BCG Vaccination for Type 1 Diabetes

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Massachusetts General Hospital

Must be taking: Insulin

Must not be taking: Glucocorticoids, Immunosuppressives, Antibiotics, NSAIDs

Disqualifiers: HIV, Hepatitis, Tuberculosis, others

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether the BCG vaccine can help people with Type 1 diabetes by enhancing their immune system and boosting insulin production. Participants will receive either the BCG vaccine or a placebo over several years to determine if the vaccine can reduce harmful immune cells and aid the pancreas in producing insulin. People with Type 1 diabetes who have been on insulin since diagnosis might be suitable candidates. The trial also includes a separate study on how BCG affects COVID-19 outcomes in these participants. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to important findings.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the BCG (Bacillus Calmette-Guérin) vaccine has been safely used for many years, primarily to prevent tuberculosis. In studies involving individuals with Type 1 diabetes, BCG has demonstrated promising results. Specifically, it has improved blood sugar control, as evidenced by a decrease in HbA1c, a measure of average blood sugar levels.

In earlier trials, some participants experienced a 10-15% reduction in blood sugar levels after receiving multiple doses of BCG. This suggests that the vaccine might help manage diabetes more effectively. Published Phase I data indicated that BCG could reduce certain harmful white blood cells, potentially improving pancreatic function for a short time.

The vaccine is generally well-tolerated, with no major safety concerns reported in these trials. However, like any treatment, some individuals might experience mild side effects, such as a sore arm or slight fever, which are common with most vaccinations. Overall, the BCG vaccine has a long history of being safe for humans. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for Type 1 Diabetes focus on insulin management and glucose monitoring. But Bacillus Calmette-Guérin (BCG) offers a unique approach by using an existing tuberculosis vaccine to potentially alter immune system behavior. Researchers are excited because BCG might help reduce the autoimmune attack on insulin-producing cells, possibly leading to better blood sugar control without solely relying on insulin. This immunomodulatory effect is what sets BCG apart from traditional treatments, offering hope for a more sustained and less burdensome management of Type 1 Diabetes.

What evidence suggests that BCG vaccination might be an effective treatment for Type 1 diabetes?

Research suggests that the BCG vaccine, which participants in this trial may receive, might benefit people with Type 1 diabetes. Studies have shown that BCG can improve HbA1C levels, a measure of blood sugar control. Some findings also indicate that BCG might reduce certain harmful antibodies linked to Type 1 diabetes. Additionally, countries administering the BCG vaccine at birth report fewer cases of Type 1 diabetes. Early research indicates that BCG might help protect against serious diabetes complications. While the evidence is promising, further research is needed to confirm these benefits. Participants in this trial may also receive a saline injection as a placebo comparator. ^{2 4 6 7 8}

Who Is on the Research Team?

Denise L Faustman, MD, PhD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

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]

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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7139880/

Therapeutic Effects of BCG Vaccination on Type 1 Diabetes ... There is no robust evidence to support the use of the BCG vaccine for the treatment of T1DM although the HbA1c levels tended to improve.

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1871402124001632

Significance of Bacillus Calmette-Guerin (BCG) vaccine ... Our systematic review and meta-analysis revealed benefits of BCG vaccine intervention in T1D patients, including improved HbA1C and GAD autoantibody levels.

3. journals.plos.org journals.plos.org/plosone/article?id=10.1371/journal.pone.0276423

Bacille Calmette Guerin (BCG) and prevention of types 1 and ... Countries that currently administer BCG have a significantly lower T1D incidence rate than those that do not administer the vaccine at birth.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT02081326

Study Details | NCT02081326 | Repeat BCG Vaccinations ... 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 ...

5. massgeneral.org massgeneral.org/news/press-release/century-old-vaccine-protects-type-1-diabetics

Century-old Vaccine Protects Type 1 Diabetics from ... The 100-year-old Bacillus Calmette-Guérin (BCG) vaccine, originally developed to prevent tuberculosis, protects individuals with type 1 diabetes from severe ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10141056/

BCG Vaccination and the Risk of Type 1 Diabetes Mellitus (4) Conclusions: Our study revealed no protective or facilitative effect of prior BCG vaccination in T1D development. Keywords: type 1 diabetes, ...

7. diabetesjournals.org diabetesjournals.org/diabetes/article/74/Supplement_1/881-P/159629/881-P-BCG-Clinical-Trial-Programs-in-Advanced-Type

881-P: BCG Clinical Trial Programs in Advanced Type 1 ... In two open-label clinical trials in adults with early onset T1D, HbA1c reduction of 10-15% was observed after multi-dose BCG treatment. A ...

8. scientificarchives.com scientificarchives.com/article/bcg-immunotherapy-promising-protection-from-covid-19-and-other-infectious-diseases-in-type-1-diabetics

BCG Immunotherapy: Promising Protection from COVID-19 ... Five found BCG to be efficacious, while seven did not. The BCG trials that failed to find benefit were often too short in duration to obtain protection. We show ...