Repeat BCG Vaccinations for the Treatment of Established Type 1 Diabetes

Repeat BCG Vaccinations for the Treatment of Established Type 1 Diabetes

This Phase II RCT using multi-dose Bacillus Calmette-Guérin (BCG) in adults with juvenile or childhood onset diabetes is based on prior clinical trials showing that even with advanced disease and little of no remaining pancreas activity, HbA1c can be lowered. Prior clinical trials with this highly desired outcome include Phase 1B and two open label clinical trials (2007p001347; IND 10435). The mechanism of restored glucose control was independent of the pancreas; BCG restored regulated sugar transport (aerobic glycolysis) throughout the lymphoid system for normoglycemia.

In the planning for this 10 year long Phase II clinical trial, with first 5 year unblinding, Dr David Schoenfeld, Chief of Biostatics at MGH in SAP 0.0 modeled that 51 long term adult diabetic subjects randomized 2:1 with BCG vaccines over 5 years, would have high probably of repeating the past success in achieving lowered HbA1c in the Phase 1B clinical trial (2012P002243). This Primary outcome and the Primary study population in adults but with juvenile onset disease was the original and continuous outcome for this Phase II clinical trial (IND16434).

In addition to routine protocol changes throughout this study, additional studies were added. These same subjects were both studied in a concurrent Phase II and Phase III infectious disease adaptive clinical trial confirming that BCG provided protection from all infectious diseases and COVID-19 in this vulnerable population, confirming past work of many investigators in Europe (2020P001462). As an early added Exploratory outcome, the trial enrollment numbers were expanded to include latent autoimmune diabetes subjects (LADA), an autoimmune type of diabetes with adult onset. As was reported prior to this trial start, LADA adults lack the necessary lymphoid aerobic defects restored by BCG in the lymphocytes of juvenile onset subjects but have the very slow decay of the pancreas. The slow decay of the pancreas tested the Exploratory outcome of the ability of BCG to induce of T regulatory cells (Treg cells) to possibly halt continued loss of insulin in the pancreas i.e. the autoimmune disease attack of the insulin secreting insulin secreting islets and impact of C-peptide secondary outcomes. Throughout all protocols the study of proteomics was contemplated from collected samples at the end of the study. Proteomics revealed important protein changes related to Alzheimer's complications. The protocol was modified to also generate confirmatory data using FDA approved Alzheimer's diagnostics (IND16434; IND 181620). Additional changes to IND 16434 at the suggestion of the FDA included adding an additional study of PET FDG uptake scan to look for the organ systems wherein BCG induced improved sugar uptake. IND 16434 also allowed a limited number of subjects to have Expanded access. IND 16434 at the 5-year mark will be unblinded for the first data analysis of the 10-year study; placebo subjects can continue with or without the BCG and previous treated BCG can continue as placebo subjects during this "cross over study".

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)