Denosumab for Type 1 Diabetes

This is a Phase 1/2, prospective, randomized, double-blind, placebo-controlled, multi-center clinical trial to evaluate the safety and efficacy of denosumab for improving beta cell function and glycemic control among patients with early T1D and detectable C-peptide. The efficacy of denosumab will be evaluated by changes in C-peptide level during mixed meal tolerance test and achieving a clinically meaningful HbA1c reduction at 12 months. Subjects will be followed for 12 months for adverse events and for changes in beta cell function and glycemic control parameters.

Subjects will be randomized with a 2:1 treatment to placebo ratio. The treatment group will enroll 30 subjects with the denosumab regimen of 60 mg given subcutaneously every 3 months for a total of 4 injections. The placebo arm will enroll 15 subjects and be administered with normal saline placebo given subcutaneously every 3 months for a total of 4 doses.

Main Inclusion Criteria

• Age: Females 18-50 years; males 21-50 years (minimum age based on skeletal maturity)
• Diagnosis of type 1 diabetes (T1D) based on ADA Criteria:

• Hyperglycemia (glycosylated hemoglobin (HbA1c) ≥ 6.5%; OR
• fasting plasma glucose ≥ 126 mg/dl (7.0 mmol/L); OR
• 2-hour plasma glucose ≥ 200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test; OR
• In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥ 200 mg/dl (11.1 mmol/L)
• Documented history of at least one type 1 diabetes associated autoantibody

• GAD specific autoantibodies (GADA);
• Islet-antigen 2 specific autoantibody (IA-2A); and/or
• Zinc Transporter 8 specific autoantibody (ZNT8A)
• Time from T1D diagnosis to screening MMTT must be ≥ 12 months but ≤ 5 years
• Non-fasting C-peptide concentrations of at least 0.2 nmol/L (0.6 ng/ml) at pre-screening and confirmed during a MMTT done at screening visit.
• Serum calcium (corrected for albumin)* within normal limits per site's local lab
• Agreement by women of childbearing potential (WOCBP) and males of childbearing potential to use a highly effective method of birth control for the course of the study through at least 5 months from the last dose of protocol therapy

Main Exclusion Criteria

• History of delayed puberty unless there is radiologic evidence of skeletal maturity
• Use of other investigational agents within 3 months of enrollment
• Vitamin D3 deficiency (< 30 ng/ml)
• History of anorexia and/or eating disorder
• BMI > 32 kg/m2
• HbA1c > 9.5%
• Severe hypoglycemia or diabetic ketoacidosis (DKA) within 3 months prior to screening. Subjects who had such episodes within 3-6 months prior to screening, must have written clearance from their treating physician.
• Use of any of the diabetes medications other than insulin within 3 months of enrollment (e.g., metformin, sulfonylurea, GLP-1 agonists, DPP4 inhibitors, Symlin, SGLT2-inhibitors, amylin)
• Treatment with any of the following drugs in past year: immunosuppressants, anticonvulsant therapy, adrenal or anabolic steroids, calcitonin, selective estrogen receptor modulator, sodium fluoride (other than dental treatment), teriparatide, abaloparatide, strontium or aromatase inhibitors; any history of bisphosphonate treatment.
• Bone fractures (excluding skull, facial bones, metacarpals, fingers, toes and spontaneous fractures associated with severe trauma) within the past 12 months
• Disorders associated with altered skeletal structure or function (Paget's disease, chronic liver disease (liver enzymes > twice the upper limit of normal), malignancy, hypoparathyroidism or hyperparathyroidism, acromegaly, Cushing's syndrome, hypopituitarism, chronic obstructive pulmonary disease, alcohol intake > 3 units/day)
• Significant dental/oral disease, including prior history or current evidence of osteonecrosis/osteomyelitis of the jaw, active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or planned invasive dental procedures for the course of the study
• Pregnancy or actively breastfeeding (within 6 months prior to screening), or planning to become pregnant with 5 months after last dose of protocol therapy