BCG Vaccination for Type 1 Diabetes

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Massachusetts General Hospital

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 7 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 4 years

150 Participants Needed

Trial Summary

What is the purpose of this trial?

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. Published Phase I data on repeat BCG vaccinations in long term diabetics showed specific death of some of the disease causing bad white blood cells and also showed a short and small pancreas effect of restored insulin secretion. In this Phase II study, the investigators will attempt to vaccinate more frequently to see if these desirable effects can be more sustained. 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. An additional adaptive trial for COVID-19 is also being conducted on these randomized double blinded type 1 diabetic subjects receiving BCG or placebo injections. An expanded study arm has been approved for repeat dosing of BCG in adult Type I diabetes.

Will I have to stop taking my current medications?

The trial requires that you do not take certain medications, such as glucocorticoids, immunosuppressive medications, high-dose aspirin, chronic NSAIDs, and antibiotics. If you are on these medications, you may need to stop them to participate in the trial.

What data supports the effectiveness of the BCG vaccine treatment for type 1 diabetes?

Research shows that the BCG vaccine can modulate the immune system, potentially slowing the progression of type 1 diabetes by reducing harmful immune cells and increasing beneficial ones. Some clinical trials have shown promise in restoring insulin production in people with long-standing type 1 diabetes. ^{1 2 3 4 5}

Is the BCG vaccine safe for humans?

The BCG vaccine, originally developed for tuberculosis prevention, has been used safely in humans for many years. Clinical trials have shown it to be generally safe, with studies in type 1 diabetes and multiple sclerosis indicating no major safety concerns. ^{1 3 4 5 6}

How does the BCG vaccine treatment for type 1 diabetes differ from other treatments?

The BCG vaccine is unique because it modulates the immune system to reduce harmful immune cells and increase beneficial ones, potentially slowing the progression of type 1 diabetes. Unlike standard treatments that focus on managing blood sugar, BCG aims to address the underlying autoimmune process. ^{1 3 5 6 7}

Research Team

Denise L Faustman, MD, PhD

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

Adults aged 18-65 with Type 1 diabetes, continuously treated with insulin and having specific levels of c-peptide are eligible. They must not have a history of tuberculosis, chronic infections like HIV or hepatitis, severe kidney disease, or be on treatments that suppress the immune system. Women participating should not be pregnant.

Inclusion Criteria

I have been on insulin since my type 1 diabetes diagnosis.

Participation in protocol #2001P001379, "Autoimmunity: In Vitro Pathogenesis and Early Detection"

I have tested positive for anti-GAD, except if my c-peptide level is below 10pmol/L.

Exclusion Criteria

I am currently taking antibiotics.

My average blood sugar level over the past 5 years has been either below 6.5% or above 8.5%.

I have a history of tuberculosis or have been vaccinated against it.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive BCG vaccinations or placebo injections over a period of four years

4 years

2 injections in the first year, then 1 injection per year

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

COVID-19 Adaptive Study

Participants are monitored for COVID-19 related outcomes

15 months

Treatment Details

Interventions

• Bacillus Calmette-Guérin

Trial Overview The trial is testing if repeated BCG vaccinations can improve Type 1 diabetes by killing bad white blood cells and possibly restoring insulin secretion from the pancreas. Participants will receive either BCG vaccines or placebo over four years to compare effects.

Participant Groups

Group I: Bacillus Calmette-Guérin Experimental Treatment 1 Intervention

2 BCG vaccinations spaced 4 weeks apart during the first year and then 1 vaccination every year for the next 4 years

Group II: Saline injection Placebo Group 1 Intervention

2 injections spaced 4 weeks apart during the first year, then 1 injection per year for the next 4 years

Bacillus Calmette-Guérin is already approved in European Union, Canada, Japan, China, India, Brazil, United States for the following indications:

Approved in European Union as BCG Vaccine for:

• Tuberculosis prevention
• Bladder cancer treatment

Approved in Canada as BCG Vaccine for:

• Tuberculosis prevention in high-risk groups
• Bladder cancer treatment

Approved in Japan as BCG Vaccine for:

• Tuberculosis prevention
• Bladder cancer treatment

Approved in China as BCG Vaccine for:

• Tuberculosis prevention
• Bladder cancer treatment

Approved in India as BCG Vaccine for:

• Tuberculosis prevention
• Bladder cancer treatment

Approved in Brazil as BCG Vaccine for:

• Tuberculosis prevention
• Bladder cancer treatment

Approved in United States as BCG Vaccine for:

• Bladder cancer treatment

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

Findings from Research

A systematic review of four randomized controlled trials involving 198 subjects found that the BCG vaccine did not significantly improve glycemic control in type 1 diabetes, as indicated by unchanged HbA1c and fasting C-peptide levels compared to placebo.

While there was a slight tendency for HbA1c levels to improve with the BCG vaccine, the evidence is not strong enough to recommend its use for treating type 1 diabetes, highlighting the need for further research on its long-term effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic Effects of BCG Vaccination on Type 1 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Chang, YC., Lin, CJ., Hsiao, YH., et al.[2022]

In a study involving 94 children with new-onset type 1 diabetes, the BCG vaccine did not significantly increase the remission rate or preserve beta-cell function compared to a placebo.

Both groups showed a decline in C-peptide levels, insulin requirements, and HbA1c levels over the 2-year period, indicating that BCG vaccination does not provide additional benefits in managing type 1 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Bacillus Calmette-Guerin vaccination on new-onset type 1 diabetes. A randomized clinical study. Allen, HF., Klingensmith, GJ., Jensen, P., et al.[2022]

The BCG vaccine, originally developed for tuberculosis, shows promise in treating type 1 diabetes and other autoimmune diseases by selectively eliminating harmful T cells and promoting beneficial regulatory T cells (Tregs).

In a Phase I trial involving adults with advanced type 1 diabetes, BCG vaccination led to a temporary restoration of insulin production and a reduction in autoreactive T cells, highlighting its potential as a therapeutic intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TNF, TNF inducers, and TNFR2 agonists: A new path to type 1 diabetes treatment. Faustman, DL.[2018]

In a study of 387,704 individuals in Quebec, BCG vaccination in early life did not show a protective effect against the development of type 1 diabetes, with a similar incidence in vaccinated and unvaccinated groups.

The analysis found no significant association between the age at which individuals received the BCG vaccine and the risk of developing type 1 diabetes, indicating that BCG vaccination is unlikely to prevent this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association between Bacillus Calmette-Guerin vaccination and type 1 diabetes in adolescence: A population-based birth cohort study in Quebec, Canada. Corsenac, P., Parent, MÉ., Benedetti, A., et al.[2022]

BCG vaccination in early life is linked to a reduced risk of developing type 1 diabetes after age 30 and type 2 diabetes in adulthood, based on a study of 396,118 individuals in Quebec.

No significant association was found between BCG vaccination and latent autoimmune diabetes (LADA), suggesting that the protective effects of BCG may vary by diabetes phenotype.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early life Bacillus Calmette-Guerin vaccination and incidence of type 1, type 2, and latent autoimmune diabetes in adulthood. Corsenac, P., Parent, MÉ., Mansaray, H., et al.[2022]

A single dose of the BCG vaccine administered at age 9 may delay the onset of type 1 diabetes (T1D) by approximately 2.5 years, based on a study of 196 patients.

The study found that BCG vaccinated individuals were diagnosed with T1D at a later age compared to non-vaccinated individuals, suggesting that multiple doses of BCG could further prolong the disease-free interval.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Role of Pediatric BCG Vaccine in Type 1 Diabetes Onset. Doupis, J., Kolokathis, K., Markopoulou, E., et al.[2021]

In animal models, Freund's complete adjuvant (CFA) and BCG vaccine significantly reduced the incidence of type 1 diabetes, suggesting a potential for these treatments to alter the autoimmune response.

In a preliminary trial with 17 newly diagnosed type 1 diabetic patients, 65% experienced clinical remission after receiving BCG, with no reported side effects, indicating a promising safety profile and efficacy that warrants further investigation in a double-blind trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of adjuvant therapy on development of diabetes in mouse and man. Shehadeh, N., Calcinaro, F., Bradley, BJ., et al.[2019]

References

1. England pubmed.ncbi.nlm.nih.gov

Therapeutic Effects of BCG Vaccination on Type 1 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Effect of Bacillus Calmette-Guerin vaccination on new-onset type 1 diabetes. A randomized clinical study. [2022]

3. England pubmed.ncbi.nlm.nih.gov

TNF, TNF inducers, and TNFR2 agonists: A new path to type 1 diabetes treatment. [2018]

4. United States pubmed.ncbi.nlm.nih.gov

Association between Bacillus Calmette-Guerin vaccination and type 1 diabetes in adolescence: A population-based birth cohort study in Quebec, Canada. [2022]

5. France pubmed.ncbi.nlm.nih.gov

Early life Bacillus Calmette-Guerin vaccination and incidence of type 1, type 2, and latent autoimmune diabetes in adulthood. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

The Role of Pediatric BCG Vaccine in Type 1 Diabetes Onset. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Effect of adjuvant therapy on development of diabetes in mouse and man. [2019]