Trial Outcomes & Findings for Study to Evaluate the Safety and Efficacy of Naldemedine (S-297995) for the Treatment of Opioid-Induced Bowel Dysfunction in Subjects With Chronic Pain (NCT NCT01122030)

NCT ID: NCT01122030

Last Updated: 2017-05-30

Results Overview

Severity of adverse events (AEs) was graded according to the following definitions: * Mild: The subject experiences awareness of symptoms but these are easily tolerated or managed without specific treatment * Moderate: The subject experiences discomfort enough to cause interference with usual activity, and/or the condition requires specific treatment * Severe: The subject is incapacitated with inability to work or do usual activity, and/or the event requires significant treatment measures. The relationship of the event to the study drug was determined by the investigator. A serious adverse event (SAE) is defined as any AE occurring at any dose that resulted in any of the following outcomes: death, life-threatening AE, hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 72 participants
• Primary outcome timeframe: From the first dose of study drug on Day 15 up to Day 24.
• Results posted on: 2017-05-30

Participant Flow

The study was conducted at a single study center in the United States.

Participants were randomized to naldemedine or placebo, screened for 13 days (Days 1-13), and admitted to the clinic on Day 14 for pre-admission assessments. Six cohorts were sequentially enrolled from Cohort 1 (0.1 mg) to Cohort 2 (0.3 mg), Cohort 3 (1 mg), and Cohort 4 (3 mg), and subsequent de-escalation in Cohorts 5 (0.03 mg) and 6 (0.01 mg).

Participant milestones

Measure	Pooled Placebo Participants received a single dose of matching placebo administered orally on Day 15 under fasted conditions.	Naldemedine 0.01 mg Participants received a single dose of 0.01 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.03 mg Participants received a single dose of 0.03 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.1 mg Participants received one 0.1 mg naldemedine tablet administered on Day 15 under fasted conditions.	Naldemedine 0.3 mg Participants received a single dose of 0.3 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 1 mg Participants received a single dose of 1 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 3 mg Participants received a single dose of 3 mg naldemedine tablets administered on Day 15 under fasted conditions.
Overall Study STARTED	18	9	9	9	9	9	9
Overall Study Received Treatment	18	9	9	9	9	9	9
Overall Study COMPLETED	18	9	9	9	9	9	9
Overall Study NOT COMPLETED	0	0	0	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Study to Evaluate the Safety and Efficacy of Naldemedine (S-297995) for the Treatment of Opioid-Induced Bowel Dysfunction in Subjects With Chronic Pain

Baseline characteristics by cohort

Measure	Pooled Placebo n=18 Participants Participants received a single dose of matching placebo administered orally on Day 15 under fasted conditions.	Naldemedine 0.01 mg n=9 Participants Participants received a single dose of 0.01 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.03 mg n=9 Participants Participants received a single dose of 0.03 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.1 mg n=9 Participants Participants received one 0.1 mg naldemedine tablet administered on Day 15 under fasted conditions.	Naldemedine 0.3 mg n=9 Participants Participants received a single dose of 0.3 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 1 mg n=9 Participants Participants received a single dose of 1 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 3 mg n=9 Participants Participants received a single dose of 3 mg naldemedine tablets administered on Day 15 under fasted conditions.	Total n=72 Participants Total of all reporting groups
Age, Continuous	46.7 years STANDARD_DEVIATION 8.55 • n=5 Participants	41.4 years STANDARD_DEVIATION 12.99 • n=7 Participants	45.2 years STANDARD_DEVIATION 13.13 • n=5 Participants	45.6 years STANDARD_DEVIATION 6.02 • n=4 Participants	39.7 years STANDARD_DEVIATION 10.64 • n=21 Participants	36.6 years STANDARD_DEVIATION 10.19 • n=10 Participants	44.8 years STANDARD_DEVIATION 9.09 • n=115 Participants	43.3 years STANDARD_DEVIATION 10.30 • n=6 Participants
Sex: Female, Male Female	7 Participants n=5 Participants	7 Participants n=7 Participants	7 Participants n=5 Participants	5 Participants n=4 Participants	6 Participants n=21 Participants	4 Participants n=10 Participants	2 Participants n=115 Participants	38 Participants n=6 Participants
Sex: Female, Male Male	11 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants	4 Participants n=4 Participants	3 Participants n=21 Participants	5 Participants n=10 Participants	7 Participants n=115 Participants	34 Participants n=6 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants	5 Participants n=6 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	16 Participants n=5 Participants	8 Participants n=7 Participants	8 Participants n=5 Participants	9 Participants n=4 Participants	8 Participants n=21 Participants	9 Participants n=10 Participants	9 Participants n=115 Participants	67 Participants n=6 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	0 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants	0 Participants n=6 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants	1 Participants n=6 Participants
Race/Ethnicity, Customized Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants	0 Participants n=6 Participants
Race/Ethnicity, Customized Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants	0 Participants n=6 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants	1 Participants n=6 Participants
Race/Ethnicity, Customized White	18 Participants n=5 Participants	8 Participants n=7 Participants	9 Participants n=5 Participants	9 Participants n=4 Participants	8 Participants n=21 Participants	9 Participants n=10 Participants	9 Participants n=115 Participants	70 Participants n=6 Participants

PRIMARY outcome

Timeframe: From the first dose of study drug on Day 15 up to Day 24.

Population: All participants who received any amount of study drug (safety population).

Severity of adverse events (AEs) was graded according to the following definitions:

• Mild: The subject experiences awareness of symptoms but these are easily tolerated or managed without specific treatment
• Moderate: The subject experiences discomfort enough to cause interference with usual activity, and/or the condition requires specific treatment
• Severe: The subject is incapacitated with inability to work or do usual activity, and/or the event requires significant treatment measures.

The relationship of the event to the study drug was determined by the investigator.

A serious adverse event (SAE) is defined as any AE occurring at any dose that resulted in any of the following outcomes: death, life-threatening AE, hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect.

Outcome measures

Measure	Pooled Placebo n=18 Participants Participants received a single dose of matching placebo administered orally on Day 15 under fasted conditions.	Naldemedine 0.01 mg n=9 Participants Participants received a single dose of 0.01 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.03 mg n=9 Participants Participants received a single dose of 0.03 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.1 mg n=9 Participants Participants received one 0.1 mg naldemedine tablet administered on Day 15 under fasted conditions.	Naldemedine 0.3 mg n=9 Participants Participants received a single dose of 0.3 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 1 mg n=9 Participants Participants received a single dose of 1 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 3 mg n=9 Participants Participants received a single dose of 3 mg naldemedine tablets administered on Day 15 under fasted conditions.
Number of Participants With Adverse Events Any adverse event	9 participants	6 participants	6 participants	5 participants	9 participants	9 participants	9 participants
Number of Participants With Adverse Events Mild adverse events	9 participants	6 participants	6 participants	4 participants	6 participants	5 participants	1 participants
Number of Participants With Adverse Events Moderate adverse events	0 participants	0 participants	0 participants	1 participants	3 participants	3 participants	2 participants
Number of Participants With Adverse Events Severe adverse events	0 participants	0 participants	0 participants	0 participants	0 participants	1 participants	6 participants
Number of Participants With Adverse Events Treatment-related adverse events	6 participants	5 participants	3 participants	1 participants	9 participants	8 participants	9 participants
Number of Participants With Adverse Events Deaths	0 participants	0 participants	0 participants	0 participants	0 participants	0 participants	0 participants
Number of Participants With Adverse Events Serious adverse events	0 participants	0 participants	0 participants	0 participants	0 participants	0 participants	0 participants
Number of Participants With Adverse Events Adverse events leading to discontinuation	0 participants	0 participants	0 participants	0 participants	0 participants	0 participants	0 participants

SECONDARY outcome

Timeframe: Baseline (Day 1 to Day 15) and Day 15 to 16 (0 to 24 hours post-dose)

Population: All randomized participants who received study drug and had at least 1 post-dose efficacy assessment completed (intent-to-treat population). Last observation carried forward (LOCF) imputation was used.

Participants completed a bowel function assessment daily diary to record information about bowel movements and constipation. A spontaneous bowel movement was defined as a bowel movement where no laxative or enema was used in the 24 hours preceding the bowel movement.

Baseline was defined as the average number of SBMs per day during the 2 weeks prior to receiving study drug (Day 1 to Day 15).

Outcome measures

Measure	Pooled Placebo n=18 Participants Participants received a single dose of matching placebo administered orally on Day 15 under fasted conditions.	Naldemedine 0.01 mg n=9 Participants Participants received a single dose of 0.01 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.03 mg n=9 Participants Participants received a single dose of 0.03 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.1 mg n=9 Participants Participants received one 0.1 mg naldemedine tablet administered on Day 15 under fasted conditions.	Naldemedine 0.3 mg n=9 Participants Participants received a single dose of 0.3 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 1 mg n=9 Participants Participants received a single dose of 1 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 3 mg n=9 Participants Participants received a single dose of 3 mg naldemedine tablets administered on Day 15 under fasted conditions.
Change From Baseline to 24 Hours Post-dose in Number of Spontaneous Bowel Movements (SBMs) Per Day Baseline	0.15 spontaneous bowel movements / day Standard Deviation 0.13	0.20 spontaneous bowel movements / day Standard Deviation 0.14	0.24 spontaneous bowel movements / day Standard Deviation 0.09	0.13 spontaneous bowel movements / day Standard Deviation 0.13	0.17 spontaneous bowel movements / day Standard Deviation 0.12	0.13 spontaneous bowel movements / day Standard Deviation 0.09	0.23 spontaneous bowel movements / day Standard Deviation 0.11
Change From Baseline to 24 Hours Post-dose in Number of Spontaneous Bowel Movements (SBMs) Per Day 24 hours post-dose	0.44 spontaneous bowel movements / day Standard Deviation 0.51	0.11 spontaneous bowel movements / day Standard Deviation 0.33	0.67 spontaneous bowel movements / day Standard Deviation 0.71	0.56 spontaneous bowel movements / day Standard Deviation 0.73	2.00 spontaneous bowel movements / day Standard Deviation 1.32	3.89 spontaneous bowel movements / day Standard Deviation 3.06	5.00 spontaneous bowel movements / day Standard Deviation 2.12
Change From Baseline to 24 Hours Post-dose in Number of Spontaneous Bowel Movements (SBMs) Per Day Change from Baseline to 24 hours post-dose	0.29 spontaneous bowel movements / day Standard Deviation 0.48	-0.09 spontaneous bowel movements / day Standard Deviation 0.41	0.42 spontaneous bowel movements / day Standard Deviation 0.72	0.43 spontaneous bowel movements / day Standard Deviation 0.68	1.83 spontaneous bowel movements / day Standard Deviation 1.34	3.76 spontaneous bowel movements / day Standard Deviation 3.06	4.77 spontaneous bowel movements / day Standard Deviation 2.15

SECONDARY outcome

Timeframe: Baseline (Day 1 to Day 15) and Day 15 to Day 17 (0 to 48 hours post-dose)

Population: Intent-to-treat population; LOCF imputation was used

Participants completed a bowel function assessment daily diary to record information about bowel movements and constipation. A spontaneous bowel movement was defined as a bowel movement where no laxative or enema was used in the 24 hours preceding the bowel movement. Baseline was defined as the average number of SBMs per day during the 2 weeks prior to receiving study drug (Day 1 to Day 15). Forty-eight hours post-dose was defined as the average number of SBMs per day from 0 to 48 hours post-dose.

Outcome measures

Measure	Pooled Placebo n=18 Participants Participants received a single dose of matching placebo administered orally on Day 15 under fasted conditions.	Naldemedine 0.01 mg n=9 Participants Participants received a single dose of 0.01 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.03 mg n=9 Participants Participants received a single dose of 0.03 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.1 mg n=9 Participants Participants received one 0.1 mg naldemedine tablet administered on Day 15 under fasted conditions.	Naldemedine 0.3 mg n=9 Participants Participants received a single dose of 0.3 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 1 mg n=9 Participants Participants received a single dose of 1 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 3 mg n=9 Participants Participants received a single dose of 3 mg naldemedine tablets administered on Day 15 under fasted conditions.
Change From Baseline to 48 Hours Post-dose in the Number of SBMs Per Day Baseline	0.15 Spontaneous bowel movements / day Standard Deviation 0.13	0.20 Spontaneous bowel movements / day Standard Deviation 0.14	0.24 Spontaneous bowel movements / day Standard Deviation 0.09	0.13 Spontaneous bowel movements / day Standard Deviation 0.13	0.17 Spontaneous bowel movements / day Standard Deviation 0.12	0.13 Spontaneous bowel movements / day Standard Deviation 0.09	0.23 Spontaneous bowel movements / day Standard Deviation 0.11
Change From Baseline to 48 Hours Post-dose in the Number of SBMs Per Day 48 hours post-dose	0.36 Spontaneous bowel movements / day Standard Deviation 0.33	0.44 Spontaneous bowel movements / day Standard Deviation 0.39	0.67 Spontaneous bowel movements / day Standard Deviation 0.61	0.39 Spontaneous bowel movements / day Standard Deviation 0.49	1.06 Spontaneous bowel movements / day Standard Deviation 0.68	2.28 Spontaneous bowel movements / day Standard Deviation 1.80	2.67 Spontaneous bowel movements / day Standard Deviation 1.03
Change From Baseline to 48 Hours Post-dose in the Number of SBMs Per Day Change from Baseline to 48 hours post-dose	0.21 Spontaneous bowel movements / day Standard Deviation 0.32	0.24 Spontaneous bowel movements / day Standard Deviation 0.39	0.42 Spontaneous bowel movements / day Standard Deviation 0.65	0.26 Spontaneous bowel movements / day Standard Deviation 0.45	0.88 Spontaneous bowel movements / day Standard Deviation 0.68	2.15 Spontaneous bowel movements / day Standard Deviation 1.81	2.44 Spontaneous bowel movements / day Standard Deviation 1.05

SECONDARY outcome

Timeframe: Baseline and 24 hours post-dose

Population: Intent-to-treat; LOCF imputation was used

Participants completed a bowel function assessment daily diary to record information about bowel movements and constipation. Baseline was defined as the average number of BMs per day during the 2 weeks prior to receiving study drug (Day 1 to Day 15).

Outcome measures

Measure	Pooled Placebo n=18 Participants Participants received a single dose of matching placebo administered orally on Day 15 under fasted conditions.	Naldemedine 0.01 mg n=9 Participants Participants received a single dose of 0.01 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.03 mg n=9 Participants Participants received a single dose of 0.03 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.1 mg n=9 Participants Participants received one 0.1 mg naldemedine tablet administered on Day 15 under fasted conditions.	Naldemedine 0.3 mg n=9 Participants Participants received a single dose of 0.3 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 1 mg n=9 Participants Participants received a single dose of 1 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 3 mg n=9 Participants Participants received a single dose of 3 mg naldemedine tablets administered on Day 15 under fasted conditions.
Change From Baseline to 24 Hours Post-dose in Number of Bowel Movements (BM) Per Day Baseline	0.35 bowel movements / day Standard Deviation 0.18	0.34 bowel movements / day Standard Deviation 0.10	0.41 bowel movements / day Standard Deviation 0.22	0.35 bowel movements / day Standard Deviation 0.17	0.33 bowel movements / day Standard Deviation 0.12	0.29 bowel movements / day Standard Deviation 0.09	0.38 bowel movements / day Standard Deviation 0.19
Change From Baseline to 24 Hours Post-dose in Number of Bowel Movements (BM) Per Day 24 hours post-dose	0.50 bowel movements / day Standard Deviation 0.62	0.11 bowel movements / day Standard Deviation 0.33	0.67 bowel movements / day Standard Deviation 0.71	0.56 bowel movements / day Standard Deviation 0.73	2.00 bowel movements / day Standard Deviation 1.32	3.89 bowel movements / day Standard Deviation 3.06	5.00 bowel movements / day Standard Deviation 2.12
Change From Baseline to 24 Hours Post-dose in Number of Bowel Movements (BM) Per Day Change from Baseline to 24 hours post-dose	0.15 bowel movements / day Standard Deviation 0.65	-0.23 bowel movements / day Standard Deviation 0.36	0.25 bowel movements / day Standard Deviation 0.75	0.21 bowel movements / day Standard Deviation 0.76	1.67 bowel movements / day Standard Deviation 1.35	3.60 bowel movements / day Standard Deviation 3.10	4.62 bowel movements / day Standard Deviation 2.06

SECONDARY outcome

Timeframe: Baseline and 48 hours post-dose

Population: Intent-to-treat population; LOCF imputation was used

Participants completed a bowel function assessment daily diary to record information about bowel movements and constipation. Baseline was defined as the average number of BMs per day during the 2 weeks prior to receiving study drug (Day 1 to Day 15). Forty-eight hours post-dose was defined as the average number of BMs per day from 0 to 48 hours post-dose.

Outcome measures

Measure	Pooled Placebo n=18 Participants Participants received a single dose of matching placebo administered orally on Day 15 under fasted conditions.	Naldemedine 0.01 mg n=9 Participants Participants received a single dose of 0.01 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.03 mg n=9 Participants Participants received a single dose of 0.03 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.1 mg n=9 Participants Participants received one 0.1 mg naldemedine tablet administered on Day 15 under fasted conditions.	Naldemedine 0.3 mg n=9 Participants Participants received a single dose of 0.3 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 1 mg n=9 Participants Participants received a single dose of 1 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 3 mg n=9 Participants Participants received a single dose of 3 mg naldemedine tablets administered on Day 15 under fasted conditions.
Change From Baseline to 48 Hours Post-dose in Number of Bowel Movements Per Day 48 hours post-dose	0.50 bowel movements / day Standard Deviation 0.51	0.61 bowel movements / day Standard Deviation 0.49	0.72 bowel movements / day Standard Deviation 0.71	0.56 bowel movements / day Standard Deviation 0.46	1.06 bowel movements / day Standard Deviation 0.68	2.28 bowel movements / day Standard Deviation 1.80	2.67 bowel movements / day Standard Deviation 1.03
Change From Baseline to 48 Hours Post-dose in Number of Bowel Movements Per Day Change from baseline to 48 hours post-dose	0.15 bowel movements / day Standard Deviation 0.53	0.27 bowel movements / day Standard Deviation 0.51	0.31 bowel movements / day Standard Deviation 0.67	0.21 bowel movements / day Standard Deviation 0.52	0.72 bowel movements / day Standard Deviation 0.70	1.99 bowel movements / day Standard Deviation 1.82	2.29 bowel movements / day Standard Deviation 0.98
Change From Baseline to 48 Hours Post-dose in Number of Bowel Movements Per Day Baseline	0.35 bowel movements / day Standard Deviation 0.18	0.34 bowel movements / day Standard Deviation 0.10	0.41 bowel movements / day Standard Deviation 0.22	0.35 bowel movements / day Standard Deviation 0.17	0.33 bowel movements / day Standard Deviation 0.12	0.29 bowel movements / day Standard Deviation 0.09	0.38 bowel movements / day Standard Deviation 0.19

SECONDARY outcome

Timeframe: Baseline and 24 hours post-dose

Population: Intent-to-treat population; LOCF imputation was used

Participants completed a bowel function assessment daily diary to record information about bowel movements and constipation. A complete spontaneous bowel movement was defined as a bowel movement where no laxative or enema was used and the bowel movement resulted in a sensation of complete evacuation (based on the question of "having a feeling of complete emptying after the bowel movement").

Baseline was defined as the average number of CSBMs per day during the 2 weeks prior to receiving study drug (Day 1 to Day 15).

Outcome measures

Measure	Pooled Placebo n=18 Participants Participants received a single dose of matching placebo administered orally on Day 15 under fasted conditions.	Naldemedine 0.01 mg n=9 Participants Participants received a single dose of 0.01 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.03 mg n=9 Participants Participants received a single dose of 0.03 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.1 mg n=9 Participants Participants received one 0.1 mg naldemedine tablet administered on Day 15 under fasted conditions.	Naldemedine 0.3 mg n=9 Participants Participants received a single dose of 0.3 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 1 mg n=9 Participants Participants received a single dose of 1 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 3 mg n=9 Participants Participants received a single dose of 3 mg naldemedine tablets administered on Day 15 under fasted conditions.
Change From Baseline to 24 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day Baseline	0.03 complete spontaneous bowel movements/day Standard Deviation 0.06	0.07 complete spontaneous bowel movements/day Standard Deviation 0.09	0.07 complete spontaneous bowel movements/day Standard Deviation 0.08	0.06 complete spontaneous bowel movements/day Standard Deviation 0.10	0.01 complete spontaneous bowel movements/day Standard Deviation 0.03	0.03 complete spontaneous bowel movements/day Standard Deviation 0.04	0.10 complete spontaneous bowel movements/day Standard Deviation 0.07
Change From Baseline to 24 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day 24 hours post-dose	0.06 complete spontaneous bowel movements/day Standard Deviation 0.24	0.00 complete spontaneous bowel movements/day Standard Deviation 0.00	0.11 complete spontaneous bowel movements/day Standard Deviation 0.33	0.22 complete spontaneous bowel movements/day Standard Deviation 0.44	0.11 complete spontaneous bowel movements/day Standard Deviation 0.33	2.44 complete spontaneous bowel movements/day Standard Deviation 2.55	3.00 complete spontaneous bowel movements/day Standard Deviation 3.20
Change From Baseline to 24 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day Change from Baseline to 24 hours post-dose	0.02 complete spontaneous bowel movements/day Standard Deviation 0.25	-0.07 complete spontaneous bowel movements/day Standard Deviation 0.09	0.04 complete spontaneous bowel movements/day Standard Deviation 0.29	0.16 complete spontaneous bowel movements/day Standard Deviation 0.44	0.10 complete spontaneous bowel movements/day Standard Deviation 0.34	2.42 complete spontaneous bowel movements/day Standard Deviation 2.55	2.90 complete spontaneous bowel movements/day Standard Deviation 3.24

SECONDARY outcome

Timeframe: Baseline and 48 hours post-dose

Population: Intent-to-treat population; LOCF imputation was used

Participants completed a bowel function assessment daily diary to record information about bowel movements and constipation. A complete spontaneous bowel movement was defined as a bowel movement where no laxative or enema was used and the bowel movement resulted in a sensation of complete evacuation (based on the question of "having a feeling of complete emptying after the bowel movement").

Baseline was defined as the average number of CSBMs per day during the 2 weeks prior to receiving study drug (Day 1 to Day 15). Forty-eight hours post-dose was defined as the average number of CSBMs per day from 0 to 48 hours post-dose.

Outcome measures

Measure	Pooled Placebo n=18 Participants Participants received a single dose of matching placebo administered orally on Day 15 under fasted conditions.	Naldemedine 0.01 mg n=9 Participants Participants received a single dose of 0.01 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.03 mg n=9 Participants Participants received a single dose of 0.03 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.1 mg n=9 Participants Participants received one 0.1 mg naldemedine tablet administered on Day 15 under fasted conditions.	Naldemedine 0.3 mg n=9 Participants Participants received a single dose of 0.3 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 1 mg n=9 Participants Participants received a single dose of 1 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 3 mg n=9 Participants Participants received a single dose of 3 mg naldemedine tablets administered on Day 15 under fasted conditions.
Change From Baseline to 48 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day Baseline	0.03 complete spontaneous bowel movements/day Standard Deviation 0.06	0.07 complete spontaneous bowel movements/day Standard Deviation 0.09	0.07 complete spontaneous bowel movements/day Standard Deviation 0.08	0.06 complete spontaneous bowel movements/day Standard Deviation 0.10	0.01 complete spontaneous bowel movements/day Standard Deviation 0.03	0.03 complete spontaneous bowel movements/day Standard Deviation 0.04	0.10 complete spontaneous bowel movements/day Standard Deviation 0.07
Change From Baseline to 48 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day 48 hours post-dose	0.08 complete spontaneous bowel movements/day Standard Deviation 0.19	0.17 complete spontaneous bowel movements/day Standard Deviation 0.25	0.17 complete spontaneous bowel movements/day Standard Deviation 0.25	0.17 complete spontaneous bowel movements/day Standard Deviation 0.35	0.06 complete spontaneous bowel movements/day Standard Deviation 0.17	1.39 complete spontaneous bowel movements/day Standard Deviation 1.34	1.61 complete spontaneous bowel movements/day Standard Deviation 1.52
Change From Baseline to 48 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day Change from baseline to 48 hours post-dose	0.05 complete spontaneous bowel movements/day Standard Deviation 0.16	0.10 complete spontaneous bowel movements/day Standard Deviation 0.18	0.10 complete spontaneous bowel movements/day Standard Deviation 0.25	0.10 complete spontaneous bowel movements/day Standard Deviation 0.34	0.04 complete spontaneous bowel movements/day Standard Deviation 0.17	1.36 complete spontaneous bowel movements/day Standard Deviation 1.34	1.51 complete spontaneous bowel movements/day Standard Deviation 1.56

SECONDARY outcome

Timeframe: From first dose on Day 15 through Day 17

Population: Intent-to-treat population

The time to first SBM during the Study Drug Administration Period was summarized using Kaplan-Meier estimates. Each participant's first SBM was counted as an event and the time to first SBM after dosing was calculated from the date and time of first dosing until the date and time of first SBM. Participants who dropped out or were lost to follow-up before the first SBM were censored.

Outcome measures

Measure	Pooled Placebo n=18 Participants Participants received a single dose of matching placebo administered orally on Day 15 under fasted conditions.	Naldemedine 0.01 mg n=9 Participants Participants received a single dose of 0.01 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.03 mg n=9 Participants Participants received a single dose of 0.03 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.1 mg n=9 Participants Participants received one 0.1 mg naldemedine tablet administered on Day 15 under fasted conditions.	Naldemedine 0.3 mg n=9 Participants Participants received a single dose of 0.3 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 1 mg n=9 Participants Participants received a single dose of 1 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 3 mg n=9 Participants Participants received a single dose of 3 mg naldemedine tablets administered on Day 15 under fasted conditions.
Time to First Spontaneous Bowel Movement	27.2 hours Interval 12.4 to Could not be estimated due to the low number of events	37.0 hours Interval 25.8 to Could not be estimated due to the low number of events	13.9 hours Interval 8.2 to Could not be estimated due to the low number of events	NA hours Interval 3.3 to Could not be estimated due to the low number of events	4.7 hours Interval 2.8 to 6.2	1.4 hours Interval 1.0 to 2.3	0.7 hours Interval 0.6 to 0.8

SECONDARY outcome

Timeframe: From first dose on Day 15 through Day 17

Population: Intent-to-treat population

The time to first BM during the Study Drug Administration Period was summarized using Kaplan-Meier estimates. Each participant's first BM was counted as an event and the time to first BM after dosing was calculated from the date and time of first dosing until the date and time of first BM. Participants who dropped out or were lost to follow-up before the first BM were censored.

Outcome measures

Measure	Pooled Placebo n=18 Participants Participants received a single dose of matching placebo administered orally on Day 15 under fasted conditions.	Naldemedine 0.01 mg n=9 Participants Participants received a single dose of 0.01 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.03 mg n=9 Participants Participants received a single dose of 0.03 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.1 mg n=9 Participants Participants received one 0.1 mg naldemedine tablet administered on Day 15 under fasted conditions.	Naldemedine 0.3 mg n=9 Participants Participants received a single dose of 0.3 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 1 mg n=9 Participants Participants received a single dose of 1 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 3 mg n=9 Participants Participants received a single dose of 3 mg naldemedine tablets administered on Day 15 under fasted conditions.
Time to First Bowel Movement	27.2 hours Interval 12.4 to Could not be estimated due to the low number of events	28.4 hours Interval 25.8 to 43.0	13.9 hours Interval 8.2 to Could not be estimated due to the low number of events	25.1 hours Interval 3.3 to 57.3	4.7 hours Interval 2.8 to 6.2	1.4 hours Interval 1.0 to 2.3	0.7 hours Interval 0.6 to 0.8

SECONDARY outcome

Timeframe: From first dose on Day 15 through Day 17

Population: Intent-to-treat population

The time to first CSBM during the Study Drug Administration Period was summarized using Kaplan-Meier estimates. Each participant's first CSBM was counted as an event and the time to first CSBM after dosing was calculated from the date and time of first dosing until the date and time of first CSBM. Participants who dropped out or were lost to follow-up before the first CSBM were censored.

Outcome measures

Measure	Pooled Placebo n=18 Participants Participants received a single dose of matching placebo administered orally on Day 15 under fasted conditions.	Naldemedine 0.01 mg n=9 Participants Participants received a single dose of 0.01 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.03 mg n=9 Participants Participants received a single dose of 0.03 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.1 mg n=9 Participants Participants received one 0.1 mg naldemedine tablet administered on Day 15 under fasted conditions.	Naldemedine 0.3 mg n=9 Participants Participants received a single dose of 0.3 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 1 mg n=9 Participants Participants received a single dose of 1 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 3 mg n=9 Participants Participants received a single dose of 3 mg naldemedine tablets administered on Day 15 under fasted conditions.
Time to First Complete Spontaneous Bowel Movement	NA hours Could not be estimated due to the low number of events	NA hours Interval 37.0 to Could not be estimated due to the low number of events	NA hours Interval 37.7 to Could not be estimated due to the low number of events	NA hours Could not be estimated due to the low number of events	NA hours Could not be estimated due to the low number of events	1.7 hours Interval 1.3 to 2.3	0.8 hours Interval 0.6 to 25.8

SECONDARY outcome

Timeframe: Baseline, 24 hours post-dose and 48 hours post-dose

Population: Intent-to-treat population with available data at each time point

Straining during BMs was graded using the following scale: 0 = Absent; 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Very Severe.

Baseline was defined as the average straining score of all BMs prior to receiving study drug (Day 1 to Day 15). The straining score at 24 and 48 hours post-dose was calculated as the average straining score from all bowel movements from 0 to 24 and 0 to 48 hours post-dose, respectively.

Outcome measures

Measure	Pooled Placebo n=18 Participants Participants received a single dose of matching placebo administered orally on Day 15 under fasted conditions.	Naldemedine 0.01 mg n=9 Participants Participants received a single dose of 0.01 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.03 mg n=9 Participants Participants received a single dose of 0.03 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.1 mg n=9 Participants Participants received one 0.1 mg naldemedine tablet administered on Day 15 under fasted conditions.	Naldemedine 0.3 mg n=9 Participants Participants received a single dose of 0.3 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 1 mg n=9 Participants Participants received a single dose of 1 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 3 mg n=9 Participants Participants received a single dose of 3 mg naldemedine tablets administered on Day 15 under fasted conditions.
Change From Baseline in Straining During Bowel Movements Baseline	2.2 units on a scale Standard Deviation 0.71	2.0 units on a scale Standard Deviation 0.78	2.2 units on a scale Standard Deviation 0.68	1.9 units on a scale Standard Deviation 0.90	2.0 units on a scale Standard Deviation 1.08	2.5 units on a scale Standard Deviation 0.97	1.7 units on a scale Standard Deviation 0.99
Change From Baseline in Straining During Bowel Movements Change from Baseline to 24 hours post-dose	0.8 units on a scale Standard Deviation 0.76	-0.8 units on a scale Standard Deviation NA Standard deviation cannot be calculated when n=1	-0.2 units on a scale Standard Deviation 0.88	-0.7 units on a scale Standard Deviation 0.43	-0.1 units on a scale Standard Deviation 0.89	-0.5 units on a scale Standard Deviation 1.37	-0.9 units on a scale Standard Deviation 1.64
Change From Baseline in Straining During Bowel Movements Change from Baseline to 48 hours post-dose	0.5 units on a scale Standard Deviation 0.87	0.2 units on a scale Standard Deviation 0.74	0.4 units on a scale Standard Deviation 0.80	-0.6 units on a scale Standard Deviation 0.67	0.1 units on a scale Standard Deviation NA Standard deviation cannot be calculated when n=1	-0.4 units on a scale Standard Deviation 0.42	-1.4 units on a scale Standard Deviation 1.40

SECONDARY outcome

Timeframe: Baseline and 24 hours post-dose

Population: Intent-to-treat population; LOCF imputation was used

A complete bowel movement (CBM) was defined as a bowel movement that resulted in a sensation of complete evacuation based on the question "Did you have a feeling of complete emptying after the bowel movement?" Baseline was defined as the average number of CBMs per day prior to receiving study drug (Day 1 to Day 15).

Outcome measures

Measure	Pooled Placebo n=18 Participants Participants received a single dose of matching placebo administered orally on Day 15 under fasted conditions.	Naldemedine 0.01 mg n=9 Participants Participants received a single dose of 0.01 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.03 mg n=9 Participants Participants received a single dose of 0.03 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.1 mg n=9 Participants Participants received one 0.1 mg naldemedine tablet administered on Day 15 under fasted conditions.	Naldemedine 0.3 mg n=9 Participants Participants received a single dose of 0.3 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 1 mg n=9 Participants Participants received a single dose of 1 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 3 mg n=9 Participants Participants received a single dose of 3 mg naldemedine tablets administered on Day 15 under fasted conditions.
Change From Baseline to 24 Hours Post-dose in Number of Complete Bowel Movements Per Day Baseline	0.13 complete bowel movements / day Standard Deviation 0.16	0.13 complete bowel movements / day Standard Deviation 0.14	0.11 complete bowel movements / day Standard Deviation 0.09	0.14 complete bowel movements / day Standard Deviation 0.12	0.04 complete bowel movements / day Standard Deviation 0.06	0.12 complete bowel movements / day Standard Deviation 0.15	0.19 complete bowel movements / day Standard Deviation 0.15
Change From Baseline to 24 Hours Post-dose in Number of Complete Bowel Movements Per Day 24 hours post-dose	0.06 complete bowel movements / day Standard Deviation 0.24	0.00 complete bowel movements / day Standard Deviation 0.00	0.11 complete bowel movements / day Standard Deviation 0.33	0.22 complete bowel movements / day Standard Deviation 0.44	0.11 complete bowel movements / day Standard Deviation 0.33	2.44 complete bowel movements / day Standard Deviation 2.55	3.00 complete bowel movements / day Standard Deviation 3.20
Change From Baseline to 24 Hours Post-dose in Number of Complete Bowel Movements Per Day Change from baseline to 24 hours post-dose	-0.07 complete bowel movements / day Standard Deviation 0.20	-0.13 complete bowel movements / day Standard Deviation 0.14	0.01 complete bowel movements / day Standard Deviation 0.31	0.09 complete bowel movements / day Standard Deviation 0.45	0.07 complete bowel movements / day Standard Deviation 0.35	2.32 complete bowel movements / day Standard Deviation 2.61	2.81 complete bowel movements / day Standard Deviation 3.21

SECONDARY outcome

Timeframe: Baseline and 48 hours post-dose

Population: Intent-to-treat population; LOCF imputation was used

A complete bowel movement (CBM) was defined as a bowel movement that resulted in a sensation of complete evacuation based on the question "Did you have a feeling of complete emptying after the bowel movement?" Baseline was defined as the average number of CBMs per day prior to receiving study drug (Day 1 to 15). Forty-eight hours post-dose was calculated as the average number of CBMs per day from 0 to 48 hours post-dose.

Outcome measures

Measure	Pooled Placebo n=18 Participants Participants received a single dose of matching placebo administered orally on Day 15 under fasted conditions.	Naldemedine 0.01 mg n=9 Participants Participants received a single dose of 0.01 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.03 mg n=9 Participants Participants received a single dose of 0.03 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.1 mg n=9 Participants Participants received one 0.1 mg naldemedine tablet administered on Day 15 under fasted conditions.	Naldemedine 0.3 mg n=9 Participants Participants received a single dose of 0.3 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 1 mg n=9 Participants Participants received a single dose of 1 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 3 mg n=9 Participants Participants received a single dose of 3 mg naldemedine tablets administered on Day 15 under fasted conditions.
Change From Baseline to 48 Hours Post-dose in Number of Complete Bowel Movements Per Day Baseline	0.13 complete bowel movements / day Standard Deviation 0.16	0.13 complete bowel movements / day Standard Deviation 0.14	0.11 complete bowel movements / day Standard Deviation 0.09	0.14 complete bowel movements / day Standard Deviation 0.12	0.04 complete bowel movements / day Standard Deviation 0.06	0.12 complete bowel movements / day Standard Deviation 0.15	0.19 complete bowel movements / day Standard Deviation 0.15
Change From Baseline to 48 Hours Post-dose in Number of Complete Bowel Movements Per Day 48 hours post-dose	0.08 complete bowel movements / day Standard Deviation 0.19	0.17 complete bowel movements / day Standard Deviation 0.25	0.17 complete bowel movements / day Standard Deviation 0.25	0.22 complete bowel movements / day Standard Deviation 0.36	0.06 complete bowel movements / day Standard Deviation 0.17	1.39 complete bowel movements / day Standard Deviation 1.34	1.61 complete bowel movements / day Standard Deviation 1.52
Change From Baseline to 48 Hours Post-dose in Number of Complete Bowel Movements Per Day Change from Baseline to 48 hours post-dose	-0.04 complete bowel movements / day Standard Deviation 0.17	0.04 complete bowel movements / day Standard Deviation 0.15	0.06 complete bowel movements / day Standard Deviation 0.28	0.09 complete bowel movements / day Standard Deviation 0.38	0.01 complete bowel movements / day Standard Deviation 0.19	1.27 complete bowel movements / day Standard Deviation 1.38	1.42 complete bowel movements / day Standard Deviation 1.53

SECONDARY outcome

Timeframe: Baseline, 24 hours post-dose and 48 hours post-dose

Population: Intent-to-treat population with available data at each time point.

Participants were asked to rate their abdominal bloating for the past 24 hours using the following scale:

0 = Absent; 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Very Severe. Baseline was defined as the average abdominal bloating score prior to receiving study drug (Day 1 to Day 15). Abdominal bloating at 24 hours and 48 hours post-dose was calculated as the mean score from 0 to 24 and 0 to 48 hours post-dose respectively.

Outcome measures

Measure	Pooled Placebo n=18 Participants Participants received a single dose of matching placebo administered orally on Day 15 under fasted conditions.	Naldemedine 0.01 mg n=9 Participants Participants received a single dose of 0.01 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.03 mg n=9 Participants Participants received a single dose of 0.03 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.1 mg n=9 Participants Participants received one 0.1 mg naldemedine tablet administered on Day 15 under fasted conditions.	Naldemedine 0.3 mg n=9 Participants Participants received a single dose of 0.3 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 1 mg n=9 Participants Participants received a single dose of 1 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 3 mg n=9 Participants Participants received a single dose of 3 mg naldemedine tablets administered on Day 15 under fasted conditions.
Change From Baseline in Abdominal Bloating Baseline	2.0 units on a scale Standard Deviation 0.65	1.4 units on a scale Standard Deviation 0.95	1.5 units on a scale Standard Deviation 0.69	1.7 units on a scale Standard Deviation 0.87	1.7 units on a scale Standard Deviation 0.66	2.5 units on a scale Standard Deviation 0.64	1.3 units on a scale Standard Deviation 0.65
Change From Baseline in Abdominal Bloating Change from Baseline to 24 hours post-dose	0.0 units on a scale Standard Deviation 0.83	0.0 units on a scale Standard Deviation NA Cannot be calculated when n=1	0.2 units on a scale Standard Deviation 1.09	-0.2 units on a scale Standard Deviation 1.03	0.3 units on a scale Standard Deviation 0.69	-0.5 units on a scale Standard Deviation 0.91	0.7 units on a scale Standard Deviation 1.53
Change From Baseline in Abdominal Bloating Change from Baseline to 48 hours post-dose	-0.5 units on a scale Standard Deviation 0.54	0.1 units on a scale Standard Deviation 0.86	0.2 units on a scale Standard Deviation 1.17	0.1 units on a scale Standard Deviation 0.89	0.4 units on a scale Standard Deviation NA Cannot be calculated when n=1	-0.8 units on a scale Standard Deviation 0.5	-0.2 units on a scale Standard Deviation 1.95

SECONDARY outcome

Timeframe: Baseline, 24 hours post-dose and 48 hours post-dose

Population: Intent-to-treat population with available data at each time point.

Participants were asked to rate their abdominal discomfort for the past 24 hours using the following scale:

0 = Absent; 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Very Severe. Baseline was defined as the average abdominal discomfort score prior to receiving study drug (Day 1 to Day 15). Abdominal discomfort at 24 hours and 48 hours post-dose was calculated as the mean score from 0 to 24 and 0 to 48 hours post-dose respectively.

Outcome measures

Measure	Pooled Placebo n=18 Participants Participants received a single dose of matching placebo administered orally on Day 15 under fasted conditions.	Naldemedine 0.01 mg n=9 Participants Participants received a single dose of 0.01 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.03 mg n=9 Participants Participants received a single dose of 0.03 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.1 mg n=9 Participants Participants received one 0.1 mg naldemedine tablet administered on Day 15 under fasted conditions.	Naldemedine 0.3 mg n=9 Participants Participants received a single dose of 0.3 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 1 mg n=9 Participants Participants received a single dose of 1 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 3 mg n=9 Participants Participants received a single dose of 3 mg naldemedine tablets administered on Day 15 under fasted conditions.
Change From Baseline in Abdominal Discomfort Baseline	2.1 units on a scale Standard Deviation 0.63	1.5 units on a scale Standard Deviation 0.98	2.0 units on a scale Standard Deviation 0.75	2.0 units on a scale Standard Deviation 0.74	1.9 units on a scale Standard Deviation 0.81	2.6 units on a scale Standard Deviation 0.77	1.7 units on a scale Standard Deviation 0.77
Change From Baseline in Abdominal Discomfort Change from Baseline to 24 hours post-dose	-0.2 units on a scale Standard Deviation 0.78	-0.8 units on a scale Standard Deviation NA Cannot be calculated when n=1	-0.5 units on a scale Standard Deviation 0.80	-0.7 units on a scale Standard Deviation 1.30	0.3 units on a scale Standard Deviation 0.60	-0.1 units on a scale Standard Deviation 0.96	1.3 units on a scale Standard Deviation 0.90
Change From Baseline in Abdominal Discomfort Change from Baseline to 48 hours post-dose	-0.4 units on a scale Standard Deviation 0.67	-0.3 units on a scale Standard Deviation 1.00	-0.2 units on a scale Standard Deviation 1.00	-0.4 units on a scale Standard Deviation 0.44	1.1 units on a scale Standard Deviation NA Cannot be calculated when n=1	-1.1 units on a scale Standard Deviation 1.07	-0.1 units on a scale Standard Deviation 1.59

SECONDARY outcome

Timeframe: Baseline, 24 hours post-dose and 48 hours post-dose

Population: Intent-to-treat population with available data at each time point.

Consistency of BMs was measured using the Bristol Stool Scale, as follows:

1 = separate hard lumps like nuts; 2 = sausage shaped but lumpy; 3 = like a sausage, but with cracks on its surface; 4 = like a sausage or a snake, smooth and soft; 5 = soft blobs and with clear-cut edges; 6 = floppy pieces with ragged edges/mushy stool; 7 = watery, no solid pieces, entirely liquid.

Baseline was defined as the average consistency of BMs prior to receiving study drug (Day 1 to Day 15). BM consistency at 24 hours and 48 hours post-dose was calculated as the average scores from all bowel movements from 0 to 24 and 0 to 48 hours post-dose, respectively.

Outcome measures

Measure	Pooled Placebo n=18 Participants Participants received a single dose of matching placebo administered orally on Day 15 under fasted conditions.	Naldemedine 0.01 mg n=9 Participants Participants received a single dose of 0.01 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.03 mg n=9 Participants Participants received a single dose of 0.03 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.1 mg n=9 Participants Participants received one 0.1 mg naldemedine tablet administered on Day 15 under fasted conditions.	Naldemedine 0.3 mg n=9 Participants Participants received a single dose of 0.3 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 1 mg n=9 Participants Participants received a single dose of 1 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 3 mg n=9 Participants Participants received a single dose of 3 mg naldemedine tablets administered on Day 15 under fasted conditions.
Change From Baseline in BM Consistency Change from Baseline to 48 hours post-dose	-1.0 units on a scale Standard Deviation 1.45	0.2 units on a scale Standard Deviation 2.45	-0.3 units on a scale Standard Deviation 1.43	-1.0 units on a scale Standard Deviation 2.00	0.6 units on a scale Standard Deviation NA Cannot be calculated when n=1	0.7 units on a scale Standard Deviation 3.66	2.5 units on a scale Standard Deviation 1.88
Change From Baseline in BM Consistency Baseline	2.9 units on a scale Standard Deviation 1.24	3.2 units on a scale Standard Deviation 1.13	2.2 units on a scale Standard Deviation 1.12	3.0 units on a scale Standard Deviation 1.71	3.2 units on a scale Standard Deviation 1.33	3.2 units on a scale Standard Deviation 2.06	2.2 units on a scale Standard Deviation 0.81
Change From Baseline in BM Consistency Change from Baseline to 24 hours post-dose	-1.4 units on a scale Standard Deviation 1.09	-3.0 units on a scale Standard Deviation NA Cannot be calculated when n=1	-0.0 units on a scale Standard Deviation 0.24	-1.4 units on a scale Standard Deviation 1.56	1.5 units on a scale Standard Deviation 1.44	1.9 units on a scale Standard Deviation 3.27	4.1 units on a scale Standard Deviation 1.07

SECONDARY outcome

Timeframe: Baseline, 24 hours post-dose and 48 hours post-dose

Population: Intent-to-treat population; LOCF imputation was used

A false start was defined as any attempted, but unsuccessful bowel movement (no solid or liquid fecal material was excreted) based on the question "In the past 24 hours, how many times did you try to have a bowel movement but were unsuccessful?" Baseline was defined as the average number of false start BMs per day prior to receiving study drug (Day 1 to Day 15).

The number of false start BMs per day at 24 hours and 48 hours post-dose was calculated as is the average number of false start BMs per day from 0 to 24 and 0 to 48 hours post-dose, respectively.

Outcome measures

Measure	Pooled Placebo n=18 Participants Participants received a single dose of matching placebo administered orally on Day 15 under fasted conditions.	Naldemedine 0.01 mg n=9 Participants Participants received a single dose of 0.01 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.03 mg n=9 Participants Participants received a single dose of 0.03 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.1 mg n=9 Participants Participants received one 0.1 mg naldemedine tablet administered on Day 15 under fasted conditions.	Naldemedine 0.3 mg n=9 Participants Participants received a single dose of 0.3 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 1 mg n=9 Participants Participants received a single dose of 1 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 3 mg n=9 Participants Participants received a single dose of 3 mg naldemedine tablets administered on Day 15 under fasted conditions.
Change From Baseline in Number of False Start Bowel Movements Per Day Baseline	0.56 false start bowel movements / day Standard Deviation 0.86	0.67 false start bowel movements / day Standard Deviation 1.00	0.67 false start bowel movements / day Standard Deviation 1.12	0.22 false start bowel movements / day Standard Deviation 0.44	0.56 false start bowel movements / day Standard Deviation 1.01	0.00 false start bowel movements / day Standard Deviation 0.00	0.33 false start bowel movements / day Standard Deviation 0.50
Change From Baseline in Number of False Start Bowel Movements Per Day Change from Baseline to 24 hours post-dose	0.28 false start bowel movements / day Standard Deviation 0.89	0.44 false start bowel movements / day Standard Deviation 1.33	-0.11 false start bowel movements / day Standard Deviation 1.17	0.00 false start bowel movements / day Standard Deviation 0.50	-0.11 false start bowel movements / day Standard Deviation 0.60	2.56 false start bowel movements / day Standard Deviation 3.81	0.78 false start bowel movements / day Standard Deviation 1.79
Change From Baseline in Number of False Start Bowel Movements Per Day Change from Baseline to 48 hours post-dose	0.25 false start bowel movements / day Standard Deviation 0.69	0.28 false start bowel movements / day Standard Deviation 1.18	0.22 false start bowel movements / day Standard Deviation 1.48	0.00 false start bowel movements / day Standard Deviation 0.50	-0.06 false start bowel movements / day Standard Deviation 0.58	1.61 false start bowel movements / day Standard Deviation 2.42	0.44 false start bowel movements / day Standard Deviation 0.77

SECONDARY outcome

Timeframe: Baseline, 24 hours post-dose and 48 hours post-dose

Population: Intent-to-treat population; LOCF imputation was used

Straining during BMs was graded using the following scale:

0 = Absent; 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Very Severe. A BM without straining was defined as a BM with a straining score = 0.

Baseline was defined as the average number of BMs without straining per day prior to receiving study drug (Day 1 to Day 15). The number of BMs without straining per day at 24 hours and 48 hours post-dose was calculated as the average number of BMs with no straining per day from 0 to 24 hours and 0 to 48 hours post-dose, respectively.

Outcome measures

Measure	Pooled Placebo n=18 Participants Participants received a single dose of matching placebo administered orally on Day 15 under fasted conditions.	Naldemedine 0.01 mg n=9 Participants Participants received a single dose of 0.01 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.03 mg n=9 Participants Participants received a single dose of 0.03 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.1 mg n=9 Participants Participants received one 0.1 mg naldemedine tablet administered on Day 15 under fasted conditions.	Naldemedine 0.3 mg n=9 Participants Participants received a single dose of 0.3 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 1 mg n=9 Participants Participants received a single dose of 1 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 3 mg n=9 Participants Participants received a single dose of 3 mg naldemedine tablets administered on Day 15 under fasted conditions.
Change From Baseline in the Number of Bowel Movements With No Straining Per Day Baseline	0.03 bowel movements with no straining / day Standard Deviation 0.07	0.09 bowel movements with no straining / day Standard Deviation 0.11	0.05 bowel movements with no straining / day Standard Deviation 0.09	0.03 bowel movements with no straining / day Standard Deviation 0.07	0.05 bowel movements with no straining / day Standard Deviation 0.07	0.03 bowel movements with no straining / day Standard Deviation 0.05	0.07 bowel movements with no straining / day Standard Deviation 0.11
Change From Baseline in the Number of Bowel Movements With No Straining Per Day Change from Baseline to 24 hours post-dose	-0.03 bowel movements with no straining / day Standard Deviation 0.07	-0.09 bowel movements with no straining / day Standard Deviation 0.11	0.06 bowel movements with no straining / day Standard Deviation 0.36	-0.03 bowel movements with no straining / day Standard Deviation 0.07	0.28 bowel movements with no straining / day Standard Deviation 0.71	0.41 bowel movements with no straining / day Standard Deviation 0.74	3.37 bowel movements with no straining / day Standard Deviation 2.16
Change From Baseline in the Number of Bowel Movements With No Straining Per Day Change from Baseline to 48 hours post-dose	-0.01 bowel movements with no straining / day Standard Deviation 0.14	-0.03 bowel movements with no straining / day Standard Deviation 0.13	0.01 bowel movements with no straining / day Standard Deviation 0.21	-0.03 bowel movements with no straining / day Standard Deviation 0.07	0.12 bowel movements with no straining / day Standard Deviation 0.36	0.19 bowel movements with no straining / day Standard Deviation 0.38	1.76 bowel movements with no straining / day Standard Deviation 1.02

SECONDARY outcome

Timeframe: Baseline, 24 hours post-dose and 48 hours post-dose

Population: Intent-to-treat population; LOCF imputation was used

Baseline was defined as the average number of rescue medications used per day prior to receiving study drug (Day 1 to Day 15). The number of rescue medications used per day at 24 hours and 48 hours post-dose was calculated as the average number of rescue medications used per day from 0 to 24 hours and 0 to 48 hours post-dose, respectively.

Outcome measures

Measure	Pooled Placebo n=18 Participants Participants received a single dose of matching placebo administered orally on Day 15 under fasted conditions.	Naldemedine 0.01 mg n=9 Participants Participants received a single dose of 0.01 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.03 mg n=9 Participants Participants received a single dose of 0.03 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.1 mg n=9 Participants Participants received one 0.1 mg naldemedine tablet administered on Day 15 under fasted conditions.	Naldemedine 0.3 mg n=9 Participants Participants received a single dose of 0.3 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 1 mg n=9 Participants Participants received a single dose of 1 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 3 mg n=9 Participants Participants received a single dose of 3 mg naldemedine tablets administered on Day 15 under fasted conditions.
Change From Baseline in Number of Rescue Medications Used Per Day Change from Baseline to 24 hours post-dose	-0.04 rescue medications / day Standard Deviation 0.70	-0.18 rescue medications / day Standard Deviation 0.21	-0.36 rescue medications / day Standard Deviation 0.43	0.02 rescue medications / day Standard Deviation 1.13	-0.52 rescue medications / day Standard Deviation 0.84	-0.28 rescue medications / day Standard Deviation 0.36	-0.20 rescue medications / day Standard Deviation 0.24
Change From Baseline in Number of Rescue Medications Used Per Day Baseline	0.31 rescue medications / day Standard Deviation 0.36	0.18 rescue medications / day Standard Deviation 0.21	0.36 rescue medications / day Standard Deviation 0.43	0.53 rescue medications / day Standard Deviation 0.68	0.52 rescue medications / day Standard Deviation 0.84	0.28 rescue medications / day Standard Deviation 0.36	0.20 rescue medications / day Standard Deviation 0.24
Change From Baseline in Number of Rescue Medications Used Per Day Change from Baseline to 48 hours post-dose	-0.04 rescue medications / day Standard Deviation 0.51	-0.01 rescue medications / day Standard Deviation 0.36	-0.25 rescue medications / day Standard Deviation 0.37	0.08 rescue medications / day Standard Deviation 0.80	-0.52 rescue medications / day Standard Deviation 0.84	-0.23 rescue medications / day Standard Deviation 0.38	-0.20 rescue medications / day Standard Deviation 0.24

SECONDARY outcome

Timeframe: The COWS assessments were performed at Screening, on Day 14, Day 15 (pre-dose and 1, 2, 3, 4, 5, 6 and 8 hours post-dose, and at unscheduled times as signs or symptoms indicate), on Days 16 and 17, and on Day 24/End of Study.

Population: Safety population

The COWS assessment consisted of 11 questions which rated the severity of opiate withdrawal symptoms, including resting pulse rate, gastrointestinal upset, sweating, restlessness, pupil size, tremor, anxiety or irritability, bone or joint aches, gooseflesh skin, yawning, and runny nose or tearing. Each symptom was rated on a scale from 0 (not present) to 4 or 5 (most severe). The total score was calculated by summing the 11 individual scores and ranged from 0 (no withdrawal symptoms) to 48 (worst symptoms).

Outcome measures

Measure	Pooled Placebo n=18 Participants Participants received a single dose of matching placebo administered orally on Day 15 under fasted conditions.	Naldemedine 0.01 mg n=9 Participants Participants received a single dose of 0.01 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.03 mg n=9 Participants Participants received a single dose of 0.03 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.1 mg n=9 Participants Participants received one 0.1 mg naldemedine tablet administered on Day 15 under fasted conditions.	Naldemedine 0.3 mg n=9 Participants Participants received a single dose of 0.3 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 1 mg n=9 Participants Participants received a single dose of 1 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 3 mg n=9 Participants Participants received a single dose of 3 mg naldemedine tablets administered on Day 15 under fasted conditions.
Percentage of Participants With Clinical Opiate Withdrawal Scale (COWS) Score > 8 at Any Time During the Study	0.0 percentage of participants Interval 0.0 to 18.5	0.0 percentage of participants Interval 0.0 to 33.6	0.0 percentage of participants Interval 0.0 to 33.6	0.0 percentage of participants Interval 0.0 to 33.6	0.0 percentage of participants Interval 0.0 to 33.6	11.1 percentage of participants Interval 0.3 to 48.2	66.7 percentage of participants Interval 29.9 to 92.5

SECONDARY outcome

Timeframe: The WOWS assessment was performed at Screening, Day 14, Day 15 at pre-dose , and 24 and 48 hours post-dose and at the Follow-up/End of Study visit (Day 24).

Population: Safety population

The Webster Opiate Withdrawal Scale (WOWS) assessment consisted of 7 questions which rate the severity of opiate withdrawal symptoms, including sweating, sleep, bone or joint aches, runny nose or tearing, gastrointestinal upset, anxiety or irritability and gooseflesh skin. Each symptom was rated on a scale from 0 (not present/no issues) to 4 or 5 (severe). The total score was calculated by summing the 7 individual scores and ranged from 0 (no withdrawal symptoms) to 29 (worst symptoms).

Outcome measures

Measure	Pooled Placebo n=18 Participants Participants received a single dose of matching placebo administered orally on Day 15 under fasted conditions.	Naldemedine 0.01 mg n=9 Participants Participants received a single dose of 0.01 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.03 mg n=9 Participants Participants received a single dose of 0.03 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.1 mg n=9 Participants Participants received one 0.1 mg naldemedine tablet administered on Day 15 under fasted conditions.	Naldemedine 0.3 mg n=9 Participants Participants received a single dose of 0.3 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 1 mg n=9 Participants Participants received a single dose of 1 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 3 mg n=9 Participants Participants received a single dose of 3 mg naldemedine tablets administered on Day 15 under fasted conditions.
Percentage of Participants With Webster Opiate Withdrawal Scale (WOWS) Score > 8 at Any Time During the Study	0.0 percentage of participants Interval 0.0 to 18.5	0.0 percentage of participants Interval 0.0 to 33.6	0.0 percentage of participants Interval 0.0 to 33.6	0.0 percentage of participants Interval 0.0 to 33.6	11.1 percentage of participants Interval 0.3 to 48.2	0.0 percentage of participants Interval 0.0 to 33.6	0.0 percentage of participants Interval 0.0 to 33.6

SECONDARY outcome

Timeframe: Blood samples were collected predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post-dose.

Population: The pharmacokinetic (PK) analysis population included all randomized participants who received study drug and had at least one post-dose PK assessment completed.

The plasma concentration of naldemedine and its metabolite Nor-S-297995 were measured by liquid chromatography/tandem mass spectrometry (LC/MS/MS) method.

Outcome measures

Measure	Pooled Placebo n=9 Participants Participants received a single dose of matching placebo administered orally on Day 15 under fasted conditions.	Naldemedine 0.01 mg n=9 Participants Participants received a single dose of 0.01 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.03 mg n=9 Participants Participants received a single dose of 0.03 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.1 mg n=9 Participants Participants received one 0.1 mg naldemedine tablet administered on Day 15 under fasted conditions.	Naldemedine 0.3 mg n=9 Participants Participants received a single dose of 0.3 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 1 mg n=9 Participants Participants received a single dose of 1 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 3 mg Participants received a single dose of 3 mg naldemedine tablets administered on Day 15 under fasted conditions.
Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995 Naldemedine	0.0837 ng/mL Geometric Coefficient of Variation 29.6	0.290 ng/mL Geometric Coefficient of Variation 28.9	1.00 ng/mL Geometric Coefficient of Variation 28.4	3.12 ng/mL Geometric Coefficient of Variation 30.2	9.68 ng/mL Geometric Coefficient of Variation 31.3	30.9 ng/mL Geometric Coefficient of Variation 44.2	—
Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995 Nor-S-297995	NA ng/mL Geometric Coefficient of Variation NA Nor-S-297995 could not be quantified	NA ng/mL Geometric Coefficient of Variation NA Nor-S-297995 could not be quantified	0.0713 ng/mL Geometric Coefficient of Variation 31.8	0.134 ng/mL Geometric Coefficient of Variation 27.6	0.526 ng/mL Geometric Coefficient of Variation 49.4	1.50 ng/mL Geometric Coefficient of Variation 53.3	—

SECONDARY outcome

Timeframe: Blood samples were collected predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post-dose.

Population: PK population

The plasma concentration of naldemedine and its metabolite Nor-S-297995 were measured by liquid chromatography/tandem mass spectrometry (LC/MS/MS) method.

Outcome measures

Measure	Pooled Placebo n=9 Participants Participants received a single dose of matching placebo administered orally on Day 15 under fasted conditions.	Naldemedine 0.01 mg n=9 Participants Participants received a single dose of 0.01 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.03 mg n=9 Participants Participants received a single dose of 0.03 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.1 mg n=9 Participants Participants received one 0.1 mg naldemedine tablet administered on Day 15 under fasted conditions.	Naldemedine 0.3 mg n=9 Participants Participants received a single dose of 0.3 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 1 mg n=9 Participants Participants received a single dose of 1 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 3 mg Participants received a single dose of 3 mg naldemedine tablets administered on Day 15 under fasted conditions.
Time to Maximum Observed Plasma Concentration of Naldemedine and Metabolite Nor-S-297995 Naldemedine	0.75 hours Interval 0.5 to 3.0	1.0 hours Interval 0.5 to 4.0	2.5 hours Interval 0.5 to 5.0	1.0 hours Interval 0.72 to 3.0	1.0 hours Interval 0.75 to 2.0	0.75 hours Interval 0.5 to 1.0	—
Time to Maximum Observed Plasma Concentration of Naldemedine and Metabolite Nor-S-297995 Nor-S-297995	NA hours Nor-S-297995 could not be quantified	NA hours Nor-S-297995 could not be quantified	5.0 hours Interval 2.5 to 12.0	4.1 hours Interval 3.0 to 8.0	8.0 hours Interval 4.0 to 12.0	5.0 hours Interval 3.0 to 10.0	—

SECONDARY outcome

Timeframe: Blood samples were collected predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post-dose.

Population: PK population

The plasma concentration of naldemedine and its metabolite Nor-S-297995 were measured by liquid chromatography/tandem mass spectrometry (LC/MS/MS) method. Area under the plasma concentration versus time curve from time zero to the last sampling time at which concentrations were at or above the limit of quantitation, calculated using the linear trapezoidal rule for increasing concentrations and the logarithmic rule for decreasing concentrations (Linear Up/ Log Down).

Outcome measures

Measure	Pooled Placebo n=9 Participants Participants received a single dose of matching placebo administered orally on Day 15 under fasted conditions.	Naldemedine 0.01 mg n=9 Participants Participants received a single dose of 0.01 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.03 mg n=9 Participants Participants received a single dose of 0.03 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.1 mg n=9 Participants Participants received one 0.1 mg naldemedine tablet administered on Day 15 under fasted conditions.	Naldemedine 0.3 mg n=9 Participants Participants received a single dose of 0.3 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 1 mg n=9 Participants Participants received a single dose of 1 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 3 mg Participants received a single dose of 3 mg naldemedine tablets administered on Day 15 under fasted conditions.
Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable Concentration of Naldemedine and Metabolite Nor-S-297995 Naldemedine	0.5863 ng*hr/mL) Geometric Coefficient of Variation 34.3	2.111 ng*hr/mL) Geometric Coefficient of Variation 31.4	11.71 ng*hr/mL) Geometric Coefficient of Variation 21.4	31.29 ng*hr/mL) Geometric Coefficient of Variation 30.5	93.60 ng*hr/mL) Geometric Coefficient of Variation 34.6	218.2 ng*hr/mL) Geometric Coefficient of Variation 37.6	—
Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable Concentration of Naldemedine and Metabolite Nor-S-297995 Nor-S-297995	NA ng*hr/mL) Geometric Coefficient of Variation NA Nor-S-297995 could not be quantified	NA ng*hr/mL) Geometric Coefficient of Variation NA Nor-S-297995 could not be quantified	0.5856 ng*hr/mL) Geometric Coefficient of Variation 232.7	1.869 ng*hr/mL) Geometric Coefficient of Variation 68.3	14.97 ng*hr/mL) Geometric Coefficient of Variation 76.3	41.94 ng*hr/mL) Geometric Coefficient of Variation 63.3	—

SECONDARY outcome

Timeframe: Blood samples were collected predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post-dose.

Population: PK population

The plasma concentration of naldemedine and its metabolite Nor-S-297995 were measured by liquid chromatography/tandem mass spectrometry (LC/MS/MS) method. Area under the plasma concentration versus time curve from time zero to infinity, calculated using the formula: AUC0-inf = AUC0-t + Ct/λZ where Ct was the last measurable concentration and λZ was the apparent terminal elimination rate constant.

Outcome measures

Measure	Pooled Placebo n=9 Participants Participants received a single dose of matching placebo administered orally on Day 15 under fasted conditions.	Naldemedine 0.01 mg n=9 Participants Participants received a single dose of 0.01 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.03 mg n=9 Participants Participants received a single dose of 0.03 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.1 mg n=9 Participants Participants received one 0.1 mg naldemedine tablet administered on Day 15 under fasted conditions.	Naldemedine 0.3 mg n=9 Participants Participants received a single dose of 0.3 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 1 mg n=9 Participants Participants received a single dose of 1 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 3 mg Participants received a single dose of 3 mg naldemedine tablets administered on Day 15 under fasted conditions.
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity for Naldemedine and Metabolite Nor-S-297995 Naldemedine	0.8023 ng*hr/mL Geometric Coefficient of Variation 33.8	2.294 ng*hr/mL Geometric Coefficient of Variation 30.2	12.04 ng*hr/mL Geometric Coefficient of Variation 21.7	31.87 ng*hr/mL Geometric Coefficient of Variation 29.9	94.53 ng*hr/mL Geometric Coefficient of Variation 34.8	219.9 ng*hr/mL Geometric Coefficient of Variation 37.8	—
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity for Naldemedine and Metabolite Nor-S-297995 Nor-S-297995	NA ng*hr/mL Geometric Coefficient of Variation NA Nor-S-297995 could not be quantified	NA ng*hr/mL Geometric Coefficient of Variation NA Nor-S-297995 could not be quantified	3.046 ng*hr/mL Geometric Coefficient of Variation 63.0	4.515 ng*hr/mL Geometric Coefficient of Variation 58.8	17.10 ng*hr/mL Geometric Coefficient of Variation 73.4	44.91 ng*hr/mL Geometric Coefficient of Variation 63.6	—

SECONDARY outcome

Timeframe: Blood samples were collected predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post-dose.

Population: PK population

The plasma concentration of naldemedine and its metabolite Nor-S-297995 were measured by liquid chromatography/tandem mass spectrometry (LC/MS/MS) method. The apparent elimination half-life was calculated using the formula t1/2,z = (ln2)/λZ

Outcome measures

Measure	Pooled Placebo n=9 Participants Participants received a single dose of matching placebo administered orally on Day 15 under fasted conditions.	Naldemedine 0.01 mg n=9 Participants Participants received a single dose of 0.01 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.03 mg n=9 Participants Participants received a single dose of 0.03 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.1 mg n=9 Participants Participants received one 0.1 mg naldemedine tablet administered on Day 15 under fasted conditions.	Naldemedine 0.3 mg n=9 Participants Participants received a single dose of 0.3 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 1 mg n=9 Participants Participants received a single dose of 1 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 3 mg Participants received a single dose of 3 mg naldemedine tablets administered on Day 15 under fasted conditions.
Apparent Elimination Half-life of Naldemedine and Metabolite Nor-S-297995 Naldemedine	8.13 hours Geometric Coefficient of Variation 58.3	7.46 hours Geometric Coefficient of Variation 38.5	12.6 hours Geometric Coefficient of Variation 35.6	12.2 hours Geometric Coefficient of Variation 34.6	10.8 hours Geometric Coefficient of Variation 20.9	11.6 hours Geometric Coefficient of Variation 20.8	—
Apparent Elimination Half-life of Naldemedine and Metabolite Nor-S-297995 Nor-S-297995	NA hours Geometric Coefficient of Variation NA Nor-S-297995 could not be quantified	NA hours Geometric Coefficient of Variation NA Nor-S-297995 could not be quantified	24.6 hours Geometric Coefficient of Variation 52.7	25.7 hours Geometric Coefficient of Variation 61.8	16.0 hours Geometric Coefficient of Variation 24.8	17.0 hours Geometric Coefficient of Variation 18.1	—

Adverse Events

Pooled Placebo

Serious events: 0 serious events

Other events: 9 other events

Deaths: 0 deaths

Naldemedine 0.01 mg

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

Naldemedine 0.03 mg

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

Naldemedine 0.1 mg

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Naldemedine 0.3 mg

Serious events: 0 serious events

Other events: 9 other events

Deaths: 0 deaths

Naldemedine 1 mg

Serious events: 0 serious events

Other events: 9 other events

Deaths: 0 deaths

Naldemedine 3 mg

Serious events: 0 serious events

Other events: 9 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Pooled Placebo n=18 participants at risk Participants received a single dose of matching placebo administered orally on Day 15 under fasted conditions.	Naldemedine 0.01 mg n=9 participants at risk Participants received a single dose of 0.01 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.03 mg n=9 participants at risk Participants received a single dose of 0.03 mg naldemedine oral solution administered on Day 15 under fasted conditions.	Naldemedine 0.1 mg n=9 participants at risk Participants received one 0.1 mg naldemedine tablet administered on Day 15 under fasted conditions.	Naldemedine 0.3 mg n=9 participants at risk Participants received a single dose of 0.3 mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 1 mg n=9 participants at risk Participants received a single dose of 1mg naldemedine tablets administered on Day 15 under fasted conditions.	Naldemedine 3 mg n=9 participants at risk Participants received a single dose of 3 mg naldemedine tablets administered on Day 15 under fasted conditions.
Gastrointestinal disorders Abdominal pain	16.7% 3/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	22.2% 2/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	66.7% 6/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	66.7% 6/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	100.0% 9/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Gastrointestinal disorders Nausea	16.7% 3/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	44.4% 4/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	77.8% 7/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	66.7% 6/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Gastrointestinal disorders Diarrhoea	5.6% 1/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	22.2% 2/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	33.3% 3/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	88.9% 8/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Gastrointestinal disorders Vomiting	5.6% 1/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	33.3% 3/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	66.7% 6/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Gastrointestinal disorders Flatulence	11.1% 2/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	22.2% 2/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	22.2% 2/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Gastrointestinal disorders Abdominal pain upper	5.6% 1/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	22.2% 2/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Gastrointestinal disorders Abdominal discomfort	5.6% 1/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Gastrointestinal disorders Abdominal distension	5.6% 1/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Gastrointestinal disorders Dyspepsia	5.6% 1/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Gastrointestinal disorders Retching	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	22.2% 2/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Gastrointestinal disorders Abdominal tenderness	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Gastrointestinal disorders Eructation	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Gastrointestinal disorders Tongue discolouration	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Gastrointestinal disorders Proctalgia	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
General disorders Chills	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	22.2% 2/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	66.7% 6/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
General disorders Oedema peripheral	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
General disorders Drug withdrawal syndrome	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
General disorders Fatigue	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
General disorders Pyrexia	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
General disorders Venipuncture site thrombosis	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
General disorders Infusion site rash	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Skin and subcutaneous tissue disorders Hyperhidrosis	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	44.4% 4/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	66.7% 6/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Skin and subcutaneous tissue disorders Cold sweat	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Skin and subcutaneous tissue disorders Rash	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Nervous system disorders Dizziness	5.6% 1/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	22.2% 2/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	22.2% 2/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	33.3% 3/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Nervous system disorders Headache	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	22.2% 2/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	33.3% 3/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Nervous system disorders Lethargy	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Nervous system disorders Hypoaesthesia	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Nervous system disorders Migraine	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Nervous system disorders Paraesthesia	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Nervous system disorders Somnolence	5.6% 1/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Investigations Oxygen saturation decreased	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	44.4% 4/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Investigations Cardiac murmur	11.1% 2/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Investigations Blood glucose decreased	5.6% 1/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Investigations Blood prolactin increased	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Investigations Heart rate irregular	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Investigations Weight decreased	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Respiratory, thoracic and mediastinal disorders Wheezing	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Vascular disorders Pallor	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	22.2% 2/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Vascular disorders Flushing	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Vascular disorders Hot flush	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Vascular disorders Hypotension	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Ear and labyrinth disorders Tinnitus	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Eye disorders Lacrimation increased	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Infections and infestations Oral herpes	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Injury, poisoning and procedural complications Sunburn	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Metabolism and nutrition disorders Dehydration	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).
Renal and urinary disorders Dysuria	0.00% 0/18 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	0.00% 0/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).	11.1% 1/9 • From first dose of study drug on Day 15 up to Day 24 (10 days).

Additional Information

Shionogi Clinical Trials Administrator

Shionogi Inc.

Phone: 800-849-9707

Email: shionogiclintrials-admin@shionogi.co.jp

Results disclosure agreements

• Principal investigator is a sponsor employee The sponsor can embargo results from a PI's center until the combined results from the completed study have been published in full or the sponsor confirms there will be no multicenter study publication. Results communications must be provided to the sponsor for review at least 60 days before submission for publication. By written request, the sponsor can extend the embargo up to an additional 60 days. The sponsor cannot require changes to scientific content and cannot further extend the embargo.
• Publication restrictions are in place

Restriction type: OTHER