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

NCT02192424 | Completed Phase 3

• 1 other identifier: 12-0263-A Main
• Study Type: interventional
• Target: 109
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Type 2 Diabetes

Keywords

beta-cell function,; type 2 diabetes,; intermittent insulin

Outcome Measures

Primary Outcomes (1)

• Baseline-adjusted beta-cell function at 2 years, measured by Insulin Secretion-Sensitivity Index-2 (ISSI-2).

  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.

  2 years

Secondary Outcomes (1)

• Baseline-adjusted glycemic control at 2-years.

  2 years

Other Outcomes (4)

• Achievement of target glycemic control

  2 years

• achievement of glucose tolerance in the non-diabetic range

  2 years

• achievement of normal glucose tolerance

  2 years

Study Arms (2)

Metformin alone

ACTIVE COMPARATOR

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).

Drug: Metformin alone

Metformin + Intermittent Insulin Therapy

EXPERIMENTAL

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.

Drug: Metformin + Intermittent Insulin Therapy

Interventions

Metformin alone DRUG

Also known as: metformin

Metformin alone

Metformin + Intermittent Insulin Therapy DRUG

Also known as: metformin,, basal insulin glargine and pre-meal insulin lispro

Metformin + Intermittent Insulin Therapy

Eligibility Criteria

• Age: 30 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men and women between the ages of 30 and 80 years inclusive
• T2DM diagnosed by a physician \</= 5 years prior to enrolment
• Negative for anti-glutamic acid decarboxylase (anti-GAD) antibodies
• On either no anti-diabetic medication or on metformin monotherapy, with no change in dose/regimen within 4 weeks prior to enrolment
• 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
• BMI \>/= 23 kg/m2
• Negative pregnancy test at recruitment for all women with childbearing potential

You may not qualify if:

• Current anti-diabetic treatment with insulin, sulfonylurea, thiazolidinedione, alpha-glucosidase inhibitor, glucagon-like peptide-1 (GLP-1) agonist or dipeptidyl peptidase-4 inhibitor
• Type 1 diabetes or secondary forms of diabetes
• History of hypoglycemia unawareness or severe hypoglycemia requiring assistance
• Any major illness with a life expectancy of \<5 years
• Hypersensitivity to insulin, metformin or the formulations of these products
• Renal dysfunction as evidenced by estimated glomerular filtration rate (eGFR) \<50 ml/min
• Hepatic disease considered to be clinically significant (includes jaundice, chronic hepatitis, previous liver transplant) or transaminases \>2.5 X upper limit of normal
• History of congestive heart failure
• Excessive alcohol consumption, defined as \>14 alcoholic drinks per week for males and \>9 alcoholic drinks per week for females
• Unwillingness to administer insulin therapy or perform capillary blood glucose monitoring at least 4 times per day while receiving IIT
• 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.
• Non-adherence to the induction phase or any factor likely to limit adherence to the study protocol, in the opinion of the investigator

Sponsors & Collaborators

• Mount Sinai Hospital, Canada: lead
• Canadian Institutes of Health Research (CIHR): collaborator

Study Sites (1)

Mount Sinai Hospital

Toronto, Ontario, M5G1X5, Canada

Location

Related Publications (1)

• Retnakaran R, Pu J, Emery A, Harris SB, Reichert SM, Gerstein HC, McInnes N, Kramer CK, Zinman B. Determinants of sustained stabilization of beta-cell function following short-term insulin therapy in type 2 diabetes. Nat Commun. 2023 Jul 27;14(1):4514. doi: 10.1038/s41467-023-40287-w.

  PMID: 37500612 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

Metformin

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Study Officials

• Ravi Retnakaran, MD

  MOUNT SINAI HOSPITAL

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 14, 2014
• First Posted: July 16, 2014
• Study Start: July 1, 2014
• Primary Completion: August 1, 2020
• Study Completion: September 1, 2020
• Last Updated: October 27, 2020

Record last verified: 2020-10

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)