A Multiple Dose Study of MK-3614 (MK-3614-002)

Study Overview
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Brief Summary
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This study will evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple doses of MK-3614 in male participants with mild to moderate hypertension. The primary hypotheses are: 1) Multiple oral doses of MK-3614 are sufficiently safe and well tolerated to permit continued clinical investigation 2) Aortic Augmentation Index (Aix) is reduced 24 hours post the last dose of MK-3614 administered compared to placebo and 3) Increase in the 12-hour weighted averages (TWA 0-12hours) of the heart rate is within 15 beats per minute (bpm) of baseline on first day of multiple dosing of MK-3614 and within 10 bpm of baseline on last day of multiple dosing of MK-3614.

Official Title
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A Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MK-3614

Conditions
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Hypertension

Intervention / Treatment
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* Drug: MK-3614
* Drug: Placebo for MK-3614


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has mild to moderate hypertension Has grade 1 or 2 arterial hypertension being treated with a single antihypertensive drug Has been a nonsmoker and/or has not used nicotine or nicotine-containing products for at least approximately 6 months; or who have discontinued smoking or the use of nicotine/nicotine-containing products for at least approximately 3 months Is in generally good health Exclusion Criteria: Has a history of clinically significant abnormalities or diseases Has a history of stroke, chronic seizures, or major neurological disorder Has a functional disability that can interfere with rising from a sitting position to the standing position Has any personal or family history of a bleeding or a clotting disorder Has a history of frequent nose bleeds or has recurrent or active gingivitis Has a history of cancer Has a history of clinically significant cardiac disease Is unable to refrain from or anticipates the use of any medication, including prescription and non-prescription drugs or herbal remedies approximately 2 weeks prior to the administration of study drug Consumes excessive amounts of alcohol Consumes excessive amounts of caffeinated beverages per day Has had major surgery, donated or lost 1 unit of blood or participated in another investigational study within 4 weeks of study Has a history of significant multiple and/or severe allergies (including latex) to prescription or non-prescription drugs or food Is currently a regular user of any illicit drugs or has a history of drug abuse within approximately 1 year

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MK-3614 0.25 mg (Panel A)<br>Participants received 0.25 mg of MK-3614 twice daily (BID) every 12 hours orally for 10 days. | Drug: MK-3614<br>* Participants were administered 0.25 mg tablet, orally for a total daily dose according to randomization.<br>|
| Experimental: MK-3614 0.50/0.25 mg (Panel B)<br>Participants received 0.50 mg of MK-3614 in the morning (AM) and 0.25 mg of MK-3614 in the evening (PM) 12 hours apart orally for 10 days. | Drug: MK-3614<br>* Participants were administered 0.25 mg tablet, orally for a total daily dose according to randomization.<br>|
| Experimental: MK-3614 0.50/0.25 mg (Panel C Repeat)<br>Participants were to receive 0.75 mg of MK-3614 BID every 12 hours orally for 10 Days. Per protocol amendment, the Panel B dose was repeated, and participants received instead 0.50 mg of MK-3614 in the AM, and 0.25 mg of MK-3614 in the PM, 12 hours apart orally for 10 days. | Drug: MK-3614<br>* Participants were administered 0.25 mg tablet, orally for a total daily dose according to randomization.<br>|
| Experimental: MK-3614 0.50 mg (Panel D)<br>Participants received 0.50 mg of MK-3614 three times a day (TID) orally every 8 hours on Day 1 followed by a wash out period for Days 2, 3 and 0.50 mg of MK-3614 every 12 hours orally for 10 days (Days 4-13). | Drug: MK-3614<br>* Participants were administered 0.25 mg tablet, orally for a total daily dose according to randomization.<br>|
| Experimental: MK-3614 0.50 mg (Panel E)<br>Participants were to receive orally 0.50 mg of MK-3614 BID every 12 hours on Day 1 followed by 3 doses (0.50/0.50/0.25 mg) of MK-3614 each 8 hours apart on Day 2; three doses of 0.50 mg of MK-3614 8 hours apart on Days 3,4; and 0.75 mg of MK-3614 BID every 12 hours on Days 5-14. No participants were enrolled in this group. | Drug: MK-3614<br>* Participants were administered 0.25 mg tablet, orally for a total daily dose according to randomization.<br>|
| Placebo Comparator: Placebo (All Panels)<br>Participants received a dose matched placebo orally according to randomization. | Drug: Placebo for MK-3614<br>* Participants were administered dose matched placebo tablets according to randomization.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced an Adverse Event (AE) | An adverse event was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study intervention, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the study intervention, was also an adverse event. The number of participants who experienced an AE was reported. | Up to approximately 27 days | 
| Number of Participants Who Discontinued Study Treatment Due to an AE | An adverse event was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study intervention, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the study intervention, was also an adverse event. The number of participants who discontinued study treatment due to an AE was reported. | Up to approximately 13 days | 
| Panel A: Area Under the Concentration Time-Curve From 0 to 12 Hours (AUC 0-12hrs) of MK-3614 | Blood samples were collected at pre-specified timepoints on first day of multiple dosing of MK-3614 (Day 1) and last day of multiple dosing of MK-3614 (Day 10) to determine the AUC 0-12hrs of MK-3614 in Panel A participants per protocol. AUC 0-12hrs was defined as the area under the concentration-time curve of MK-3614 from time zero to 12 hours postdose. | Days 1, 10: Predose and 1, 2, 4, 6, 8 & 12 hours postdose | 
| Panel D: Area Under the Concentration Time-Curve From 0 to 12 Hours (AUC 0-12hrs) of MK-3614 | Blood samples were collected at pre-specified timepoints to determine the AUC 0-12hrs on first day of multiple dosing of MK-3614 (Day 4) and last day of multiple dosing of MK-3614 (Day 13) to determine the AUC 0-12hrs of MK-3614 in Panel D participants per protocol. AUC 0-12hrs was defined as the area under the concentration-time curve of MK-3614 from time zero to 12 hours postdose. | Days 4, 13: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8 & 12 hours postdose | 
| Panel D: Area Under the Concentration Time-Curve From 0 to Infinity (AUC 0-inf) of MK-3614 | Blood samples were collected at pre-specified timepoints to determine the AUC 0-inf of MK-3614 in Panel D participants who received single daily dosing on Day 1. AUC 0-inf was defined as the area under the concentration-time curve of MK-3614 from time zero to infinity. Geometric mean and 95%CI were not reported because the single day dosing of MK-3614 was only administered on Day 1 for Panel D participants. Instead, AUC 0-24 hours was reported for Panel D participants on Day 1 which is included in the 'other pre-specified outcomes'. | Day 1: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 14, & 24 hours postdose | 
| Panels B, C: Area Under the Concentration Time-Curve From 0 to 24 Hours (AUC 0-24hrs) of MK-3614 | Blood samples were collected at pre-specified timepoints to determine the AUC 0-24hrs on first day of multiple dosing of MK-3614 (Day 1) and last day of multiple dosing of MK-3614 (Day 10) to determine the AUC 0-24hrs of MK-3614 in Panel B & C participants per protocol. AUC0-24hrs was defined as the area under the concentration-time curve of MK-3614 from time zero to 24 hours postdose. | Days 1, 10: Predose and 1, 2, 4, 6, 8, 12, 16, & 24 hours postdose | 
| Panel A: Maximum Concentration (Cmax) of MK-3614 | Blood samples were collected predose and up to 12 hours postdose on first day of multiple dosing of MK-3614 (Day 1) and last day of multiple dosing (Day 10) for the determination of Cmax in Panel A participants. Cmax was defined as the maximum concentration of MK-3614 reached over 12 hours. | Days 1, 10: Predose and 1, 2, 4, 6, 8 & 12 hours postdose | 
| Panel D: Maximum Concentration (Cmax) of MK-3614 | Blood samples were collected at predose and up to 12 hours postdose on first day of multiple dosing of MK-3614 (Day 4) and last day of multiple dosing of MK-3614 (Day 13) for the determination of Cmax in Panel D participants. Cmax was defined as the maximum concentration of MK-3614 reached over 12 hours after administration of multiple doses of MK-3614. | Days 4, 13: Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, & 12 hours postdose | 
| Panels B, C: Maximum Concentration (Cmax) of MK-3614 | Blood samples were collected at predose and up to 24 hours postdose on first day of multiple dosing of MK-3614 (Day 1) and last day of multiple dosing of MK-3614 (Day 10) for the determination of Cmax in Panel B & C participants. Cmax was defined as the maximum concentration of MK-3614 reached over 24 hours. | Days 1, 10: Predose and 1, 2, 4, 6, 8, 12, 16, & 24 hours postdose | 
| Panel A: Time to Maximum Concentration (Tmax) of MK-3614 | Blood samples were collected at predose and up to 12 hours postdose on first day of multiple dosing of MK-3614 (Day 1) and last day of multiple dosing of MK-3614 (Day 10) to determine the Tmax in Panel A participants. Tmax was defined as time to the maximum concentration of MK-3614 reached over 12 hours. | Days 1, 10: Predose and 1, 2, 4, 6, 8, & 12 hours postdose | 
| Panel D: Time to Maximum Concentration (Tmax) of MK-3614 | Blood samples were collected at predose and up to 12 hours on first day of multiple dosing of MK-3614 (Day 4) and last day of multiple dosing of MK-3614 (Day 13) to determine the Tmax in Panel D participants. Tmax was defined as time to the maximum concentration of MK-3614 reached over 12 hours among participants in Panel D. | Days 4, 13: Predose and 0.5, 1, 2, 3 ,4, 5, 6, 8 & 12 hours postdose | 
| Panels B, C: Time to Maximum Concentration (Tmax) of MK-3614 | Blood samples were collected at predose and up to 24 hours on first day of multiple dosing of MK-3614 (Day 1) and last day of multiple dosing of MK-3614 (Day 10) to determine the Tmax in Panel B & C participants. Tmax was defined as time to the maximum concentration of MK-3614 reached over 24 hours. | Days 1, 10: Predose and 1, 2, 4, 6, 8, 12, 16, & 24 hours postdose | 
| Panels A, B & C: Apparent Terminal Half-Life (t1/2) of MK-3614 | Blood samples were collected at pre-specified time points on Day 10 to determine t½ in Panels A, B, & C participants who received multiple doses of MK-3614. Apparent t½ was defined as the time required to eliminate half the amount of MK-3614 from plasma concentration. | Day 10: Predose and 1, 2, 4, 6, 8, 12, 16, 24, 36, & 48 hours postdose | 
| Panel D: Apparent Terminal Half-Life (t1/2) of MK-3614 | Blood samples were collected at pre-specified time points on Day 13 to determine t½ in Panel D participants who received multiple doses of MK-3614. Apparent t½ was defined as the time required to eliminate half the amount of MK-3614 from plasma concentration. | Day 13: Predose and 0.5 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, & 48 hours postdose | 
| Change From Baseline in Aortic Augmentation Index (AIx) at 24 Hours Postdose After Multiple Doses of MK-3614 or Placebo | Aortic AIx is the percentage of the central pulse pressure attributed to the reflected pulse wave, and is an indirect measure of systemic arterial stiffness. Aortic AIx was measured at pre-specified timepoints by aplanation tonometry of radial artery. Linear model containing panel as a fixed effect was used to report the change from baseline in aortic Aix at 24 hours postdose. The 90% confidence intervals (CIs) for the true mean difference (MK-3614-placebo) in change from baseline were obtained using the mean square error from the linear model. Placebo data was pooled across all panels for the analysis. A decrease in the point estimate of ≥ 5 percentage points was considered clinically meaningful. | Panels A, B & C: Day 10: Baseline & 24 hours postdose; Panel D: Day 13: Baseline & 24 hours postdose; Placebo: Day 10 or Day 13: Baseline & 24 hours postdose | 
| Time-weighted Average Across 12 Hours (TWA 0-12hrs) for Heart Rate (HR) After Administration of MK-3614 or Placebo | HR was measured with a validated automatic device. TWA 0-12hrs equals all HR values over 12-hr observation period multiplied by length of time participant spent at each HR value by that HR value; added products together,& divided by observation period duration. Linear mixed effects model with panel, day, panel by day interaction as fixed effects & participant-within-panel as random effect was used to generate TWA 0-12hrs on 1st day of single dosing (Panel D: Day 1) or 1st day of multiple dosing of MK-3614/placebo (Panels A,B,C: Day 1; Panel D: Day 4) and last day of multiple dosing of MK-3614/placebo (Panels A,B,C: Day 10; Panel D: Day 13) & 90% CIs for true TWA using appropriate components of variance. Pooled placebo data at Day 1 indicates first day of single dosing (Panel D: Day 1) & first day of multiple dosing of placebo (Panels A,B,C: Day 1; Panel D: Day 4) & at Day 10 indicates last day of multiple dosing of placebo from all panels (Panels A,B,C: Day 10; Panel D: Day 13). | Panels A, B, C: Days 1, 10: Predose & 1, 2, 3, 4, 5, 6, 8, 10, 12 hours postdose; Panel D: Days 1, 4, 13: Predose & 1, 2, 3, 4, 5, 6, 8, 10, 12 hours postdose; Placebo: Days 1 & 10 or 1, 4, 13: Predose & 1, 2, 3, 4, 5, 6, 8, 10, 12 hours postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Time-Weighted Average Across 12 Hours (TWA 0-12hrs) of Peripheral Systolic Blood Pressure (SBP) on First Day of Multiple Dosing of MK-3614 or Placebo | Peripheral SBP was measured by the SphygmoCor® device. TWA 0-12hrs was obtained as follows: For all peripheral SBP values obtained over the 12-hour observation period (1, 2, 3, 4, 5, 6, 8, 10, 12 hours postdose), multiplied the length of time that the participant spent at each peripheral SBP value by that peripheral SBP value, added these products together, and then divided by duration of the observation period. Multiple dose effects of MK-3614 or placebo on peripheral SBP were estimated as a TWA change from baseline (0 hours) over the 12 hour postdose on first day of multiple dosing (Panels A, B, C: Day 1; Panel D: Day 4) and summarized descriptively. Placebo data was pooled across all panels for the analysis. Linear model containing panel as a fixed effect was used report the mean difference from placebo and associated 90% CIs after multiple doses of MK-3614 or placebo. | Panels A, B, C: Day 1: Baseline (0 hours) & up to 12 hours postdose; Panel D: Day 4: Baseline (0 hours) & up to 12 hours postdose; Placebo: Day 1 or Day 4: Baseline (0 hours) & up to 12 hours postdose | 
| Change From Baseline in Time-Weighted Average Across 12 Hours (TWA 0-12hrs) of Peripheral Systolic Blood Pressure (SBP) on Last Day After Multiple Dosing of MK-3614 or Placebo | Peripheral SBP was measured by the SphygmoCor® device. TWA 0-12hrs was obtained as follows: For all peripheral SBP values obtained over the 12-hour observation period (1, 2, 3, 4, 5, 6, 8, 10, and 12 hours postdose), multiplied the length of time that the participant spent at each peripheral SBP value by that peripheral SBP value, added these products together, and then divided by duration of the observation period. Multiple dose effects of MK-3614 or placebo on peripheral SBP were estimated as a TWA change from baseline (0 hours) over the 12 hour postdose on last day of multiple dosing (Panels A, B, C: Day 10; Panel D: Day 13) and summarized descriptively. Placebo data was pooled across all panels for the analysis. Linear model containing panel as a fixed effect was used report the mean difference from placebo and associated 90% CIs after multiple doses of MK-3614 or placebo. | Panels A, B, C: Day 1: Baseline (0 hours) & up to 12 hours; Panel D: Day 4: Baseline (0 hours) & up to 12 hours; Placebo: Day 1 or Day 4: Baseline (0 hours) & up to 12 hours | 
| Change From Baseline in Time-Weighted Average Across 24 Hours (TWA 0-24hrs) of Peripheral Systolic Blood Pressure (SBP) on Last Day of Multiple Dosing of MK-3614 or Placebo | Peripheral SBP was measured by the SphygmoCor® device. TWA 0-24hrs was obtained as follows: For all peripheral SBP values obtained over the 24-hour observation period (1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, and 24 hours postdose), multiplied the length of time that the participant spent at each peripheral SBP value by that peripheral SBP value, added these products together, and then divided by duration of the observation period. Multiple dose effects of MK-3614 or placebo on peripheral SBP were estimated as a TWA change from baseline (0 hours) over the 24 hour postdose on last day of multiple dosing (Panels A, B & C - Day 10; Panel D - Day 13) and summarized descriptively. Placebo data was pooled across all panels for the analysis. Linear model containing panel as a fixed effect was used report the mean difference from placebo and associated 90% CIs after multiple doses of MK-3614 or placebo. | Panels A, B, C: Day 10: Baseline (0 hours) & up to 24 hours postdose; Panel D: Day 13: Baseline (0 hours) & up to 24 hours postdose; Placebo: Day 10 or Day 13: Baseline (0 hours) & up to 24 hours postdose | 
| Change From Baseline in Time-Weighted Average Across 12 Hours (TWA 0-12hrs) of Peripheral Diastolic Blood Pressure (DBP) on First Day of Multiple Dosing of MK-3614 or Placebo | Peripheral DBP was measured by the SphygmoCor® device. TWA 0-12hrs was obtained as follows: For all peripheral DBP values obtained over the 12-hour observation period (1, 2, 3, 4, 5, 6, 8, 10, and 12 hours postdose), multiplied the length of time that the participant spent at each peripheral DBP value by that peripheral DBP value, added these products together, and then divided by duration of the observation period. Multiple dose effects of MK-3614 or placebo on peripheral DBP were estimated as a TWA change from baseline (0 hours) over the 12 hour postdose on first day of multiple dosing (Panels A, B, C: Day 1; Panel D: Day 4) and summarized descriptively. Placebo data was pooled across all panels for the analysis. Linear model containing panel as a fixed effect was used report the mean difference from placebo and associated 90% CIs after multiple doses of MK-3614 or placebo. | Panels A, B, C: Day 1: Baseline (0 hours) & up to 12 hours postdose; Panel D: Day 4: Baseline (0 hours) & up to 12 hours postdose; Placebo: Day 1 or Day 4: Baseline (0 hours) & up to 12 hours postdose | 
| Change From Baseline in Time-Weighted Average Across 12 Hours (TWA 0-12hrs) of Peripheral Diastolic Blood Pressure (DBP) on Last Day of Multiple Dosing of MK-3614 or Placebo | Peripheral DBP was measured by the SphygmoCor® device. TWA 0-12hrs was obtained as follows: For all peripheral DBP values obtained over the 12-hour observation period (1, 2, 3, 4, 5, 6, 8, 10, and 12 hours postdose), multiplied the length of time that the participant spent at each peripheral DBP value by that peripheral DBP value, added these products together, and then divided by duration of the observation period. Multiple dose effects of MK-3614 or placebo on peripheral DBP were estimated as a TWA change from baseline (0 hours) over the 12 hour postdose on last day of multiple dosing (Panels A, B, C: Day 10; Panel D: Day 13) and summarized descriptively. Placebo data was pooled across all panels for the analysis. Linear model containing panel as a fixed effect was used report the mean difference from placebo and associated 90% CIs after multiple doses of MK-3614 or placebo. | Panels A, B, C: Day 10: Baseline (0 hours) & up to 12 hours postdose; Panel D: Day 13: Baseline (0 hours) & up to 12 hours postdose; Placebo: Day 10 or Day 13: Baseline (0 hours) & up to 12 hours postdose | 
| Change From Baseline in Time-Weighted Average Across 24 Hours (TWA 0-24hrs) of Peripheral Diastolic Blood Pressure (DBP) on Last Day of Multiple Dosing of MK-3614 or Placebo | Peripheral DBP was measured by the SphygmoCor® device. TWA 0-24hrs was obtained as follows: For all peripheral DBP values obtained over the 24-hour observation period (1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, and 24 hours postdose), multiplied the length of time that the participant spent at each peripheral DBP value by that peripheral DBP value, added these products together, and then divided by duration of the observation period. Multiple dose effects of MK-3614 or placebo on peripheral DBP were estimated as a TWA change from baseline (0 hours) over the 12 hour postdose on last day of multiple dosing (Panels A, B, C: Day 10; Panel D: Day 13) and summarized descriptively. Placebo data was pooled across all panels for the analysis. Linear model containing panel as a fixed effect was used report the mean difference from placebo and associated 90% CIs after multiple doses of MK-3614 or placebo. | Panels A, B, C: Day 10: Baseline (0 hours) & up to 24 hours postdose; Panel D: Day 13: Baseline (0 hours) & up to 24 hours postdose; Placebo: Day 10 or Day 13: Baseline (0 hours) & up to 24 hours postdose | 
| Panels B, C, & D: Change From Baseline in Bleeding Time (BT) at 5 Hours Postdose on Last Day After Multiple Doses of MK-3614 or Placebo | Blood was drawn at baseline (0 hours) and 5 hours postdose on last day (Panels B, C: Day 10; Panel D: Day 13 per protocol) to assess bleeding time using a Newborn Surgicutt device. Linear model containing panel as a fixed effect was used to generate fold change from baseline and associated 90% CIs. Placebo data was pooled across panels B, C and D for the analysis. | Panels B, C: Day 10: Baseline (0 hours) & 5 hours postdose; Panel D: Day 13: Baseline (0 hours) & 5 hours postdose; Placebo: Day 10 or Day 13: Baseline (0 hours) & 5 hours postdose | 
| Cyclic Guanosine Monophosphate (cGMP) Concentration Levels After Multiple Doses of MK-3614 | Whole Blood was drawn at predose (baseline) and at 4, 24 hours postdose on last day of multiple dosing of MK-3614 (Panels A, B & C: Day 10; Panel D: Day 13) to measure cGMP concentration levels. Linear mixed effects model containing panel, time, and panel by time interaction as fixed effects and participant within panel as a random effect was used to generate geometric mean and associated 90% CIs. Placebo data was pooled across all panels for the analysis. | Panels A, B & C: Day 10: Predose & 4, 24 hours postdose; Panel D: Day 13: Predose & 4, 24 hours postdose; Placebo: Day 10 or Day 13: Predose & 4, 24 hours postdose |