Trial Outcomes & Findings for Study to Evaluate the Efficacy, Safety, and Tolerability of BOS-589 in the Treatment of Patients With Diarrhea-predominant Irritable Bowel Syndrome (IBS-D) (NCT NCT03977155)

Last Updated: 2021-06-07

Results Overview

To evaluate in participants with diarrhea-predominant irritable bowel syndrome (IBS-D) the abdominal pain response to BOS-589 after 4 weeks of treatment, relative to placebo. Throughout the 4 weeks of the double blind treatment phase, participants were asked to rate their WAP in the past 24 hours. The participant-reported WAP in the past 24 hours was recorded on a 0 to 10 scale, where 0 corresponded to no pain and 10 corresponded to worst imaginable pain. Higher scores indicated worse outcome.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

133 participants

Primary outcome timeframe

Baseline; Day 29

Results posted on

2021-06-07

Participant Flow

This study was conducted at 47 study centers in the United States.

During the pretreatment phase, participants were evaluated for up to 5 weeks to assess eligibility. The pretreatment phase consisted of initial screening assessments and a run in period.

Participant milestones

Participant milestones
Measure	High Dose of BOS-589 Randomized participants received a high dose of BOS-589 tablets orally twice a day (BID).	Low Dose of BOS-589 Randomized participants received a low dose of BOS-589 tablets orally BID.	Placebo Randomized participants received matching placebo tablets orally BID.
Overall Study STARTED	43	48	42
Overall Study COMPLETED	38	46	40
Overall Study NOT COMPLETED	5	2	2

Reasons for withdrawal

Reasons for withdrawal
Measure	High Dose of BOS-589 Randomized participants received a high dose of BOS-589 tablets orally twice a day (BID).	Low Dose of BOS-589 Randomized participants received a low dose of BOS-589 tablets orally BID.	Placebo Randomized participants received matching placebo tablets orally BID.
Overall Study Adverse Event	3	0	0
Overall Study Lost to Follow-up	0	1	0
Overall Study Withdrawal by Subject	1	1	2
Overall Study Participant was unable to come in for the Visit	1	0	0

Baseline Characteristics

Study to Evaluate the Efficacy, Safety, and Tolerability of BOS-589 in the Treatment of Patients With Diarrhea-predominant Irritable Bowel Syndrome (IBS-D)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	High Dose of BOS-589 n=43 Participants Randomized participants received a high dose of BOS-589 tablets orally BID.	Low Dose of BOS-589 n=48 Participants Randomized participants received a low dose of BOS-589 tablets orally BID.	Placebo n=42 Participants Randomized participants received matching placebo tablets orally BID.	Total n=133 Participants Total of all reporting groups
Age, Continuous	41.0 Years STANDARD_DEVIATION 13.15 • n=5 Participants	39.9 Years STANDARD_DEVIATION 13.26 • n=7 Participants	40.0 Years STANDARD_DEVIATION 12.84 • n=5 Participants	40.3 Years STANDARD_DEVIATION 13.00 • n=4 Participants
Sex: Female, Male Female	30 Participants n=5 Participants	31 Participants n=7 Participants	26 Participants n=5 Participants	87 Participants n=4 Participants
Sex: Female, Male Male	13 Participants n=5 Participants	17 Participants n=7 Participants	16 Participants n=5 Participants	46 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	6 Participants n=5 Participants	7 Participants n=7 Participants	7 Participants n=5 Participants	20 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	37 Participants n=5 Participants	41 Participants n=7 Participants	35 Participants n=5 Participants	113 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race (NIH/OMB) Asian	3 Participants n=5 Participants	7 Participants n=7 Participants	6 Participants n=5 Participants	16 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race (NIH/OMB) Black or African American	2 Participants n=5 Participants	8 Participants n=7 Participants	2 Participants n=5 Participants	12 Participants n=4 Participants
Race (NIH/OMB) White	36 Participants n=5 Participants	33 Participants n=7 Participants	34 Participants n=5 Participants	103 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline; Day 29

Population: The Intent to Treat (ITT) Analysis Set included all randomized participants. Here, overall number of participants analyzed signifies only the participants with available data that were analyzed for the outcome measure.

Outcome measures

Outcome measures
Measure	High Dose of BOS-589 n=39 Participants Randomized participants received a high dose of BOS-589 tablets orally BID.	Low Dose of BOS-589 n=46 Participants Randomized participants received a low dose of BOS-589 tablets orally BID.	BOS-589: Active Treatment n=85 Participants High Dose of BOS-589: Randomized participants received a high dose of BOS-589 tablets orally BID. Low Dose of BOS-589: Randomized participants received a low dose of BOS-589 tablets orally BID. Data were pooled from the above mentioned doses for analysis.	Placebo n=40 Participants Randomized participants received matching placebo tablets orally BID.
24-hour Worst Abdominal Pain Scores (WAP) at Day 29 Compared to Baseline (Averaged Over the Week Prior to Each Respective Time Point)	-1.64 Score on a scale Standard Deviation 1.684	-2.30 Score on a scale Standard Deviation 1.933	-2.00 Score on a scale Standard Deviation 1.842	-1.69 Score on a scale Standard Deviation 1.783

PRIMARY outcome

Timeframe: Up to Day 43/end-of-study follow up visit

Population: The Safety Analysis Set included all participants who received at least 1 dose of study drug.

To evaluate the overall safety and tolerability of BOS-589 in the treatment of IBS-D during 4 weeks of treatment, relative to placebo.

Outcome measures

Outcome measures
Measure	High Dose of BOS-589 n=43 Participants Randomized participants received a high dose of BOS-589 tablets orally BID.	Low Dose of BOS-589 n=48 Participants Randomized participants received a low dose of BOS-589 tablets orally BID.	BOS-589: Active Treatment n=42 Participants High Dose of BOS-589: Randomized participants received a high dose of BOS-589 tablets orally BID. Low Dose of BOS-589: Randomized participants received a low dose of BOS-589 tablets orally BID. Data were pooled from the above mentioned doses for analysis.	Placebo Randomized participants received matching placebo tablets orally BID.
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Because of AEs, and Any Treatment-related Severe AEs Any Treatment-emergent adverse event (TEAE)	23 Participants	23 Participants	15 Participants	—
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Because of AEs, and Any Treatment-related Severe AEs Any TEAE Related to Study Drug	8 Participants	5 Participants	4 Participants	—
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Because of AEs, and Any Treatment-related Severe AEs Any Moderate or Severe TEAE	10 Participants	10 Participants	6 Participants	—
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Because of AEs, and Any Treatment-related Severe AEs Any Moderate or Severe TEAE Related to Study Drug	3 Participants	3 Participants	1 Participants	—
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Because of AEs, and Any Treatment-related Severe AEs Any Treatment-Emergent SAE	0 Participants	0 Participants	0 Participants	—
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Because of AEs, and Any Treatment-related Severe AEs Any Treatment-Emergent SAE Related to Study Drug	0 Participants	0 Participants	0 Participants	—
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Because of AEs, and Any Treatment-related Severe AEs Any TEAE Causing Discontinuation of Study Drug	3 Participants	0 Participants	0 Participants	—
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Because of AEs, and Any Treatment-related Severe AEs Any TEAE Leading to Withdrawal from the Study	3 Participants	0 Participants	0 Participants	—
Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Discontinuations Because of AEs, and Any Treatment-related Severe AEs Any TEAE with Outcome of Death	0 Participants	0 Participants	0 Participants	—

SECONDARY outcome

Timeframe: Baseline; Day 29

Population: The ITT Analysis Set included all randomized participants. Here, overall number of participants analyzed signifies only the participants with available data that were analyzed for the outcome measure.

To evaluate the treatment effect of BOS-589 on defecation after 4 weeks, relative to placebo. Participants were asked to record daily stool consistency according to the BSFS most representative of the past 24 hours. The participant-reported BSFS consistency score was based on a 1 to 7 scale where 1 corresponded to a hard stool and 7 corresponded to watery diarrhea. Higher scores indicated worse outcome.

Outcome measures

Outcome measures
Measure	High Dose of BOS-589 n=39 Participants Randomized participants received a high dose of BOS-589 tablets orally BID.	Low Dose of BOS-589 n=45 Participants Randomized participants received a low dose of BOS-589 tablets orally BID.	BOS-589: Active Treatment n=84 Participants High Dose of BOS-589: Randomized participants received a high dose of BOS-589 tablets orally BID. Low Dose of BOS-589: Randomized participants received a low dose of BOS-589 tablets orally BID. Data were pooled from the above mentioned doses for analysis.	Placebo n=40 Participants Randomized participants received matching placebo tablets orally BID.
Change in Stool Consistency, Measured by the Daily Bristol Stool Form Score (BSFS) Most Representative Stool Consistency Scores at Day 29 Compared to Baseline (Averaged Over the Week Prior to Each Respective Time Point)	-1.11 Score on a scale Standard Deviation 1.179	-0.97 Score on a scale Standard Deviation 1.087	-1.04 Score on a scale Standard Deviation 1.125	-1.01 Score on a scale Standard Deviation 1.034

SECONDARY outcome

Timeframe: Baseline; Day 29

To evaluate the treatment effect of BOS-589 on defecation after 4 weeks, relative to placebo. Participants were asked to record daily stool consistency according to the BSFS worst stool consistency (defined as the loosest stool with the highest BSFS score) in the past 24 hours. The participant-reported BSFS consistency score was based on a 1 to 7 scale where 1 corresponded to a hard stool and 7 corresponded to watery diarrhea. Higher scores indicated worse outcome.

Outcome measures

Outcome measures
Measure	High Dose of BOS-589 n=37 Participants Randomized participants received a high dose of BOS-589 tablets orally BID.	Low Dose of BOS-589 n=40 Participants Randomized participants received a low dose of BOS-589 tablets orally BID.	BOS-589: Active Treatment n=77 Participants High Dose of BOS-589: Randomized participants received a high dose of BOS-589 tablets orally BID. Low Dose of BOS-589: Randomized participants received a low dose of BOS-589 tablets orally BID. Data were pooled from the above mentioned doses for analysis.	Placebo n=32 Participants Randomized participants received matching placebo tablets orally BID.
Change in Stool Consistency, Measured by the Daily BSFS Worst (Loosest) Stool Consistency Scores at Day 29 Compared to Baseline (Averaged Over the Week Prior to Each Respective Time Point)	-1.13 Score on a scale Standard Deviation 1.167	-1.06 Score on a scale Standard Deviation 1.132	-1.09 Score on a scale Standard Deviation 1.142	-0.93 Score on a scale Standard Deviation 0.926

SECONDARY outcome

Timeframe: Baseline; Day 29

To evaluate the treatment effect of BOS-589 on defecation after 4 weeks, relative to placebo. Participants were asked to record stool frequency based on the total number of spontaneous bowel movements in the past 24 hours.

Outcome measures

Outcome measures
Measure	High Dose of BOS-589 n=39 Participants Randomized participants received a high dose of BOS-589 tablets orally BID.	Low Dose of BOS-589 n=46 Participants Randomized participants received a low dose of BOS-589 tablets orally BID.	BOS-589: Active Treatment n=85 Participants High Dose of BOS-589: Randomized participants received a high dose of BOS-589 tablets orally BID. Low Dose of BOS-589: Randomized participants received a low dose of BOS-589 tablets orally BID. Data were pooled from the above mentioned doses for analysis.	Placebo n=40 Participants Randomized participants received matching placebo tablets orally BID.
Change in Stool Frequency, Measured by the Total Number of Spontaneous Bowel Movements in 24 Hours at Day 29 Compared to Baseline (Averaged Over the Week Prior to Each Respective Time Point)	-0.69 Number of spontaneous bowel movements Standard Deviation 1.190	-0.74 Number of spontaneous bowel movements Standard Deviation 0.944	-0.71 Number of spontaneous bowel movements Standard Deviation 1.057	-0.83 Number of spontaneous bowel movements Standard Deviation 1.006

SECONDARY outcome

Timeframe: Baseline; Day 29

To evaluate the treatment effect of BOS-589 on IBS-related signs and symptoms. Participants were asked to complete 5 questions regarding the severity of their IBS. Each of the 5 questions generated a maximum score of 100, leading to a total possible IBS-SS of 500. The IBS-SS scale ranges from 0 to 500. A higher score indicated greater severity.

Outcome measures

Outcome measures
Measure	High Dose of BOS-589 n=30 Participants Randomized participants received a high dose of BOS-589 tablets orally BID.	Low Dose of BOS-589 n=37 Participants Randomized participants received a low dose of BOS-589 tablets orally BID.	BOS-589: Active Treatment n=67 Participants High Dose of BOS-589: Randomized participants received a high dose of BOS-589 tablets orally BID. Low Dose of BOS-589: Randomized participants received a low dose of BOS-589 tablets orally BID. Data were pooled from the above mentioned doses for analysis.	Placebo n=30 Participants Randomized participants received matching placebo tablets orally BID.
Changes in the Irritable Bowel Syndrome-Severity Score (IBS-SS) at Day 29 Compared to Baseline	-89.3 Score on a scale Standard Deviation 116.65	-146.8 Score on a scale Standard Deviation 113.06	-121.0 Score on a scale Standard Deviation 117.38	-113.3 Score on a scale Standard Deviation 108.51

SECONDARY outcome

Timeframe: Baseline; Day 29

To evaluate the treatment effect of BOS-589 on IBS related signs and symptoms. Participants were asked to record daily their overall diarrhea-predominant Irritable Bowel Syndrome (IBS-D) global symptoms in the prior 24 hours. The participant-reported daily IBS-GS was based on a 0 to 4 scale where: 0 corresponded to no symptoms; 1 corresponded to mild symptoms; 2 corresponded to moderate symptoms; 3 corresponded to severe symptoms; and 4 corresponded to very severe symptoms. Higher scores indicated severe symptoms.

Outcome measures

Outcome measures
Measure	High Dose of BOS-589 n=39 Participants Randomized participants received a high dose of BOS-589 tablets orally BID.	Low Dose of BOS-589 n=46 Participants Randomized participants received a low dose of BOS-589 tablets orally BID.	BOS-589: Active Treatment n=85 Participants High Dose of BOS-589: Randomized participants received a high dose of BOS-589 tablets orally BID. Low Dose of BOS-589: Randomized participants received a low dose of BOS-589 tablets orally BID. Data were pooled from the above mentioned doses for analysis.	Placebo n=40 Participants Randomized participants received matching placebo tablets orally BID.
Change in the IBS Global Scale (IBS-GS) at Day 29 Compared to Baseline (Averaged Over the Week Prior to Each Respective Time Point)	-0.56 Score on a scale Standard Deviation 0.629	-0.89 Score on a scale Standard Deviation 0.815	-0.74 Score on a scale Standard Deviation 0.750	-0.57 Score on a scale Standard Deviation 0.626

SECONDARY outcome

Timeframe: Day 1, Day 15 and Day 22 at pre-dose and at 0.5, 1, 2, and 4 hours post-dose

Population: The PK population included all participants who took any amount of BOS-589 and had sufficient concentration time data to report at least a maximum concentration (Cmax). Here, number analyzed in each row signifies only the participants with available data that were analyzed for that day.

To evaluate the steady state pharmacokinetics (PK) of BOS-589.

Outcome measures

Outcome measures
Measure	High Dose of BOS-589 n=43 Participants Randomized participants received a high dose of BOS-589 tablets orally BID.	Low Dose of BOS-589 n=48 Participants Randomized participants received a low dose of BOS-589 tablets orally BID.	BOS-589: Active Treatment High Dose of BOS-589: Randomized participants received a high dose of BOS-589 tablets orally BID. Low Dose of BOS-589: Randomized participants received a low dose of BOS-589 tablets orally BID. Data were pooled from the above mentioned doses for analysis.	Placebo Randomized participants received matching placebo tablets orally BID.
Maximum Observed Plasma Concentration (Cmax) for BOS-589 Day 1	1840 pg/mL Geometric Coefficient of Variation 90.4	999 pg/mL Geometric Coefficient of Variation 72.0	—	—
Maximum Observed Plasma Concentration (Cmax) for BOS-589 Day 15	2050 pg/mL Geometric Coefficient of Variation 109	1280 pg/mL Geometric Coefficient of Variation 91.2	—	—
Maximum Observed Plasma Concentration (Cmax) for BOS-589 Day 22	984 pg/mL Geometric Coefficient of Variation 105	1620 pg/mL Geometric Coefficient of Variation 117	—	—

SECONDARY outcome

Timeframe: Day 1, Day 15 and Day 22 at pre-dose and at 0.5, 1, 2, and 4 hours post-dose

To evaluate the steady state PK of BOS-589.

Outcome measures

Outcome measures
Measure	High Dose of BOS-589 n=43 Participants Randomized participants received a high dose of BOS-589 tablets orally BID.	Low Dose of BOS-589 n=48 Participants Randomized participants received a low dose of BOS-589 tablets orally BID.	BOS-589: Active Treatment High Dose of BOS-589: Randomized participants received a high dose of BOS-589 tablets orally BID. Low Dose of BOS-589: Randomized participants received a low dose of BOS-589 tablets orally BID. Data were pooled from the above mentioned doses for analysis.	Placebo Randomized participants received matching placebo tablets orally BID.
Time to Reach Cmax (Tmax) for BOS-589 Day 1	1.02 Hour Interval 0.42 to 4.0	1.21 Hour Interval 0.5 to 4.05	—	—
Time to Reach Cmax (Tmax) for BOS-589 Day 15	1.44 Hour Interval 0.5 to 4.02	1.05 Hour Interval 0.0 to 4.0	—	—
Time to Reach Cmax (Tmax) for BOS-589 Day 22	1.00 Hour Interval 0.0 to 2.0	1.92 Hour Interval 1.92 to 2.03	—	—

SECONDARY outcome

Timeframe: Day 1, Day 15 and Day 22 at pre-dose and at 0.5, 1, 2, and 4 hours post-dose

To evaluate the steady state PK of BOS-589.

Outcome measures

Outcome measures
Measure	High Dose of BOS-589 n=43 Participants Randomized participants received a high dose of BOS-589 tablets orally BID.	Low Dose of BOS-589 n=48 Participants Randomized participants received a low dose of BOS-589 tablets orally BID.	BOS-589: Active Treatment High Dose of BOS-589: Randomized participants received a high dose of BOS-589 tablets orally BID. Low Dose of BOS-589: Randomized participants received a low dose of BOS-589 tablets orally BID. Data were pooled from the above mentioned doses for analysis.	Placebo Randomized participants received matching placebo tablets orally BID.
Area Under the Concentration-versus-time Curve (AUC) From Time Zero to 4 Hours Post Dose (AUC0-4) for BOS-589 Day 1	4250 h*pg/mL Geometric Coefficient of Variation 90.5	2460 h*pg/mL Geometric Coefficient of Variation 65.3	—	—
Area Under the Concentration-versus-time Curve (AUC) From Time Zero to 4 Hours Post Dose (AUC0-4) for BOS-589 Day 15	6080 h*pg/mL Geometric Coefficient of Variation 85.4	3090 h*pg/mL Geometric Coefficient of Variation 91.5	—	—
Area Under the Concentration-versus-time Curve (AUC) From Time Zero to 4 Hours Post Dose (AUC0-4) for BOS-589 Day 22	2210 h*pg/mL Geometric Coefficient of Variation 85.9	7360 h*pg/mL Geometric Coefficient of Variation 38.9	—	—

SECONDARY outcome

Timeframe: Day 1, Day 15 and Day 22 at pre-dose and at 0.5, 1, 2, and 4 hours post-dose

To evaluate the steady state PK of BOS-589.

Outcome measures

Outcome measures
Measure	High Dose of BOS-589 n=43 Participants Randomized participants received a high dose of BOS-589 tablets orally BID.	Low Dose of BOS-589 n=48 Participants Randomized participants received a low dose of BOS-589 tablets orally BID.	BOS-589: Active Treatment High Dose of BOS-589: Randomized participants received a high dose of BOS-589 tablets orally BID. Low Dose of BOS-589: Randomized participants received a low dose of BOS-589 tablets orally BID. Data were pooled from the above mentioned doses for analysis.	Placebo Randomized participants received matching placebo tablets orally BID.
AUC From Time Zero to the Last Quantifiable Concentration (AUC0-t) for BOS-589 Day 1	4330 h*pg/mL Geometric Coefficient of Variation 90.3	2470 h*pg/mL Geometric Coefficient of Variation 63.7	—	—
AUC From Time Zero to the Last Quantifiable Concentration (AUC0-t) for BOS-589 Day 15	6080 h*pg/mL Geometric Coefficient of Variation 85.4	3220 h*pg/mL Geometric Coefficient of Variation 96.9	—	—
AUC From Time Zero to the Last Quantifiable Concentration (AUC0-t) for BOS-589 Day 22	2480 h*pg/mL Geometric Coefficient of Variation 78.5	4640 h*pg/mL Geometric Coefficient of Variation 149	—	—

Adverse Events

High Dose of BOS-589

Serious events: 0 serious events

Other events: 23 other events

Deaths: 0 deaths

Low Dose of BOS-589

Serious events: 0 serious events

Other events: 23 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 15 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Craig Basson

Boston Pharmaceuticals, Inc.

Phone: (617) 655-9681

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60

Measure	High Dose of BOS-589 n=43 participants at risk Randomized participants received a high dose of BOS-589 tablets orally BID.	Low Dose of BOS-589 n=48 participants at risk Randomized participants received a low dose of BOS-589 tablets orally BID.	Placebo n=42 participants at risk Randomized participants received matching placebo tablets orally BID.
Infections and infestations Nasopharyngitis	4.7% 2/43 • Up to Day 43/end-of-study follow up visit	8.3% 4/48 • Up to Day 43/end-of-study follow up visit	2.4% 1/42 • Up to Day 43/end-of-study follow up visit
Infections and infestations Upper respiratory tract infection	4.7% 2/43 • Up to Day 43/end-of-study follow up visit	4.2% 2/48 • Up to Day 43/end-of-study follow up visit	2.4% 1/42 • Up to Day 43/end-of-study follow up visit
Infections and infestations Urinary tract infection	4.7% 2/43 • Up to Day 43/end-of-study follow up visit	4.2% 2/48 • Up to Day 43/end-of-study follow up visit	0.00% 0/42 • Up to Day 43/end-of-study follow up visit
Infections and infestations Influenza	0.00% 0/43 • Up to Day 43/end-of-study follow up visit	4.2% 2/48 • Up to Day 43/end-of-study follow up visit	2.4% 1/42 • Up to Day 43/end-of-study follow up visit
Infections and infestations Gastroenteritis viral	2.3% 1/43 • Up to Day 43/end-of-study follow up visit	2.1% 1/48 • Up to Day 43/end-of-study follow up visit	0.00% 0/42 • Up to Day 43/end-of-study follow up visit
Infections and infestations Atypical pneumonia	0.00% 0/43 • Up to Day 43/end-of-study follow up visit	2.1% 1/48 • Up to Day 43/end-of-study follow up visit	0.00% 0/42 • Up to Day 43/end-of-study follow up visit
Infections and infestations Pneumonia	0.00% 0/43 • Up to Day 43/end-of-study follow up visit	2.1% 1/48 • Up to Day 43/end-of-study follow up visit	0.00% 0/42 • Up to Day 43/end-of-study follow up visit
Infections and infestations Sinusitis	0.00% 0/43 • Up to Day 43/end-of-study follow up visit	2.1% 1/48 • Up to Day 43/end-of-study follow up visit	0.00% 0/42 • Up to Day 43/end-of-study follow up visit
Infections and infestations Vulvovaginal candidiasis	2.3% 1/43 • Up to Day 43/end-of-study follow up visit	0.00% 0/48 • Up to Day 43/end-of-study follow up visit	0.00% 0/42 • Up to Day 43/end-of-study follow up visit
Gastrointestinal disorders Nausea	4.7% 2/43 • Up to Day 43/end-of-study follow up visit	4.2% 2/48 • Up to Day 43/end-of-study follow up visit	4.8% 2/42 • Up to Day 43/end-of-study follow up visit
Gastrointestinal disorders Abdominal distension	9.3% 4/43 • Up to Day 43/end-of-study follow up visit	0.00% 0/48 • Up to Day 43/end-of-study follow up visit	0.00% 0/42 • Up to Day 43/end-of-study follow up visit
Gastrointestinal disorders Vomiting	4.7% 2/43 • Up to Day 43/end-of-study follow up visit	4.2% 2/48 • Up to Day 43/end-of-study follow up visit	0.00% 0/42 • Up to Day 43/end-of-study follow up visit
Gastrointestinal disorders Constipation	4.7% 2/43 • Up to Day 43/end-of-study follow up visit	0.00% 0/48 • Up to Day 43/end-of-study follow up visit	2.4% 1/42 • Up to Day 43/end-of-study follow up visit
Gastrointestinal disorders Diarrhoea	2.3% 1/43 • Up to Day 43/end-of-study follow up visit	4.2% 2/48 • Up to Day 43/end-of-study follow up visit	0.00% 0/42 • Up to Day 43/end-of-study follow up visit
Gastrointestinal disorders Flatulence	4.7% 2/43 • Up to Day 43/end-of-study follow up visit	0.00% 0/48 • Up to Day 43/end-of-study follow up visit	2.4% 1/42 • Up to Day 43/end-of-study follow up visit
Gastrointestinal disorders Food poisoning	0.00% 0/43 • Up to Day 43/end-of-study follow up visit	4.2% 2/48 • Up to Day 43/end-of-study follow up visit	2.4% 1/42 • Up to Day 43/end-of-study follow up visit
Gastrointestinal disorders Abdominal pain upper	2.3% 1/43 • Up to Day 43/end-of-study follow up visit	0.00% 0/48 • Up to Day 43/end-of-study follow up visit	2.4% 1/42 • Up to Day 43/end-of-study follow up visit
Gastrointestinal disorders Abdominal discomfort	0.00% 0/43 • Up to Day 43/end-of-study follow up visit	0.00% 0/48 • Up to Day 43/end-of-study follow up visit	2.4% 1/42 • Up to Day 43/end-of-study follow up visit
Gastrointestinal disorders Abdominal rigidity	2.3% 1/43 • Up to Day 43/end-of-study follow up visit	0.00% 0/48 • Up to Day 43/end-of-study follow up visit	0.00% 0/42 • Up to Day 43/end-of-study follow up visit
Gastrointestinal disorders Aphthous ulcer	2.3% 1/43 • Up to Day 43/end-of-study follow up visit	0.00% 0/48 • Up to Day 43/end-of-study follow up visit	0.00% 0/42 • Up to Day 43/end-of-study follow up visit
Gastrointestinal disorders Dry mouth	0.00% 0/43 • Up to Day 43/end-of-study follow up visit	0.00% 0/48 • Up to Day 43/end-of-study follow up visit	2.4% 1/42 • Up to Day 43/end-of-study follow up visit
Gastrointestinal disorders Gastrointestinal sounds abnormal	0.00% 0/43 • Up to Day 43/end-of-study follow up visit	2.1% 1/48 • Up to Day 43/end-of-study follow up visit	0.00% 0/42 • Up to Day 43/end-of-study follow up visit
Gastrointestinal disorders Toothache	2.3% 1/43 • Up to Day 43/end-of-study follow up visit	0.00% 0/48 • Up to Day 43/end-of-study follow up visit	0.00% 0/42 • Up to Day 43/end-of-study follow up visit
Nervous system disorders Headache	0.00% 0/43 • Up to Day 43/end-of-study follow up visit	8.3% 4/48 • Up to Day 43/end-of-study follow up visit	9.5% 4/42 • Up to Day 43/end-of-study follow up visit
Nervous system disorders Dizziness	4.7% 2/43 • Up to Day 43/end-of-study follow up visit	2.1% 1/48 • Up to Day 43/end-of-study follow up visit	4.8% 2/42 • Up to Day 43/end-of-study follow up visit
Nervous system disorders Migraine	2.3% 1/43 • Up to Day 43/end-of-study follow up visit	0.00% 0/48 • Up to Day 43/end-of-study follow up visit	0.00% 0/42 • Up to Day 43/end-of-study follow up visit
Nervous system disorders Neuropathy peripheral	0.00% 0/43 • Up to Day 43/end-of-study follow up visit	0.00% 0/48 • Up to Day 43/end-of-study follow up visit	2.4% 1/42 • Up to Day 43/end-of-study follow up visit
Nervous system disorders Paraesthesia	0.00% 0/43 • Up to Day 43/end-of-study follow up visit	0.00% 0/48 • Up to Day 43/end-of-study follow up visit	2.4% 1/42 • Up to Day 43/end-of-study follow up visit
Injury, poisoning and procedural complications Ligament sprain	4.7% 2/43 • Up to Day 43/end-of-study follow up visit	0.00% 0/48 • Up to Day 43/end-of-study follow up visit	2.4% 1/42 • Up to Day 43/end-of-study follow up visit
Injury, poisoning and procedural complications Post procedural contusion	2.3% 1/43 • Up to Day 43/end-of-study follow up visit	0.00% 0/48 • Up to Day 43/end-of-study follow up visit	0.00% 0/42 • Up to Day 43/end-of-study follow up visit
Injury, poisoning and procedural complications Tooth fracture	2.3% 1/43 • Up to Day 43/end-of-study follow up visit	0.00% 0/48 • Up to Day 43/end-of-study follow up visit	0.00% 0/42 • Up to Day 43/end-of-study follow up visit
Injury, poisoning and procedural complications Wound	2.3% 1/43 • Up to Day 43/end-of-study follow up visit	0.00% 0/48 • Up to Day 43/end-of-study follow up visit	0.00% 0/42 • Up to Day 43/end-of-study follow up visit
Musculoskeletal and connective tissue disorders Flank pain	0.00% 0/43 • Up to Day 43/end-of-study follow up visit	0.00% 0/48 • Up to Day 43/end-of-study follow up visit	2.4% 1/42 • Up to Day 43/end-of-study follow up visit
Musculoskeletal and connective tissue disorders Muscle spasms	0.00% 0/43 • Up to Day 43/end-of-study follow up visit	2.1% 1/48 • Up to Day 43/end-of-study follow up visit	0.00% 0/42 • Up to Day 43/end-of-study follow up visit
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	0.00% 0/43 • Up to Day 43/end-of-study follow up visit	2.1% 1/48 • Up to Day 43/end-of-study follow up visit	0.00% 0/42 • Up to Day 43/end-of-study follow up visit
Musculoskeletal and connective tissue disorders Musculoskeletal pain	2.3% 1/43 • Up to Day 43/end-of-study follow up visit	0.00% 0/48 • Up to Day 43/end-of-study follow up visit	0.00% 0/42 • Up to Day 43/end-of-study follow up visit
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/43 • Up to Day 43/end-of-study follow up visit	0.00% 0/48 • Up to Day 43/end-of-study follow up visit	2.4% 1/42 • Up to Day 43/end-of-study follow up visit
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	2.3% 1/43 • Up to Day 43/end-of-study follow up visit	2.1% 1/48 • Up to Day 43/end-of-study follow up visit	0.00% 0/42 • Up to Day 43/end-of-study follow up visit
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/43 • Up to Day 43/end-of-study follow up visit	2.1% 1/48 • Up to Day 43/end-of-study follow up visit	0.00% 0/42 • Up to Day 43/end-of-study follow up visit
Respiratory, thoracic and mediastinal disorders Throat irritation	0.00% 0/43 • Up to Day 43/end-of-study follow up visit	0.00% 0/48 • Up to Day 43/end-of-study follow up visit	2.4% 1/42 • Up to Day 43/end-of-study follow up visit
General disorders Catheter site bruise	2.3% 1/43 • Up to Day 43/end-of-study follow up visit	0.00% 0/48 • Up to Day 43/end-of-study follow up visit	2.4% 1/42 • Up to Day 43/end-of-study follow up visit
General disorders Catheter site pain	2.3% 1/43 • Up to Day 43/end-of-study follow up visit	0.00% 0/48 • Up to Day 43/end-of-study follow up visit	0.00% 0/42 • Up to Day 43/end-of-study follow up visit
General disorders Fatigue	2.3% 1/43 • Up to Day 43/end-of-study follow up visit	0.00% 0/48 • Up to Day 43/end-of-study follow up visit	0.00% 0/42 • Up to Day 43/end-of-study follow up visit
Skin and subcutaneous tissue disorders Ecchymosis	0.00% 0/43 • Up to Day 43/end-of-study follow up visit	2.1% 1/48 • Up to Day 43/end-of-study follow up visit	0.00% 0/42 • Up to Day 43/end-of-study follow up visit
Skin and subcutaneous tissue disorders Hyperhidrosis	0.00% 0/43 • Up to Day 43/end-of-study follow up visit	2.1% 1/48 • Up to Day 43/end-of-study follow up visit	0.00% 0/42 • Up to Day 43/end-of-study follow up visit
Skin and subcutaneous tissue disorders Rash	2.3% 1/43 • Up to Day 43/end-of-study follow up visit	0.00% 0/48 • Up to Day 43/end-of-study follow up visit	0.00% 0/42 • Up to Day 43/end-of-study follow up visit
Psychiatric disorders Anxiety	0.00% 0/43 • Up to Day 43/end-of-study follow up visit	0.00% 0/48 • Up to Day 43/end-of-study follow up visit	2.4% 1/42 • Up to Day 43/end-of-study follow up visit
Psychiatric disorders Mental status changes	2.3% 1/43 • Up to Day 43/end-of-study follow up visit	0.00% 0/48 • Up to Day 43/end-of-study follow up visit	0.00% 0/42 • Up to Day 43/end-of-study follow up visit
Cardiac disorders Tachycardia	0.00% 0/43 • Up to Day 43/end-of-study follow up visit	2.1% 1/48 • Up to Day 43/end-of-study follow up visit	0.00% 0/42 • Up to Day 43/end-of-study follow up visit
Eye disorders Eye irritation	2.3% 1/43 • Up to Day 43/end-of-study follow up visit	0.00% 0/48 • Up to Day 43/end-of-study follow up visit	0.00% 0/42 • Up to Day 43/end-of-study follow up visit
Investigations Blood alkaline phosphatase increased	2.3% 1/43 • Up to Day 43/end-of-study follow up visit	0.00% 0/48 • Up to Day 43/end-of-study follow up visit	0.00% 0/42 • Up to Day 43/end-of-study follow up visit
Investigations C-reactive protein increased	2.3% 1/43 • Up to Day 43/end-of-study follow up visit	0.00% 0/48 • Up to Day 43/end-of-study follow up visit	0.00% 0/42 • Up to Day 43/end-of-study follow up visit
Investigations Red blood cell sedimentation rate increased	2.3% 1/43 • Up to Day 43/end-of-study follow up visit	0.00% 0/48 • Up to Day 43/end-of-study follow up visit	0.00% 0/42 • Up to Day 43/end-of-study follow up visit
Renal and urinary disorders Pollakiuria	0.00% 0/43 • Up to Day 43/end-of-study follow up visit	0.00% 0/48 • Up to Day 43/end-of-study follow up visit	2.4% 1/42 • Up to Day 43/end-of-study follow up visit
Vascular disorders Hypertension	2.3% 1/43 • Up to Day 43/end-of-study follow up visit	0.00% 0/48 • Up to Day 43/end-of-study follow up visit	0.00% 0/42 • Up to Day 43/end-of-study follow up visit