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

Phase 3

Completed

• Conditions: Type 2 Diabetes
• Interventions: Drug: Basal insulin and exenatide; Drug: Basal insulin only; Drug: Basal insulin and bolus insulin

• Registration Number: NCT02194595
• Lead Sponsor: Mount Sinai Hospital, Canada

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 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.

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 Timeline

• Study First Submitted: 2014-07-16
• Study First Submitted QC: 2014-07-16
• Study First Posted: 2014-07-18
• Study Start: 2014-09
• Primary Completion: 2021-12
• Study Completion: 2022-02
• Status Verified: 2022-04
• Last Update Submitted: 2022-04-07
• Last Update Posted: 2022-04-11

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 105

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Basal insulin and exenatide	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.
Basal insulin only	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.
Basal Insulin and bolus insulin	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.

Primary Outcome Measures

Name	Time	Method
Mean beta-cell function over the 8-week treatment period, measured using the Insulin Secretion-Sensitivity Index-2 (ISSI-2)	8 weeks	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.

Secondary Outcome Measures

Name	Time	Method
Baseline-adjusted beta-cell function at 20 weeks	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)
Endothelial function at 8 weeks	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)
Baseline-adjusted glycemic control at 8 weeks	8 weeks	Baseline-adjusted glycemic control at 8 weeks will be measured by A1c
Baseline-adjusted glycemic control at 20 weeks	20 weeks	The secondary outcome of baseline-adjusted glycemic control at 20 weeks will be assessed by A1c (glycated hemoglobin)

Trial Locations

Locations (1)

Mount Sinai Hospital; 🇨🇦 Toronto, Ontario, Canada