Imatinib Treatment in Recent Onset Type 1 Diabetes Mellitus

• Mean area under the stimulated C-peptide curve (AUC) curve at 12 months [ Time Frame: Visit 9 (Week 52) ] [ Designated as safety issue: No ]
  MMTT-stimulated peak and 4 hour C-peptide AUC at weeks 52
• Mean area under the stimulated C-peptide curve (AUC) over 4 hours at 24 months [ Time Frame: Visit 13 (Week 104) ] [ Designated as safety issue: No ]
  MMTT-stimulated peak, 2 hour C-peptide, and 4 hour C-peptide AUC at week 104.
• Change in HbA1c levels over time [ Time Frame: Visit 9 (Week 52) and Visit 13 (Week 104) ] [ Designated as safety issue: No ]
• Change in Insulin dose (units/kg) over time [ Time Frame: Visit 9 (Week 52) and Visit 13 (Week 104) ] [ Designated as safety issue: No ]
  Assess insulin use in units per kilogram body weight per day at weeks 52 and 104.
• Number of severe hypoglycemic events [ Time Frame: Visit 0 (Week 0), Visit 9 (Week 52), and Visit 13 (Week 52) ] [ Designated as safety issue: Yes ]
  Major hypoglycemic events occurring from randomization at weeks 0, 52 and 104.
• Number and severity of adverse events [ Time Frame: Adverse Events will be assessed at Visit 0 (week 0), Visit 1 (Week 2), Visit 2 (Week 4), and every month thereafter. ] [ Designated as safety issue: Yes ]

Type 1 diabetes mellitus (T1DM) results from the autoimmune destruction of insulin-producing ß cells. Although exogenous insulin is widely available, it is not possible for affected individuals to consistently achieve euglycemia with current technology, and thus they are at risk for devastating long-term complications. This phase II study is designed to evaluate the safety and efficacy of imatinib mesylate as a novel therapy for new-onset T1DM. Imatinib is a first-in-class tyrosine kinase inhibitor.

This study will explore the potential role of short-term therapy with imatinib to induce tolerance and possibly lead to a durable long-term remission of T1DM.

Eligible participants will be randomized to receive either imatinib mesylate or placebo daily.

All participants randomized into this study will be seen at a study site for a follow-up evaluation, 2 weeks and 4 weeks after randomization, and every month month thereafter for the first year. Participants will come in for a visit ever 6 months for the second year.

At the study visits, participants will undergo assessments of their insulin production, immunologic status, and overall health. Subjects will be followed until the conclusion of the study. The trial is expected to last approximately 2-4 years or until the required amount of information is gathered.

• Diabetes Mellitus, Type I
• Diabetes Mellitus, Insulin-Dependent, 1
• Type 1 Diabetes Mellitus
• Insulin-Dependent Diabetes Mellitus 1
• IDDM

• Drug: Imatinib Mesylate
  Other Names:

  • GLEEVEC
  • Glivec
• Drug: Placebo (For imatinib mesylate)

• Experimental: Imatinib Mesylate
  400 mg imatinib given once daily basis.
  Intervention: Drug: Imatinib Mesylate
• Placebo Comparator: Placebo
  Placebo given once daily basis.
  Intervention: Drug: Placebo (For imatinib mesylate)

Inclusion Criteria:

• Males and females age 12-35 years of age who meet the ADA standard T1DM criteria1. Positive for at least one islet cell autoantibody.
• Diagnosis of T1DM within 100 days of Visit 0.
• Peak stimulated C-peptide level >0.2 pmol/mL following an MMTT.
• Participants of childbearing age who are sexually active must agree to use an effective form of birth control (e.g., barrier method, oral contraception, or surgery). For females, these contraceptive measures must be maintained throughout the study; for males these measures must be followed for a minimum of 3 months after discontinuation of imatinib therapy.

Exclusion Criteria:

• Prior history of any significant cardiac disease such as congestive heart failure, myocardial infarction, arrhythmia, or structural defects or suspicion thereof.
• Leukopenia (<3,000 leukocytes/µL), neutropenia (<1,500 neutrophils/µL), or thrombocytopenia (<125,000 platelets/µL).
• Low Hemoglobin
• Any sign of significant chronic active infection (e.g., hepatitis, tuberculosis, EBV, CMV, or toxoplasmosis), or screening laboratory evidence consistent with a significant chronic active infection (such as positive for HIV, PPD, or HBSAg). Significant acute infections must be resolved before treatment may commence, e.g., acute respiratory tract, urinary tract, or gastrointestinal tract infections.
• Anticipated ongoing use of diabetes medications other than insulin that affect glucose homeostasis, such as metformin, sulfonylureas, thiazolidinediones, glucagon-like peptide 1 (GLP-1) mimetics, dipeptidyl peptidase IV (DPP-IV) inhibitors, or amylin.
• Prior or current treatment that is known to cause a significant, ongoing change in the course of T1DM or immunologic status, including high-dose inhaled, extensive topical or systemic glucocorticoids.
• Evidence of liver dysfunction, with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.0 times the upper limit of normal persistent for 1 week or greater.
• Evidence of renal insufficiency as indicated by serum creatinine of >1.2 times the upper limit of normal confirmed in a repeat test at least 1 week apart.
• Evidence of clinically significant metabolic bone disease (except adequately treated rickets).
• Females who are pregnant at the time of screening or unwilling to defer pregnancy during the 24-month study period.
• Prior treatment with imatinib or related tyrosine kinase inhibitor.
• Unable to avoid medications that affect CYP3A4: either inducers that may decrease imatinib levels, or inhibitors that may increase drug concentrations. (Refer to section 1.5.1.12 for a complete list of inducers and inhibitors.)
• Height standard deviation score ≥2 standard deviations below mean
• Any sign of QT prolongation on Visit 0 and Visit 1 ECG
• Known coagulation disorders or use of anticoagulants
• Any condition that, in the investigator's opinion, may compromise study participation or may confound the interpretation of the study results.