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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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)

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Drug: Metformin alone
* Drug: Metformin + Intermittent Insulin Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Metformin alone<br>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<br> <br> * Other names: metformin;|
| Experimental: Metformin + Intermittent Insulin Therapy<br>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<br> <br> * Other names: basal insulin glargine and pre-meal insulin lispro;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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beta-cell function,, type 2 diabetes,, intermittent insulin