Trial Outcomes & Findings for Absolute BA and OZ439 PK Effect of Different OZ439 Dose Volumes and Cobicistat Co-administration Study (NCT NCT04069221)

NCT ID: NCT04069221

Last Updated: 2019-11-26

Results Overview

OZ439 Absolute oral bioavailability

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

26 participants

Primary outcome timeframe

OZ439: Pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96, 168 hours post-dose. [14C]-OZ439: 10, 15, 20, 30 and 45 minutes after start of iv infusion then 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96, 168 hours

Results posted on

2019-11-26

Participant Flow

Screened volunteers: 48 Screening failures: ECG: 7 Clinical laboratory: 3 Medical history: 2 Vital signs: 1 Physical examination: 1 Other: 1 Approved but not dosed Reserve: 5 Not in clinic/Personal: 2

Participant milestones

Participant milestones
Measure	Part 1 open-label study in 8 healthy subjects to determine the absolute bioavailability of OZ439 following a single oral dose of OZ439 and co-administration of a single iv infusion of a \[14C\] OZ439 radiolabeled microdose	Part 2 Treatment B, Then C and D open-label, randomized, single-dose, 3-way cross-over study in 18 healthy subjects. Each subject participated in 3 treatment periods and each subject received a single dose of each of the following 3 treatments in a randomized order with a 14-day wash-out period between each treatment * Treatment B: a single oral dose of 800 mg OZ439 simple granules administered as a 64.5-mL dispersion * Treatment C: a single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion * Treatment D: a single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion and co-administered with a 150 mg cobicistat tablet (CYP3A4 inhibitor)	Part 2 Treatment C, Then D and B open-label, randomized, single-dose, 3-way cross-over study in 18 healthy subjects. Each subject participated in 3 treatment periods and each subject received a single dose of each of the following 3 treatments in a randomized order with a 14-day wash-out period between each treatment * Treatment C: a single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion * Treatment D: a single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion and co-administered with a 150 mg cobicistat tablet (CYP3A4 inhibitor) * Treatment B: a single oral dose of 800 mg OZ439 simple granules administered as a 64.5-mL dispersion	Part 2 Treatment D, Then B and C open-label, randomized, single-dose, 3-way cross-over study in 18 healthy subjects. Each subject participated in 3 treatment periods and each subject received a single dose of each of the following 3 treatments in a randomized order with a 14-day wash-out period between each treatment * Treatment D: a single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion and co-administered with a 150 mg cobicistat tablet (CYP3A4 inhibitor) * Treatment B: a single oral dose of 800 mg OZ439 simple granules administered as a 64.5-mL dispersion * Treatment C: a single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion
Overall Study STARTED	8	6	6	6
Overall Study COMPLETED	8	6	6	6
Overall Study NOT COMPLETED	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Absolute BA and OZ439 PK Effect of Different OZ439 Dose Volumes and Cobicistat Co-administration Study

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Part 1 n=8 Participants open-label study in 8 healthy subjects to determine the absolute bioavailability of OZ439 following a single oral dose of OZ439 and co-administration of a single iv infusion of a \[14C\] OZ439 radiolabeled microdose	Part 2 n=18 Participants open-label, randomized, single-dose, 3-way cross-over study in 18 healthy subjects. Each subject participated in 3 treatment periods and each subject received a single dose of each of the following 3 treatments in a randomized order with a 14-day wash-out period between each treatment	Total n=26 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
Age, Categorical Between 18 and 65 years	8 Participants n=5 Participants	18 Participants n=7 Participants	26 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Sex: Female, Male Male	8 Participants n=5 Participants	18 Participants n=7 Participants	26 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race/Ethnicity, Customized Asian	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Black	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized White	5 Participants n=5 Participants	15 Participants n=7 Participants	20 Participants n=5 Participants
Race/Ethnicity, Customized Hispano or Latino	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants

PRIMARY outcome

Timeframe: OZ439: Pre-dose, 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96, 168 hours post-dose. [14C]-OZ439: 10, 15, 20, 30 and 45 minutes after start of iv infusion then 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96, 168 hours

OZ439 Absolute oral bioavailability

Outcome measures

Outcome measures
Measure	Part 1 n=8 Participants open-label study in 8 healthy subjects to determine the absolute bioavailability of OZ439 following a single oral dose of OZ439 and co-administration of a single iv infusion of a \[14C\] OZ439 radiolabeled microdose at the anticipated tmax of the oral dose. Treatment A: a single oral dose of 800 mg OZ439 simple granules administered as a 100-mL dispersion followed by a 15-minute 10-mL iv infusion of 100 μg \[14C\] OZ439 (47 kBq \[1.27 µCi\]) beginning 3 hours after the oral dose administration.	Part 2, Treatment C: Single Oral Dose of 400 mg OZ439 This was an open-label, randomized, single-dose, 3-way cross-over study in 18 healthy subjects. Each subject participated in 3 treatment periods and each subject received a single dose of each of the following 3 treatments in a randomized order with a 14-day wash-out period between each treatment: Treatment B: A single oral dose of 800 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment C: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment D: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion and co-administered with a 150 mg cobicistat tablet (CYP3A4 inhibitor) Single oral dose of 400 mg OZ439: Single oral dose of 400 mg OZ439	Part 2, Treatment D:Single Oral Dose 400 mg OZ439+Cobicistat This was an open-label, randomized, single-dose, 3-way cross-over study in 18 healthy subjects. Each subject participated in 3 treatment periods and each subject received a single dose of each of the following 3 treatments in a randomized order with a 14-day wash-out period between each treatment: Treatment B: A single oral dose of 800 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment C: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment D: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion and co-administered with a 150 mg cobicistat tablet (CYP3A4 inhibitor) Single oral dose of 400 mg OZ439: Single oral dose of 400 mg OZ439 Single oral dose of cobicistat: Single oral dose of 150 mg cobicistat
OZ439 Fpo	35 Absolute bioavailability in % Interval 29.0 to 41.0	—	—

PRIMARY outcome

Timeframe: Pre-dose, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96, 168, 216, 264, 312 hours post-dose

OZ439 maximum concentration observed

Outcome measures

Outcome measures
Measure	Part 1 n=18 Participants open-label study in 8 healthy subjects to determine the absolute bioavailability of OZ439 following a single oral dose of OZ439 and co-administration of a single iv infusion of a \[14C\] OZ439 radiolabeled microdose at the anticipated tmax of the oral dose. Treatment A: a single oral dose of 800 mg OZ439 simple granules administered as a 100-mL dispersion followed by a 15-minute 10-mL iv infusion of 100 μg \[14C\] OZ439 (47 kBq \[1.27 µCi\]) beginning 3 hours after the oral dose administration.	Part 2, Treatment C: Single Oral Dose of 400 mg OZ439 n=18 Participants This was an open-label, randomized, single-dose, 3-way cross-over study in 18 healthy subjects. Each subject participated in 3 treatment periods and each subject received a single dose of each of the following 3 treatments in a randomized order with a 14-day wash-out period between each treatment: Treatment B: A single oral dose of 800 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment C: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment D: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion and co-administered with a 150 mg cobicistat tablet (CYP3A4 inhibitor) Single oral dose of 400 mg OZ439: Single oral dose of 400 mg OZ439	Part 2, Treatment D:Single Oral Dose 400 mg OZ439+Cobicistat n=18 Participants This was an open-label, randomized, single-dose, 3-way cross-over study in 18 healthy subjects. Each subject participated in 3 treatment periods and each subject received a single dose of each of the following 3 treatments in a randomized order with a 14-day wash-out period between each treatment: Treatment B: A single oral dose of 800 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment C: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment D: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion and co-administered with a 150 mg cobicistat tablet (CYP3A4 inhibitor) Single oral dose of 400 mg OZ439: Single oral dose of 400 mg OZ439 Single oral dose of cobicistat: Single oral dose of 150 mg cobicistat
OZ439 Cmax	949 ng/mL Geometric Coefficient of Variation 36.1	649 ng/mL Geometric Coefficient of Variation 40.7	966 ng/mL Geometric Coefficient of Variation 18.3

PRIMARY outcome

Timeframe: 168 hours post-dose

OZ439 concentration observed at 168h

Outcome measures

Outcome measures
Measure	Part 1 n=18 Participants open-label study in 8 healthy subjects to determine the absolute bioavailability of OZ439 following a single oral dose of OZ439 and co-administration of a single iv infusion of a \[14C\] OZ439 radiolabeled microdose at the anticipated tmax of the oral dose. Treatment A: a single oral dose of 800 mg OZ439 simple granules administered as a 100-mL dispersion followed by a 15-minute 10-mL iv infusion of 100 μg \[14C\] OZ439 (47 kBq \[1.27 µCi\]) beginning 3 hours after the oral dose administration.	Part 2, Treatment C: Single Oral Dose of 400 mg OZ439 n=18 Participants This was an open-label, randomized, single-dose, 3-way cross-over study in 18 healthy subjects. Each subject participated in 3 treatment periods and each subject received a single dose of each of the following 3 treatments in a randomized order with a 14-day wash-out period between each treatment: Treatment B: A single oral dose of 800 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment C: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment D: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion and co-administered with a 150 mg cobicistat tablet (CYP3A4 inhibitor) Single oral dose of 400 mg OZ439: Single oral dose of 400 mg OZ439	Part 2, Treatment D:Single Oral Dose 400 mg OZ439+Cobicistat n=18 Participants This was an open-label, randomized, single-dose, 3-way cross-over study in 18 healthy subjects. Each subject participated in 3 treatment periods and each subject received a single dose of each of the following 3 treatments in a randomized order with a 14-day wash-out period between each treatment: Treatment B: A single oral dose of 800 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment C: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment D: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion and co-administered with a 150 mg cobicistat tablet (CYP3A4 inhibitor) Single oral dose of 400 mg OZ439: Single oral dose of 400 mg OZ439 Single oral dose of cobicistat: Single oral dose of 150 mg cobicistat
OZ439 C168h	3.54 ng/mL Geometric Coefficient of Variation 65.3	2.48 ng/mL Geometric Coefficient of Variation 83.1	6.07 ng/mL Geometric Coefficient of Variation 46.6

PRIMARY outcome

Timeframe: Pre-dose, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96, 168 hours post-dose

Area under the OZ439 plasma concentration time curve from time zero to 168h

Outcome measures

Outcome measures
Measure	Part 1 n=18 Participants open-label study in 8 healthy subjects to determine the absolute bioavailability of OZ439 following a single oral dose of OZ439 and co-administration of a single iv infusion of a \[14C\] OZ439 radiolabeled microdose at the anticipated tmax of the oral dose. Treatment A: a single oral dose of 800 mg OZ439 simple granules administered as a 100-mL dispersion followed by a 15-minute 10-mL iv infusion of 100 μg \[14C\] OZ439 (47 kBq \[1.27 µCi\]) beginning 3 hours after the oral dose administration.	Part 2, Treatment C: Single Oral Dose of 400 mg OZ439 n=18 Participants This was an open-label, randomized, single-dose, 3-way cross-over study in 18 healthy subjects. Each subject participated in 3 treatment periods and each subject received a single dose of each of the following 3 treatments in a randomized order with a 14-day wash-out period between each treatment: Treatment B: A single oral dose of 800 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment C: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment D: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion and co-administered with a 150 mg cobicistat tablet (CYP3A4 inhibitor) Single oral dose of 400 mg OZ439: Single oral dose of 400 mg OZ439	Part 2, Treatment D:Single Oral Dose 400 mg OZ439+Cobicistat n=18 Participants This was an open-label, randomized, single-dose, 3-way cross-over study in 18 healthy subjects. Each subject participated in 3 treatment periods and each subject received a single dose of each of the following 3 treatments in a randomized order with a 14-day wash-out period between each treatment: Treatment B: A single oral dose of 800 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment C: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment D: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion and co-administered with a 150 mg cobicistat tablet (CYP3A4 inhibitor) Single oral dose of 400 mg OZ439: Single oral dose of 400 mg OZ439 Single oral dose of cobicistat: Single oral dose of 150 mg cobicistat
OZ439 AUC0-168h	9857 ng.h/mL Geometric Coefficient of Variation 37.3	6049 ng.h/mL Geometric Coefficient of Variation 51.5	13949 ng.h/mL Geometric Coefficient of Variation 25.6

PRIMARY outcome

Timeframe: Pre-dose, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 48, 72, 96, 168, 216, 264, 312 hours post-dose

Area under the OZ439 plasma concentration time curve from time zero to infinity

Outcome measures

Outcome measures
Measure	Part 1 n=18 Participants open-label study in 8 healthy subjects to determine the absolute bioavailability of OZ439 following a single oral dose of OZ439 and co-administration of a single iv infusion of a \[14C\] OZ439 radiolabeled microdose at the anticipated tmax of the oral dose. Treatment A: a single oral dose of 800 mg OZ439 simple granules administered as a 100-mL dispersion followed by a 15-minute 10-mL iv infusion of 100 μg \[14C\] OZ439 (47 kBq \[1.27 µCi\]) beginning 3 hours after the oral dose administration.	Part 2, Treatment C: Single Oral Dose of 400 mg OZ439 n=18 Participants This was an open-label, randomized, single-dose, 3-way cross-over study in 18 healthy subjects. Each subject participated in 3 treatment periods and each subject received a single dose of each of the following 3 treatments in a randomized order with a 14-day wash-out period between each treatment: Treatment B: A single oral dose of 800 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment C: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment D: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion and co-administered with a 150 mg cobicistat tablet (CYP3A4 inhibitor) Single oral dose of 400 mg OZ439: Single oral dose of 400 mg OZ439	Part 2, Treatment D:Single Oral Dose 400 mg OZ439+Cobicistat n=18 Participants This was an open-label, randomized, single-dose, 3-way cross-over study in 18 healthy subjects. Each subject participated in 3 treatment periods and each subject received a single dose of each of the following 3 treatments in a randomized order with a 14-day wash-out period between each treatment: Treatment B: A single oral dose of 800 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment C: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment D: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion and co-administered with a 150 mg cobicistat tablet (CYP3A4 inhibitor) Single oral dose of 400 mg OZ439: Single oral dose of 400 mg OZ439 Single oral dose of cobicistat: Single oral dose of 150 mg cobicistat
OZ439 AUC0-inf	10222 ng.h/mL Geometric Coefficient of Variation 37.4	6378 ng.h/mL Geometric Coefficient of Variation 52.3	14984 ng.h/mL Geometric Coefficient of Variation 25.7

Adverse Events

Part 1, Single Arm

Serious events: 0 serious events

Other events: 1 other events

Deaths: 0 deaths

Part 2, Treatment B: Single Oral Dose of 800 mg OZ439

Serious events: 0 serious events

Other events: 10 other events

Deaths: 0 deaths

Part 2, Treatment C: Single Oral Dose of 400 mg OZ439

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Part 2, Treatment D:Single Oral Dose 400 mg OZ439+Cobicistat

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Dr Myriam El Gaaloul, PharmD

Medicines for Malaria Venture

Phone: +41 22 555 0377

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee PRA shall have the right to publish the results of the research, subject to the sponsor's prior written consent, which shall not be unreasonably withheld or delayed. Following the receipt of such consent, PRA shall submit a copy of the proposed publication to the sponsor who shall have 30 days in which to request amendments thereto which, to the extent that such proposed amendments are reasonable, PRA shall be obliged to incorporate prior to such publication.
Publication restrictions are in place

Restriction type: OTHER

Other adverse events
Measure	Part 1, Single Arm n=8 participants at risk This was an open-label study in 8 healthy subjects to determine the absolute bioavailability of OZ439 following a single oral dose of OZ439 and co-administration of a single iv infusion of a \[14C\]-OZ439 radiolabeled microdose at the anticipated Tmax of the oral dose. Subjects received the following treatment: Treatment A: A single oral dose of 800 mg OZ439 simple granules administered as a 100-mL dispersion followed by a 15-minute 10-mL iv infusion of 100 μg \[14C\]-OZ439 (47 kBq \[1.27 μCi\]) beginning 3 hours after the oral dose administration. Single oral dose of 800 mg OZ439: Single oral dose of 800 mg OZ439 iv infusion of \[14C\]-OZ439: 15-minute 10-mL iv infusion of 100 μg \[14C\]-OZ439	Part 2, Treatment B: Single Oral Dose of 800 mg OZ439 n=18 participants at risk This was an open-label, randomized, single-dose, 3-way cross-over study in 18 healthy subjects. Each subject participated in 3 treatment periods and each subject received a single dose of each of the following 3 treatments in a randomized order with a 14-day wash-out period between each treatment: Treatment B: A single oral dose of 800 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment C: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment D: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion and co-administered with a 150 mg cobicistat tablet (CYP3A4 inhibitor)	Part 2, Treatment C: Single Oral Dose of 400 mg OZ439 n=18 participants at risk This was an open-label, randomized, single-dose, 3-way cross-over study in 18 healthy subjects. Each subject participated in 3 treatment periods and each subject received a single dose of each of the following 3 treatments in a randomized order with a 14-day wash-out period between each treatment: Treatment B: A single oral dose of 800 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment C: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment D: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion and co-administered with a 150 mg cobicistat tablet (CYP3A4 inhibitor)	Part 2, Treatment D:Single Oral Dose 400 mg OZ439+Cobicistat n=18 participants at risk This was an open-label, randomized, single-dose, 3-way cross-over study in 18 healthy subjects. Each subject participated in 3 treatment periods and each subject received a single dose of each of the following 3 treatments in a randomized order with a 14-day wash-out period between each treatment: Treatment B: A single oral dose of 800 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment C: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion Treatment D: A single oral dose of 400 mg OZ439 simple granules administered as a 64.5-mL dispersion and co-administered with a 150 mg cobicistat tablet (CYP3A4 inhibitor)
General disorders Injection Site Irritation	0.00% 0/8 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	11.1% 2/18 • Number of events 2 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	5.6% 1/18 • Number of events 1 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	5.6% 1/18 • Number of events 1 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.
General disorders Feeling Cold	0.00% 0/8 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	5.6% 1/18 • Number of events 1 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	0.00% 0/18 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	0.00% 0/18 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.
General disorders Influenza Like Illness	0.00% 0/8 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	5.6% 1/18 • Number of events 1 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	0.00% 0/18 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	0.00% 0/18 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.
General disorders Injection Site Haematoma	0.00% 0/8 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	5.6% 1/18 • Number of events 1 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	0.00% 0/18 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	0.00% 0/18 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.
Nervous system disorders Headache	12.5% 1/8 • Number of events 1 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	5.6% 1/18 • Number of events 1 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	11.1% 2/18 • Number of events 2 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	5.6% 1/18 • Number of events 1 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.
Gastrointestinal disorders Diarrhea	12.5% 1/8 • Number of events 1 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	5.6% 1/18 • Number of events 1 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	0.00% 0/18 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	0.00% 0/18 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.
Gastrointestinal disorders Abdominal Pain	12.5% 1/8 • Number of events 1 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	0.00% 0/18 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	0.00% 0/18 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	0.00% 0/18 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.
Gastrointestinal disorders Nausea	0.00% 0/8 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	0.00% 0/18 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	0.00% 0/18 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	5.6% 1/18 • Number of events 1 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.
Gastrointestinal disorders Oropharyngeal Pain	0.00% 0/8 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	11.1% 2/18 • Number of events 2 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	0.00% 0/18 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	0.00% 0/18 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.
Gastrointestinal disorders Dysphonia	0.00% 0/8 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	0.00% 0/18 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	0.00% 0/18 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	5.6% 1/18 • Number of events 1 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.
Infections and infestations Conjunctivitis	0.00% 0/8 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	0.00% 0/18 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	5.6% 1/18 • Number of events 1 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	0.00% 0/18 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.
Infections and infestations Viral Upper Respiratory Tract Infection	0.00% 0/8 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	0.00% 0/18 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	5.6% 1/18 • Number of events 1 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	0.00% 0/18 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.
Musculoskeletal and connective tissue disorders Myalgia	0.00% 0/8 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	11.1% 2/18 • Number of events 2 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	0.00% 0/18 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	0.00% 0/18 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.
Skin and subcutaneous tissue disorders Skin Irritation	0.00% 0/8 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	5.6% 1/18 • Number of events 1 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	5.6% 1/18 • Number of events 1 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	0.00% 0/18 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.
Eye disorders Eye Irritation	0.00% 0/8 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	0.00% 0/18 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	0.00% 0/18 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	5.6% 1/18 • Number of events 1 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.
Hepatobiliary disorders Hyperbilirubinaemia	0.00% 0/8 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	5.6% 1/18 • Number of events 1 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	0.00% 0/18 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	0.00% 0/18 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.
Injury, poisoning and procedural complications Post-Traumatic Pain	0.00% 0/8 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	5.6% 1/18 • Number of events 1 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	0.00% 0/18 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	0.00% 0/18 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.
Psychiatric disorders Insomnia	0.00% 0/8 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	0.00% 0/18 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	5.6% 1/18 • Number of events 1 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.	0.00% 0/18 • Day -28 (screening) to Day 15 (follow-up) 13 subjects (50%) reported a total of 29 TEAEs. In addition, a total of 3 AEs that had started prior to dosing were reported. These AEs did not preclude randomization and dosing of the subjects. There were no deaths or SAEs reported during the study. All TEAEs were transient and resolved without sequelae. One TEAE was still ongoing at the time of follow-up. None of the subjects were discontinued during the study due to TEAEs.