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.


jamie said...


Thank you so much for what you are doing. What are your opinions on this company? Any insight would be appreciated.

Thank you

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M said...

Thank you so much for the breakdown. I have type 1 also and want us all to have a cure so badly.