Preserving Beta-cell Function in Type 2 Diabetes With Exenatide and Insulin (PREVAIL) (PREVAIL)

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 combining basal insulin with a new medication called exenatide is a therapeutic strategy that can preserve beta-cell function early in the course of type 2 diabetes.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Drug: Basal insulin and exenatide; Drug: Basal insulin only; Drug: Basal insulin and bolus insulin

Detailed Description

In this open-label, parallel-arm randomized controlled trial, adults with T2DM of ≤7 years duration on 0-2 anti-diabetic medications will be randomized to 8-weeks treatment with either (i) basal insulin glargine, (ii) intensive insulin therapy consisting of glargine and pre-meal insulin lispro, or (iii) glargine and the GLP-1 agonist exenatide (twice daily). They will then go into a 12-week washout on lifestyle modification only. Beta-cell function will be assessed by determining the Insulin Secretion-Sensitivity Index-2 (ISSI-2) on oral glucose tolerance test (OGTT) performed at baseline, 4-weeks, 8-weeks, and 20-weeks. The primary outcome will be mean beta-cell function (ISSI-2) over the 8-week treatment period.

• Study Type: Interventional
• Enrollment (Actual): 105
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G1X5
      • Mount Sinai Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Men and women between the ages of 30 and 80 years inclusive
2. T2DM diagnosed by a physician ≤7 years prior to enrolment
3. On 0-2 anti-diabetic medications, with no change in dose/regimen in the preceding 4 weeks
4. A1c at screening between 5.5% and 9.0% inclusive if on anti-diabetic medications, or between 6.0% and 9.5% inclusive if on no oral anti-diabetic medication
5. BMI ≥ 23 kg/m2
6. Negative pregnancy test at recruitment for all women with childbearing potential

Exclusion Criteria:

1. Current anti-diabetic treatment with insulin or a glucagon-like peptide-1 (GLP-1) agonist
2. Type 1 diabetes or secondary forms of diabetes
3. History of hypoglycemia unawareness or severe hypoglycemia requiring assistance
4. Hypersensitivity to insulin, exenatide, or the formulations of these products
5. Renal dysfunction as evidenced by estimated glomerular filtration rate (eGFR)<30 ml/min by Modification of Diet in Renal Disease (MDRD) formula
6. History of pancreatitis
7. Family or personal history of Multiple Endocrine Neoplasia type 2 (MEN-2) or familial medullary thyroid carcinoma (MTC)
8. Personal history of non-familial medullary thyroid carcinoma (MTC)
9. Malignant neoplasm requiring chemotherapy, surgery, radiation or palliative therapy within the previous 5 years (with the exception of basal cell skin cancer)
10. Unwillingness to perform capillary glucose monitoring at least 4 times a day during treatment
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. Any factor likely to limit adherence to the protocol, in the opinion of investigator

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Basal insulin and exenatide; Participants in this arm will undergo an 8-week course of treatment with exenatide and insulin glargine. Exenatide will be initiated at 5ug subcutaneous (sc) bid (before breakfast and before dinner) for the first 4 weeks, followed by 10ug bid for the next 4 weeks. Glargine sc injection at bedtime will be titrated to fasting glucose.	Drug: Basal insulin and exenatide; Other Names: Exenatide; Basal insulin glargine
Active Comparator: Basal insulin only; Participants in this arm will undergo an 8-week course of treatment with glargine sc injection at bedtime, titrated to target fasting glucose.	Drug: Basal insulin only; Other Names: Basal insulin glargine
Active Comparator: Basal Insulin and bolus insulin; Participants in this arm will undergo an 8-week course of multiple daily insulin injection therapy, consisting of titrated basal insulin glargine at bedtime and insulin lispro before each meal.	Drug: Basal insulin and bolus insulin; Other Names: Basal insulin glargine; Pre-meal insulin lispro

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean beta-cell function over the 8-week treatment period, measured using the 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. The primary outcome comparison is between the glargine/exenatide and glargine only arms.	8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline-adjusted beta-cell function at 20 weeks	The secondary outcome of baseline-adjusted beta-cell function at 20 weeks will be measured with the Insulin Secretion-Sensitivity Index-2 (ISSI-2)	20 weeks
Baseline-adjusted glycemic control at 20 weeks	The secondary outcome of baseline-adjusted glycemic control at 20 weeks will be assessed by A1c (glycated hemoglobin)	20 weeks
Endothelial function at 8 weeks	Endothelial function will be assessed as the digital endothelial vasomotor function in response to reactive hyperemia using pulse amplitude tonometry, which will be measured by the pulse amplitude response to hyperemia (PAT ratio)	8 weeks
Baseline-adjusted glycemic control at 8 weeks	Baseline-adjusted glycemic control at 8 weeks will be measured by A1c	8 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline-adjusted insulin sensitivity at 8 weeks	Baseline-adjusted insulin sensitivity at 8 weeks will be measured by Matsuda index	8 weeks
Baseline-adjusted insulin sensitivity at 20 weeks	Baseline-adjusted insulin sensitivity at 20 weeks will be measured by Matsuda index	20 weeks

Collaborators and Investigators

• Sponsor: Mount Sinai Hospital, Canada
• Collaborators: Canadian Institutes of Health Research (CIHR); University of Toronto
• Investigators: Principal Investigator: Ravi Retnakaran, MD, Mount Sinai Hospital

Study record dates

Study Major Dates

• Study Start: September 1, 2014
• Primary Completion (Actual): December 1, 2021
• Study Completion (Actual): February 1, 2022

Study Registration Dates

• First Submitted: July 16, 2014
• First Submitted That Met QC Criteria: July 16, 2014
• First Posted (Estimate): July 18, 2014

Study Record Updates

• Last Update Posted (Actual): April 11, 2022
• Last Update Submitted That Met QC Criteria: April 7, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: GLP-1; type 2 diabetes; insulin; beta-cell function
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Anti-Obesity Agents; Incretins; Insulin; Insulin, Globin Zinc; Insulin Glargine; Insulin Lispro; Exenatide
• Other Study ID Numbers: 14-0128-A