Imatinib Treatment in Recent Onset Type 1 Diabetes Mellitus

NCT01781975 | Completed Phase 2 Results DMC

• 1 other identifier: 17-2013-6
• Study Type: interventional
• Target: 67
• Locations: 2 countries
• Sites: 9

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.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• 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

  The primary outcome of each participant is the area under the stimulated c-peptide curve (AUC) mean based on data collected at time 0 to 2 hours of a 4-hour mixed meal tolerance test (MMTT) conducted at the primary endpoint visit. The timed measurements are done at: 0, 15, 30, 60, 90, and 120 minutes. The term "AUC mean" comes from the mean value theorem in calculus. It is the value on the scale of the y-axis that is equal to the AUC divided by the range on the x-axis (in this case 120 minutes).

  Visit 9 (Week 52) at 0, 15, 30, 60, 90, 120 minutes post-dose

Secondary Outcomes (5)

• Area Under the Stimulated C-peptide Curve (AUC) Mean Over 4 Hours at 24 Months

  Visit 13 (Week 104)

• Change in HbA1c Levels Over Time

  Visit 9 (Week 52) and Visit 13 (Week 104)

• Change in Insulin Dose (Units/kg) Over Time

  Visit 9 (Week 52) and Visit 13 (Week 104)

• Number of Severe Hypoglycemic Events

  Visit 0 (Week 0), Visit 9 (Week 52), and Visit 13 (Week 104)

• Number of Adverse Events

  Adverse Events will be assessed at Visit 0 (week 0), Visit 1 (Week 2), Visit 2 (Week 4), and every month thereafter.

Study Arms (2)

Imatinib Mesylate

EXPERIMENTAL

400 mg imatinib given once daily basis.

Drug: Imatinib Mesylate

Placebo

PLACEBO COMPARATOR

Placebo given once daily basis.

Drug: Placebo (For imatinib mesylate)

Interventions

Imatinib Mesylate DRUG

Also known as: GLEEVEC, Glivec

Imatinib Mesylate

Placebo (For imatinib mesylate) DRUG

Placebo

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• University of California, San Francisco: lead
• Juvenile Diabetes Research Foundation: collaborator

Study Sites (9)

University of California-San Francisco

San Francisco, California, 94143, United States

Location

Barbara Davis Center

Aurora, Colorado, 80045, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

Indiana University

Indianapolis, Indiana, 46202, United States

Location

University of Iowa

Iowa City, Iowa, 52242, United States

Location

Joslin Diabetes Center

Boston, Massachusetts, 02215, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

University of Texas Southwestern

Dallas, Texas, 75390, United States

Location

Walter and Eliza Hall Institute of Medical Research

Melbourne, Victoria, 3050, Australia

Location

Related Publications (2)

• 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.

  PMID: 34214479 DERIVED

• 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.

  PMID: 32715853 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 1

Interventions

Imatinib Mesylate

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Benzamides; Amides; Organic Chemicals; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines

Limitations and Caveats

FDA did not approve for hold on enrollment of pediatric population to be lifted; only adult population was recruited.

Results Point of Contact

• Title: Melissa Parker
• Organization: University of South Florida

MELISSA.PARKER@EPI.USF.EDU

8133969378

Study Officials

• Stephen E Gitelman, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director, Pediatric Diabetes Program

Study Record Dates

• First Submitted: January 17, 2013
• First Posted: February 1, 2013
• Study Start: January 1, 2014
• Primary Completion: May 1, 2017
• Study Completion: May 1, 2018
• Last Updated: February 11, 2020
• Results First Posted: August 8, 2018

Record last verified: 2020-02

Locations

AU (1); US (8)