A Safety Study to Assess the Effects of Therapeutic and Supratherapeutic Exenatide Concentrations on QT Interval in Healthy Subjects

• ClinicalTrials.gov Identifier: NCT01297062
• Recruitment Status: Completed
• First Posted: February 16, 2011
• Results First Posted: May 31, 2012
• Last Update Posted: April 14, 2015
• Sponsor: AstraZeneca
• Collaborator: Eli Lilly and Company
• Information provided by (Responsible Party): AstraZeneca

Study Description

Brief Summary:

Compare the effect of exenatide (therapeutic and supratherapeutic concentrations), moxifloxacin and placebo on the QT interval.

Condition or disease	Intervention/treatment	Phase
Healthy Subjects	Drug: Exenatide; Drug: Moxifloxacin; Drug: Placebo comparator	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 94 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Official Title: A Randomized, Phase 1, Three-Period, Placebo- and Positive-Controlled, Double-Blind, Crossover Study to Assess the Electrophysiological Effects of Exenatide at Therapeutic and Supratherapeutic Concentrations on the 12-Lead Electrocardiogram QT Interval in Healthy Subjects
• Study Start Date: February 2011
• Actual Primary Completion Date: April 2011
• Actual Study Completion Date: May 2011

Arms and Interventions

Arm	Intervention/treatment
Experimental: Exenatide	Drug: Exenatide; IV Exenatide (therapeutic and supratherapeutic concentrations)
Placebo Comparator: Placebo	Drug: Placebo comparator; IV Placebo (matching volume of placebo)
Active Comparator: Moxifloxacin	Drug: Moxifloxacin; Oral Moxifloxacin (400 mg)

Outcome Measures

Primary Outcome Measures :

1. Comparison of Least Squares (LS) Mean Changes From Baseline in Population-based Corrected QT Intervals (QTcP) Between Exenatide and Placebo on Day 1 Averaged Over 1300h, 1400h, 1500h (Target Steady State Exenatide Concentration of 200 pg/mL) [ Time Frame: Baseline, Day 1 ]
   Factors in QT correction formulas were first estimated using pre-therapy data. The most appropriate correction method (QTcP) minimized the mean squared individual QTc/RR regression slope with on-exenatide data. Adequacy of correction was validated with on-placebo data. Change from baseline in QTcP was analyzed by a mixed-effects model for repeated measures (MMRM) between exenatide and placebo.
2. Comparison of LS Mean Changes From Baseline in QTcP Intervals Between Exenatide and Placebo on Day 2 Averaged Over 1300h, 1400h, 1500h (Target Steady State Exenatide Concentration of 300 pg/mL) [ Time Frame: Baseline, Day 2 ]
   Factors in QT correction formulas were first estimated using pre-therapy data. The most appropriate correction method (QTcP) minimized the mean squared individual QTc/RR regression slope with on-exenatide data. Adequacy of correction was validated with on-placebo data. Change from baseline in QTcP was analyzed by a MMRM between exenatide and placebo.
3. Comparison of LS Mean Changes From Baseline in QTcP Intervals Between Exenatide and Placebo on Day 3 Averaged Over 1300h, 1400h, 1500h (Target Steady State Exenatide Concentration of 500 pg/mL) [ Time Frame: Baseline, Day 3 ]
   Factors in QT correction formulas were first estimated using pre-therapy data. The most appropriate correction method (QTcP) minimized the mean squared individual QTc/RR regression slope with on-exenatide data. Adequacy of correction was validated with on-placebo data. Change from baseline in QTcP was analyzed by a MMRM between exenatide and placebo.

Secondary Outcome Measures :

1. Assay Sensitivity of Moxifloxacin at 1000h (1 Hour Post-administration of Moxifloxacin) on Day 2 [ Time Frame: Baseline, Day 2 ]
   Change from baseline in QTcP was analyzed by a MMRM between moxifloxacin and placebo.
2. Assay Sensitivity of Moxifloxacin at 1100h (2 Hour Post-administration of Moxifloxacin) on Day 2 [ Time Frame: Baseline, Day 2 ]
   Change from baseline in QTcP was analyzed by a MMRM between moxifloxacin and placebo.
3. Assay Sensitivity of Moxifloxacin at 1200h (3 Hour Post-administration of Moxifloxacin) on Day 2 [ Time Frame: Baseline, Day 2 ]
   Change from baseline in QTcP was analyzed by a MMRM between moxifloxacin and placebo.
4. Number of Subjects With QTcP Interval >450msec at Any Timepoint on Any Day in Exenatide and Placebo [ Time Frame: Day 1, 2, or 3 ]
   Number of subjects with QTcP > 450 msec at any timepoint on any day was summarized by frequency for exenatide and placebo.
5. Number of Subjects With Increase of QTcP Interval From Baseline >30msec at Any Timepoint on Any Day in Exenatide and Placebo [ Time Frame: Baseline, Day 1, 2, or 3 ]
   Number of subjects with increase of QTcP interval from baseline >30 msec at any timepoint on any day was summarized by frequency for exenatide and placebo.
6. Plasma Exenatide Concentrations at Steady State on Day 1, 2 and 3 [ Time Frame: Baseline, Day 1, 2, and 3 ]
   The plasma exenatide concentration at steady state was descriptively summarized by geometric mean, standard error, and its effect on placebo-adjusted change from baseline in QTcP was assessed.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Is overtly healthy, as determined by medical history and physical examination
• Has body mass index (BMI) between 25 and 35 kg/m2
• Has fasting serum glucose <110 mg/dL
• Has no clinically significant blood pressure or heart rate readings as judged by the investigator at study start
• Has electrocardiogram (ECG) results judged as not clinically significant by the investigator at study start

Exclusion Criteria:

• Has a clinically significant medical condition that could potentially affect study participation and/or personal well-being
• Has an abnormality in the 12-lead ECG that, in the opinion of the investigator, increases the risk of participating in the study, such as a Bazett's corrected QT (QTcB) interval >450 ms.
• Family history of sudden death
• Personal history of unexplained syncope within last year, or family history of Long QT Syndrome, or significant active cardiac disease, or symptoms of angina pectoris or transient ischemic attacks within the previous 6 months

Contacts and Locations

Locations

United States, Florida

Research Site

Daytona Beach, Florida, United States

United States, Indiana

Research Site

Evansville, Indiana, United States

Sponsors and Collaborators

AstraZeneca

Eli Lilly and Company

Investigators

• Study Director: Vice President Research and Development, MD; Amylin Pharmaceuticals, LLC.

More Information

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT01297062
• Other Study ID Numbers: BCB112
• First Posted: February 16, 2011
• Results First Posted: May 31, 2012
• Last Update Posted: April 14, 2015
• Last Verified: March 2015

Keywords provided by AstraZeneca:

Diabetes; exenatide; Amylin; Lilly; QT interval

Additional relevant MeSH terms:

Exenatide; Moxifloxacin; Anti-Bacterial Agents; Anti-Infective Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Physiological Effects of Drugs; Hypoglycemic Agents; Anti-Obesity Agents; Incretins; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists