Response to JDRF Public Statement Of BCG Human Trial

Many of you may be aware of the recent publication and related news coverage of the 8-year long phase I human trial, which shows that the generic vaccine BCG appears to restore blood sugars to near normal in type I diabetics with long standing disease. This research was performed at the Massachusetts General Hospital and Harvard Medical School and published in a peer-reviewed journal, Nature Vaccine, with Dr. Denise Faustman as the principle investor.

In response to the public announcement of this research, JDRF released a joint statement with the ADA. Of note, JDRF has never supported this research despite many requests for funding. We find that their choice to proactively issue a public statement in response to the media coverage of this human trial is somewhat odd. Although it is certainly within their right, it is not appropriate and not in the best interest of the diabetes community to issue such a statement that deeply understates the potential of this research, implies claims that MGH and Dr. Faustman never make and most of all contains factual errors. We feel compelled to address their minimization of the results and the inaccuracies, which are easily verified in the publication. Specifically:

The BCG treatment resulted in only moderately low HbA1cs and were marginally statistically significant. Untrue. The new data reports highly statistically significant lowering of HbA1c (p<0.0002) in the BCG-treated long-term diabetics. Furthermore, BCG-induced lowering of HbA1c was sustained beyond 5 years in all BCG vaccinated subjects. Hemoglobin A1c of 6.5 is considered the threshold of diabetes diagnosis. The published results showed a durable and statistically significant lowering of HbA1c in the BCG treated group compared to the control group. The BCG treated group started with an average HbA1c of 7.36 and decreased to an average of 6.38 over years 5-8 followed. This is in contrast with the control group’s average HbA1c remaining the same and even slightly increasing from the initial 7.08-7.10 range over the same time period. The HbA1c persistently remained lowered in response to the 2 BCG vaccines and to this day continues to be lowered compared to the placebo treated TID people. This information is in the published paper. As we all know, HbA1c is clinically important because prolonged higher HbA1c levels are directly correlated with greater risks of developing diabetes-related complications.

The newly published data does not account for the natural variability in HbA1c levels over time, which is well known to occur in this population: they tend to improve in people with TID as they age, particularly as they move out of their teens and early 20’s. Untrue. The clinical trial had a simultaneously studied cohort group of untreated type I diabetics that accounted for the natural variability of HbA1c over the entire study. This statement also implies that the BCG treated group may have included people in their teens and early 20’s accounting for HbA1c improvement when in fact the published paper reports that the BCG treated group included nine people at an average age of 45 who were diagnosed between the ages of 22-30 and living with TID for an average of 19 years.

There are no details on the standard of care. Untrue. One person was on a pump in the BCG treated group and no one used a continuous glucose monitor (CGM). There was no change in their therapy regimen as it related to devices such as pumps and CGM devices throughout the trial as stated in the published paper.

All study participants continued to use standard insulin therapy throughout the trial. The published data in this paper does not yet report on the degree or the duration of changes in insulin therapy. However, it is important to point out that semi-annual surveys confirmed that after BCG vaccinations, there were no reports of significant hypoglycemia episodes by any of the BCG treated patients within the years 5-8 followed. This change occurred even with their HbA1c levels lowered and sustained to the near normal range. The placebo group continued to show hypoglycemia events during the same time periods of monitoring. We are all well aware that the recommended target HbA1c has been 7.0 to obtain the best possible blood sugar average while minimizing or eliminating the dangerous lows that often accompany HbA1c values in the low to mid 6.0 range. This is true especially as the years living with the disease increase and hypoglycemia unawareness can develop.

The study only followed a very small number of patients…and must be interpreted with caution. The scientific community uses statistical analysis (relayed in p values) to quantitatively measure the significance of outcomes, and the p values in this study were highly significant. Further, two weeks ago the JDRF issued a very positive public review of a Phase II clinical study using a blood pressure lowering drug in new-onset diabetics of a similar group size.

The JDRF indirectly implies that Dr. Faustman is advocating BCG as a current therapy. Based on the reading of her online materials and our conversations with her, this is not true. The state of this research and that BCG is not yet approved as a treatment for type I diabetes is clearly stated in all of the MGH media materials.

The phase I human clinical trial was a double blinded study using the 100-year old generic and safe BCG vaccine. BCG has been known for over 30 years to boost a cytokine in the body called Tumor Necrosis Factor (TNF). It has been published that TNF directly eliminates the auto-reactive T cells that are responsible for autoimmune disease. A surprise finding in this human study was an increase in the beneficial regulatory T cells called T regs to almost normal levels. The T regs are critical for immune balance and decreasing inflammation and the autoimmune response. Even more impressive was the discovery that blood sugar control may have been driven by a shift in the body’s ability to metabolize glucose from oxidative phosphorylation to aerobic glycolysis (a state of high glucose utilization) on a tightly regulated cellular level systemically. In other words, glucose uptake and regulation of this uptake by the cells appears to prevent severe hypoglycemia since the cells stop transporting glucose when the blood sugar is in the normal range.

The intent of this phase I human clinical trial was never to get the people with long-standing disease off of insulin with 2 BCG vaccinations. We are not aware that MGH ever made that claim because the trial was not designed to answer that question. There is a six-dose 150 patient Phase II trial currently underway at MGH that is designed to do just that. This early phase I trial’s purpose was to satisfy FDA safety requirements and perform specific analysis to detect any immune system effects and document any clinical changes in the participants, no matter how temporary. Surprisingly, the data shows that the clinical changes have been sustained for many years and the immune system effects are profound.

We try to follow many areas of research involving possible treatments that may improve the lives of those living with TID and perhaps lead to a true cure because our children were diagnosed with diabetes in the mid-1990s at 3 years and 18 month of age respectively. We believe that all research should continue as quickly and safely as possible until it rules out if an idea can work or not. With that said, we will stand up and question any person(s) or organization that sheds falsehoods that may be detrimental to the progression of a possible treatment and specifically the ability to obtain funding to continue.

In an environment where health care costs are already unaffordable, and our fears as parents that our children may suffer from a deadly hypoglycemic episode or develop long-term complications, these early findings that BCG may be available as an affordable and safe adjunct therapy for normal blood sugar control in humans with longstanding disease, is something to be excited about. Expanding research to include the pediatric population and newly diagnosed needs to be done as quickly as possibly, especially given the impeccable 100-year safety record of BCG. We urge you to contact JDRF headquarters and tell them to engage with MGH on these current and future BCG human trials.

To learn more about BCG and the research that has been done to validate its potential, including a copy of the recent publication, please visit www.faustmanlab.org.

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Hi @Suelr, and welcome to TUD. Can you please identify what the source of this document is? Faustman obviously arouses a lot of strong feelings in the community, so it’s important to be explicit when posting something like this. Who is the “we” here?

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The document was an email letter written by myself and another woman named Jackie Fusco. We emailed it out to all of the JDRF Chapters in response to the JDRF Statement. I can add that information if you want. Thanks for reaching out.

I read the 2018 Faustman paper. Some of the claims just sound too good to be true e.g. zero cases of extreme hypo in the BCG treated diabetics while many cases of extreme hypo in the placebo group. I also found it odd that the BCG treated diabetics didn’t show a drop in A1C until 4 years after receiving the BCG vaccine. Again, this was all published in a peer-reviewed journal, at same time it doesn’t match any of my mental models having been a T1 diabetic for 36 years now.

Link to paper: https://www.nature.com/articles/s41541-018-0062-8

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The research was published in a peer reviewed journal and those were the results. All nine of the BCG treated diabetics having the disease for an average of 19 years reported no significant hypoglycemia events with near normal A1c’s for the 5-8 years followed. These clinical effects did not come out for 3 years after the 2 doses of BCG. Dr. Faustman has been corroborating with other scientists who are researching BCG effects in allergies and other autoimmune diseases. A group in Italy using BCG on MS patients have similar results coming out 3 years later as well and following their subjects for 5 years. The phase II trial started 3 years ago at MGH and they are administering 6 vaccinated doses of BCG hoping that it may speed up the reaction time.

Yes, please, thanks @Suelr. I think it’s a useful perspective, but these days sourcing things seems more important than ever, and I think it would help to have that bit of context.

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In the interest of full disclosure, the author(s) of this post are identified on the MGH website as private benefactors of Dr Faustman’s research. This doesn’t invalidate their response to the JDRF, but should be noted as a matter of transparency.

ETA: changed “financial supporters” to “benefactors” to more clearly avoid suggesting any pecuniary interest was involved.

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The best results achieved were a 20% reduction in HbA1c, so, for example, if you’re usually getting an HbA1c of 8, you could have the supreme pleasure of winding up with a 6. You would still have to take insulin, deal with hypoglycemia, and face diabetic complications, but your HbA1c would be lower. Alternatively, you might say that instead of the horror of having to draw the syringe down all the way to 10 units in the morning, you might enjoy the medical breakthrough of being able just to draw it down to 8 units. It is just not a big deal for type 1 diabetics.

I’m sorry but your statement is not fully accurate based on the published research. The surprising clinical results in all of the 9 BCG treated people included a reduction in HbA1c to near normal range and no accounts of significant hypoglycemic events for the 5-8 years followed. We all know that prolonged high HbA1c is directly correlated to developing longterm complications. So, after having TID for more than 15+ years, these sustained clinical changes are quite impressive to help avoid the complications while not having the fear of a deadly hypoglycemic episode. Again, this phase I trial included only 9 people who received 2 doses of BCG. That is a small group but, very statistically significant as the effects were seen in all of them. Seeing that BCG has an impeccable 100 year safety record, broadening this research to include early onset patients and the pediatric population would be compelling to see what the results could be.

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Well, in Figure 1 in the article, the results never get any lower than close to a 20% HbA1c reduction. BCG has been used for a long time to treat tuberculosis in diabetics, which used to be a major complication of the disease, and there have never been any reports of those patients experiencing a significant improvement in their condition. BCG is also used for bladder cancer, and yet again, of the diabetics in that group, none has had clinically significant amelioration of their diabetes. In any case, there is considerable research showing that many of the complications are heavily determined by genetics, so even if the blood sugar problem in diabetes were entirely solved, which Faustman’s work by no means does, the threat of complications would not completely vanish.

Consider the statement from the article:

“The 8 year long followed and BCG-treated T1Ds showed a reduction in HbA1c levels of greater than 10% after year 03, 18% at year 04, and the HbA1c remained low for the next 5 years (p = 0.0002 at year 8) (Fig. 1a, b).”

My blood sugar rises and falls spontaneously by amounts in that range all the time, and, aside from requiring adjustments in the insulin dose, that makes no difference in my experience of the disease. I still have to take insulin, I still develop complications, I still suffer hypoglycemia, so what good does it do, when we can reduce blood sugar as much as we like with insulin, if we can also reduce it a bit with BCG?

I find it interesting the JDRF & ADA felt compelled to issue a joint statement against Faustman’s research. Admittedly, I rarely pay attention to the JDRF. Do they make a habit of issuing statements like this?

An HbA1c of 6.5 is considered the threshold of diabetes diagnosis. In the supplemental data of this study, the BCG group started with an average HbA1c of 7.36 and decreased to an average of 6.38 over the years 5-8 followed. In contrast, the control’s group average HbA1c remained relatively the same and even slightly increased from the initial 7.08-7.10 range over the same time period. The data is highly statistically significant (p<0.0002). Semi-annual surveys confirmed the BCG group reported no significant hypoglycemia episodes within the years 5-8 followed. The placebo group continued to show hypoglycemia events during the same time periods of monitoring. Dr Faustman investigated why these significant changes occurred in the BCG treated group when they discovered it was not due to regeneration of islets (based on C-peptide levels). Through extensive research, they found that the blood sugar control was attributed to a shift in the body’s ability to metabolize glucose from “oxidative phosphorylation” to “aerobic glycolysis” (a state of high glucose utilization) on a tightly regulated cellular level throughout the body. In other words, blood glucose uptake and regulation of this uptake by the cells appears to prevent hypoglycemia since the cells stop transporting glucose when the blood sugar is in the normal range.
Dr. Faustman has been corroborating her research with other scientists around the globe who are all part of a BCG coalition meeting annually. These scientists have been studying the history of BCG (it’s been around for 100 years) and its effects on the immune system, other autoimmune diseases and allergies. The strain of BCG and the # of doses one receives is very important on how it effects the immune system. Dr. Faustman and a group of scientists in Italy who are using the same strain and dosing for human trials in MS patients are sharing very similar results. In fact, they are the ones who told her that the changes that they started to see in MS patients did not come out until 2-3 years after dosing and they followed them for 5 years out. This is why Dr. Faustman applied for FDA approval to extend her phase I trial and continued analyzing and monitoring subjects from the 3 year - 8 year time frame.

With JDRF and Faustman, the oddly worded public official communications goes back at least 14 years: https://www.diabeteshealth.com/why-did-the-jdrf-try-to-discredit-cure-research/

JDRF’s internal “mission creep struggles” aka “insider baseball” occasionally surface in terms of odd public official communications but are actually quite common in terms of internal communications between HQ and chapters and members. I think what we are seeing here, is Suelr joining tudiabetes to promote her viewpoint in this internal-to-JDRF discussion/disagreement. I think JDRF has done a great job re-orienting itself to a world where kids with T1 grow up to live a good chunk of a century as adults with T1, to include treatment and long lives as well as cure-cure-cure, but it wasn’t easy or automatic for the factions inside JDRF to make this change.

I’m not interested in second guessing any member’s motive for joining/posting. I’m aware of past history between JDRF & Faustman. The fact remains that JDRF has issued a public statement disputing (attacking) Faustman’s research. I can’t recall that happening any time over the past several years, & I can’t help but wonder why.

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At same time, you should recognize that Suelr joined tudiabetes only to post this internal-to-JDRF disagreement. She posted that the same day she joined tudiabetes so it’s not like she’s part of the community here.

I’m fine with folks inside JDRF refining their mission, and I think they’ve done a good job at it recent years. But I don’t see how them taking their disagreements to tudiabetes helps anyone.

On Faustman - it’s interesting stuff but many odd disconnects and I see why some in the establishment are suspicious. I’m more willing to believe that a couple folks in the study markedly improved their bg control through hard work. The 4 year delay after BCG dose before claimed A1C improvement is really odd and makes me doubt cause and effect. The Faustman proposed effect, an entirely new non-insulin-moderated process for glucose metabolism, certainly wasn’t in any of my 40-year old textbooks so makes me scratch my head. Like Seydlitz wrote earlier, we see our bg’s change all the time anyway not only for good reason but also for no reason!

Also, it is important to keep in mind that the human immune system is a vastly complex, finely-tuned instrument, and tinkering it in any way, as BCG does here, is always dangerous. For example, the immunosuppression required for organ transplants causes, as a side-effect, a 30% chance of cancer after a decade.

BCG has an impeccable 100 year safety record and has been administered to millions. It is not in the same category as an immune suppressant.

I too might have thought any relation BCG and T1 diabetes might be related through the immune system.

Faustman, at least in the 2018 paper, is not hypothesizing that BCG is changing the immune system.

Faustman in the 2018 paper proposes (invents?) a novel previously unknown channel for glucose metabolism that doesn’t require insulin, they call aerobic glycolysis, that results in lowered bg’s.

I wholeheartedly support Dr. Faustman’s BCG research and am hoping to get into her next trial. I have read all of her papers on BCG and although so far it doesn’t seem to be a cure it would certainly improve my quality of life. BCG is less dangerous than a modern flu shot IMO (you couldn’t pay me to get one of those).

I stick to a strict protocol of low carb, CGM, exercise, and umpteem other things to try and control my diabetes but I often fall short of my goals and the lowest I’ve ever got my A1C is 6.7. I am usually very skeptical of studies that claim they can cure diabetes and while that is Dr. Faustmans goal she has clearly stated that that hasn’t been achieved yet, but that is why they are doing more trials to see if they can increase the effectiveness of the BCG vaccine. Even if they never figure out how to cure diabetes with the BCG vaccine I still want to get it and will enjoy the possible benefits in approximately 3 years.

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Dr. Faustman published in 2017 the effects of BCG found on the immune system based on this phase I human trial. She presented this research at the 2017 ADA conference.

“In the past decade, interest in the century-old tuberculosis vaccine, bacillus Calmette-Guerin (BCG), has been revived for potential new therapeutic uses in type 1 diabetes and other forms of autoimmunity. Diverse clinical trials are now proving the value of BCG in prevention and treatment of type 1 diabetes, in the treatment of new onset multiple sclerosis and other immune conditions. BCG contains the avirulent tuberculosis strain Mycobacterium bovis, a vaccine originally developed for tuberculosis prevention. BCG induces a host response that is driven in part by tumour necrosis factor (TNF). Induction of TNF through BCG vaccination or through selective agonism of TNF receptor 2 (TNFR2) has 2 desired cellular immune effects: (1) selective death of autoreactive T cells and (2) expansion of beneficial regulatory T cells (Tregs). In human clinical trials in both type 1 diabetes and multiple sclerosis, administration of the BCG vaccine to diseased adults has shown great promise. In a Phase I trial in advanced type 1 diabetes (mean duration of diabetes 15 years), 2 BCG vaccinations spaced 4 weeks apart selectively eliminated autoreactive T cells, induced beneficial Tregs, and allowed for a transient and small restoration of insulin production. The advancing global clinical trials using BCG combined with mechanistic data on BCGs induction of Tregs suggest value in this generic agent and possible immune reversal of the type 1 diabetic autoimmune process.”

https://www.ncbi.nlm.nih.gov/pubmed/28843039

In this 2018 publication of the long term results of the phase I BCG trial, it does explain the surprise finding of 2 doses of BCG increasing the beneficial T regulatory (Tregs) cells of the immune system to almost normal limits.