Repeat BCG Vaccinations For The Treatment Of Pediatric Type 1 Diabetes

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to investigate if repeat bacillus Calmette-Guérin (BCG) vaccinations can confer a beneficial immune and metabolic effect on pediatric Type 1 diabetes.

Detailed Description
-----------------
Published Phase I data on repeat BCG vaccinations in long term adult type 1 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. The BCG vaccine also had beneficial metabolic effects that resets the utilization of sugars and significantly improves blood sugars by stably lowering HbA1c values for up to 8 years in subjects in the treatment group and not in the placebo group. In this Phase II Pediatric study, the investigators will attempt to test if even more significant effects can be seen in a pediatric population. Eligible volunteers will either be vaccinated with BCG twice, one month apart or receive a placebo treatment. Both groups will be followed for five years.

Official Title
-----------------
Repeat BCG Vaccinations For The Treatment Of Pediatric Type 1 Diabetes

Conditions
-----------------
Diabetes Mellitus, Type 1, Diabetes type1, Autoimmune Diabetes

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Type 1 diabetic subjects treated with insulin and >24 months since diagnosis (existing diabetes). Male or female, age 12-<18 years at the time of study entry and <18 at the time of randomization. HIV antibody negative, TB negative (QuantiFERON-TB test negative), hCG negative. Normal CBC and chemistries and only Grade 1 creatinine elevations. Currently on a CGM and willing to be on a CGM for the entire study. Has detectable C-peptide (1.5 pmol/L - 300 pmol/L). Informed consent and child assent, as age-appropriate, obtained before any trial-related activities. Trial related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial. Legally Acceptable Representative (LAR) of the Subject must sign and date the Informed Consent Form (according to local requirements). The child must sign and date the Child Assent Form or provide oral assent, if required according to local requirements. Previously diagnosed with type 1 diabetes mellitus (based on clinical judgement and supported by laboratory analysis as per local guidelines) prior to study enrollment by WHO/ADA diagnostic criteria for glucose levels (FPG = 7.0 mmol/L [126 mg/dL]) or plasma glucose levels 2-hours after 75-gm oral glucose load of = 11.1 mmol/L (200 mg/dL) or a casual plasma glucose >200 mg/dL with symptoms. Presence of one or more of the following: antibodies to glutamic acid decarboxylase (GAD), islet cell autoantibody (ICA), protein tyrosine phosphatase-like protein antibodies (IA-2), insulin autoantibodies (IAA), zinc transporter 8 antibodies (ZnT8). Ongoing daily treatment with a basal-bolus insulin regimen using a basal insulin analogue or insulin pump therapy. Ability and willingness to take at least 3 daily meal-time related bolus insulin injections throughout the trial (Subject and LAR(s) should be evaluated as a unit). Ability and willingness to adhere to the protocol, including performing self-measured plasma glucose profiles (Subject and LAR(s) should be evaluated as a unit). Exclusion Criteria: History of chronic infectious disease, such as HIV or untreated or active hepatitis. History of tuberculosis, positive interferon-gamma release assay (IGRA, also known as the QuantiFERON-TB test), including a test with a high reactivity to mycobacteria of non-tuberculosis variety. Current treatment with glucocorticoids (other than intermittent nasal or eye steroids, asthma inhaler, or topical steroids), or disease or condition likely to require high dose steroid or immunosuppressive therapy. This does not include replacement therapies for conditions such as growth hormone deficiencies, Addison's disease, or hypothyroidism. Simultaneous participation in any other clinical trial while enrolled in this clinical trial or participation in another clinical trial within 28 days before the screening visit. Note: Clinical trials do not include non-interventional studies. Previous participation in the treatment group in biologic or drug intervention trials for Type 1 Diabetes such as anti-CD3. Other chronic conditions, diseases and/or treatments associated with increased risk of serious side effects or morbidities. Such conditions that increase the risk of infections with immunosuppressive therapies for other autoimmune diseases, 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 chronic antibiotics that interfere with BCG viability. History of recurrent ketoacidosis with hospitalizations due to non-compliance. History of keloid formation. Average HbA1c over the past 3 months <7.0% or >9.0% History or evidence of chronic kidney disease (serum creatinine > 1.5 mg/dL), significant protein in the urine, or other significant and/or active diabetes related complication. Current BMI of <5th percentile or >95th percentile Blood pressure >90th percentile for their age and sex Temperature >98.6 F Heart rate outside of 50-120 bpm History of active proliferative diabetic retinopathy. History of type 2 diabetes or severe obesity. Age of diabetes onset <1 Monogenetic diabetes Diabetes secondary to cystic fibrosis. Diabetes lacking at least 1 diabetes-specific autoantibody. History of significant neuropathy, myocardial infarcts, active psychiatric disease that might preclude travel and long-term participation, dementia, foot ulcers, severe diabetes non-compliance, amputations, or kidney disease. History of medical condition(s) that may impact red blood cell turnover such as polycythemia, chronic anemia, vitamin E infusion, transfusion, sickle cell or thalassemia, vitamin C injections, lead poisoning, uremia, or asplenia. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using adequate contraceptive methods (adequate contraceptive measures as required by local regulation or practice). Living with someone who is immunosuppressed and/or at high risk for infectious diseases (for example, HIV+ or taking immunosuppressive medications for any reason) as judged by the investigator. Current participation in the Phase I or II BCG clinical trial or other immunotherapy diabetes clinical trials. Currently on or planning to be taking any oral type 2 diabetes drug or other oral blood sugar lowering medication or dramatically changing their standard of care. History of prior BCG vaccination, positive T-spot tuberculosis test or a T-spot test showing significant Mycobacteria exposure. Not born in the US or born in a country with mandatory BCG vaccinations. Known or suspected hypersensitivity to trial products or related products. Anticipated initiation or change in concomitant medication in excess of 14 days known to affect glucose metabolism (e.g., thyroid hormones, corticosteroids). Any condition, which, in the opinion of the Investigator, might jeopardize the Subject's safety or compliance with the protocol. Diagnosis of malignant neoplasms within the last five years prior to the screening visit. Known hypoglycemic unawareness or recurrent severe hypoglycemic episodes as judged by the Investigator. More than one episode of diabetic ketoacidosis requiring hospitalization within the last 90 days prior to the screening. Treatment with any medication for the indication of diabetes other than stated in the inclusion criteria in a period of 90 days before screening. History of lupus

Ages Eligible for Study
-----------------
Minimum Age: 12 Years
Maximum Age: 17 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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 at the beginning of the trial | Biological: Bacillus Calmette-Guérin<br>* 2 BCG vaccinations spaced 4 weeks apart at the beginning of the trial<br>* Other names: BCG;|
| Placebo Comparator: Saline Injection<br>2 placebo injections spaced 4 weeks apart at the beginning of the trial | Biological: Saline Injection<br>* 2 BCG vaccinations spaced 4 weeks apart at the beginning of the trial<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in HbA1c values | A change in hemoglobin A1c (HbA1c) values for pediatric type 1 diabetics compared to self. | 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, and 5 years after initial BCG/placebo injection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in hypoglycemia | A change in hypoglycemic episodes or the magnitude of blood sugar fluctuations compared to self. | 1, 2, 3, 4, and 5 years after initial BCG/placebo injection | 
| Change in C-peptide | A change of fasting or stimulated C-peptide (as an analog for endogenous insulin) in the blood compared to self. | 1, 2, 3, 4, and 5 years after initial BCG/placebo injection | 
| Change in insulin usage | A change in insulin usage with IDAA1c calculation (adjusting for weight and HbA1c) compared to self. | 1, 2, 3, 4, and 5 years after initial BCG/placebo injection | 
| Change in adjusted HbA1c | A change in adjusted hemoglobin A1c (HbA1c) for insulin usage and weight compared to self. | 1, 2, 3, 4, and 5 years after initial BCG/placebo injection | 

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