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

Primary Purpose

Type 2 Diabetes

Status
Completed
Phase
Phase 3
Locations
Canada
Study Type
Interventional
Intervention
Intermittent insulin therapy
Continuous metformin
Sponsored by
Mount Sinai Hospital, Canada
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Type 2 Diabetes focused on measuring beta-cell function, type 2 diabetes, intermittent insulin

Eligibility Criteria

30 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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, 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

Sites / Locations

  • Mount Sinai Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Continuous metformin

Intermittent insulin therapy

Arm Description

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).

After a 3-week course of intensive insulin therapy, participants will receive intermittent intensive insulin therapy for 2 weeks every 3 months. 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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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)

Full Information

First Posted
December 19, 2012
Last Updated
August 14, 2018
Sponsor
Mount Sinai Hospital, Canada
Collaborators
Canadian Institutes of Health Research (CIHR)
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1. Study Identification

Unique Protocol Identification Number
NCT01755468
Brief Title
Early Intermittent Intensive Insulin Therapy as an Effective Treatment of Type 2 Diabetes (RESET-IT Pilot Study)
Official Title
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 Pilot Study)
Study Type
Interventional

2. Study Status

Record Verification Date
August 2018
Overall Recruitment Status
Completed
Study Start Date
April 2013 (undefined)
Primary Completion Date
October 2017 (Actual)
Study Completion Date
October 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Mount Sinai Hospital, Canada
Collaborators
Canadian Institutes of Health Research (CIHR)

4. Oversight

Data Monitoring Committee
No

5. Study Description

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 pilot 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
In this study, eligible patients with type 2 diabetes will be randomized to either intermittent insulin therapy or continuous metformin therapy, after both arms have first undergone a short course of intensive insulin therapy. The hypothesis under study is whether intermittent insulin therapy can better preserve beta-cell function.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 2 Diabetes
Keywords
beta-cell function, type 2 diabetes, intermittent insulin

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
24 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Continuous metformin
Arm Type
Active Comparator
Arm Description
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).
Arm Title
Intermittent insulin therapy
Arm Type
Experimental
Arm Description
After a 3-week course of intensive insulin therapy, participants will receive intermittent intensive insulin therapy for 2 weeks every 3 months. 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
Intervention Type
Drug
Intervention Name(s)
Intermittent insulin therapy
Other Intervention Name(s)
Basal insulin glargine and pre-meal insulin lispro
Intervention Type
Drug
Intervention Name(s)
Continuous metformin
Other Intervention Name(s)
Metformin
Primary Outcome Measure Information:
Title
Baseline-adjusted beta-cell function at 2 years, measured by Insulin Secretion-Sensitivity Index-2 (ISSI-2).
Description
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.
Time Frame
2 years
Secondary Outcome Measure Information:
Title
Baseline-adjusted glycemic control at 2-years.
Description
The secondary outcome of baseline-adjusted glycemic control at 2-years will be assessed by A1c (glycated hemoglobin)
Time Frame
2 years
Other Pre-specified Outcome Measures:
Title
Achievement of target glycemic control
Description
Achievement of target glycemic control will be assessed by the proportion of participants with A1c <7.0%
Time Frame
2 years
Title
achievement of glucose tolerance in the non-diabetic range
Description
The proportion of participants with glucose tolerance in the non-diabetic range will be determined on oral glucose tolerance test (OGTT) and defined based on current Canadian Diabetes Association classifications for glucose tolerance status on OGTT.
Time Frame
2 years
Title
achievement of normal glucose tolerance
Description
The proportion of participants with normal glucose tolerance will be determined on oral glucose tolerance test (OGTT) and defined based on current Canadian Diabetes Association classifications for glucose tolerance status on OGTT.
Time Frame
2 years
Title
insulin sensitivity
Description
Insulin sensitivity will be measured by Matsuda index, a clamp-validated measure of whole-body insulin sensitivity that can be obtained from the oral glucose tolerance test
Time Frame
2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
30 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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, 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ravi Retnakaran, MD
Organizational Affiliation
Mount Sinai Hospital, Canada
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Bernard Zinman, MD
Organizational Affiliation
Mount Sinai Hospital, Canada
Official's Role
Principal Investigator
Facility Information:
Facility Name
Mount Sinai Hospital
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G1X5
Country
Canada

12. IPD Sharing Statement

Citations:
PubMed Identifier
29377408
Citation
Retnakaran R, Choi H, Ye C, Kramer CK, Zinman B. Two-year trial of intermittent insulin therapy vs metformin for the preservation of beta-cell function after initial short-term intensive insulin induction in early type 2 diabetes. Diabetes Obes Metab. 2018 Jun;20(6):1399-1407. doi: 10.1111/dom.13236. Epub 2018 Feb 23.
Results Reference
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Early Intermittent Intensive Insulin Therapy as an Effective Treatment of Type 2 Diabetes (RESET-IT Pilot Study)

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