Imatinib Treatment in Recent Onset Type 1 Diabetes Mellitus
Imatinib Treatment in Recent Onset Type 1 Diabetes Mellitus
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.
Inclusion Criteria:

 -  Males and females age 12-45 years of age who meet the ADA standard T1DM criteria1.
 Positive for at least one islet cell autoantibody. Initial enrollment will be for
 subjects ages 18-45, with the goal to lower the age down to 12 upon acceptable safety
 review and prospect of benefit for this initial older cohort.

 -  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 (baseline hemoglobin below lower limit of normal)

 -  Prior history of anaphylaxis, angioedema or serious cutaneous drug reactions

 -  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 > 1.2 times the upper
 limit of normal and confirmed in a repeat test at least one 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 -1 noted on ECG (> 450 ms in males and > 470 ms
 in females)

 -  Known coagulation disorders or use of anticoagulants

 -  Current and anticipated on-going treatment with drugs that may increase or decrease
 imatinib plasma concentrations (CYP3A4 family inhibitors or inducers) or drugs that
 may have their plasma concentration altered by imatinib (drugs metabolized by CYP3A4/5
 and CYP2D6).

 -  Any condition that, in the investigator's opinion, may compromise study participation
 or may confound the interpretation of the study results.