Effects of Exenatide Long-Acting Release on Glucose Control and Safety in Subjects With Type 2 Diabetes Mellitus(DURATION - 1)

A Randomized, Open-Label, Multicenter, Comparator-Controlled Study to Examine the Effects of Exenatide Long-Acting Release on Glucose Control (HbA1c) and Safety in Subjects With Type 2 Diabetes Mellitus Managed With Diet Modification and Exercise and/or Oral Antidiabetic Medications

A Randomized, Open-Label, Multicenter, Comparator-Controlled Study to Examine the Effects of Exenatide Long-Acting Release (LAR) on Glucose Control (HbA1c) and Safety in Subjects with Type 2 Diabetes Mellitus Managed with Diet Modification and Exercise and/or Oral Antidiabetic Medications.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: exenatide, long acting release; Drug: exenatide

Detailed Description

This trial is designed to examine the effect of exenatide once weekly compared to exenatide twice daily on glucose control and safety in subjects for at least 30 weeks. The study is also designed to examine glucose control during the transition from exenatide twice daily for 30 weeks to exenatide once weekly. Long-term safety and efficacy will be monitored during the open-ended assessment periods. This study will be conducted in approximately 300 subjects with type 2 diabetes treated with diet modification and exercise alone or in combination with a stable regimen of metformin, SU, thiazolidinedione (TZD), a combination of metformin and SU, a combination of metformin and TZD, or a combination of SU and TZD.

• Study Type: Interventional
• Enrollment (Actual): 303
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada
      • Research Site
• United States
  • California
    • Encino, California, United States, 91436
      • Research Site 182
    • La Jolla, California, United States, 92037
      • Research Site 171
    • San Diego, California, United States, 92161
      • Research Site 518
    • Walnut Creek, California, United States, 94598
      • Research Site 024
  • Colorado
    • Colorado Springs, Colorado, United States
      • Research Site
  • Florida
    • Miami, Florida, United States, 33156
      • Research Site 057
  • Illinois
    • Chicago, Illinois, United States
      • Research Site
  • Indiana
    • Indianapolis, Indiana, United States, 46254
      • Research Site 149
  • Kentucky
    • Lexington, Kentucky, United States, 40503
      • Research Site 099
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Research Site 017
  • Minnesota
    • Minneapolis, Minnesota, United States, 55416
      • Research Site 224
  • Missouri
    • St. Louis, Missouri, United States, 63141
      • Research Site 312
  • Montana
    • Butte, Montana, United States, 59701
      • Research Site 023
  • New York
    • Rochester, New York, United States, 14609
      • Research Site 053
  • North Carolina
    • Durham, North Carolina, United States, 27713
      • Research Site 002
    • Winston-Salem, North Carolina, United States, 27103
      • Research Site 123
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • Research Site 405
    • Marion, Ohio, United States, 43302
      • Research Site 557
  • Oregon
    • Portland, Oregon, United States, 97239
      • Research Site 231
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19146
      • Research Site 152
  • South Carolina
    • Greer, South Carolina, United States, 29651
      • Research Site 587
  • Texas
    • Dallas, Texas, United States, 75230
      • Research Site 015
    • San Antonio, Texas, United States, 78229
      • Research Site 009
  • Washington
    • Olympia, Washington, United States, 98502
      • Research Site 108

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Has type 2 diabetes mellitus treated with diet modification and exercise alone or in combination with a stable regimen of a combination of metformin, sulphonylureas, and thiazolidinediones for a minimum of 2 months at screening.
• Hemoglobin A1c (HbA1c) of 7.1% to 11.0%, inclusive, at screening.
• Body mass index (BMI) of 25 kg/m2 to 45 kg/m2, inclusive, at screening.
• (For sub-study) Currently participating in open ended assessment period of main study 2993 LAR105

Exclusion Criteria:

• Has been previously exposed to exenatide (Byetta®), exenatide LAR, or any glucagon-like peptide-1 (GLP-1) analog.
• Received any investigational drug or has participated in any type of clinical trial within 30 days prior to screening.

• Has been treated, is currently treated, or is expected to require or undergo treatment with any of the following excluded medications:

  • Alpha glucosidase inhibitor or meglitinide within 30 days of screening;
  • Insulin within 2 weeks prior to screening or insulin for longer than 1 week within 3 months of screening;
  • Regular use (> 14 days) of drugs that directly affect gastrointestinal motility;
  • Regular use (> 14 days) of systemic corticosteroids by oral, intravenous, or intramuscular route; or potent, inhaled, or intrapulmonary steroids known to have a high rate of systemic absorption;
  • Regular use (> 14 days) of medications with addictive potential such as opiates and opioids;
  • Prescription or over-the-counter weight loss medications within 6 months of screening.
• (For sub-study) Subjects will be terminated from study who do not participate in the dual chamber pen substudy

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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Exenatide Once Weekly; Subcutaneous injection (SC), once a week of long acting release (LAR) exenatide.	Drug: exenatide, long acting release; Other Names: BYDUREON
Active Comparator: Exenatide Twice Daily; subcutaneous injection (SC), twice a day for the first 30 weeks, followed by exenatide LAR SC injection weekly for the remainder of the study. Sub-study: Exenatide 2 mg subcutaneous injection, Administered Using the Exenatide Once Weekly Single-Dose Tray , once a week for 11 visits, switch to Exenatide 2 mg subcutaneous injection, Administered Using the Dual chamber pen device. Exenatide 2mg SC injection administered using the Dual chamber pen device.	Drug: exenatide; Other Names: Byetta

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in HbA1c From Baseline to Week 30	Absolute change in HbA1c from Baseline (Day -3) to Week 30 [Week 30 - Baseline]	Day -3, Week 30
Sub-study Relative Bioavailability of Exenatide When Administered Using the Exenatide Once Weekly Dual Chambered Pen and the Exenatide Once Weekly Single Dose Tray (Single Dose Tray-11 Weekly Doses Switch to Dual Chamber Pen-11 Weekly Dose)	Measure by Geometric mean ratio (GMR) of plasma exenatide average steady state concentration Css,avg at Visit 11-14 to Visit 24-27 with 90% confidence interval	Week 22

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in HbA1c From Baseline to Week 364	Absolute change in HbA1c from Baseline (Day -3) to Week 364	Day -3, Week 364
Percentage of Subjects Achieving HbA1c Target of <7%	Percentage of subjects achieving HbA1c target value of <7% at Week 30.	Week 30
Percentage of Subjects Achieving HbA1c Target of <7%	Percentages of subjects achieving HbA1c target value of <7% at Week 364	Week 364
Percentage of Subjects Achieving HbA1c Target of <=6.5%	Percentages of subjects achieving HbA1c target values of <=6.5% at Week 30.	Week 30
Percentage of Subjects Achieving HbA1c Target of <=6.5%	Percentages of subjects achieving HbA1c target values of <=6.5% at Week 364	Week 364
Percentage of Subjects Achieving HbA1c Target of <=6.0%	Percentage of subjects achieving HbA1c target values of <=6.0% at Week 30.	Week 30
Exenatide LAR Steady State Concentration From Week 29 to Week 30	Steady-state plasma exenatide concentration over the dosing interval of Week 29 to Week 30 (0-168 hours) was evaluated. Geometric mean for the average steady-state concentration and its 10th and 90th percentiles were reported.	Week 29 to Week 30
Change in 2 Hours (2h) Postprandial Glucose From Baseline to Week 14	Change in 2h Postprandial Glucose from baseline (Day -3) to Week 14	Day -3, Week 14
Sub-study Safety and Tolerability of Exenatide When Administered Using the Once Weekly Single Dose Tray and the Once Weekly Dual (Single Dose Tray-11 Weekly Doses Switch to Dual Chamber Pen-11 Weekly Dose)	Measure by geometric mean ratio of the maximum steady state plasma exenatide concentration Css, max at Visit 11-14 to Visit 24-27 with 90% confidence interval and incidence of treatment-emergent injection site adverse events.	Week 22
Change in Body Weight From Baseline to Week 30	Change in body weight from baseline (Day -3) to Week 30	Day -3, Week 30
Change in Body Weight From Baseline to Week 364	Change in body weight from baseline (Day -3) to Week 364	Day -3, Week 364
Change in Fasting Plasma Glucose From Baseline to Week 30	Change in fasting plasma glucose from baseline (Day -3) to Week 30.	Day -3, Week 30
Change in Fasting Plasma Glucose From Baseline to Week 364	Change in fasting plasma glucose from baseline (Day -3) to Week 364.	Day -3, Week 364
Change in Blood Pressure From Baseline to Week 30	Change in Sitting Diastolic Blood Pressure and Sitting Systolic Blood Pressure from baseline to Week 30	Day -3, Week 30
Change in Blood Pressure From Baseline to Week 364	Change in Sitting Diastolic Blood Pressure and Sitting Systolic Blood Pressure from baseline to Week 364	Day -3, Week 364
Change in Total Cholesterol From Baseline to Week 30	Change in total cholesterol from baseline (Day -3) to Week 30.	Day -3, Week 30
Change in Total Cholesterol From Baseline to Week 364	Change in total cholesterol from baseline (Day -3) to Week 364.	Day -3, Week 364
Change in High-density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 30	Change in high-density lipoprotein cholesterol (HDL-C) from baseline (Day -3) to Week 30.	Day -3, Week 30
Change in High-density Lipoprotein Cholesterol (HDL-C) From Baseline to Week 364	Change in high-density lipoprotein cholesterol (HDL-C) from baseline (Day -3) to Week 364.	Day -3, Week 364
Change in Low-density Lipoprotein Cholesterol (LDL-C) From Baseline to Week 364	Change in low-density lipoprotein cholesterol (LDL-C) from baseline (Day -3) to Week 364.	Day -3, Week 364
Ratio of Triglycerides at Week 30 to Baseline	Ratio of triglycerides (measured in mg/dL) at Week 30 to baseline (Day -3). Log (Postbaseline Triglycerides) - log (Baseline Triglycerides); change from baseline to endpoint is presented as ratio of endpoint to baseline.	Day -3, Week 30
Ratio of Triglycerides at Week 364 to Baseline	Ratio of triglycerides (measured in mg/dL) at Week 364 to baseline (Day -3). Log (Postbaseline Triglycerides) - log (Baseline Triglycerides); change from baseline to endpoint is presented as ratio of endpoint to baseline.	Day -3, Week 364
Assessment on Event Rate of Treatment-emergent Hypoglycemic Events With SU Use at Screening	The major hypoglycemia category included events that, in the judgment of the investigator or physician, resulted in loss of consciousness, seizure, coma, or other change in mental status consistent with neuroglycopenia, in which symptoms resolved after administration of intramuscular glucagon or intravenous glucose, required third-party assistance, and was accompanied by a blood glucose concentration of less than 54 mg/dL prior to treatment, whether or not symptoms of hypoglycemia were perceived by the subject. The minor hypoglycemia were accompanied by a blood glucose concentration of less than 54 mg/dL prior to treatment and not classified as major hypoglycemia.	Day 1 to Week 364
Assessment on Event Rate of Treatment-emergent Hypoglycemic Events With Non-SU Use at Screening	The major hypoglycemia category included events that, in the judgment of the investigator or physician, resulted in loss of consciousness, seizure, coma, or other change in mental status consistent with neuroglycopenia, in which symptoms resolved after administration of intramuscular glucagon or intravenous glucose, required third-party assistance, and was accompanied by a blood glucose concentration of less than 54 mg/dL prior to treatment, whether or not symptoms of hypoglycemia were perceived by the subject. The minor hypoglycemia were accompanied by a blood glucose concentration of less than 54 mg/dL prior to treatment and not classified as major hypoglycemia.	Day 1 to Week 364

Collaborators and Investigators

• Sponsor: AstraZeneca

Publications and helpful links

General Publications

• Fineman MS, Mace KF, Diamant M, Darsow T, Cirincione BB, Booker Porter TK, Kinninger LA, Trautmann ME. Clinical relevance of anti-exenatide antibodies: safety, efficacy and cross-reactivity with long-term treatment. Diabetes Obes Metab. 2012 Jun;14(6):546-54. doi: 10.1111/j.1463-1326.2012.01561.x. Epub 2012 Feb 10.
• Philis-Tsimikas A, Wysham CH, Hardy E, Han J, Iqbal N. Efficacy and tolerability of exenatide once weekly over 7 years in patients with type 2 diabetes: An open-label extension of the DURATION-1 study. J Diabetes Complications. 2019 Mar;33(3):223-230. doi: 10.1016/j.jdiacomp.2018.11.012. Epub 2018 Dec 5.
• Henry RR, Klein EJ, Han J, Iqbal N. Efficacy and Tolerability of Exenatide Once Weekly Over 6 Years in Patients with Type 2 Diabetes: An Uncontrolled Open-Label Extension of the DURATION-1 Study. Diabetes Technol Ther. 2016 Nov;18(11):677-686. doi: 10.1089/dia.2016.0107. Epub 2016 Aug 15.
• Wysham CH, MacConell LA, Maggs DG, Zhou M, Griffin PS, Trautmann ME. Five-year efficacy and safety data of exenatide once weekly: long-term results from the DURATION-1 randomized clinical trial. Mayo Clin Proc. 2015 Mar;90(3):356-65. doi: 10.1016/j.mayocp.2015.01.008.
• Grimm M, Han J, Weaver C, Griffin P, Schulteis CT, Dong H, Malloy J. Efficacy, safety, and tolerability of exenatide once weekly in patients with type 2 diabetes mellitus: an integrated analysis of the DURATION trials. Postgrad Med. 2013 May;125(3):47-57. doi: 10.3810/pgm.2013.05.2660.
• Macconell L, Pencek R, Li Y, Maggs D, Porter L. Exenatide once weekly: sustained improvement in glycemic control and cardiometabolic measures through 3 years. Diabetes Metab Syndr Obes. 2013;6:31-41. doi: 10.2147/DMSO.S35801. Epub 2013 Jan 21.
• Chiquette E, Toth PP, Ramirez G, Cobble M, Chilton R. Treatment with exenatide once weekly or twice daily for 30 weeks is associated with changes in several cardiovascular risk markers. Vasc Health Risk Manag. 2012;8:621-9. doi: 10.2147/VHRM.S37969. Epub 2012 Nov 12.
• Taylor K, Gurney K, Han J, Pencek R, Walsh B, Trautmann M. Exenatide once weekly treatment maintained improvements in glycemic control and weight loss over 2 years. BMC Endocr Disord. 2011 Apr 29;11:9. doi: 10.1186/1472-6823-11-9.
• Buse JB, Drucker DJ, Taylor KL, Kim T, Walsh B, Hu H, Wilhelm K, Trautmann M, Shen LZ, Porter LE; DURATION-1 Study Group. DURATION-1: exenatide once weekly produces sustained glycemic control and weight loss over 52 weeks. Diabetes Care. 2010 Jun;33(6):1255-61. doi: 10.2337/dc09-1914. Epub 2010 Mar 9.
• Drucker DJ, Buse JB, Taylor K, Kendall DM, Trautmann M, Zhuang D, Porter L; DURATION-1 Study Group. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet. 2008 Oct 4;372(9645):1240-50. doi: 10.1016/S0140-6736(08)61206-4. Epub 2008 Sep 7.

Study record dates

Study Major Dates

• Study Start: April 1, 2006
• Primary Completion (Actual): July 1, 2008
• Study Completion (Actual): August 1, 2014

Study Registration Dates

• First Submitted: March 27, 2006
• First Submitted That Met QC Criteria: March 27, 2006
• First Posted (Estimate): March 29, 2006

Study Record Updates

• Last Update Posted (Estimate): August 26, 2015
• Last Update Submitted That Met QC Criteria: July 29, 2015
• Last Verified: July 1, 2015

More Information

Terms related to this study

• Keywords: diabetes; exenatide; Lilly; Amylin; long acting release; LAR
• 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; Exenatide
• Other Study ID Numbers: 2993LAR-105 (DURATION - 1); MB001-010 (Other Identifier: Bristol Myers Squibb)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No