Clinical trial NCT01781975: Imatinib Treatment in Recent Onset Type 1 Diabetes Mellitus
Official title: Safety and Efficacy of Imatinib for Preserving Beta-Cell Function in New-Onset Type 1 Diabetes Mellitus
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Diabetes Mellitus, Type I
Diabetes Mellitus, Insulin-Dependent, 1
Type 1 Diabetes Mellitus
Insulin-Dependent Diabetes Mellitus 1
IDDM
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: Juvenile Diabetes Research Foundation
First posted: 2013-02-01
Enrollment: 67
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Area Under the Stimulated C-peptide Curve (AUC) Mean Over the First 2 Hours of a 4 Hour Mixed Meal Tolerance Test at the 1 Year Visit
timeFrame: Visit 9 (Week 52) at 0, 15, 30, 60, 90, 120 minutes post-dose
Secondary outcomes:
measure: Area Under the Stimulated C-peptide Curve (AUC) Mean Over 4 Hours at 24 Months
timeFrame: Visit 13 (Week 104)
measure: Change in HbA1c Levels Over Time
timeFrame: Visit 9 (Week 52) and Visit 13 (Week 104)
measure: Change in Insulin Dose (Units/kg) Over Time
timeFrame: Visit 9 (Week 52) and Visit 13 (Week 104)
measure: Number of Severe Hypoglycemic Events
timeFrame: Visit 0 (Week 0), Visit 9 (Week 52), and Visit 13 (Week 104)
measure: Number of Adverse Events
timeFrame: Adverse Events will be assessed at Visit 0 (week 0), Visit 1 (Week 2), Visit 2 (Week 4), and every month thereafter.
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California-San Francisco
state: California
city: Aurora
country: United States
facility: Barbara Davis Center
state: Colorado
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Boston
country: United States
facility: Joslin Diabetes Center
state: Massachusetts
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Dallas
country: United States
facility: University of Texas Southwestern
state: Texas
city: Melbourne
country: Australia
facility: Walter and Eliza Hall Institute of Medical Research
state: Victoria
Study officials:
affiliation: University of California, San Francisco
name: Stephen E Gitelman, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gitelman SE, Bundy BN, Ferrannini E, Lim N, Blanchfield JL, DiMeglio LA, Felner EI, Gaglia JL, Gottlieb PA, Long SA, Mari A, Mirmira RG, Raskin P, Sanda S, Tsalikian E, Wentworth JM, Willi SM, Krischer JP, Bluestone JA; Gleevec Trial Study Group. Imatinib therapy for patients with recent-onset type 1 diabetes: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Diabetes Endocrinol. 2021 Aug;9(8):502-514. doi: 10.1016/S2213-8587(21)00139-X. Epub 2021 Jun 29.
citation: Robertson MA, Padgett LR, Fine JA, Chopra G, Mastracci TL. Targeting polyamine biosynthesis to stimulate beta cell regeneration in zebrafish. Islets. 2020 Sep 2;12(5):99-107. doi: 10.1080/19382014.2020.1791530. Epub 2020 Jul 25.