Healthy Subjects
Conditions
Keywords
Diabetes, exenatide, Amylin, Lilly, QT interval
Brief summary
Compare the effect of exenatide (therapeutic and supratherapeutic concentrations), moxifloxacin and placebo on the QT interval.
Interventions
DRUGExenatide
IV Exenatide (therapeutic and supratherapeutic concentrations)
DRUGMoxifloxacin
Oral Moxifloxacin (400 mg)
DRUGPlacebo comparator
IV Placebo (matching volume of placebo)
Sponsors
Eli Lilly and Company
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) | 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. |
| 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) | 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. |
| 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) | 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
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With QTcP Interval >450msec at Any Timepoint on Any Day in Exenatide and Placebo | 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. |
| Assay Sensitivity of Moxifloxacin at 1000h (1 Hour Post-administration of Moxifloxacin) on Day 2 | Baseline, Day 2 | Change from baseline in QTcP was analyzed by a MMRM between moxifloxacin and placebo. |
| Plasma Exenatide Concentrations at Steady State on Day 1, 2 and 3 | 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. |
| Number of Subjects With Increase of QTcP Interval From Baseline >30msec at Any Timepoint on Any Day in Exenatide and Placebo | 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. |
| Assay Sensitivity of Moxifloxacin at 1100h (2 Hour Post-administration of Moxifloxacin) on Day 2 | Baseline, Day 2 | Change from baseline in QTcP was analyzed by a MMRM between moxifloxacin and placebo. |
| Assay Sensitivity of Moxifloxacin at 1200h (3 Hour Post-administration of Moxifloxacin) on Day 2 | Baseline, Day 2 | Change from baseline in QTcP was analyzed by a MMRM between moxifloxacin and placebo. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo-Exenatide-Moxifloxacin Sequence Placebo comparator in Period I; Exenatide in Period II; Moxifloxacin with placebo infusion in Period III | 15 |
| Exenatide-Moxifloxacin-Placebo Sequence Exenatide in Period I; Moxifloxacin with placebo infusion in Period II; Placebo comparator in Period III | 14 |
| Moxifloxacin-Placebo-Exenatide Sequence Moxifloxacin with placebo infusion in Period I; Placebo comparator in Period II; Exenatide in Period III | 14 |
| Moxifloxacin-Exenatide-Placebo Sequence Moxifloxacin with placebo infusion in Period I; Exenatide in Period II; Placebo comparator in Period III | 14 |
| Placebo-Moxifloxacin-Exenatiden Sequence Placebo comparator in Period I; Moxifloxacin with placebo infusion in Period II; Exenatide in Period III | 15 |
| Exenatide-Placebo-Moxifloxacin Sequence Exenatide in Period I; Placebo comparator in Period II; Moxifloxacin with placebo infusion in Period III | 14 |
| Total | 86 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Physician Decision | 1 | 0 | 1 | 0 | 0 | 0 | 6 |
| Overall Study | Protocol Violation | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Subject Decision | 1 | 1 | 0 | 1 | 1 | 1 | 2 |
Baseline characteristics
| Characteristic | Placebo-Exenatide-Moxifloxacin Sequence | Exenatide-Moxifloxacin-Placebo Sequence | Moxifloxacin-Placebo-Exenatide Sequence | Moxifloxacin-Exenatide-Placebo Sequence | Placebo-Moxifloxacin-Exenatiden Sequence | Exenatide-Placebo-Moxifloxacin Sequence | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 41.5 years STANDARD_DEVIATION 8.98 | 45.1 years STANDARD_DEVIATION 11.43 | 43.7 years STANDARD_DEVIATION 11.56 | 37.8 years STANDARD_DEVIATION 10.66 | 43.3 years STANDARD_DEVIATION 13.74 | 41.0 years STANDARD_DEVIATION 10.5 | 42.1 years STANDARD_DEVIATION 11.16 |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 3 Participants | 0 Participants | 2 Participants | 1 Participants | 8 Participants |
| Sex: Female, Male Male | 15 Participants | 12 Participants | 11 Participants | 14 Participants | 13 Participants | 13 Participants | 78 Participants |
| Weight | 87.66 kilogram STANDARD_DEVIATION 8.107 | 81.16 kilogram STANDARD_DEVIATION 11.235 | 90.77 kilogram STANDARD_DEVIATION 12.375 | 93.66 kilogram STANDARD_DEVIATION 11.704 | 89.71 kilogram STANDARD_DEVIATION 7.726 | 90.71 kilogram STANDARD_DEVIATION 11.251 | 88.94 kilogram STANDARD_DEVIATION 10.899 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 65 / 80 | 10 / 84 | 8 / 80 |
| serious Total, serious adverse events | 0 / 80 | 0 / 84 | 1 / 80 |
Outcome results
Primary
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)
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.
Time frame: Baseline, Day 1
Population: Evaluable Population included all ITT subjects who completed all ECG assessment periods and have valid ECG measurements and no vomiting in any ECG data extraction window. No missing value was imputed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | 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) | -2.25 msec | 90% Confidence Interval 0.636 |
| Placebo | 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) | -0.89 msec | 90% Confidence Interval 0.599 |
Comparison: 60 evaluable subjects gives more than 90% power to show non-inferiority of exenatide versus placebo, using t-test in 2-way crossover, alpha=0.05, true difference of 5 msec, and standard deviation of the within-subject difference of 10.04 msec.90% CI: [-2.21, -0.5]Mixed Models Analysis
Primary
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)
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.
Time frame: Baseline, Day 2
Population: Evaluable Population. No imputation for missing value was used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | 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) | -2.58 msec | 90% Confidence Interval 0.64 |
| Placebo | 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) | -0.56 msec | 90% Confidence Interval 0.596 |
Comparison: 60 evaluable subjects gives more than 90% power to show non-inferiority of exenatide versus placebo, using t-test in 2-way crossover, alpha=0.05, true difference of 5 msec, and standard deviation of the within-subject difference of 10.04 msec.90% CI: [-2.88, -1.16]Mixed Models Analysis
Primary
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)
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.
Time frame: Baseline, Day 3
Population: Evaluable Population. No imputation for missing value was used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | 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) | -3.54 msec | 90% Confidence Interval 0.675 |
| Placebo | 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) | -2.41 msec | 90% Confidence Interval 0.623 |
Comparison: 60 evaluable subjects gives more than 90% power to show non-inferiority of exenatide versus placebo, using t-test in 2-way crossover, alpha=0.05, true difference of 5 msec, and standard deviation of the within-subject difference of 10.04 msec.90% CI: [-2.11, -0.15]Mixed Models Analysis
Secondary
Assay Sensitivity of Moxifloxacin at 1000h (1 Hour Post-administration of Moxifloxacin) on Day 2
Change from baseline in QTcP was analyzed by a MMRM between moxifloxacin and placebo.
Time frame: Baseline, Day 2
Population: Evaluable Population. No imputation for missing value was used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | Assay Sensitivity of Moxifloxacin at 1000h (1 Hour Post-administration of Moxifloxacin) on Day 2 | 1.91 msec | 90% Confidence Interval 1.079 |
| Placebo | Assay Sensitivity of Moxifloxacin at 1000h (1 Hour Post-administration of Moxifloxacin) on Day 2 | -3.56 msec | 90% Confidence Interval 0.953 |
Comparison: Assay sensitivity of moxifloxacin is established if the lower limit of the 2-sided 90% CI for difference in change from baseline in QTcP (moxifloxacin - placebo) is greater than 5 msec.90% CI: [2.82, 8.12]Mixed Models Analysis
Secondary
Assay Sensitivity of Moxifloxacin at 1100h (2 Hour Post-administration of Moxifloxacin) on Day 2
Change from baseline in QTcP was analyzed by a MMRM between moxifloxacin and placebo.
Time frame: Baseline, Day 2
Population: Evaluable Population. No imputation for missing value was used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | Assay Sensitivity of Moxifloxacin at 1100h (2 Hour Post-administration of Moxifloxacin) on Day 2 | 9.75 msec | 90% Confidence Interval 0.934 |
| Placebo | Assay Sensitivity of Moxifloxacin at 1100h (2 Hour Post-administration of Moxifloxacin) on Day 2 | -0.81 msec | 90% Confidence Interval 0.872 |
Comparison: Assay sensitivity of moxifloxacin is established if the lower limit of the 2-sided 90% CI for difference in change from baseline in QTcP (moxifloxacin - placebo) is greater than 5 msec.90% CI: [8.46, 12.67]Mixed Models Analysis
Secondary
Assay Sensitivity of Moxifloxacin at 1200h (3 Hour Post-administration of Moxifloxacin) on Day 2
Change from baseline in QTcP was analyzed by a MMRM between moxifloxacin and placebo.
Time frame: Baseline, Day 2
Population: Evaluable Population. No imputation for missing value was used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | Assay Sensitivity of Moxifloxacin at 1200h (3 Hour Post-administration of Moxifloxacin) on Day 2 | 12.47 msec | 90% Confidence Interval 1.011 |
| Placebo | Assay Sensitivity of Moxifloxacin at 1200h (3 Hour Post-administration of Moxifloxacin) on Day 2 | 1.56 msec | 90% Confidence Interval 0.828 |
Comparison: Assay sensitivity of moxifloxacin is established if the lower limit of the 2-sided 90% CI for difference in change from baseline in QTcP (moxifloxacin - placebo) is greater than 5 msec.90% CI: [8.71, 13.13]Mixed Models Analysis
Secondary
Number of Subjects With Increase of QTcP Interval From Baseline >30msec at Any Timepoint on Any Day in Exenatide and Placebo
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.
Time frame: Baseline, Day 1, 2, or 3
Population: Evaluable Population. No imputation for missing value was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide | Number of Subjects With Increase of QTcP Interval From Baseline >30msec at Any Timepoint on Any Day in Exenatide and Placebo | 0 particpants |
| Placebo | Number of Subjects With Increase of QTcP Interval From Baseline >30msec at Any Timepoint on Any Day in Exenatide and Placebo | 0 particpants |
Secondary
Number of Subjects With QTcP Interval >450msec at Any Timepoint on Any Day in Exenatide and Placebo
Number of subjects with QTcP \> 450 msec at any timepoint on any day was summarized by frequency for exenatide and placebo.
Time frame: Day 1, 2, or 3
Population: Evaluable Population. No imputation for missing value was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide | Number of Subjects With QTcP Interval >450msec at Any Timepoint on Any Day in Exenatide and Placebo | 0 participants |
| Placebo | Number of Subjects With QTcP Interval >450msec at Any Timepoint on Any Day in Exenatide and Placebo | 0 participants |
Secondary
Plasma Exenatide Concentrations at Steady State on 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.
Time frame: Baseline, Day 1, 2, and 3
Population: Evaluable Population. No imputation for missing value was used. Day 1, 2, and 3 exenatide concentration \< LLOQ was set to missing.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide | Plasma Exenatide Concentrations at Steady State on Day 1, 2 and 3 | Day 1 | 252.74 pg/mL | Standard Error 8.454 |
| Exenatide | Plasma Exenatide Concentrations at Steady State on Day 1, 2 and 3 | Day 2 | 399.14 pg/mL | Standard Error 11.936 |
| Exenatide | Plasma Exenatide Concentrations at Steady State on Day 1, 2 and 3 | Day 3 | 626.65 pg/mL | Standard Error 21.159 |
Comparison: The analysis is to test the significance of the linear regression slope (null hypothesis: slope equal to zero) between placebo-adjusted change from baseline in QTcP and exenatide concentration.p-value: 0.596290% CI: [-0.0017, 0.0033]Mixed Models Analysis