Trial Outcomes & Findings for Safety, Tolerability, Pharmacokinetics (PK) of the Anti-Orthopox Drug, ST-246 (NCT NCT00907803)

Last Updated: 2010-09-21

Results Overview

Subjects were administered a single, daily oral dose of ST-246 (400 or 600 mg)and changes in safety parameteres were monitored. Safety parameters included adverse events, vital signs, physical examinations, laboratory tests (hematology, blood chemistry, and urinalysis) and electrocardiograms. The DAIDS AE grading table is a list of common terms and severity (intensity) of parameters used to describe adverse events occurring in NIAID-sponsored clinical studies/trials.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

107 participants

Primary outcome timeframe

Days 1 to 14; then 24, 48, 72, 96 and 120 hours and 4 weeks after final dose

Results posted on

2010-09-21

Participant Flow

This study was conducted at three sites: Apex Research Institute, Santa Ana, CA, Hawaii Clinical Research Center, Honolulu, HI, and Orlando Clinical Research Center, Orlando, FL. The study was conducted in male and female volunteers ages 18 - 75 years inclusive from the sites' databases.

Following an up to 14-day Screening Period, eligible subjects were randomly assigned to receive either ST-246 400 mg (n=45) or ST-246 600 mg (n=46) or placebo (n=16). Treatment was orally administered after a light meal over a 14-day Treatment Period. There was a 28-day Follow-up Period.

Participant milestones

Participant milestones
Measure	ST-246 400 mg 400 mg ST-246 (2 x 200 mg capsules) given as a single daily oral dose to 45 subjects for 14 days.	ST-246 600 mg 600 mg ST-246 (3 x 200 mg capsules) given as a single daily oral dose to 46 subjects for 14 days.	Placebo Matching Placebo capsules given as a single daily oral dose to 16 subjects for 14 days.
Overall Study STARTED	45	46	16
Overall Study COMPLETED	42	43	16
Overall Study NOT COMPLETED	3	3	0

Reasons for withdrawal

Reasons for withdrawal
Measure	ST-246 400 mg 400 mg ST-246 (2 x 200 mg capsules) given as a single daily oral dose to 45 subjects for 14 days.	ST-246 600 mg 600 mg ST-246 (3 x 200 mg capsules) given as a single daily oral dose to 46 subjects for 14 days.
Overall Study Withdrawal of consent - long commute	1	0
Overall Study Adverse Event	2	0
Overall Study Withdrawal by Subject	0	1
Overall Study Lost to Follow-up	0	1
Overall Study Protocol Violation	0	1

Baseline Characteristics

Safety, Tolerability, Pharmacokinetics (PK) of the Anti-Orthopox Drug, ST-246

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	ST-246 400 mg n=45 Participants 400 mg ST-246 (2 x 200 mg capsules) given as a single daily oral dose to 45 subjects for 14 days.	ST-246 600 mg n=46 Participants 600 mg ST-246 (3 x 200 mg capsules) given as a single daily oral dose to 46 subjects for 14 days.	Placebo n=16 Participants Matching Placebo capsules given as a single daily oral dose to 16 subjects for 14 days.	Total n=107 Participants Total of all reporting groups
Age, Categorical <=18 years	2 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	2 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	41 Participants n=5 Participants	40 Participants n=7 Participants	13 Participants n=5 Participants	94 Participants n=4 Participants
Age, Categorical >=65 years	2 Participants n=5 Participants	6 Participants n=7 Participants	3 Participants n=5 Participants	11 Participants n=4 Participants
Age Continuous	41.3 years STANDARD_DEVIATION 15.22 • n=5 Participants	43.7 years STANDARD_DEVIATION 15.81 • n=7 Participants	42.5 years STANDARD_DEVIATION 17.03 • n=5 Participants	42.5 years STANDARD_DEVIATION 15.64 • n=4 Participants
Sex: Female, Male Female	27 Participants n=5 Participants	22 Participants n=7 Participants	9 Participants n=5 Participants	58 Participants n=4 Participants
Sex: Female, Male Male	18 Participants n=5 Participants	24 Participants n=7 Participants	7 Participants n=5 Participants	49 Participants n=4 Participants
Region of Enrollment United States	45 participants n=5 Participants	46 participants n=7 Participants	16 participants n=5 Participants	107 participants n=4 Participants

PRIMARY outcome

Timeframe: Days 1 to 14; then 24, 48, 72, 96 and 120 hours and 4 weeks after final dose

Population: As per protocol. During the study, a total of 6 withdrawals occurred. These were due to adverse events (2) and consent withdrawal (1) in the 400 mg group, and subject request (1), lost to follow-up (1) and protocol violation (1) in the 600 mg group.

Outcome measures

Outcome measures
Measure	ST-246 400 mg n=45 Participants 400 mg ST-246 (2 x 200 mg capsules) given as a single daily oral dose to 45 subjects for 14 days.	ST-246 600 mg n=46 Participants 600 mg ST-246 (3 x 200 mg capsules) given as a single daily oral dose to 46 subjects for 14 days.	Placebo n=16 Participants Matching Placebo capsules given as a single daily oral dose to 16 subjects for 14 days.
Number of Study Participants Who Tolerated a Single Daily Oral ST-246 Dose as Determined by Safety Parameter Changes According to the DAIDS (Division of Acquired Immunodeficiency Syndrome) Adverse Events (AE) Grading Table.	34 Participants	38 Participants	15 Participants

SECONDARY outcome

Timeframe: Day 1 post-dose

Population: As per protocol. All 16 subjects in the placebo group were excluded from the PK population. In addition, 2 subjects in each of the ST-246 400 mg and 600 mg groups were excluded due to early withdrawals.

Cmax: Maximum drug concentration in plasma determined directly from individual concentration-time data

Outcome measures

Outcome measures
Measure	ST-246 400 mg n=43 Participants 400 mg ST-246 (2 x 200 mg capsules) given as a single daily oral dose to 45 subjects for 14 days.	ST-246 600 mg n=44 Participants 600 mg ST-246 (3 x 200 mg capsules) given as a single daily oral dose to 46 subjects for 14 days.	Placebo Matching Placebo capsules given as a single daily oral dose to 16 subjects for 14 days.
Evaluation of Pharmacokinetic Parameters to Assess Interventions: Cmax	1170 ng/mL Standard Deviation 429	1467 ng/mL Standard Deviation 626	—

SECONDARY outcome

Timeframe: Day 14 post-dose

Population: As per protocol. All 16 subjects in the placebo group were excluded from the PK population. In addition, 4 subjects in each of the ST-246 400 mg and 600 mg groups were excluded from PK analysis due to withdrawals or because PK data fell below the limit of quantitation (BLQ).

Cmax: Maximum drug concentration in plasma determined directly from individual concentration-time data

Outcome measures

Outcome measures
Measure	ST-246 400 mg n=41 Participants 400 mg ST-246 (2 x 200 mg capsules) given as a single daily oral dose to 45 subjects for 14 days.	ST-246 600 mg n=42 Participants 600 mg ST-246 (3 x 200 mg capsules) given as a single daily oral dose to 46 subjects for 14 days.	Placebo Matching Placebo capsules given as a single daily oral dose to 16 subjects for 14 days.
Evaluation of Pharmacokinetic Parameters to Assess Interventions: Cmax	1286 ng/mL Standard Deviation 449	1523 ng/mL Standard Deviation 607	—

SECONDARY outcome

Timeframe: Day 1 post-dose

Tmax: Time to reach maximum drug concentration in plasma calculated from \[plasma\] versus time profiles

Outcome measures

Outcome measures
Measure	ST-246 400 mg n=43 Participants 400 mg ST-246 (2 x 200 mg capsules) given as a single daily oral dose to 45 subjects for 14 days.	ST-246 600 mg n=44 Participants 600 mg ST-246 (3 x 200 mg capsules) given as a single daily oral dose to 46 subjects for 14 days.	Placebo Matching Placebo capsules given as a single daily oral dose to 16 subjects for 14 days.
Evaluation of Pharmacokinetic Parameters to Assess Interventions: Tmax	4 hours Standard Deviation 1	4 hours Standard Deviation 1	—

SECONDARY outcome

Timeframe: Day 14 post-dose

Population: As per protocol. All 16 subjects in the placebo group were excluded from the PK population. In addition, 4 and 5 subjects in the ST-246 400 mg and 600 mg groups respectively, were excluded from PK analysis due to withdrawals or because PK data fell below the limit of quantitation (BLQ).

Tmax: Time to reach maximum drug concentration in plasma calculated from \[plasma\] versus time profiles

Outcome measures

Outcome measures
Measure	ST-246 400 mg n=41 Participants 400 mg ST-246 (2 x 200 mg capsules) given as a single daily oral dose to 45 subjects for 14 days.	ST-246 600 mg n=41 Participants 600 mg ST-246 (3 x 200 mg capsules) given as a single daily oral dose to 46 subjects for 14 days.	Placebo Matching Placebo capsules given as a single daily oral dose to 16 subjects for 14 days.
Evaluation of Pharmacokinetic Parameters to Assess Interventions: Tmax	4 hours Standard Deviation 1	3 hours Standard Deviation 1	—

SECONDARY outcome

Timeframe: Day 1 post-dose

Population: As per protocol. All 16 subjects in the placebo group were excluded from the PK population. In addition, 23 subjects in each of the ST-246 400 mg and 600 mg groups were excluded from PK analysis due to early withdrawals or because PK data fell below the limit of quantitation (BLQ) before the 24-hour dosing interval was complete.

AUCtau: Area under the plasma concentration-time curve for each dosing interval (from time 0 to 24 hours sample) determined using the linear trapezoidal rule

Outcome measures

Outcome measures
Measure	ST-246 400 mg n=22 Participants 400 mg ST-246 (2 x 200 mg capsules) given as a single daily oral dose to 45 subjects for 14 days.	ST-246 600 mg n=23 Participants 600 mg ST-246 (3 x 200 mg capsules) given as a single daily oral dose to 46 subjects for 14 days.	Placebo Matching Placebo capsules given as a single daily oral dose to 16 subjects for 14 days.
Evaluation of Pharmacokinetic Parameters to Assess Interventions: AUCtau	11329 ng*hr/mL Standard Deviation 4945	13895 ng*hr/mL Standard Deviation 5702	—

SECONDARY outcome

Timeframe: Day 14 post-dose

Population: As per protocol. All 16 subjects in the placebo group were excluded from the PK population. In addition, 5 and 6 subjects in the ST-246 400 mg and 600 mg groups respectively, were excluded from PK analysis due to withdrawals or because PK data fell below the limit of quantitation (BLQ).

AUCtau: Area under the plasma concentration-time curve for each dosing interval (from time 0 to 24 hours sample) determined using the linear trapezoidal rule

Outcome measures

Outcome measures
Measure	ST-246 400 mg n=40 Participants 400 mg ST-246 (2 x 200 mg capsules) given as a single daily oral dose to 45 subjects for 14 days.	ST-246 600 mg n=40 Participants 600 mg ST-246 (3 x 200 mg capsules) given as a single daily oral dose to 46 subjects for 14 days.	Placebo Matching Placebo capsules given as a single daily oral dose to 16 subjects for 14 days.
Evaluation of Pharmacokinetic Parameters to Assess Interventions: AUCtau	12026 ng*hr/mL Standard Deviation 4255	14791 ng*hr/mL Standard Deviation 5712	—

SECONDARY outcome

Timeframe: Day 14 post-dose

Population: As per protocol. All 16 subjects in the placebo group were excluded from the PK population. In addition, 21 and 20 subjects in the ST-246 400 mg and 600 mg groups respectively, were excluded from PK analysis due to early withdrawals or because PK data fell below the limit of quantitation (BLQ).

t½: Observed terminal elimination half-life determined after the last dose on Day 14

Outcome measures

Outcome measures
Measure	ST-246 400 mg n=24 Participants 400 mg ST-246 (2 x 200 mg capsules) given as a single daily oral dose to 45 subjects for 14 days.	ST-246 600 mg n=26 Participants 600 mg ST-246 (3 x 200 mg capsules) given as a single daily oral dose to 46 subjects for 14 days.	Placebo Matching Placebo capsules given as a single daily oral dose to 16 subjects for 14 days.
Evaluation of Pharmacokinetic Parameters to Assess Interventions: t½	26 hours Standard Deviation 11	24 hours Standard Deviation 15	—

Adverse Events

ST-246 400 mg

Serious events: 0 serious events

Other events: 11 other events

Deaths: 0 deaths

ST-246 600 mg

Serious events: 0 serious events

Other events: 8 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Annie Frimm, Vice President, Regulatory Affairs

SIGA Technologies, Inc.

Phone: 951-303-8797

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The PI must obtain the sponsor's written consent to publish any study results and must notify the sponsor within 30 working days prior to publishing.
Publication restrictions are in place

Restriction type: OTHER

Measure	ST-246 400 mg n=45 participants at risk 400 mg ST-246 (2 x 200 mg capsules) given as a single daily oral dose to 45 subjects for 14 days.	ST-246 600 mg n=46 participants at risk 600 mg ST-246 (3 x 200 mg capsules) given as a single daily oral dose to 46 subjects for 14 days.	Placebo n=16 participants at risk Matching Placebo capsules given as a single daily oral dose to 16 subjects for 14 days.
Gastrointestinal disorders Abdominal distension	2.2% 1/45 • Number of events 1 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	0.00% 0/46 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	0.00% 0/16 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.
General disorders Axillary pain	2.2% 1/45 • Number of events 1 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	0.00% 0/46 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	0.00% 0/16 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.
Musculoskeletal and connective tissue disorders Back pain	2.2% 1/45 • Number of events 1 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	0.00% 0/46 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	0.00% 0/16 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.
Gastrointestinal disorders Constipation	0.00% 0/45 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	2.2% 1/46 • Number of events 1 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	0.00% 0/16 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.
Gastrointestinal disorders Diarrhoea	0.00% 0/45 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	2.2% 1/46 • Number of events 1 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	0.00% 0/16 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.
Nervous system disorders Dizziness	2.2% 1/45 • Number of events 1 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	2.2% 1/46 • Number of events 1 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	0.00% 0/16 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.
Gastrointestinal disorders Dry mouth	0.00% 0/45 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	2.2% 1/46 • Number of events 1 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	6.2% 1/16 • Number of events 1 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.
Respiratory, thoracic and mediastinal disorders Dry throat	2.2% 1/45 • Number of events 1 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	0.00% 0/46 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	0.00% 0/16 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.
Gastrointestinal disorders Dyspepsia	2.2% 1/45 • Number of events 1 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	2.2% 1/46 • Number of events 1 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	0.00% 0/16 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.
General disorders Fatigue	2.2% 1/45 • Number of events 1 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	4.3% 2/46 • Number of events 2 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	0.00% 0/16 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.
Gastrointestinal disorders Flatulence	2.2% 1/45 • Number of events 1 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	2.2% 1/46 • Number of events 1 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	0.00% 0/16 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.
Vascular disorders Flushing	2.2% 1/45 • Number of events 1 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	0.00% 0/46 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	0.00% 0/16 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.
Nervous system disorders Headache	4.4% 2/45 • Number of events 2 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	10.9% 5/46 • Number of events 5 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	6.2% 1/16 • Number of events 1 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	2.2% 1/45 • Number of events 1 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	0.00% 0/46 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	0.00% 0/16 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.
Musculoskeletal and connective tissue disorders Myalgia	0.00% 0/45 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	2.2% 1/46 • Number of events 1 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	0.00% 0/16 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.
Gastrointestinal disorders Nausea	6.7% 3/45 • Number of events 3 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	4.3% 2/46 • Number of events 2 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	6.2% 1/16 • Number of events 1 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.
Musculoskeletal and connective tissue disorders Neck pain	2.2% 1/45 • Number of events 1 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	0.00% 0/46 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	0.00% 0/16 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.
Investigations Neutropenia	2.2% 1/45 • Number of events 1 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	0.00% 0/46 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	0.00% 0/16 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.
Cardiac disorders Palpitations	0.00% 0/45 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	0.00% 0/46 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	6.2% 1/16 • Number of events 1 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.
Nervous system disorders Paraesthesia	2.2% 1/45 • Number of events 1 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	0.00% 0/46 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	0.00% 0/16 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.
Skin and subcutaneous tissue disorders Pruritus	2.2% 1/45 • Number of events 1 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	0.00% 0/46 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	0.00% 0/16 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.
Nervous system disorders Tension headache	0.00% 0/45 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	2.2% 1/46 • Number of events 1 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	0.00% 0/16 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.
Respiratory, thoracic and mediastinal disorders Throat irritation	2.2% 1/45 • Number of events 1 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	0.00% 0/46 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	0.00% 0/16 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.
Skin and subcutaneous tissue disorders Urticaria	2.2% 1/45 • Number of events 1 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	0.00% 0/46 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.	0.00% 0/16 • 6 weeks Study drug was administered once a day to each dosing group for 14 days, and subjects were followed for an additional 28 days. AEs were recorded throughout this time period.