suggest that they are actually curing anything.

Finally, I would be very careful about clinics that claim to cure type-1 diabetes, but only provide evidence that they are "helping" type-1 diabetes.  Often these clinics will provide personal testimony from people who say things like "my son's type-1 got much better after the treatment" or "he stopped having lows (or highs or big spikes after meals) after the treatment".  If this is the kind of improvement they advertise, then personal testimonials are the absolute worst way to document it. This is the kind of results where you need to see average BG numbers, or A1c improvements or other hard data that things are getting better.  One of the good things about type-1 as a disease, is that a cure is obvious.  No one can scam a cure.  But "improvements" are easy to scam, so that is what is claimed, then data points are even more important.  (And in reality, if they claim the treatment results in better control, how can they possibly claim that if they don't have specific data showing it?)

In Conclusion

Quack doctors and clinics will always have a good story. They tell you what you most want to hear, and so can be the siren song of hope. Selling cures to people with incurable diseases is a lucrative market for them. So I hope that when you see such cures available, you will ask the questions I discuss here, and think about the data you get in response.


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.

Thursday, November 20, 2014

Extra Reading


JDCA "State of the Cure" Update

Each year the JDCA (Juvenile Diabetes Cure Alliance) puts together a summary of cure research.  As a JDCA fellow I contributed information to this effort, although I did not help write the report.  In my opinion, it's a excellent document, well worth reading.  It's only about 15 pages long.  In addition to scientific information on a cure, it also includes information on money: how it's raised, who spends how much, etc.

http://www.thejdca.org/wp-content/uploads/2014/11/SOTC-2014-Final.pdf

JDRF Slide Show On Prevention

This is a great slide show put together by Jessica Dunne who is the Director of Discovery Research for the Juvenile Diabetes Research Foundation.  It is 12 slides.  In addition to material on possible viral and microbiome ("gut") triggers of type-1, it also includes data on growth in type-1 diagnosis, genetics, and so on.

http://www.tudiabetes.org/forum/attachment/download?id=583967%3AUploadedFile%3A3546968


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.

Saturday, November 15, 2014

Artificial Pancreas Update (Nov 2014)

This is a quick update on several artificial pancreas (AP) projects.  The term "artificial pancreas" refers to using a continuous glucose monitor (CGM) to feed data to a computer, which controls an insulin pump, and in some models, a glucagon pump as well.  Artificial pancreas refers to using existing technology in all these areas, but connecting them together so that a person does not need to worry about counting carbs or blood glucose levels.  It is all done automatically.

Medtronic Starts Two Phase-III Trials 

Medtronic is currently the leader in commercial development of an artificial pancreas.  They have already released CGM/pump combination that automatically shuts down insulin injection if blood glucose levels go too low for too long.  This existing technology is very likely to prevent "dead in bed", and it is the first small step towards an artificial pancreas.

The next step will be what's called "predictive shutoff".  While the existing system will only stop insulin when blood glucose levels have already gone too low for too long, the new system will use knowledge of insulin on board and blood glucose trends to cut off insulin before blood glucose levels drop below acceptable levels.  This is a big step forward in terms of keeping people in healthy blood glucose ranges, and it is also a big regulatory step forward.  It means that software will be making changes based on the expected (future) situation, not the known (past) situation.

Medtronic is starting two studies of this feature.  An American study will use 84 people at several different sites, while an international study will have 100.  The American study specifically says it is phase-III, and I suspect the other one is as well, but it doesn't say that specifically.  This would be great news, because a new device needs two phase-III trials before it can be approved for marketing in the United States, and both of these studies hope to finish by December 2014.  I view these studies as an attempt to get to market with a "step 2" artificial pancreas device as described in the diagram below.

The American study has one contact person:
Julie Sekella (818) 5765171 julie.sekella@medtronic.com

For all these locations (not all of which have started recruiting, yet):
  • AMCR Institute, Inc.  Escondido California
  • Stanford University Department of Pediatric Endocrinology, Palo Alto California (Bruce Buckingham)
  • Barbara Davis Center of Childhood Diabetes, Denver Colorado (Satish Garg)
  • Yale University Diabetes Research Program, New Haven Connecticut
  • Atlanta Diabetes Associates, Atlanta Georgia (Bruce Bode)
  • University of Virgina, Charlottesville Virginia (Stacey Anderson)
  • Rainier Clinical Research, Renton Washington (Ronald Brazg)
The international study has these two locations:
  • Schneider Children's Medical Center of Israel, Contact: Moshe Phillip, PhD + 972 3 9253747 mosheph@post.tau.ac.il
  • University of Ljubljana, Faculty of Medicine, Contact: Tadej Battelino, PhD +386 1 5229235 tadej.battelino@mf.uni-lj.si
Clinical Trial Records:
http://clinicaltrials.gov/ct2/show/NCT02130284
http://clinicaltrials.gov/ct2/show/NCT02179281
News: http://www.marketwatch.com/story/medtronic-begins-pivotal-study-of-first-predictive-low-glucose-management-technology-for-people-with-diabetes-2014-10-14?reflink=MW_news_stmp

There is a third clinical trial, which is described here: http://clinicaltrials.gov/ct2/show/NCT02160184 and which is expected to enroll 12 people and finish Feb 2015.  It's not clear to me if it is testing the same predictive shutoff feature as the other two.  It is being run in Spain.  Contact: Mercedes Rigla, MD, PhD +34-93-745-8412 mrigla@tauli.cat

Two of the three studies described here refer to a commercial model number: 640G.  

MD-Logic Update

MD-Logic refers to another group of researchers working on a different artificial pancreas.  This AP is in Step 3 or 4 in the diagram below.  They recently published new data.  People used their artificial pancreas for 6 weeks (night only) in their regular lives.  So they were "out and about".  This was a cross over trial, meaning each person spent 6 weeks using the closed loop and six weeks not.  Half the group used the closed loop first, and half of them used closed loop second.  The results were all very good:
  • Reduced time spent in hypoglycemia 
  • Increased the percentage of time spent in the target range of 70–140 mg/dL 
  • Time spent in substantial hyperglycemia above 240 mg/dL was reduced by a median of 52.2% 
  • Overnight total insulin doses were lower in the closed-loop nights
  • The average daytime glucose levels after closed-loop operation were reduced by a median of 10 mg/dL
Clinical Trial: http://care.diabetesjournals.org/content/37/11/3025?etoc

Interview with JDRF's Dr. Kowalski

This interview has a lot of interesting information about how JDRF and AP research interact:
https://myglu.org/articles/a-pathway-to-an-artificial-pancreas-an-interview-with-jdrf-s-aaron-kowalski

It includes the JDRF "AP Step/Generations" diagram, which is how they think an AP will be developed over time.  You can read more about these steps here:
http://jdrf.org/research/treat/artificial-pancreas-project/

New Artificial Pancreas Project

Another new artificial pancreas project is getting underway at Rensselaer Polytechnic Institute, which you can read about here:
http://news.rpi.edu/content/2014/10/21/1-million-nih-grant-enables-clinical-trials-artificial-pancreas
http://www.meddeviceonline.com/doc/artificial-pancreas-to-begin-clinical-trials-0001
they have not started human trials yet, but it sounds like they will, soon.

Are They Working Together?

One question I get asked about different groups doing similar research is: are they working together?  And usually, I don't know.  However, in the case of Artificial Pancreas research, I know that the different groups are working together, because in some cases, there is overlap among the researchers.  To give you just two examples:
  • Bruce Buckingham is working on the Medtronic clinical trial, the University of Virginia clinical trials, and the planned Rensselaer clinical trial.  Plus algorithms that he worked on were used in the Cambridge AP work.
  • Moshe Phillip is working on both the Medtronic and the MD-Logic clinical trials.
It's clear that the AP groups are not working "in a vacuum".  They are all aware of each others work.

Direct Comparison (Updated)

The chart below is a comparison of all AP projects which I know about that are either in clinical trials, or about to start them.  Some of these projects are not included in this blog posting, but are described in previous postings: http://cureresearch4type1diabetes.blogspot.com/search/label/Artificial%20Pancreas

Group
FDA
Phase
JDRF
Step
Average BG
Estimated A1c
Size
Adolescents?
Duration
AP Use
Boston University
II
6
138
6.4
53
Yes5 days24 Hours/Day
Cambridge
II
3
146
6.7
17
No
8 days24 Hours/Day
MD-Logic
II
3

24
Yes
90 days
Night Only
Virginia
II
3
135?
13
No
2 days
24 Hours/Day

Medtronic
III
2
Just
Started
184
Yes
2 days
24 Hours/Day

Rensselaer
Not
Started



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

Wednesday, November 5, 2014

Beta-O2 Starts a Phase-I Trial (and an update on encapsulated beta cells generally)

Introduction to Encapsulated Beta Cells

Encapsulated beta cells are implanted devices.  The encapsulation coating allows blood sugar in, and insulin out, but does not allow the body's immune system to attack the beta cells. It also allows nutrients in and waste products out. This allows the beta cells to naturally grow and to react to the body's sugar by generating insulin which goes into the body's blood system. Meanwhile, the body's autoimmune attack cannot target these beta cells, and you don't need to take any immunosuppressive drugs (as you would for a normal beta cell transplantation).  The cells inside the coating are human beta cells, and different companies get their beta cells from different sources.

Beta-O2 Starts a Phase-I Clinical Trial

Beta-O2 is starting a phase-I clinical trial of their "ßAir Bio-Artificial Pancreas" (encapsulated beta cell) device as a possible cure for type-1 diabetes.  The devices itself is similar to other encapsulated beta cell devices (ie. Diabcell by LCT, Encaptra by ViaCyte, etc.) with one important difference: the device is injected with oxygen once a day.  This is a manual step performed by the patient.  The company claims it will take about 2 minutes, and provides pictures of the device used, which looks like a needle attached to tubing.  You can read about the device here: http://beta-o2.com/living-with-sair/

The clinical trial is pretty standard for a phase-I trial: 8 people will use the device for 6 months, and be followed for an additional 6 months.  They will test for safety and effectiveness (C-peptides, Insulin usage, and A1c numbers), and hope to finish in March 2016.

The clinical trial is being run by the Uppsala University Hospital.  Contact information is: Per-Ola Carlsson, MD, PhD  Phone number:  +46 18 4714425  Email:  Per-Ola.Carlsson@mcb.uu.se.  This trial is for adults with long established (5 years or more) type-1 diabetes.  One unusual requirement for this trial is that patients must start out using 1 unit of insulin per day per kilo of weight (or less).

The clinical trial is expected to cost about US$ 1 million, with JDRF paying for half.

Press release: http://www.fiercemedicaldevices.com/press-releases/first-patient-successfully-implanted-safetyefficacy-study-beta-o2s-air-bio
Clinical Trial Record: http://clinicaltrials.gov/ct2/show/NCT02064309

Other Encapsulated Beta Cells Research Underway

Interest in encapsulated beta cells seems to be cyclical.  When my daughter was first diagnosed, about 10 years ago, encapsulated beta cell devices were a strong area of research.  But one by one, most of the devices failed.  We then went through several years with only one company (LCT) in human trials.  Now, however, interest appears to be picking up with a new generation of human trials underway.  Here is a quick summary of the encapsulated beta cell devices that I know of:

Beta-O2: Just started a phase-I clinical trial.
Viacyte: Just started a phase-I clinical trial.
LCT: Has been doing phase-II trials for several years, but has not made any forward progress (in terms of better results), in years.
Hospital St. Luc research project: Completed (?) a phase-I trial, but not sure about any progress recently.
AZ-VUB: In phase-I, but I don't know any details.
DRI Biohub: Started clinical trials for infrastructure for such a device, but still using immunosuppression.
Sernova: Started clinical trials for infrastructure for such a device, but still using immunosuppression.
Islet Sheet Project: In animal testing.
Harvard Project: In animal testing (?).
Chicago Diabetes Project: Still using immunosuppression.
Nuvilex: Starting animal testing soon.

In my opinion, these are a lot of different research groups, all focused on the same type of cure.  For me, that's good news, because it suggests that many people believe this technology is ready to lead to a cure.  And that makes me optimistic.  Unfortunately, previous "waves" of encapsulated beta cell devices did not lead to a cure, so that makes me nervous.

Background Information

http://en.wikipedia.org/wiki/Cell_encapsulation
https://www.landesbioscience.com/pdf/HunkelerPDF.pdf

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

Friday, October 24, 2014

Type-1 and Obstructive Sleep Apnea


A reader of this blog asked me what I knew about the relationship between Obstructive Sleep Apnea (OSA) and Type-1 Diabetes.  I didn't know anything, but over the last few weeks, I've been looking through the research.  There is not a lot, but what there is, I've summarized here.

The sound track for this posting is Bon Jovi's I'll Sleep When I'm Dead:
http://grooveshark.com/#!/s/I+ll+Sleep+When+I+m+Dead/wu1oT

This is an area where it is important not to mix up type-2 and type-1 diabetes, and to remember that people who say "diabetes" almost always mean "type-2 diabetes".  One of the more common causes of OSA is being overweight, and this is also one of the more common causes of type-2 diabetes (although in neither case is it the only cause).  The result is that OSA is highly correlated with type-2 diabetes.

However, there has been a little research on type-1 diabetes and Obstructive Sleep Apnea (OSA), and that is what I'm focusing on here.

But first, a little background on OSA:
http://en.wikipedia.org/wiki/Obstructive_sleep_apnea
http://www.webmd.com/sleep-disorders/guide/understanding-obstructive-sleep-apnea-syndrome

Question 1: How common is OSA?

Simple Answer: about 5% of the general population, and about twice that in people with T1D.

Detailed Answer: The overall rate is about 4% [r2] or 5.7% [r4] of the population, but the rate for people who have T1D is about 10% [r3] or 12.7% [r4].  One study [r6] found that sleep apneas were much more common in type-1 diabetics, than in type-2 diabetics.  Study [r8] found high levels of sleep apneas in people with type-1 diabetes, but had no comparison group.

Question 2: Is OSA a danger sign for people who have T1D?

The [r4] study found no connection between sleep issues and HbA1c numbers.  But [r5] found that patients' poor glycemic control and worse apneas were correlated (but no way to tell which caused the other, or if they were both caused by something else entirely). The "Sleep and Glucose Regulation in Youth With Type 1 Diabetes Mellitus" study [r7] is clearly based on the idea that bad sleep results in worse BG control.  Their data shows a clear correlation, but again,I don't see a causal direction.  Although it seems reasonable to me to think that if you BG was out of range, that would cause sleeping problems, rather than the other way around.

Question 3: Is OSA an early warning signal of T1D?

While there is no question that OSA can be an early warning sign of type-2 diabetes, I was not able to find any studies suggesting that it was an early warning sign for type-1.

Question 4: Does OSA cause T1D?
Question 5: Does T1D cause OSA?

I could not find any research on these questions.

Ongoing Studies

There is only one related clinical trial currently running.  They are comparing people who have type-1 diabetes to those without, and are investigating relative rates of OSA, type-1 issues which might cause OSA, and OSA impacts on complications of type-1.  The study includes 145 people, and is expected to be completed in Sept. 2016.  They are recruiting in Paris, France.
Clinical Trial Record: http://clinicaltrials.gov/ct2/show/NCT01935765

There is another small study at the University of Arizona, where students with type-1 will be asked to extend their sleeping hours.
Clinical Trial Record: http://clinicaltrials.gov/ct2/show/NCT01739712

My Summary

My basic conclusion from all this, is that there is very little research in this area.  Based on what we have, it looks like OSA is much more common in people who have type-1 diabetes than in others, and maybe even more common in people with type-1 than type-2 diabetes.   This is a major change in perspective, since OSA is traditionally associated (in people's minds) with type-2 diabetes. Unfortunately, almost nothing else is known about the causality or effects of OSA in people who have type-1 diabetes.

References

[r1] http://en.wikipedia.org/wiki/Obstructive_sleep_apnea
[r2] http://www.webmd.com/sleep-disorders/guide/understanding-obstructive-sleep-apnea-syndrome
[r3] http://www.ncbi.nlm.nih.gov/pubmed/21679352
[r4] http://www.ncbi.nlm.nih.gov/pubmed/21573904
[r5] http://www.ncbi.nlm.nih.gov/pubmed/10907113 (this study uses the term "insulin dependant diabetes", but they are clearly studying children, so I'm assuming they are type-1)
[r6] http://www.ncbi.nlm.nih.gov/pubmed/4004160
[r7] http://www.ncbi.nlm.nih.gov/pubmed/22215921  mass media report here:
http://www.medpagetoday.com/Endocrinology/Diabetes/30460 and clinical trial record here:
http://clinicaltrials.gov/ct2/show/NCT00848822
[r8] http://www.endocrinology.dk/index.php/spor-24-blandet-endokrinologi/488-96-prevalence-of-sleep-apnea-in-danish-type-1-diabetes-patients



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.

Thursday, October 16, 2014

Three Unsuccessful Trials


This blog posting summarizes several clinical trials aimed at curing type-1 diabetes which have failed.  These are never fun, happy blog postings, but they are important.  One of the big problems with trying to understand research based on mass media reporting is that failures are rarely covered at all.  The soundtrack for this posting is "Down" by Melissa Lambert:
http://grooveshark.com/#!/s/Down/4BHhwn

Sitagliptin and Lansoprazole Unsuccessful in Phase-II Trial

This was a combination therapy.  The researchers were attempting to combine a drug to stop the autoimmune attack and another drug to trigger beta cell growth.  Both drugs were approved for other purposes, and commonly used.  Unfortunately, it didn't work.  Summary from abstract:
At 12 months, the mean change in C-peptide area under curve was −229 pmol/L for the treatment group and −253 pmol/L for the placebo group; this difference was not significant (p=0·77).
Abstract: http://www.sciencedirect.com/science/article/pii/S2213858714701159
Blog at start of trial: http://cureresearch4type1diabetes.blogspot.com/2010/08/possible-cures-for-type-1-in-news-mid.html

Pioglitazone Unsuccessful in Phase-I Trial

Pioglitazone has been approved for use in type-2 diabetes for over 10 years. It is part of a larger drug family called thiazolidinediones which have been shown to preserve beta cells in animals with type-1 diabetes, and to reduce death of beta cells in petri dishes.  It was being tested as a honeymoon cure, but did not pan out:
Conclusion: In this pilot study, pioglitazone did not preserve β cell function when compared to placebo.
Article: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3890222/
Previous blogging: http://cureresearch4type1diabetes.blogspot.com/search/label/Pioglitazone

Stop Covering Lisofylline

As far as I can tell, no one has done human trials of this treatment for over two years, so I'm going to stop considering it as a possible cure, unless something new comes to light.  Lisofylline is an anti-inflammatory.

Previous coverage (one blog posting) is here:
http://cureresearch4type1diabetes.blogspot.com/search/label/Lisofylline


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.