Early Intermittent Intensive Insulin Therapy as an Effective Treatment of Type 2 Diabetes (RESET-IT Main Trial)

Overview

Type 2 diabetes mellitus is a chronic metabolic disorder characterized by progressive deterioration in the function of the pancreatic beta-cells, which are the cells that produce and secrete insulin (the hormone primarily responsible for the handling of glucose in the body). The investigators propose a randomized controlled trial to determine whether intermittent intensive insulin therapy is an effective therapeutic strategy that can preserve pancreatic beta-cell function and maintain glycemic control early in the course of type 2 diabetes.

Full Title of Study: “A Randomized Controlled Trial to Evaluate Early Intermittent Intensive Insulin Therapy as an Effective Treatment of Type 2 Diabetes: REmission Studies Evaluating Type 2 DM – Intermittent Insulin Therapy (RESET-IT)”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Single (Outcomes Assessor)
  • Study Primary Completion Date: August 2020

Detailed Description

In this study, eligible patients with type 2 diabetes will be randomized to either intermittent insulin therapy or not, on a background of metformin, after first undergoing a short course of intensive insulin therapy. The hypothesis under study is whether intermittent insulin therapy can preserve beta-cell function.

Interventions

  • Drug: Metformin alone
  • Drug: Metformin + Intermittent Insulin Therapy

Arms, Groups and Cohorts

  • Active Comparator: Metformin alone
    • After a 3-week course of intensive insulin therapy, participants will be treated with ongoing metformin monotherapy. Metformin will be initiated at 500mg twice a day for the first 2 weeks, before progressing to 1000mg twice a day for the duration of the trial (24 months).
  • Experimental: Metformin + Intermittent Insulin Therapy
    • After a 3-week course of intensive insulin therapy, participants will be treated with ongoing metformin monotherapy, initiated at 500mg twice a day for the first 2 weeks, before progressing to 1000mg twice a day for the duration of the trial (24 months). Participants will stop their metformin for 2 weeks every 3 months, during which time they will receive intermittent intensive insulin therapy for 2 weeks. The 2-week course of insulin therapy will be repeated at 3-, 6-, 9-, 12-, 15-,18- and 21-months, with final outcome measurement performed at 24-months.

Clinical Trial Outcome Measures

Primary Measures

  • Baseline-adjusted beta-cell function at 2 years, measured by Insulin Secretion-Sensitivity Index-2 (ISSI-2).
    • Time Frame: 2 years
    • ISSI-2 is an established measure of beta-cell function. ISSI-2 is defined as the product of (i) insulin secretion measured by the ratio of the area-under-the-insulin-curve to the area-under-the-glucose curve and (ii) insulin sensitivity measured by the Matsuda index.

Secondary Measures

  • Baseline-adjusted glycemic control at 2-years.
    • Time Frame: 2 years
    • The secondary outcome of baseline-adjusted glycemic control at 2-years will be assessed by A1c (glycated hemoglobin)

Participating in This Clinical Trial

Inclusion Criteria

1. Men and women between the ages of 30 and 80 years inclusive 2. T2DM diagnosed by a physician </= 5 years prior to enrolment 3. Negative for anti-glutamic acid decarboxylase (anti-GAD) antibodies 4. On either no anti-diabetic medication or on metformin monotherapy, with no change in dose/regimen within 4 weeks prior to enrolment 5. A1c at screening between 5.5% and 9.0% inclusive if on metformin, or between 6.0% and 9.5% inclusive if on no oral anti-diabetic medication 6. BMI >/= 23 kg/m2 7. Negative pregnancy test at recruitment for all women with childbearing potential Exclusion Criteria:

1. Current anti-diabetic treatment with insulin, sulfonylurea, thiazolidinedione, alpha-glucosidase inhibitor, glucagon-like peptide-1 (GLP-1) agonist or dipeptidyl peptidase-4 inhibitor 2. Type 1 diabetes or secondary forms of diabetes 3. History of hypoglycemia unawareness or severe hypoglycemia requiring assistance 4. Any major illness with a life expectancy of <5 years 5. Hypersensitivity to insulin, metformin or the formulations of these products 6. Renal dysfunction as evidenced by estimated glomerular filtration rate (eGFR) <50 ml/min 7. Hepatic disease considered to be clinically significant (includes jaundice, chronic hepatitis, previous liver transplant) or transaminases >2.5 X upper limit of normal 8. History of congestive heart failure 9. Excessive alcohol consumption, defined as >14 alcoholic drinks per week for males and >9 alcoholic drinks per week for females 10. Unwillingness to administer insulin therapy or perform capillary blood glucose monitoring at least 4 times per day while receiving IIT 11. Pregnancy or unwillingness to use reliable contraception. Women should not be planning pregnancy for the duration of the study or the first 3 months after the study. Reliable contraception includes birth control pill, intra-uterine device, abstinence, tubal ligation, partner vasectomy, or condoms with spermicide. 12. Non-adherence to the induction phase or any factor likely to limit adherence to the study protocol, in the opinion of the investigator

Gender Eligibility: All

Minimum Age: 30 Years

Maximum Age: 80 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Mount Sinai Hospital, Canada
  • Collaborator
    • Canadian Institutes of Health Research (CIHR)
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Ravi Retnakaran, MD, Principal Investigator, MOUNT SINAI HOSPITAL

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