Repeat BCG Vaccinations for the Treatment of Established Type 1 Diabetes

Study Overview
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Brief Summary
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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.

Official Title
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Repeat BCG Vaccinations for the Treatment of Established Type 1 Diabetes

Conditions
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Diabetes Mellitus, Type One, Diabetes Mellitus, Type I, Autoimmune Diabetes, Covid19

Intervention / Treatment
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* Biological: Bacillus Calmette-Guérin
* Biological: Saline injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 1 diabetes treated continuously with insulin from time of diagnosis Age 18-65 HIV antibody negative Normal CBC HCG negative (females) Anti-GAD Positive (except for subjects with c-peptide <10pmol/L) Fasting or stimulated c-peptide between 5-200 pmol/L Participation in protocol #2001P001379, Autoimmunity: In Vitro Pathogenesis and Early Detection Exclusion Criteria: History of chronic infectious disease such as HIV or hepatitis History of tuberculosis, TB risk factors, positive interferon-gamma release assay (IGRA, also known as the T-SPOT.TB test), or BCG vaccination Current treatment with glucocorticoids (other than intermittent nasal or eye steroids), or disease or condition likely to require steroid therapy Other conditions or treatments associated with increased risk of infections such as patients with a previous history of severe burns, or treatment with immunosuppressive medications of any type (e.g. imuran, methotrexate, cyclosporine, etanercept, infliximab) for any reason Current treatment with aspirin > 160 mg/day or chronic, daily NSAIDs Current treatment with antibiotics History of keloid formation Average HbA1c over the past 5 years (or since diagnosis if duration is less than 5 years) <6.5 or > 8.5% History or evidence of chronic kidney disease (serum creatinine > 1.5mg/dL) History of proliferative diabetic retinopathy that has not been treated with laser therapy History of neuropathy, foot ulcers, amputations, or kidney disease Pregnant or not using acceptable birth control Living with someone who is immunosuppressed and/or at high risk for infectious diseases (for example HIV+ or taking immunosuppressive medications for any reason)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bacillus Calmette-Guérin<br>2 BCG vaccinations spaced 4 weeks apart during the first year and then 1 vaccination every year for the next 4 years | Biological: Bacillus Calmette-Guérin<br>* 2 BCG vaccinations spaced 4 weeks apart during the first year and then 1 vaccination every year for the next 4 years<br>|
| Placebo Comparator: Saline injection<br>2 injections spaced 4 weeks apart during the first year, then 1 injection per year for the next 4 years | Biological: Saline injection<br>* 2 injections spaced 4 weeks apart during the first year, then 1 injection per year for the next 4 years<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HbA1c values in juvenile onset type 1 diabetics | A change in the hemoglobin A1c (HbA1c) measurement compared to self | 1, 2, 3, 4, and 5 years after initial BCG/placebo injection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Insulin use in juvenile onset type 1 diabetics (AOO<21 years) | A change in insulin (IDAA1c) use as reported at study visits compared to self in juvenile onset type 1 diabetes. | 4 weeks and 1, 2, 3, 4, and 5 years after initial BCG/placebo injection | 
| Endogenous insulin levels in the blood in juvenile onset type 1 diabetics (AOO<21 years) | A change in c-peptide and proinsulin levels (as an analog for endogenous insulin) in the blood compared to self. | 4 weeks and 1, 2, 3, 4, and 5 years after initial BCG/placebo injection | 
| Autoimmunity in juvenile onset type 1 diabetes (AOO<21 years) | A change in autoantibodies and autoreactive T cells to monitor the drug mechanism for autoimmune changes. | 4 weeks and 1, 2, 3, 4, and 5 years after initial BCG/placebo injection | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes Mellitus, Type One, Diabetes Mellitus, Type I, Autoimmune Diabetes, Insulin Dependent Diabetes Mellitus 1, IDDM, COVID-19