Friday, April 25, 2014

Personal Note: JDCA Fellowship

I'm very honored to have been selected as a JDCA Fellow.  The JDCA (Juvenile Diabetes Cure Alliance) is an organization which encourages people donating money to type-1 research to direct that money specifically to projects more likely to lead to a cure, and to projects which are closer to a cure.   You can read more about them at their web site:

Their motto is
The voice of the donor for a cure.

And their mission is:
To direct donor contributions to the charitable organizations that most effectively fund research with the goal of delivering a type 1 Practical Cure by 2025.
The JDCA is a dynamic organization with the sole purpose of curing type I diabetes by 2025.
The JDCA asked me to be a JDCA Fellow, and I was happy to agree.  In that capacity, I'll be providing whatever knowledge and insight I can into type-1 research, especially focusing on clinical trials.  In particular, I will help with some of their research reports.   Additionally, being a fellow means that they will update me about the various researchers who they are talking to.  This is no small benefit, as they have excellent contacts with researchers.

You can see the first JDCA report that I helped with, here:
I think that this report will give anyone touched by type-1 diabetes useful background knowledge to understand how different lines of research are leading to a cure.  The meat of the report is 4 pages, at it is well worth reading, if you are following the research.

Obviously, we are both interested in research targeting a cure, and in research far enough advanced to be tested in people.  We also both tend to evaluate research based on the data produced (rather than on promises about the future).  So we have a lot in common.

My understanding is that some JDCA fellows will receive stipends for their help, however I'm not comfortable getting money for blogging, so I'm not getting a stipend.  However, the JDCA is willing to pay for research expenses, so I might get reimbursed for on-line medical journals or a bigger screen for my computer.  (I seem to be staring at it more and more these days, and my eyes are getting older and older.)

Please don't make the mistake of thinking that I agree with every detail of everything they do or say.  Nor do I expect them to agree with every detail of everything that I say or do.  And certainly, my blog speaks for me, and not for them.   However, I am always very happy when I can work with type-1 diabetes organizations which are accelerating research into a cure. Finally, remember that I don't "belong" to any organization.  I put a lot of work into the research behind this blog, and so I'm happy to feed that information into the JDCA.  But I'm equally happy to feed it into any other organization that can put it to good use.

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

Saturday, April 19, 2014

The Bihormonal Artificial Pancreas

This posting focuses on one specific type of artificial pancreas (AP), called a bihormonal artificial pancreas, or sometimes a "bionic pancreas".  As with all artificial pancreas discussion, some people don't think these devices are a cure (they are just treatment methods), while others do consider them a cure.

Many months ago, I attended a CarbDM event, where Dr. Ed Damiano discussed recent testing of bihormonal artificial pancreas.  (CarbDM is a support group for families with type-1 diabetes, which operates in several cities in Northern California, including San Francisco, San Jose, and Sacramento.  If you live there, you should see what they're doing:  Anyway, as soon as I heard the presentation, and the great results, I knew I needed to blog on it.  But there was never time, and it got pushed out, and now it's six months later.  My bad.

The good news is that diaTribe has published really good summaries of Dr. Damiano's work, so I encourage you to read their postings now, and then come back to finish reading this posting:

(Brief digression on diaTribe It is a free news service covering diabetes (both type-1 and type-2) which was spun off from Close Concerns, which is a commercial news service covering diabetes.  DiaTribe is a great source of news, because they are covering in depth something they understand very well.  They do their own analysis, so they are not just mindlessly reprinting other people's press releases, which is common from other news sources.)

Now, back to the bihormonal artificial pancreas:  The bihormonal artificial pancreas delivered a level of control (without human intervention) good enough to be called a cure.  The estimated A1c numbers were 6.2 in one study and 6.6 in the other.  The average BG numbers were 133 and 142.   At the same time, the number of BG measures below 60 was lower when using the bihormonal artificial pancreas.  So they had better control and fewer lows.

What is a Bi-hormonal Artificial Pancreas?

Artificial Pancreas refers to a pump / continuous blood glucose monitor / computer combination that controls blood sugar automatically based on data from the monitor.  All of these are existing technologies, but used together in a new way.  It is also called the "closed loop".  Bi-hormonal refers to using both insulin and glucagon.  So a bi-hormonal AP can give both insulin and glucagon, based on blood sugar levels, to automatically keep a person's blood sugar levels in range, using existing hardware technology.

The current bi-hormonal AP is composed of a G4 CGM, two T:slim pumps, and iPhone hardware that has had the phone software removed and replaced by software to control the pumps.  The current experimental prototype sounds "clunky" in the extreme.  Basically, you are wearing two pumps and a CGM device.  There are three separate sets, etc.

Take a look at this photo (hosted on diaTribe's site), to see just how "clunky" and crowded it is:

A "classic" AP is insulin only, so it can lower blood glucose, but not raise it.  A person eats sugar to raise their BG levels, but the AP doesn't control that.  A bi-hormonal AP can both raise and lower a person's BG levels, so it can have much better control.

As I said before, the current blood glucose control, as seen in already completed clinical trials, is spectacular.  In my opinion, it is good enough for a cure right now, even if they don't improve it at all moving forward.

What's the Plan Moving Forward?

The plan is to do one large, multiple site clinical trial on adults who work in hospitals and have type-1 diabetes.  The goal of this study is to have people living their normal lives, including going to work, and using the bihormonal AP, and yet be close to medical help, for trial safety.  I think of this as being a large phase-II trial.  This trial will use the current "prototype" hardware.

Next, the researchers will develop the real hardware: the hardware they expect to sell, and use that to run two large phase-III ("pivotal") trials.

The lead researcher, Dr. Ed Damiano, is totally committed to getting this device on the market by 2017.


So the big question is, will it be on the market by 2017?  And the answer is "no one knows".  But nobody likes that answer, so there is rampant speculation, starting right here.  In my opinion, there are several risks to the 2017 date:
  • Glucagon.  A bi-hormonal pump needs glucagon which can stay in the pump for 3 days, and longer would be better.  Current glucagon is not stable for long periods of time, which is why you mix a powder with water just before injecting it.  People in the current studies had to refill their glucagon every day, so that it was fresh and active when used.  That's ok for testing, but not in real use.  There are two mitigation strategies, for this risk: First there are two companies who are trying to get FDA approval for long lasting Glucagon right now.  If either one gets approval before 2017, the problem is solved.  Second, even if this problem is not solved at all, early users will need to refill glucagon each day, which is a hassle, but can be done.
  • FDA Approval.  For APs this has not been predictable.  The Medtronic Veo took 31 months, after it had been approved in Europe!  However, the phase-II trials show a level of BG control much better than existing pumps or insulin injections. I would expect the phase-III trials to be even better, and therefore there will be strong data to help the FDA grant approval.  Plus (as with the Veo) I assume that patient advocacy organizations, such as JDRF, will be willing to launch a publicity program to "help" the FDA move forward.
  • Business Issues.  The bihormonal AP will need a company behind it, to become reality.  Type-1 diabetics are not going to buy a research project, and insurance will not pay for one.  So there must be a commercial company that builds, markets, and sells these things.  There are several ways this could happen: they could create a new company to build and sell a bi-hormonal artificial pancreas, or they could form a company which owns the intellectual property (patents and fabrication know-how).  That company would then either licence an existing pump manufacturer to produce bihormonal APs, or sell itself to an existing pump company, which would then own the necessary patents to make bihormonal APs. In any case there is risk, but it is the "normal" risk of commercial development, not the extra risk of scientific research.
  • Engineering Issues.  This bi-hormonal pump is a integration of several different components: two pumps, two hormones, a computer algorithm, a controller, a CGM, etc.  None of this is really new technology, but the current schedule assume that putting it all together will happen quickly and without a serious issue cropping up.  But there is always the risk of one of these issues cropping up, at the worst possible time.

But Is It A Cure?

I think that each of us has to decide for themselves what is a cure, and what is not.  So I'm not going to tell you this is a cure, or this is not.  (I am going to ask that you not write me nasty emails saying I'm an shill for even talking about APs as a possible cure: just because you don't think they are a cure, doesn't mean that everyone agrees with you.  All kinds of different people read this blog.)

When I talk to people, most of them accept an implanted (internal) AP as a cure for type-1, however if you take that same functionality and carry it outside the body, then most people do not consider it a cure.

The bi-hormonal prototype (ie. the thing they are testing now) requires the user to check blood glucose only to calibrate the CGM.  It requests that the user tell it about meals, but does not require any carb counting (the user clicks a button to say breakfast, lunch, or dinner).  The user does need to refill the insulin every 3 days, and during testing, refill the glucagon every day.   However, the researchers expect long lasting glucagon to be available as part of the commercial product.

In testing done so far, about 2/3s of the meals were actually warned by the user.  In the other 1/3 of the cases, the user forgot or didn't bother.  So the numbers above include failure to warn 1/3 of the time.  The researcher estimate that if the users never warned of a meal, that their average BG numbers would rise about 10, and the average A1C would rise about 0.1.

Abstracts on papers for the bihormonal artificial pancreas:

Here is a link to diaTribe coverage long storage Glucagon:!

Clinical Trial Records for these studies:

Let me leave you with a diagram showing what happened to a group of people on the bihormonal artificial pancreas.  Notice that every single person ended up with an average BG between about 100 and 150.  My slogan for this diagram is "no diabetic left behind".  Even the guy who started out averaging over 220, ended up in range:

(Note: this diagram comes from a children-with-diabetes page which is collecting tax deductable donations for this research:

Other Bi-hormonal Artificial Pancreas Projects

The only other research that I know of into bihormonal APs is being done in Europe, and is called the "PCDIAB" project.  You can read about it here:
and see a related clinical trial record here:

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

Saturday, April 12, 2014

Dr. Faustman Starts a Phase-II Trial for BCG

Dr. Denise Faustman, of Harvard, has filed the paperwork to start a phase-II trial testing BCG (Bacillus Calmette–Guérin) as a cure for type-1 diabetes.  She is not recruiting patients quite yet, but should start very soon.  This study will be done in Boston.


The essence of Dr. Faustman's theory on how to cure type-1 diabetes is:
  1. BCG causes the body to generate TNF
  2. TNF causes fewer autoreactive T-cells
  3. Fewer autoreactive T-cells results in natural beta cell regrowth and more insulin generation
  4. More insulin generation is the path to curing type-1
BCG (Bacillus Calmette–Guérin) is a biologic which has been given to over a billion people (in low dose) as a tuberculosis vaccine, and is also approved (in much higher doses) as a bladder cancer treatment. It is a generic drug with a very long record of safety.

TNF ("Tumor necrosis factor" or TNF-alpha) is a naturally occurring protein that can cause cells to die. It is involved in the natural regulation of immune cells.

"Autoreactive" refers to immune cells which mistakenly attack the body's own beta cells. The destruction of these beta cells leads to type-1 diabetes. This is sometimes referred to as an "autoimmune attack" because the body's own immune system attacks the body itself.

A timeline for Dr. Faustman's research can be found here:

But the important milestones are:
  • Dr. Faustman announced cures for NOD mice in 2002-2003
  • Dr. Faustman ran a phase-I trial in people from 2007 to 2012
  • Dr. Faustman is starting a phase-II trial, now (in 2014)
This Trial

With all that as background, here are the key design points for the phase-II clinical trial, all taken from the clinical trials record:
  • 120 people involved.
  • Some will get BCG, some will be part of the untreated, placebo group.
  • Double blind (meaning neither the patient nor the researcher will know who got what).
  • Randomized (meaning people will be randomly assigned BCG or placebo group)
  • Patients will get two doses of BCG, one month apart in the first year, and one dose per year for four years after that.
  • Primary end points (most important outcome measure):
    • A1c
    • C-peptide after a meal
  • Secondary end points (other important outcomes):
    • Targeted death of auto reactive T cells (ie. "bad" killer T cells)
    • Autoantibody levels
    • Urinary C-peptide levels
  • The trial is expected to finish collecting data in 2019, and complete in 2022. 
Here are the two key paragraphs from the clinical trials record:
The purpose of this study is to see if repeat bacillus Calmette-Guérin (BCG) vaccinations can confer a beneficial immune and metabolic effect on Type 1 diabetes. ... 
Eligible volunteers will either be vaccinated with BCG in a repeat fashion over a period of four years or receive a placebo treatment. The investigators hypothesize that each BCG vaccination will eliminate more and more of the disease causing white blood cells that could offer relief to the pancreas for increased survival and restoration of insulin secretion from the pancreas.

There is a lot to like about this trial (as described in the paperwork).  It's much stronger than the phase-I trial.  Its size (120 people) is large for a phase-II trial for type-1 diabetes, and certainly it will run long enough to see if there is any result at all.  It's double blind and randomized, and is measuring things important both to people with type-1 and to researchers into type-1.

For me, the important numbers being gathered are the C-peptide data after a meal.  That's what the FDA looks for in type-1 drug approval, and that is the most direct measure that the treatment is helping.

But, it's going to take a very long time.  The current plan is to complete data collection in 2019, and finish the study in 2022.  That means it is reasonable to expect publication in the 2022-2023 time frame.  I specifically asked if they were going to publish interim results (for example: after one or two years), and the answer was no.  But they certainly do understand that 2022 is a long time to wait.

I'm also worried about the BCG dose they are using.  It is only very slightly different than the dose on their previous phase-I trial.  The phase-I trial (which saw only tiny results, and maybe not even that) dosed twice, a month apart.  This trial does the exact same, then waits a year, and doses once more, repeating the one dose per year for a total of four years.  They hope to see improvements after each yearly dose.  Some recent work in using BCG to treat multiple sclerosis (another autoimmune disease) gives them optimism about this dose.  But in the phase-I trial, the results after 2 doses were so tiny that even if they saw 5x that size result, it will be no where near a cure.  Still far to small.  To repeat: if the two doses a month apart did little/nothing the first time, why should they do more now?  And the additional one dose per year, seems like a small difference for large hopes.

There is another worry as well, which comes directly from Dr. Faustman's phase-I trial.  That trial (as first described in their clinical trials record) was quite different than the actual trial (as published).  The paperwork included 25 people and a standard placebo group.  However, the completed trial only involved dosing 3 people, and several different comparison groups (used for different end-point measurements).  Hopefully we will not see that kind of downsizing or design change in this clinical trial.

Other Data Relating to BCG and Type-1 Diabetes

In 2012 an article was published showing correlation between more BCG immunizations (for Tuberculosis) and a lower risk of type-1 diabetes.  I did not report it at the time, because it was not indexed in pubmed (the huge US government database of medical publications), and so I did not know about it. The paper itself is in Turkish, and so I have not been able to read it.  However, there is an English abstract, and that is the basis of this summary.

TB vaccinations with BCG leave a mark, which is usually visible for many years.  The researchers simply counted these marks for patients who had type-1 diabetes, and for a matched control group that did not.  What they found was that the people who had type-1 diabetes had fewer BCG vaccinations:

Type-1 Diabetes: 2.3% zero scars, 55.4% one scar, 37.7% two scars, and 4.6% three scars
No Diabetes:          0% zero scars, 17.7% one scar, 74.2% two scars, and 8.19% three scars.

Obviously, this supports the idea that BCG could prevent type-1 diabetes (although it does not directly support BCG as a cure for established type-1).  However, it is important to realize that at least three previous studies have reported that TB vaccinations do not impact type-1 diabetes rates:

None of these four studies (the three negative and the one positive) was identical to each other, and there is no way for me to tell if the positive one was a better study than the three negative ones.  In general, I think it's safest to go with either the most recent study (positive, in this case), or the largest number of studies (negative, in this case).

But that summary of studies treats all BCG trials together, assuming that all BCG used everywhere is the same.   But that's not strictly true.  BCG is a biologic, and there are different strains.   It's not a chemical were all batches are identical.  Some researchers believe that some strains of BCG will be effective in treating type-1 diabetes, while others will not.  They tend to view previous failures as caused by using the wrong brand of BCG, together with other experimental designs which minimize BCG's effectiveness.  I tend to view these arguments "backwards", meaning that if some experiments fail while other succeed, then there will be discussion of BCG strains and experimental designs.  Right now, for type-1 diabetes, there aren't any clear successes at all, so no need to discuss strains or experimental design.


My summary is simple: all we have to do is wait, and see what data comes out of Dr. Faustman's study.

More information:
Clinical Trial Record:
Dr. Faustman's Lab:

Dr. Faustman's recently published book on BCG, TNF and Autoimmunity:
(I have not read it, yet.)

Joshua Levy 
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.