Trial Outcomes & Findings for Phase I, Escalating, Multiple-Dose, ST-246 Safety, Tolerability and Pharmacokinetics 21-Day Trial in Healthy Volunteers (NCT NCT00431951)

Results Overview

Evaluated safety parameters included: 1. physical examination/vital signs 2. electrocardiograms (heart rate, PR interval, QRS duration, QT interval, and QTc Bazett) 3. laboratory safety tests (hematology, chemistry, urinalysis) 4. adverse events (AEs) For a)-c), statistical values (mean, standard deviation, median, minimum, maximum) and changes from baseline (Day 1 pre-dose) to each time-point, were compared to laboratory normal reference ranges. If values for a)-d) were a Grade 3 or higher (in DAIDS AE Table)and ST-246-related, they were considered severe and significant, respectively.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

30 participants

Primary outcome timeframe

Days 1, 6, 14-16, 21-24, 28-31, and 51-53

Results posted on

2017-07-27

Participant Flow

This study was conducted at one site, Orlando Clinical Research Center, Orlando, FL. The study was conducted in healthy volunteers from the site's database.

After a 28-day screening and 1-day enrollment period, study drug was administered on Day 1. Ten participants (8 drug:2 placebo) were randomized in each of three dosing groups (250, 400, and 800 mg ST-246). Each group was divided into 2 cohorts of 5 subjects (4 drug:1 placebo), with one cohort receiving drug 4-8 weeks before the other cohort.

Participant milestones

Participant milestones
Measure	ST-246 250 mg 250 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	ST-246 400mg 400 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days. Blood and urine samples for PK taken on Days 1, 6, and 21.	ST-246 800 mg 800 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days. Blood and urine samples for PK taken on Days 1, 6, and 21.	Placebo Placebo given as a single daily oral dose for 21 days to 6 subjects, to match ST-246 doses (2 patients for each dose equivalent). Blood and urine samples for PK taken on Days 1, 6, and 21.
Overall Study STARTED	8	8	8	6
Overall Study COMPLETED	7	6	6	4
Overall Study NOT COMPLETED	1	2	2	2

Reasons for withdrawal

Reasons for withdrawal
Measure	ST-246 250 mg 250 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	ST-246 400mg 400 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days. Blood and urine samples for PK taken on Days 1, 6, and 21.	ST-246 800 mg 800 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days. Blood and urine samples for PK taken on Days 1, 6, and 21.	Placebo Placebo given as a single daily oral dose for 21 days to 6 subjects, to match ST-246 doses (2 patients for each dose equivalent). Blood and urine samples for PK taken on Days 1, 6, and 21.
Overall Study Inability to follow study procedures	1	0	1	2
Overall Study Lost to Follow-up	0	1	0	0
Overall Study Withdrawal by Subject	0	1	0	0
Overall Study Adverse Event	0	0	1	0

Baseline Characteristics

Phase I, Escalating, Multiple-Dose, ST-246 Safety, Tolerability and Pharmacokinetics 21-Day Trial in Healthy Volunteers

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	ST-246 250 mg n=8 Participants 250 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	ST-246 400mg n=8 Participants 400 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days. Blood and urine samples for PK taken on Days 1, 6, and 21.	ST-246 800 mg n=8 Participants 800 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days. Blood and urine samples for PK taken on Days 1, 6, and 21.	Placebo n=6 Participants Placebo given as a single daily oral dose for 21 days to 6 subjects, to match ST-246 doses (2 patients for each dose equivalent). Blood and urine samples for PK taken on Days 1, 6, and 21.	Total n=30 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Age, Categorical Between 18 and 65 years	8 Participants n=5 Participants	8 Participants n=7 Participants	8 Participants n=5 Participants	6 Participants n=4 Participants	30 Participants n=21 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Age, Continuous	36.5 years STANDARD_DEVIATION 8.2 • n=5 Participants	27.6 years STANDARD_DEVIATION 7.8 • n=7 Participants	37.5 years STANDARD_DEVIATION 7.6 • n=5 Participants	34.8 years STANDARD_DEVIATION 8.9 • n=4 Participants	33.9 years STANDARD_DEVIATION 8.8 • n=21 Participants
Sex: Female, Male Female	3 Participants n=5 Participants	4 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants	10 Participants n=21 Participants
Sex: Female, Male Male	5 Participants n=5 Participants	4 Participants n=7 Participants	7 Participants n=5 Participants	4 Participants n=4 Participants	20 Participants n=21 Participants
Region of Enrollment United States	8 participants n=5 Participants	8 participants n=7 Participants	8 participants n=5 Participants	6 participants n=4 Participants	30 participants n=21 Participants

PRIMARY outcome

Timeframe: Days 1, 6, 14-16, 21-24, 28-31, and 51-53

Population: Post-screening, 30 healthy subjects were randomized into three active drug groups with 8 subjects each, and one placebo group with 6 subjects. A total of 7 withdrawals during the entire study were due to inability to follow procedure (4), lost to follow-up (1), requested due to concomitant medication (1), and an adverse event (1)

Evaluated safety parameters included: 1. physical examination/vital signs 2. electrocardiograms (heart rate, PR interval, QRS duration, QT interval, and QTc Bazett) 3. laboratory safety tests (hematology, chemistry, urinalysis) 4. adverse events (AEs) For a)-c), statistical values (mean, standard deviation, median, minimum, maximum) and changes from baseline (Day 1 pre-dose) to each time-point, were compared to laboratory normal reference ranges. If values for a)-d) were a Grade 3 or higher (in DAIDS AE Table)and ST-246-related, they were considered severe and significant, respectively.

Outcome measures

Outcome measures
Measure	ST-246 250 mg n=8 Participants 250 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	ST-246 400mg n=8 Participants 400 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	ST-246 800 mg n=8 Participants 800 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	Placebo n=6 Participants Placebo given as a single daily oral dose for 21 days to 6 subjects, to match ST-246 doses (2 patients for each dose equivalent).
Number of Study Participants Who Tolerated ST-246 (250, 400 or 800mg) as Determined by Changes in Safety Parameters, According to the Division of Acquired Immunodeficiency Syndrome (DAIDS) Adverse Events (AE) Grading Table	8 Participants	8 Participants	7 Participants	6 Participants

SECONDARY outcome

Timeframe: Day 1

Population: Post-screening, 30 healthy subjects were randomized on Day 1 into three active drug groups with 8 subjects each and one placebo group with 6 subjects

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

Outcome measures

Outcome measures
Measure	ST-246 250 mg n=8 Participants 250 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	ST-246 400mg n=8 Participants 400 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	ST-246 800 mg n=8 Participants 800 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	Placebo n=6 Participants Placebo given as a single daily oral dose for 21 days to 6 subjects, to match ST-246 doses (2 patients for each dose equivalent).
Evaluation of Pharmacokinetic Parameters to Assess Interventions: Cmax	985 ng/mL Standard Deviation 346	1392 ng/mL Standard Deviation 411	2279 ng/mL Standard Deviation 395	0 ng/mL Standard Deviation 0

SECONDARY outcome

Timeframe: Day 6

Population: Post-screening, 30 healthy subjects were randomized into three active drug groups with 8 subjects each and one placebo group with 6 subjects. By Day 6 there were 3 (out of 7 total) withdrawals from the study due to inability to follow procedure (2; 800mg and placebo groups), and requested due to concomitant medication (1; 400mg group)

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

Outcome measures

Outcome measures
Measure	ST-246 250 mg n=8 Participants 250 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	ST-246 400mg n=7 Participants 400 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	ST-246 800 mg n=7 Participants 800 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	Placebo n=5 Participants Placebo given as a single daily oral dose for 21 days to 6 subjects, to match ST-246 doses (2 patients for each dose equivalent).
Evaluation of Pharmacokinetic Parameters to Assess Interventions: Cmax	1212 ng/mL Standard Deviation 350	1298 ng/mL Standard Deviation 277	2337 ng/mL Standard Deviation 437	0 ng/mL Standard Deviation 0

SECONDARY outcome

Timeframe: Day 21

Population: Post-screening, 30 healthy subjects were randomized into three active drug groups with 8 subjects each and one placebo group with 6 subjects. Between Days 6 and 21, there were 4 (out of 7 total) withdrawals due to inability to follow procedure (2; 250mg and placebo groups), lost to follow-up (1; 400mg group), and adverse event (1; 800mg group)

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

Outcome measures

Outcome measures
Measure	ST-246 250 mg n=7 Participants 250 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	ST-246 400mg n=6 Participants 400 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	ST-246 800 mg n=6 Participants 800 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	Placebo n=4 Participants Placebo given as a single daily oral dose for 21 days to 6 subjects, to match ST-246 doses (2 patients for each dose equivalent).
Evaluation of Pharmacokinetic Parameters to Assess Interventions: Cmax	1101 ng/mL Standard Deviation 378	1457 ng/mL Standard Deviation 451	2437 ng/mL Standard Deviation 496	0 ng/mL Standard Deviation 0

SECONDARY outcome

Timeframe: Day 1

Population: Post-screening, 30 healthy subjects were randomized on Day 1 into three active drug groups with 8 subjects each and one placebo group with 6 subjects

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

Outcome measures

Outcome measures
Measure	ST-246 250 mg n=8 Participants 250 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	ST-246 400mg n=8 Participants 400 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	ST-246 800 mg n=8 Participants 800 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	Placebo n=6 Participants Placebo given as a single daily oral dose for 21 days to 6 subjects, to match ST-246 doses (2 patients for each dose equivalent).
Evaluation of Pharmacokinetic Parameters to Assess Interventions: Tmax	3.0 hours Standard Deviation 1.1	3.3 hours Standard Deviation 1.0	2.9 hours Standard Deviation 1.3	0 hours Standard Deviation 0

SECONDARY outcome

Timeframe: Day 6

Population: Post-screening, 30 healthy subjects were randomized into three active drug groups with 8 subjects each and one placebo group with 6 subjects. By Day 6 there were 3 (out of 7 total) withdrawals from the study due to inability to follow procedure (2; 800mg and placebo groups), and requested due to concomitant medication (1; 400mg group)

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

Outcome measures

Outcome measures
Measure	ST-246 250 mg n=8 Participants 250 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	ST-246 400mg n=7 Participants 400 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	ST-246 800 mg n=7 Participants 800 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	Placebo n=5 Participants Placebo given as a single daily oral dose for 21 days to 6 subjects, to match ST-246 doses (2 patients for each dose equivalent).
Evaluation of Pharmacokinetic Parameters to Assess Interventions: Tmax	2.6 hours Standard Deviation 1.2	3.7 hours Standard Deviation 2.1	3.6 hours Standard Deviation 2.3	0 hours Standard Deviation 0

SECONDARY outcome

Timeframe: Day 21

Population: Post-screening, 30 healthy subjects were randomized into three active drug groups with 8 subjects each and one placebo group with 6 subjects. Between Days 6 and 21, there were 4 (out of 7 total) withdrawals due to inability to follow procedure (2; 250mg and placebo groups), lost to follow-up (1; 400mg group), and adverse event (1; 800mg group)

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

Outcome measures

Outcome measures
Measure	ST-246 250 mg n=7 Participants 250 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	ST-246 400mg n=6 Participants 400 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	ST-246 800 mg n=6 Participants 800 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	Placebo n=4 Participants Placebo given as a single daily oral dose for 21 days to 6 subjects, to match ST-246 doses (2 patients for each dose equivalent).
Evaluation of Pharmacokinetic Parameters to Assess Interventions: Tmax	2.9 hours Standard Deviation 1.1	2.7 hours Standard Deviation 1.0	3.2 hours Standard Deviation 1.3	0 hours Standard Deviation 0

SECONDARY outcome

Timeframe: Day 21

Population: Post-screening, 30 healthy subjects were randomized into three active drug groups with 8 subjects each and one placebo group with 6 subjects. Between Days 6 and 21, there were 4 (out of 7 total) withdrawals due to inability to follow procedure (2; 250mg and placebo groups), lost to follow-up (1; 400mg group), and adverse event (1; 800mg group).

t½: Observed terminal elimination half-life determined after the last dose on Day 21

Outcome measures

Outcome measures
Measure	ST-246 250 mg n=7 Participants 250 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	ST-246 400mg n=6 Participants 400 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	ST-246 800 mg n=6 Participants 800 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	Placebo n=4 Participants Placebo given as a single daily oral dose for 21 days to 6 subjects, to match ST-246 doses (2 patients for each dose equivalent).
Evaluation of Pharmacokinetic Parameters to Assess Interventions: t½	18.8 hours Standard Deviation 10.4	19.9 hours Standard Deviation 8.9	20.7 hours Standard Deviation 8.4	0 hours Standard Deviation 0

SECONDARY outcome

Timeframe: Day 1

Population: Post-screening, 30 healthy subjects were randomized on Day 1 into three active drug groups with 8 subjects each and one placebo group with 6 subjects

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-246 250 mg n=8 Participants 250 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	ST-246 400mg n=8 Participants 400 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	ST-246 800 mg n=8 Participants 800 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	Placebo n=6 Participants Placebo given as a single daily oral dose for 21 days to 6 subjects, to match ST-246 doses (2 patients for each dose equivalent).
Evaluation of Pharmacokinetic Parameters to Assess Interventions: AUCtau	9101 ng*hr/mL Standard Deviation 3492	13146 ng*hr/mL Standard Deviation 3626	20959 ng*hr/mL Standard Deviation 6091	0 ng*hr/mL Standard Deviation 0

SECONDARY outcome

Timeframe: Day 6

Population: Post-screening, 30 healthy subjects were randomized into three active drug groups with 8 subjects each and one placebo group with 6 subjects. By Day 6 there were 3 (out of 7 total) withdrawals from the study due to inability to follow procedure (2; 800mg and placebo groups), and requested due to concomitant medication (1; 400mg group)

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-246 250 mg n=8 Participants 250 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	ST-246 400mg n=7 Participants 400 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	ST-246 800 mg n=7 Participants 800 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	Placebo n=5 Participants Placebo given as a single daily oral dose for 21 days to 6 subjects, to match ST-246 doses (2 patients for each dose equivalent).
Evaluation of Pharmacokinetic Parameters to Assess Interventions: AUCtau	11892 ng*hr/mL Standard Deviation 4389	15432 ng*hr/mL Standard Deviation 4708	23352 ng*hr/mL Standard Deviation 4696	0 ng*hr/mL Standard Deviation 0

SECONDARY outcome

Timeframe: Day 21

Population: Post-screening, 30 healthy subjects were randomized into three active drug groups with 8 subjects each and one placebo group with 6 subjects. Between Days 6 and 21, there were 4 (out of 7 total) withdrawals due to inability to follow procedure (2; 250mg and placebo groups), lost to follow-up (1; 400mg group), and adverse event (1; 800mg group).

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-246 250 mg n=7 Participants 250 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	ST-246 400mg n=6 Participants 400 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	ST-246 800 mg n=6 Participants 800 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	Placebo n=4 Participants Placebo given as a single daily oral dose for 21 days to 6 subjects, to match ST-246 doses (2 patients for each dose equivalent).
Evaluation of Pharmacokinetic Parameters to Assess Interventions: AUCtau	10083 ng*hr/mL Standard Deviation 2843	16182 ng*hr/mL Standard Deviation 5534	22684 ng*hr/mL Standard Deviation 4579	0 ng*hr/mL Standard Deviation 0

SECONDARY outcome

Timeframe: Day 1

Population: Post-screening, 30 healthy subjects were randomized on Day 1 into three active drug groups with 8 subjects each and one placebo group with 6 subjects

Ae(0-24): Cumulative amount of drug excreted unchanged in urine over 24 hours (three 8-hour collection periods), determined on Days 1 and 21

Outcome measures

Outcome measures
Measure	ST-246 250 mg n=8 Participants 250 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	ST-246 400mg n=8 Participants 400 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	ST-246 800 mg n=8 Participants 800 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	Placebo n=6 Participants Placebo given as a single daily oral dose for 21 days to 6 subjects, to match ST-246 doses (2 patients for each dose equivalent).
Evaluation of Pharmacokinetic Parameters to Assess Interventions: Ae(0-24)	0.041 mg Standard Deviation 0.031	0.110 mg Standard Deviation 0.066	0.157 mg Standard Deviation 0.048	0 mg Standard Deviation 0

SECONDARY outcome

Timeframe: Day 21

Population: Post-screening, 30 healthy subjects were randomized into three active drug groups with 8 subjects each and one placebo group with 6 subjects. Between Days 6 and 21, there were 4 (out of 7 total) withdrawals due to inability to follow procedure (2; 250mg and placebo groups), lost to follow-up (1; 400mg group), and adverse event (1; 800mg group).

Ae(0-24): Cumulative amount of drug excreted unchanged in urine over 24 hours (three 8-hour collection periods), determined on Days 1 and 21

Outcome measures

Outcome measures
Measure	ST-246 250 mg n=7 Participants 250 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	ST-246 400mg n=6 Participants 400 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	ST-246 800 mg n=6 Participants 800 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	Placebo n=4 Participants Placebo given as a single daily oral dose for 21 days to 6 subjects, to match ST-246 doses (2 patients for each dose equivalent).
Evaluation of Pharmacokinetic Parameters to Assess Interventions: Ae(0-24)	0.049 mg Standard Deviation 0.026	0.108 mg Standard Deviation 0.046	0.213 mg Standard Deviation 0.165	0 mg Standard Deviation 0

Adverse Events

ST-246 250 mg

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

ST-246 400mg

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

ST-246 800 mg

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 4 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-246 250 mg n=8 participants at risk 250 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days.	ST-246 400mg n=8 participants at risk 400 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days. Blood and urine samples for PK taken on Days 1, 6, and 21.	ST-246 800 mg n=8 participants at risk 800 mg ST-246 given as a single daily oral dose to 8 subjects for 21 days. Blood and urine samples for PK taken on Days 1, 6, and 21.	Placebo n=6 participants at risk Placebo given as a single daily oral dose for 21 days to 6 subjects, to match ST-246 doses (2 patients for each dose equivalent). Blood and urine samples for PK taken on Days 1, 6, and 21.
Eye disorders Abnormal Eye Sensation	0.00% 0/8 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	0.00% 0/8 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	12.5% 1/8 • Number of events 1 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	0.00% 0/6 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.
Musculoskeletal and connective tissue disorders Backpain	12.5% 1/8 • Number of events 1 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	0.00% 0/8 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	0.00% 0/8 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	0.00% 0/6 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.
Gastrointestinal disorders Dry mouth	12.5% 1/8 • Number of events 1 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	0.00% 0/8 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	12.5% 1/8 • Number of events 1 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	0.00% 0/6 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.
Skin and subcutaneous tissue disorders Ecchymosis	0.00% 0/8 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	12.5% 1/8 • Number of events 1 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	0.00% 0/8 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	0.00% 0/6 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.
General disorders Fatigue	12.5% 1/8 • Number of events 1 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	0.00% 0/8 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	0.00% 0/8 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	0.00% 0/6 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.
Gastrointestinal disorders Flatulence	0.00% 0/8 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	0.00% 0/8 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	25.0% 2/8 • Number of events 2 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	0.00% 0/6 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.
Injury, poisoning and procedural complications Hand Fracture	12.5% 1/8 • Number of events 1 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	0.00% 0/8 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	0.00% 0/8 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	0.00% 0/6 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.
Nervous system disorders Headache	62.5% 5/8 • Number of events 5 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	25.0% 2/8 • Number of events 2 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	50.0% 4/8 • Number of events 4 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	33.3% 2/6 • Number of events 2 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.
Respiratory, thoracic and mediastinal disorders Nasal congestion	0.00% 0/8 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	0.00% 0/8 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	0.00% 0/8 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	16.7% 1/6 • Number of events 1 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.
Gastrointestinal disorders Nausea	12.5% 1/8 • Number of events 1 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	12.5% 1/8 • Number of events 1 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	12.5% 1/8 • Number of events 1 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	0.00% 0/6 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.
Respiratory, thoracic and mediastinal disorders Pharyngolaryngeal Pain	0.00% 0/8 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	0.00% 0/8 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	0.00% 0/8 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	16.7% 1/6 • Number of events 1 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.
Injury, poisoning and procedural complications Procedural Complication	0.00% 0/8 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	12.5% 1/8 • Number of events 1 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	0.00% 0/8 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	0.00% 0/6 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.
Nervous system disorders Somnolence	0.00% 0/8 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	0.00% 0/8 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	12.5% 1/8 • Number of events 1 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	0.00% 0/6 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.
Skin and subcutaneous tissue disorders Urticaria	0.00% 0/8 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	0.00% 0/8 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	0.00% 0/8 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	16.7% 1/6 • Number of events 1 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.
Gastrointestinal disorders Vomiting	12.5% 1/8 • Number of events 1 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	12.5% 1/8 • Number of events 1 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	0.00% 0/8 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.	0.00% 0/6 • 7 weeks Study drug was administered to each dosing group cohort for 21 days and subjects were followed for an additional 30 to 32 days. AEs were recorded throughout this time period.