Trial Outcomes & Findings for Evaluation of Celecoxib Effects on Amlodipine in Subjects With Existing Hypertension Requiring Antihypertensives (NCT NCT02979197)

NCT ID: NCT02979197

Last Updated: 2019-10-21

Results Overview

An ambulatory blood pressure monitor (ABPM) fitted to upper arm was used for continuous recording of blood pressure over three 25-hour periods: Days -1 to 0 (Baseline), Days 6 to 7, \& Days 13 to 14. The ABPM recorded blood pressure every 20 minutes between 09:00 and 21:59 and every 30 minutes between 22:00 and 08:59. SBPday was calculated by averaging all of the systolic blood pressure measurements between the protocol-defined first \& last study measurements of the period that fell between 9:00 and 21:00; measurements during the first hour (white-coat window) were not included. Change in SBPday was calculated by subtracting the Baseline value from the end of study value (Day 13 to Day 14 period). If the Day 13 to Day 14 value was not available, the Day 6 to Day 7 value was used \[last observation carried forward (LOCF) method\]. A negative value for change in SBPday indicates a decrease in systolic blood pressure and a positive value indicates an increase.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 105 participants
• Primary outcome timeframe: Baseline and 14 days
• Results posted on: 2019-10-21

Participant Flow

Eligibility assessments were made at Initial Screening (Day -14 to -10), Final Screening (Day -1), and prior to randomization (Day 0). Subjects who met eligibility criteria at Initial Screening underwent a 10- to 14-day washout from their blood pressure medication and those who continued to meet criteria at the end of the washout were randomized.

Participant milestones

Measure	Amlodipine+Celecoxib OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days	Amlodipine+Placebo OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days	Placebo+Placebo Matched placebo for OE amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days
Overall Study STARTED	48	49	8
Overall Study COMPLETED	44	45	8
Overall Study NOT COMPLETED	4	4	0

Reasons for withdrawal

Measure	Amlodipine+Celecoxib OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days	Amlodipine+Placebo OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days	Placebo+Placebo Matched placebo for OE amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days
Overall Study Adverse Event	4	2	0
Overall Study Protocol Violation	0	1	0
Overall Study Subject unable to commit to study dates	0	1	0

Baseline Characteristics

Evaluation of Celecoxib Effects on Amlodipine in Subjects With Existing Hypertension Requiring Antihypertensives

Baseline characteristics by cohort

Measure	Amlodipine+Celecoxib n=48 Participants OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days	Amlodipine+Placebo n=49 Participants OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days	Placebo+Placebo n=8 Participants Matched placebo for OE amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days	Total n=105 Participants Total of all reporting groups
Age, Continuous	55.5 years STANDARD_DEVIATION 7.13 • n=5 Participants	56.7 years STANDARD_DEVIATION 7.43 • n=7 Participants	52.5 years STANDARD_DEVIATION 7.84 • n=5 Participants	55.8 years STANDARD_DEVIATION 7.34 • n=4 Participants
Sex: Female, Male Female	17 Participants n=5 Participants	18 Participants n=7 Participants	4 Participants n=5 Participants	39 Participants n=4 Participants
Sex: Female, Male Male	31 Participants n=5 Participants	31 Participants n=7 Participants	4 Participants n=5 Participants	66 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race (NIH/OMB) White	46 Participants n=5 Participants	47 Participants n=7 Participants	7 Participants n=5 Participants	100 Participants n=4 Participants
Race (NIH/OMB) More than one race	1 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	2 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Region of Enrollment United Kingdom	48 participants n=5 Participants	49 participants n=7 Participants	8 participants n=5 Participants	105 participants n=4 Participants
SBPday	148.0 mmHg STANDARD_DEVIATION 7.95 • n=5 Participants	150.0 mmHg STANDARD_DEVIATION 8.25 • n=7 Participants	151.5 mmHg STANDARD_DEVIATION 10.91 • n=5 Participants	149.2 mmHg STANDARD_DEVIATION 8.33 • n=4 Participants

PRIMARY outcome

Timeframe: Baseline and 14 days

Population: Intent-to-treat (ITT) population = all randomized subjects with a valid Baseline (Day -1 to Day 0) ABPM measurement. The primary endpoint of this trial was a comparison of the mean change in SBPday between the amlodipine+celecoxib and amlodipine+placebo arms (non-inferiority trial). Comparison to placebo+placebo was not part of primary endpoint.

An ambulatory blood pressure monitor (ABPM) fitted to upper arm was used for continuous recording of blood pressure over three 25-hour periods: Days -1 to 0 (Baseline), Days 6 to 7, & Days 13 to 14. The ABPM recorded blood pressure every 20 minutes between 09:00 and 21:59 and every 30 minutes between 22:00 and 08:59. SBPday was calculated by averaging all of the systolic blood pressure measurements between the protocol-defined first & last study measurements of the period that fell between 9:00 and 21:00; measurements during the first hour (white-coat window) were not included. Change in SBPday was calculated by subtracting the Baseline value from the end of study value (Day 13 to Day 14 period). If the Day 13 to Day 14 value was not available, the Day 6 to Day 7 value was used [last observation carried forward (LOCF) method]. A negative value for change in SBPday indicates a decrease in systolic blood pressure and a positive value indicates an increase.

Outcome measures

Measure	Amlodipine+Celecoxib n=48 Participants OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days	Amlodipine+Placebo n=48 Participants OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days	Placebo+Placebo Matched placebo for OE amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days
Change in Average Daytime (9:00 to 21:00) Ambulatory Systolic Blood Pressure (SBPday)	-8.0 mmHg Standard Deviation 8.24	-9.8 mmHg Standard Deviation 8.89	—

SECONDARY outcome

Timeframe: Baseline and 14 days

Population: ITT population \[i.e., all randomized subjects with a valid Baseline (Day -1 to Day 0) ABPM measurement\]. A secondary endpoint of this trial was a comparison of the mean change in body weight between all three treatment arms \[analysis of variance (ANOVA) F test\]. Thus, mean values for all three arms are presented.

Body weight was measured at the Initial Screening Visit (Day -10 to -14), at Baseline (Day 0), and at Days 7 and 14. The measurements were made using a calibrated scale with the subject wearing underwear and a light gown. Change in body weight was calculated by subtracting the Baseline value from the end of treatment value (recorded on Day 14). If the Day 14 value was not available, the Day 7 value was used (LOCF method). A negative value for change in body weight indicates a decrease in body weight and a positive value indicates an increase.

Outcome measures

Measure	Amlodipine+Celecoxib n=48 Participants OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days	Amlodipine+Placebo n=48 Participants OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days	Placebo+Placebo n=8 Participants Matched placebo for OE amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days
Change in Body Weight	0.3 kg Standard Deviation 1.02	-0.3 kg Standard Deviation 1.03	-1.5 kg Standard Deviation 3.95

SECONDARY outcome

Timeframe: Baseline and 14 days

Population: ITT population \[i.e., all randomized subjects with a valid Baseline (Day -1 to Day 0) ABPM measurement\]. A secondary endpoint of this trial was the comparison of the mean change in SBP24h between the amlodipine+celecoxib and amlodipine+placebo arms (superiority trial). Comparison to placebo+placebo was not part of this endpoint.

An ABPM fitted to upper arm was used for continuous recording of blood pressure over three 25-hour periods: Days -1 to 0 (Baseline), Days 6 to 7, & Days 13 to 14. The ABPM recorded blood pressure every 20 minutes between 09:00 and 21:59 and every 30 minutes between 22:00 and 08:59. SBP24h was calculated by averaging all of the systolic blood pressure measurements between the protocol-defined first & last study measurements of the period; measurements during the first hour (white-coat window) were not included. Change in SBP24h was calculated by subtracting the Baseline value from the end of study value (Day 13 to Day 14 period). If the Day 13 to Day 14 value was not available, the Day 6 to Day 7 value was used (LOCF method). A negative value for change in SBP24h indicates a decrease in systolic blood pressure and a positive value indicates an increase.

Outcome measures

Measure	Amlodipine+Celecoxib n=48 Participants OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days	Amlodipine+Placebo n=48 Participants OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days	Placebo+Placebo Matched placebo for OE amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days
Change in Average 24-hour Ambulatory Systolic Blood Pressure (SBP24h)	-8.2 mmHg Standard Deviation 7.80	-8.5 mmHg Standard Deviation 8.47	—

SECONDARY outcome

Timeframe: Baseline and 14 days

Population: ITT population \[i.e., all randomized subjects with a valid Baseline (Day -1 to Day 0) ABPM measurement\]. A secondary endpoint of this trial was the comparison of the mean change in DBP24h between the amlodipine+celecoxib and amlodipine+placebo arms (superiority trial). Comparison to placebo+placebo was not part of this endpoint.

An ABPM fitted to upper arm was used for continuous recording of blood pressure over three 25-hour periods: Days -1 to 0 (Baseline), Days 6 to 7, & Days 13 to 14. The ABPM recorded blood pressure every 20 minutes between 09:00 and 21:59 and every 30 minutes between 22:00 and 08:59. DBP24h was calculated by averaging all of the diastolic blood pressure measurements between the protocol-defined first & last study measurements of the period; measurements during the first hour (white-coat window) were not included. Change in DBP24h was calculated by subtracting the Baseline value from the end of study value (Day 13 to Day 14 period). If the Day 13 to Day 14 value was not available, the Day 6 to Day 7 value was used (LOCF method). A negative value for change in DBP24h indicates a decrease in diastolic blood pressure and a positive value indicates an increase.

Outcome measures

Measure	Amlodipine+Celecoxib n=48 Participants OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days	Amlodipine+Placebo n=48 Participants OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days	Placebo+Placebo Matched placebo for OE amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days
Change in Average 24-hour Ambulatory Diastolic Blood Pressure (DBP24h)	-4.4 mmHg Standard Deviation 4.68	-3.8 mmHg Standard Deviation 5.27	—

SECONDARY outcome

Timeframe: Baseline and 14 days

Population: ITT population \[i.e., all randomized subjects with a valid Baseline (Day -1 to Day 0) ABPM measurement\]. A secondary endpoint of this trial was the comparison of the mean change in creatinine clearance between the amlodipine+celecoxib and amlodipine+placebo arms (superiority trial). Comparison to placebo+placebo was not part of this endpoint.

Subjects had blood collected for the measurement of creatinine at the Initial Screening Visit (Day -10 to -14), at Baseline (Day 0), and at Days 7 and 14. Estimated creatinine clearance was calculated using Cockcroft-Gault equation: (140 - age) X body weight (kg)/72 X serum creatinine concentration (mg/dL); multiplied by 0.85 for women. Change in creatinine clearance was calculated by subtracting the Baseline value from the end of treatment value (recorded on Day 14). If the Day 14 value was not available, the Day 7 value was used (LOCF method). A negative value for change in creatinine clearance indicates a decrease in creatinine clearance and a positive value indicates an increase.

Outcome measures

Measure	Amlodipine+Celecoxib n=48 Participants OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days	Amlodipine+Placebo n=48 Participants OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days	Placebo+Placebo Matched placebo for OE amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days
Change in Creatinine Clearance	4.9 mL/min Standard Deviation 10.62	3.4 mL/min Standard Deviation 20.96	—

SECONDARY outcome

Timeframe: 1 month

Population: Safety population = all randomized subjects who received at least one dose of study drug. The occurrence of TEAEs was compared between all three arms (Chi-square test), as well as between the amlodipine+celecoxib and amlodipine+placebo arms (exact logistic regression model). Comparison to placebo+placebo was not part of this latter analysis.

Treatment emergent adverse events (TEAEs) included any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs.

Outcome measures

Measure	Amlodipine+Celecoxib n=48 Participants OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days	Amlodipine+Placebo n=49 Participants OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days	Placebo+Placebo n=8 Participants Matched placebo for OE amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days
Occurrence of Treatment Emergent Adverse Events	35 Participants	32 Participants	6 Participants

SECONDARY outcome

Timeframe: 24 hours post-dose on Day 14

Population: Pharmacokinetic (PK) population = all subjects enrolled at an Investigational Site with ultraviolet- (UV-) shielded lights who had blood drawn on Day 14, 24 hours ± 1 hour after receiving the final dose of study drugs for the measurement of plasma amlodipine concentration; only treatment arms that included amlodipine were included in the analyses.

A venous blood sample was collected 24 hours ± 1 hour after the last dose of study drugs (i.e., on Day 14). The blood sample was processed to plasma and the concentration of amlodipine measured using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The resulting concentrations, without logarithmic transformation, were used for the comparison between the amlodipine+celecoxib and amlodipine+placebo arms to evaluate the effect of celecoxib on the mean non-transformed plasma concentrations of amlodipine.

Outcome measures

Measure	Amlodipine+Celecoxib n=23 Participants OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days	Amlodipine+Placebo n=20 Participants OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days	Placebo+Placebo Matched placebo for OE amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days
Non-transformed Plasma Concentration of Amlodipine	15.9 ng/mL Standard Deviation 5.72	18.3 ng/mL Standard Deviation 7.21	—

SECONDARY outcome

Timeframe: 24 hours post-dose on Day 14

Population: PK population = all subjects enrolled at an Investigational Site with ultraviolet- (UV-) shielded lights who had blood drawn on Day 14, 24 hours ± 1 hour after receiving the final dose of study drugs for the measurement of plasma amlodipine concentration; only treatment arms that included amlodipine were included in the analyses.

A venous blood sample was collected 24 hours ± 1 hour after the last dose of study drugs (i.e., on Day 14). The blood sample was processed to plasma and the concentration of amlodipine measured using a validated LC-MS/MS method. The concentrations were logarithmically transformed and used for the comparison between the amlodipine+celecoxib and amlodipine+placebo arms to evaluate the effect of celecoxib on the mean log-transformed plasma concentrations of amlodipine.

Outcome measures

Measure	Amlodipine+Celecoxib n=23 Participants OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days	Amlodipine+Placebo n=20 Participants OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days	Placebo+Placebo Matched placebo for OE amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days
Log-transformed Plasma Concentration of Amlodipine	2.7 ng/mL Standard Deviation 0.44	2.8 ng/mL Standard Deviation 0.36	—

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline and 14 Days

Population: Safety population = all randomized subjects who received at least one dose of study drug

Subjects had blood collected for the measurement of creatinine at the Initial Screening Visit (Day -10 to -14), at Baseline (Day 0), and at Days 7 and 14. Change in serum creatinine was calculated by subtracting the Baseline value from the end of treatment value (recorded on Day 14). A negative value for change in serum creatinine indicates a decrease in creatinine and a positive value indicates an increase.

Outcome measures

Measure	Amlodipine+Celecoxib n=48 Participants OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days	Amlodipine+Placebo n=49 Participants OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days	Placebo+Placebo n=8 Participants Matched placebo for OE amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days
Change in Serum Creatinine	-2.8 μmol/L Standard Deviation 5.56	-2.4 μmol/L Standard Deviation 10.19	-1.9 μmol/L Standard Deviation 4.61

Adverse Events

Amlodipine+Celecoxib

Serious events: 0 serious events

Other events: 25 other events

Deaths: 0 deaths

Amlodipine+Placebo

Serious events: 0 serious events

Other events: 23 other events

Deaths: 0 deaths

Placebo+Placebo

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Amlodipine+Celecoxib n=48 participants at risk OE 10 mg amlodipine besylate tablet + OE 200 mg celecoxib capsule qd for 14 days	Amlodipine+Placebo n=49 participants at risk OE 10 mg amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days	Placebo+Placebo n=8 participants at risk Matched placebo for OE amlodipine besylate tablet + matched placebo for OE celecoxib capsule qd for 14 days
Eye disorders Eye swelling	0.00% 0/48 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	0.00% 0/49 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	12.5% 1/8 • Number of events 1 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.
Eye disorders Vision blurred	0.00% 0/48 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	0.00% 0/49 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	12.5% 1/8 • Number of events 1 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.
Gastrointestinal disorders Dyspepsia	0.00% 0/48 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	2.0% 1/49 • Number of events 1 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	12.5% 1/8 • Number of events 1 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.
Gastrointestinal disorders Flatulence	2.1% 1/48 • Number of events 1 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	0.00% 0/49 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	12.5% 1/8 • Number of events 1 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.
General disorders Chest discomfort	0.00% 0/48 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	0.00% 0/49 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	12.5% 1/8 • Number of events 1 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.
General disorders Fatigue	4.2% 2/48 • Number of events 2 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	0.00% 0/49 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	12.5% 1/8 • Number of events 1 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.
General disorders Feeling cold	0.00% 0/48 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	0.00% 0/49 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	12.5% 1/8 • Number of events 1 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.
General disorders Feeling hot	2.1% 1/48 • Number of events 1 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	6.1% 3/49 • Number of events 6 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	0.00% 0/8 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.
General disorders Oedema peripheral	14.6% 7/48 • Number of events 7 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	8.2% 4/49 • Number of events 5 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	0.00% 0/8 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.
General disorders Pain	2.1% 1/48 • Number of events 1 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	0.00% 0/49 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	12.5% 1/8 • Number of events 2 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.
Infections and infestations Rhinitis	0.00% 0/48 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	2.0% 1/49 • Number of events 1 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	12.5% 1/8 • Number of events 1 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.
Infections and infestations Sinusitis	0.00% 0/48 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	0.00% 0/49 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	12.5% 1/8 • Number of events 1 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.
Metabolism and nutrition disorders Increased appetite	2.1% 1/48 • Number of events 1 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	0.00% 0/49 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	12.5% 1/8 • Number of events 1 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/48 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	6.1% 3/49 • Number of events 8 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	0.00% 0/8 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.
Musculoskeletal and connective tissue disorders Joint swelling	20.8% 10/48 • Number of events 12 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	18.4% 9/49 • Number of events 13 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	12.5% 1/8 • Number of events 1 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.
Nervous system disorders Dizziness	6.2% 3/48 • Number of events 4 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	2.0% 1/49 • Number of events 1 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	0.00% 0/8 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.
Nervous system disorders Headache	10.4% 5/48 • Number of events 10 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	18.4% 9/49 • Number of events 10 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	25.0% 2/8 • Number of events 3 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.
Nervous system disorders Lethargy	0.00% 0/48 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	0.00% 0/49 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	12.5% 1/8 • Number of events 1 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.
Respiratory, thoracic and mediastinal disorders Cough	2.1% 1/48 • Number of events 1 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	4.1% 2/49 • Number of events 2 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	12.5% 1/8 • Number of events 1 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.
Skin and subcutaneous tissue disorders Dry skin	0.00% 0/48 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	4.1% 2/49 • Number of events 2 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	12.5% 1/8 • Number of events 1 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.
Skin and subcutaneous tissue disorders Rash	6.2% 3/48 • Number of events 3 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	0.00% 0/49 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	0.00% 0/8 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.
Vascular disorders Flushing	4.2% 2/48 • Number of events 2 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	4.1% 2/49 • Number of events 2 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.	25.0% 2/8 • Number of events 2 • 1 month; TEAEs include any untoward medical occurrence that initiated or worsened after the first dose of study drugs and within 14 days of the last dose of study drugs. Subjects were instructed to report all adverse events (AEs) experienced during the study, and subjects were assessed for the occurrence of AEs throughout the study. Secondary safety assessments included physical examination, body weight, vital signs, orthostatic hypotension evaluations, 12-lead electrocardiogram, hematology, serum chemistry and urinalysis, and any clinically significant findings on these assessments were reported as AEs.

Additional Information

J. Paul Waymack, M.D., Chief Medical Officer

Kitov Pharma Ltd.

Phone: (202) 965-2215

Email: paul@kitovpharma.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place

Restriction type: GT60