Trial Outcomes & Findings for A Study of Naldemedine (S-297995) for the Treatment of Opioid-Induced Constipation in Adults With Non-Malignant Chronic Pain Receiving Opioid Therapy (NCT NCT01443403)

NCT ID: NCT01443403

Last Updated: 2017-06-26

Results Overview

Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation. A spontaneous bowel movement was defined as a bowel movement unassisted by rescue medication (laxative or enema) taken within the 24 hours preceding the bowel movement. Baseline was defined as the average number of SBMs per week during the 2 weeks prior to randomization. The number of SBMs per week in the last 2 weeks of treatment is defined as the average number of SBMs per week recorded in the diary for the 14 days prior to the last dose of study drug.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 244 participants
• Primary outcome timeframe: Baseline (2 weeks prior to randomization) and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)
• Results posted on: 2017-06-26

Participant Flow

This study was conducted at 53 clinical sites in the United States. The first participant was enrolled on August 17, 2011 and the last participant completed on August 22, 2012. Participants must have met eligibility criteria and completed the Bowel Movement and Constipation Assessment (BMCA) Diary for a minimum of 14 days to enroll in the study.

Participants were randomized in a 1:1:1:1 ratio to receive placebo, naldemedine 0.1 mg, 0.2 mg, or 0.4 mg once daily. One participant was randomized twice, first to placebo and subsequently to naldemedine 0.4 mg, and is counted in both arms below and for safety analyses.

Participant milestones

Measure	Placebo Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg Participants received 0.4 mg naldemedine orally once daily for 28 days.
Overall Study STARTED	61	61	61	61
Overall Study Received Treatment	61	61	60	61
Overall Study COMPLETED	55	55	54	52
Overall Study NOT COMPLETED	6	6	7	9

Reasons for withdrawal

Measure	Placebo Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg Participants received 0.4 mg naldemedine orally once daily for 28 days.
Overall Study Adverse Event	1	1	4	5
Overall Study Withdrawal by Subject	0	1	2	1
Overall Study Lost to Follow-up	0	0	0	1
Overall Study Protocol Violation	2	1	1	1
Overall Study Use of Prohibited Treatment	2	3	0	0
Overall Study Other - Miscellaneous	1	0	0	1

Baseline Characteristics

A Study of Naldemedine (S-297995) for the Treatment of Opioid-Induced Constipation in Adults With Non-Malignant Chronic Pain Receiving Opioid Therapy

Baseline characteristics by cohort

Measure	Placebo n=61 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=59 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=57 Participants Participants received 0.4 mg naldemedine orally once daily for 28 days.	Total n=238 Participants Total of all reporting groups
Age, Continuous	53.1 Years STANDARD_DEVIATION 10.88 • n=5 Participants	49.5 Years STANDARD_DEVIATION 9.71 • n=7 Participants	50.7 Years STANDARD_DEVIATION 11.40 • n=5 Participants	54.1 Years STANDARD_DEVIATION 11.19 • n=4 Participants	51.9 Years STANDARD_DEVIATION 10.80 • n=21 Participants
Age, Customized ≥ 18 - < 40 years	6 participants n=5 Participants	10 participants n=7 Participants	13 participants n=5 Participants	7 participants n=4 Participants	36 participants n=21 Participants
Age, Customized ≥ 40 - < 50 years	14 participants n=5 Participants	18 participants n=7 Participants	8 participants n=5 Participants	12 participants n=4 Participants	52 participants n=21 Participants
Age, Customized ≥ 50 - < 65 years	33 participants n=5 Participants	31 participants n=7 Participants	34 participants n=5 Participants	29 participants n=4 Participants	127 participants n=21 Participants
Age, Customized ≥ 65 - < 75 years	6 participants n=5 Participants	2 participants n=7 Participants	3 participants n=5 Participants	8 participants n=4 Participants	19 participants n=21 Participants
Age, Customized ≥ 75 years	2 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants	1 participants n=4 Participants	4 participants n=21 Participants
Sex: Female, Male Female	45 Participants n=5 Participants	47 Participants n=7 Participants	38 Participants n=5 Participants	37 Participants n=4 Participants	167 Participants n=21 Participants
Sex: Female, Male Male	16 Participants n=5 Participants	14 Participants n=7 Participants	21 Participants n=5 Participants	20 Participants n=4 Participants	71 Participants n=21 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	4 Participants n=5 Participants	6 Participants n=7 Participants	2 Participants n=5 Participants	4 Participants n=4 Participants	16 Participants n=21 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	57 Participants n=5 Participants	55 Participants n=7 Participants	57 Participants n=5 Participants	53 Participants n=4 Participants	222 Participants n=21 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
Race/Ethnicity, Customized American Indian or Alaska Naive	2 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	0 participants n=4 Participants	2 participants n=21 Participants
Race/Ethnicity, Customized Asian	1 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	0 participants n=4 Participants	1 participants n=21 Participants
Race/Ethnicity, Customized Black or African American	9 participants n=5 Participants	11 participants n=7 Participants	12 participants n=5 Participants	6 participants n=4 Participants	38 participants n=21 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	0 participants n=21 Participants
Race/Ethnicity, Customized White	49 participants n=5 Participants	49 participants n=7 Participants	47 participants n=5 Participants	51 participants n=4 Participants	196 participants n=21 Participants
Race/Ethnicity, Customized Other	0 participants n=5 Participants	1 participants n=7 Participants	0 participants n=5 Participants	0 participants n=4 Participants	1 participants n=21 Participants
Spontaneous Bowel Movement (SBM) Frequency per Week	1.22 SBMs/week STANDARD_DEVIATION 0.720 • n=5 Participants	1.51 SBMs/week STANDARD_DEVIATION 0.820 • n=7 Participants	1.52 SBMs/week STANDARD_DEVIATION 0.916 • n=5 Participants	1.20 SBMs/week STANDARD_DEVIATION 0.948 • n=4 Participants	1.36 SBMs/week STANDARD_DEVIATION 0.851 • n=21 Participants

PRIMARY outcome

Timeframe: Baseline (2 weeks prior to randomization) and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)

Population: Modified intention-to-treat population

Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation.

A spontaneous bowel movement was defined as a bowel movement unassisted by rescue medication (laxative or enema) taken within the 24 hours preceding the bowel movement. Baseline was defined as the average number of SBMs per week during the 2 weeks prior to randomization. The number of SBMs per week in the last 2 weeks of treatment is defined as the average number of SBMs per week recorded in the diary for the 14 days prior to the last dose of study drug.

Outcome measures

Measure	Placebo n=61 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=59 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=57 Participants Participants received 0.4 mg naldemedine orally once daily for 28 days.
Change From Baseline to Last 2 Weeks of the Treatment Period in the Number of Spontaneous Bowel Movements Per Week	1.42 spontaneous bowel movements per week Standard Error 0.422	1.98 spontaneous bowel movements per week Standard Error 0.422	3.37 spontaneous bowel movements per week Standard Error 0.429	3.64 spontaneous bowel movements per week Standard Error 0.437

SECONDARY outcome

Timeframe: Baseline and Weeks 1, 2, 3, and 4

Population: mITT population with values at both baseline and the specified time point.

Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation.

A spontaneous bowel movement was defined as a bowel movement unassisted by rescue medication (laxative or enema) taken within the 24 hours preceding the bowel movement. Baseline was defined as the average number of SBMs per day during the 2 weeks prior to randomization.

Outcome measures

Measure	Placebo n=61 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=59 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=57 Participants Participants received 0.4 mg naldemedine orally once daily for 28 days.
Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Spontaneous Bowel Movements Per Week Week 1 (n = 61, 61, 59, 57)	1.61 spontaneous bowel movements per week Standard Error 0.507	2.21 spontaneous bowel movements per week Standard Error 0.507	4.05 spontaneous bowel movements per week Standard Error 0.516	4.52 spontaneous bowel movements per week Standard Error 0.525
Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Spontaneous Bowel Movements Per Week Week 2 (n = 61, 60, 59, 56)	1.53 spontaneous bowel movements per week Standard Error 0.402	2.06 spontaneous bowel movements per week Standard Error 0.402	2.99 spontaneous bowel movements per week Standard Error 0.410	3.87 spontaneous bowel movements per week Standard Error 0.416
Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Spontaneous Bowel Movements Per Week Week 3 (n = 60, 60, 59, 57)	1.32 spontaneous bowel movements per week Standard Error 0.374	2.27 spontaneous bowel movements per week Standard Error 0.372	3.07 spontaneous bowel movements per week Standard Error 0.380	3.33 spontaneous bowel movements per week Standard Error 0.384
Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Spontaneous Bowel Movements Per Week Week 4 (n = 60, 60, 59, 57)	1.36 spontaneous bowel movements per week Standard Error 0.409	1.69 spontaneous bowel movements per week Standard Error 0.409	3.30 spontaneous bowel movements per week Standard Error 0.415	3.41 spontaneous bowel movements per week Standard Error 0.420

SECONDARY outcome

Timeframe: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)

Population: mITT population

Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation.

A BM was defined as all bowel movements observed irrespective of the use of a laxative agent.

Outcome measures

Measure	Placebo n=61 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=59 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=57 Participants Participants received 0.4 mg naldemedine orally once daily for 28 days.
Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Bowel Movements (BMs) Per Week	1.43 bowel movements per week Standard Error 0.396	2.07 bowel movements per week Standard Error 0.394	3.35 bowel movements per week Standard Error 0.404	3.36 bowel movements per week Standard Error 0.408

SECONDARY outcome

Timeframe: Baseline and Weeks 1, 2, 3, and 4

Population: mITT population with values at both baseline and the specified time point.

Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation.

A BM was defined as all bowel movements observed irrespective of the use of a laxative agent.

Outcome measures

Measure	Placebo n=61 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=59 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=57 Participants Participants received 0.4 mg naldemedine orally once daily for 28 days.
Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Bowel Movements Per Week Week 1 (n = 61, 61, 59, 57)	1.67 bowel movements per week Standard Error 0.457	2.27 bowel movements per week Standard Error 0.456	4.25 bowel movements per week Standard Error 0.466	4.60 bowel movements per week Standard Error 0.472
Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Bowel Movements Per Week Week 2 (n = 61, 60, 59, 56)	1.65 bowel movements per week Standard Error 0.361	1.97 bowel movements per week Standard Error 0.360	2.96 bowel movements per week Standard Error 0.369	3.75 bowel movements per week Standard Error 0.373
Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Bowel Movements Per Week Week 3 (n = 60, 60, 59, 57)	1.36 bowel movements per week Standard Error 0.347	2.36 bowel movements per week Standard Error 0.344	3.02 bowel movements per week Standard Error 0.352	2.93 bowel movements per week Standard Error 0.354
Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Bowel Movements Per Week Week 4 (n = 60, 60, 59, 57)	1.52 bowel movements per week Standard Error 0.373	1.68 bowel movements per week Standard Error 0.372	3.06 bowel movements per week Standard Error 0.379	3.16 bowel movements per week Standard Error 0.381

SECONDARY outcome

Timeframe: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)

Population: mITT population

Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation.

A complete BM (CBM) was defined as a BM where the participant answered 'Yes' to the following question: 'Did you have a feeling of complete emptying after the bowel movement?'

Outcome measures

Measure	Placebo n=61 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=59 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=57 Participants Participants received 0.4 mg naldemedine orally once daily for 28 days.
Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Complete Bowel Movements (CBMs) Per Week	1.08 complete bowel movements per week Standard Error 0.336	1.58 complete bowel movements per week Standard Error 0.336	2.71 complete bowel movements per week Standard Error 0.344	2.41 complete bowel movements per week Standard Error 0.348

SECONDARY outcome

Timeframe: Baseline and Weeks 1, 2, 3, and 4

Population: mITT population with values at both baseline and the specified time point.

Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation.

A complete BM (CBM) was defined as a BM where the participant answered 'Yes' to the following question: 'Did you have a feeling of complete emptying after the bowel movement?'

Outcome measures

Measure	Placebo n=61 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=59 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=57 Participants Participants received 0.4 mg naldemedine orally once daily for 28 days.
Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Complete Bowel Movements Per Week Week 1 (n = 61, 61, 59, 57)	0.73 complete bowel movements per week Standard Error 0.381	1.38 complete bowel movements per week Standard Error 0.380	2.88 complete bowel movements per week Standard Error 0.388	3.14 complete bowel movements per week Standard Error 0.394
Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Complete Bowel Movements Per Week Week 2 (n = 61, 60, 59, 56)	1.07 complete bowel movements per week Standard Error 0.324	1.54 complete bowel movements per week Standard Error 0.324	1.99 complete bowel movements per week Standard Error 0.331	2.50 complete bowel movements per week Standard Error 0.336
Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Complete Bowel Movements Per Week Week 3 (n = 60, 60, 59, 57)	1.11 complete bowel movements per week Standard Error 0.297	1.62 complete bowel movements per week Standard Error 0.296	2.29 complete bowel movements per week Standard Error 0.302	2.12 complete bowel movements per week Standard Error 0.305
Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Complete Bowel Movements Per Week Week 4 (n = 60, 60, 59, 57)	1.09 complete bowel movements per week Standard Error 0.334	1.60 complete bowel movements per week Standard Error 0.333	2.77 complete bowel movements per week Standard Error 0.339	2.56 complete bowel movements per week Standard Error 0.342

SECONDARY outcome

Timeframe: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)

Population: mITT population

Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation.

A CSBM was defined as a spontaneous BM which was accompanied by the feeling of complete evacuation.

Outcome measures

Measure	Placebo n=61 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=59 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=57 Participants Participants received 0.4 mg naldemedine orally once daily for 28 days.
Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Complete Spontaneous Bowel Movements (CSBMs) Per Week	0.99 complete spontaneous BMs per week Standard Error 0.345	1.49 complete spontaneous BMs per week Standard Error 0.344	2.69 complete spontaneous BMs per week Standard Error 0.351	2.44 complete spontaneous BMs per week Standard Error 0.356

SECONDARY outcome

Timeframe: Baseline and Weeks 1, 2, 3, and 4

Population: mITT population with values at both baseline and the specified time point.

Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation.

A CSBM was defined as a spontaneous BM which was accompanied by the feeling of complete evacuation.

Outcome measures

Measure	Placebo n=61 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=59 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=57 Participants Participants received 0.4 mg naldemedine orally once daily for 28 days.
Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Complete Spontaneous Bowel Movements Per Week Week 1 (n = 61, 61, 59, 57)	0.71 complete spontaneous BMs per week Standard Error 0.386	1.31 complete spontaneous BMs per week Standard Error 0.386	2.63 complete spontaneous BMs per week Standard Error 0.393	2.99 complete spontaneous BMs per week Standard Error 0.399
Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Complete Spontaneous Bowel Movements Per Week Week 2 (n = 61, 60, 59, 56)	1.09 complete spontaneous BMs per week Standard Error 0.326	1.41 complete spontaneous BMs per week Standard Error 0.326	2.08 complete spontaneous BMs per week Standard Error 0.332	2.50 complete spontaneous BMs per week Standard Error 0.337
Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Complete Spontaneous Bowel Movements Per Week Week 3 (n = 60, 60, 59, 57)	1.02 complete spontaneous BMs per week Standard Error 0.303	1.53 complete spontaneous BMs per week Standard Error 0.301	2.28 complete spontaneous BMs per week Standard Error 0.307	2.21 complete spontaneous BMs per week Standard Error 0.311
Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Complete Spontaneous Bowel Movements Per Week Week 4 (n = 60, 60, 59, 57)	0.90 complete spontaneous BMs per week Standard Error 0.340	1.51 complete spontaneous BMs per week Standard Error 0.340	2.77 complete spontaneous BMs per week Standard Error 0.345	2.58 complete spontaneous BMs per week Standard Error 0.349

SECONDARY outcome

Timeframe: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)

Population: mITT population

Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation.

An SBM responder was defined as a participant whose frequency of SBMs within the last 2 weeks of the treatment period was 3 times or more per week and who had an average increase in the frequency of SBMs from baseline of 1 or more per week.

Outcome measures

Measure	Placebo n=61 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=59 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=57 Participants Participants received 0.4 mg naldemedine orally once daily for 28 days.
Percentage of Participants With an SBM Response in the Last 2 Weeks of the Treatment Period	39.3 percentage of participants	52.5 percentage of participants	71.2 percentage of participants	66.7 percentage of participants

SECONDARY outcome

Timeframe: Baseline and Weeks 1, 2, 3, and 4

Population: mITT population; missing data were imputed using last observation carried forward (LOCF).

Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation.

An SBM responder was defined as any participant whose frequency of SBM per week during the treatment period was 3 times or more per week, and who had an average increase from baseline of 1 or more per week.

Outcome measures

Measure	Placebo n=61 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=59 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=57 Participants Participants received 0.4 mg naldemedine orally once daily for 28 days.
Percentage of Participants With an SBM Response at Weeks 1, 2, 3 and 4 Week1	45.9 percentage of participants	62.3 percentage of participants	72.9 percentage of participants	70.2 percentage of participants
Percentage of Participants With an SBM Response at Weeks 1, 2, 3 and 4 Week 2	45.9 percentage of participants	55.7 percentage of participants	69.5 percentage of participants	70.2 percentage of participants
Percentage of Participants With an SBM Response at Weeks 1, 2, 3 and 4 Week 3	45.9 percentage of participants	55.7 percentage of participants	74.6 percentage of participants	73.7 percentage of participants
Percentage of Participants With an SBM Response at Weeks 1, 2, 3 and 4 Week 4	39.3 percentage of participants	42.6 percentage of participants	64.4 percentage of participants	64.9 percentage of participants

SECONDARY outcome

Timeframe: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)

Population: mITT population

Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation.

A CSBM responder was defined as a participant whose frequency of CSBMs within the last 2 weeks of the treatment period was 3 times or more per week and who had an average increase in the frequency of CSBMs from baseline of 1 or more per week.

Outcome measures

Measure	Placebo n=61 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=59 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=57 Participants Participants received 0.4 mg naldemedine orally once daily for 28 days.
Percentage of Participants With a CSBM Response in the Last 2 Weeks of the Treatment Period	21.3 percentage of participants	29.5 percentage of participants	45.8 percentage of participants	45.6 percentage of participants

SECONDARY outcome

Timeframe: Baseline and Weeks 1, 2, 3, and 4

Population: mITT population; missing data were imputed using last observation carried forward (LOCF).

Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation.

A CSBM responder was defined as a participant whose frequency of CSBMs during the treatment period was 3 times or more per week and who had an average increase in the frequency of CSBMs from baseline of 1 or more per week.

Outcome measures

Measure	Placebo n=61 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=59 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=57 Participants Participants received 0.4 mg naldemedine orally once daily for 28 days.
Percentage of Participants With a CSBM Response at Weeks 1, 2, 3, and 4 Week 1	21.3 percentage of participants	31.1 percentage of participants	42.4 percentage of participants	50.9 percentage of participants
Percentage of Participants With a CSBM Response at Weeks 1, 2, 3, and 4 Week 2	23.0 percentage of participants	29.5 percentage of participants	42.4 percentage of participants	40.4 percentage of participants
Percentage of Participants With a CSBM Response at Weeks 1, 2, 3, and 4 Week 3	24.6 percentage of participants	37.7 percentage of participants	44.1 percentage of participants	45.6 percentage of participants
Percentage of Participants With a CSBM Response at Weeks 1, 2, 3, and 4 Week 4	21.3 percentage of participants	27.9 percentage of participants	45.8 percentage of participants	43.9 percentage of participants

SECONDARY outcome

Timeframe: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)

Population: mITT population

Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation.

An SBM is defined as a bowel movement unassisted by rescue medication (laxative or enema) taken within the 24 hours preceding the bowel movement.

Outcome measures

Measure	Placebo n=61 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=59 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=57 Participants Participants received 0.4 mg naldemedine orally once daily for 28 days.
Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of Days Per Week With SBMs	0.88 days/week Standard Error 0.223	1.46 days/week Standard Error 0.223	2.10 days/week Standard Error 0.227	2.42 days/week Standard Error 0.232

SECONDARY outcome

Timeframe: Baseline and Weeks 1, 2, 3, and 4

Population: mITT population with values at both baseline and the specified time point.

Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation.

An SBM is defined as a bowel movement unassisted by rescue medication (laxative or enema) taken within the 24 hours preceding the bowel movement.

Outcome measures

Measure	Placebo n=61 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=59 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=57 Participants Participants received 0.4 mg naldemedine orally once daily for 28 days.
Change From Baseline to Weeks 1, 2, 3 and 4 in Number of Days Per Week With SBMs Week 1 (n = 61, 61, 59, 57)	1.12 days/week Standard Error 0.250	1.62 days/week Standard Error 0.251	2.35 days/week Standard Error 0.255	2.38 days/week Standard Error 0.260
Change From Baseline to Weeks 1, 2, 3 and 4 in Number of Days Per Week With SBMs Week 2 (n = 61, 60, 59, 56)	1.03 days/week Standard Error 0.240	1.56 days/week Standard Error 0.240	2.03 days/week Standard Error 0.245	2.45 days/week Standard Error 0.250
Change From Baseline to Weeks 1, 2, 3 and 4 in Number of Days Per Week With SBMs Week 3 (n = 60, 60, 59, 57)	0.89 days/week Standard Error 0.233	1.57 days/week Standard Error 0.232	2.07 days/week Standard Error 0.237	2.37 days/week Standard Error 0.240
Change From Baseline to Weeks 1, 2, 3 and 4 in Number of Days Per Week With SBMs Week 4 (n = 60, 60, 59, 57)	0.75 days/week Standard Error 0.274	1.27 days/week Standard Error 0.274	2.20 days/week Standard Error 0.278	2.52 days/week Standard Error 0.281

SECONDARY outcome

Timeframe: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)

Population: mITT population

Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation.

A CSBM was defined as a spontaneous BM which was accompanied by the feeling of complete evacuation.

Outcome measures

Measure	Placebo n=61 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=59 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=57 Participants Participants received 0.4 mg naldemedine orally once daily for 28 days.
Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of Days Per Week With CSBMs	0.83 days/week Standard Error 0.214	1.25 days/week Standard Error 0.213	1.93 days/week Standard Error 0.217	2.02 days/week Standard Error 0.221

SECONDARY outcome

Timeframe: Baseline and Weeks 1, 2, 3, and 4

Population: mITT population with values at both baseline and the specified time point.

Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation.

A CSBM was defined as a spontaneous BM which was accompanied by the feeling of complete evacuation.

Outcome measures

Measure	Placebo n=61 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=59 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=57 Participants Participants received 0.4 mg naldemedine orally once daily for 28 days.
Change From Baseline to Weeks 1, 2, 3 and 4 in Number of Days Per Week With CSBMs Week 1 (n = 61, 61, 59, 57)	0.65 days/week Standard Error 0.234	1.17 days/week Standard Error 0.234	1.74 days/week Standard Error 0.238	2.14 days/week Standard Error 0.242
Change From Baseline to Weeks 1, 2, 3 and 4 in Number of Days Per Week With CSBMs Week 2 (n = 61, 60, 59, 56)	0.90 days/week Standard Error 0.226	1.18 days/week Standard Error 0.226	1.65 days/week Standard Error 0.230	1.93 days/week Standard Error 0.234
Change From Baseline to Weeks 1, 2, 3 and 4 in Number of Days Per Week With CSBMs Week 3 (n = 60, 60, 59, 57)	0.86 days/week Standard Error 0.224	1.26 days/week Standard Error 0.223	1.71 days/week Standard Error 0.228	1.98 days/week Standard Error 0.230
Change From Baseline to Weeks 1, 2, 3 and 4 in Number of Days Per Week With CSBMs Week 4 (n = 60, 60, 59, 57)	0.71 days/week Standard Error 0.256	1.31 days/week Standard Error 0.256	2.17 days/week Standard Error 0.260	2.10 days/week Standard Error 0.262

SECONDARY outcome

Timeframe: 28 days

Population: mITT population

Time to the first SBM was defined as the time to the first SBM after the initial administration of study drug. Participants who withdrew from the study before an SBM was observed or had no SBM during the treatment period were treated as censored.

Outcome measures

Measure	Placebo n=61 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=59 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=57 Participants Participants received 0.4 mg naldemedine orally once daily for 28 days.
Time to the First Spontaneous Bowel Movement	49.57 hours Interval 34.7 to 71.25	28.15 hours Interval 15.75 to 45.02	11.08 hours Interval 4.15 to 25.25	21.33 hours Interval 4.67 to 26.92

SECONDARY outcome

Timeframe: 28 days

Population: mITT population

Time to the first CSBM was defined as the time to the first CSBM after the initial administration of study drug. Participants who withdrew from the study before a CSBM was observed or had no CSBM during the treatment period were treated as censored.

Outcome measures

Measure	Placebo n=61 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=59 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=57 Participants Participants received 0.4 mg naldemedine orally once daily for 28 days.
Time to the First Complete Spontaneous Bowel Movement	223.92 hours Interval 101.25 to 350.4	82.50 hours Interval 49.3 to 140.4	44.83 hours Interval 25.58 to 107.17	32.93 hours Interval 18.0 to 55.08

SECONDARY outcome

Timeframe: 4, 8, 12, and 24 hours

Population: mITT population

The percentage of participants who experienced at least one SBM within 4, 8, 12, and 24 hours after the initial administration of study drug and before the second administration.

Outcome measures

Measure	Placebo n=61 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=59 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=57 Participants Participants received 0.4 mg naldemedine orally once daily for 28 days.
Percentage of Participants With SBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug Up to 4 hours	8.2 percentage of participants	18.0 percentage of participants	35.6 percentage of participants	31.6 percentage of participants
Percentage of Participants With SBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug Up to 8 hours	16.4 percentage of participants	29.5 percentage of participants	47.5 percentage of participants	42.1 percentage of participants
Percentage of Participants With SBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug Up to 12 hours	18.0 percentage of participants	34.4 percentage of participants	50.8 percentage of participants	43.9 percentage of participants
Percentage of Participants With SBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug Up to 24 hours	27.9 percentage of participants	44.3 percentage of participants	59.3 percentage of participants	59.6 percentage of participants

SECONDARY outcome

Timeframe: 4, 8, 12, and 24 hours

Population: mITT population

The percentage of participants who experienced at least one CSBM within 4, 8, 12, and 24 hours after the initial administration of study drug and before the second administration.

Outcome measures

Measure	Placebo n=61 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=59 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=57 Participants Participants received 0.4 mg naldemedine orally once daily for 28 days.
Percentage of Participants With CSBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug Up to 4 hours	1.6 percentage of participants	11.5 percentage of participants	18.6 percentage of participants	12.3 percentage of participants
Percentage of Participants With CSBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug Up to 8 hours	6.6 percentage of participants	16.4 percentage of participants	20.3 percentage of participants	24.6 percentage of participants
Percentage of Participants With CSBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug Up to 12 hours	6.6 percentage of participants	21.3 percentage of participants	23.7 percentage of participants	33.3 percentage of participants
Percentage of Participants With CSBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug Up to 24 hours	14.8 percentage of participants	27.9 percentage of participants	30.5 percentage of participants	43.9 percentage of participants

SECONDARY outcome

Timeframe: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)

Population: mITT population

Consistency of BMs was measured using the Bristol Stool Scale, according to the following: 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.

Outcome measures

Measure	Placebo n=61 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=59 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=57 Participants Participants received 0.4 mg naldemedine orally once daily for 28 days.
Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of SBMs Per Week Rated as 3 or 4 on the Bristol Stool Scale	0.54 spontaneous bowel movements/week Standard Error 0.249	1.08 spontaneous bowel movements/week Standard Error 0.249	2.05 spontaneous bowel movements/week Standard Error 0.256	1.87 spontaneous bowel movements/week Standard Error 0.259

SECONDARY outcome

Timeframe: Baseline and Weeks 1, 2, 3, and 4

Population: mITT population with values at both baseline and the specified time point.

Consistency of BMs was measured using the Bristol Stool Scale, according to the following: 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.

Outcome measures

Measure	Placebo n=61 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=59 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=57 Participants Participants received 0.4 mg naldemedine orally once daily for 28 days.
Change From Baseline to Weeks 1, 2, 3, and 4 in Number of SBMs Rated as 3 or 4 on the Bristol Stool Scale Per Week Week 1 (n = 61, 61, 59, 57)	0.60 spontaneous bowel movements/week Standard Error 0.278	0.97 spontaneous bowel movements/week Standard Error 0.278	2.16 spontaneous bowel movements/week Standard Error 0.285	1.76 spontaneous bowel movements/week Standard Error 0.288
Change From Baseline to Weeks 1, 2, 3, and 4 in Number of SBMs Rated as 3 or 4 on the Bristol Stool Scale Per Week Week 2 (n = 61, 60, 59, 56)	0.62 spontaneous bowel movements/week Standard Error 0.271	1.19 spontaneous bowel movements/week Standard Error 0.270	2.03 spontaneous bowel movements/week Standard Error 0.278	1.98 spontaneous bowel movements/week Standard Error 0.281
Change From Baseline to Weeks 1, 2, 3, and 4 in Number of SBMs Rated as 3 or 4 on the Bristol Stool Scale Per Week Week 3 (n = 60, 60, 59, 57)	0.58 spontaneous bowel movements/week Standard Error 0.262	1.08 spontaneous bowel movements/week Standard Error 0.261	2.03 spontaneous bowel movements/week Standard Error 0.268	1.91 spontaneous bowel movements/week Standard Error 0.270
Change From Baseline to Weeks 1, 2, 3, and 4 in Number of SBMs Rated as 3 or 4 on the Bristol Stool Scale Per Week Week 4 (n = 60, 60, 59, 57)	0.50 spontaneous bowel movements/week Standard Error 0.307	1.10 spontaneous bowel movements/week Standard Error 0.307	2.01 spontaneous bowel movements/week Standard Error 0.313	1.94 spontaneous bowel movements/week Standard Error 0.315

SECONDARY outcome

Timeframe: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)

Population: mITT population

Straining during BMs was graded using the following scale: 0 = No straining; 1 = Mild straining; 2 = Moderate; 3 = Severe; 4 = Very Severe. A BM without straining was defined as a BM with a straining score of 0 or 1.

Outcome measures

Measure	Placebo n=61 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=59 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=57 Participants Participants received 0.4 mg naldemedine orally once daily for 28 days.
Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of SBMs Per Week With no Straining	0.85 bowel movements/week Standard Error 0.384	1.54 bowel movements/week Standard Error 0.383	2.92 bowel movements/week Standard Error 0.391	3.21 bowel movements/week Standard Error 0.396

SECONDARY outcome

Timeframe: Baseline and Weeks 1, 2, 3, and 4

Population: mITT population with values at both baseline and the specified time point.

Straining during BMs was graded using the following scale: 0 = No straining; 1 = Mild straining; 2 = Moderate; 3 = Severe; 4 = Very Severe. A BM without straining is defined as a BM with a straining score of 0 or 1.

Outcome measures

Measure	Placebo n=61 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=59 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=57 Participants Participants received 0.4 mg naldemedine orally once daily for 28 days.
Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of SBMs Per Week Without Straining Week 1 (n = 61, 61, 59, 57)	0.97 bowel movements/week Standard Error 0.443	1.42 bowel movements/week Standard Error 0.442	3.23 bowel movements/week Standard Error 0.451	3.46 bowel movements/week Standard Error 0.457
Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of SBMs Per Week Without Straining Week 2 (n = 61, 60, 59, 56)	0.97 bowel movements/week Standard Error 0.382	1.43 bowel movements/week Standard Error 0.382	2.54 bowel movements/week Standard Error 0.390	3.27 bowel movements/week Standard Error 0.394
Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of SBMs Per Week Without Straining Week 3 (n = 60, 60, 59, 57)	0.94 bowel movements/week Standard Error 0.371	1.70 bowel movements/week Standard Error 0.369	2.67 bowel movements/week Standard Error 0.377	3.06 bowel movements/week Standard Error 0.381
Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of SBMs Per Week Without Straining Week 4 (n = 60, 60, 59, 57)	0.61 bowel movements/week Standard Error 0.359	1.39 bowel movements/week Standard Error 0.358	2.82 bowel movements/week Standard Error 0.365	2.84 bowel movements/week Standard Error 0.368

SECONDARY outcome

Timeframe: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)

Population: mITT population with values at both baseline and the last 2 weeks of the treatment period

Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation.

A false start was defined as any attempted, but unsuccessful bowel movement (no solid or liquid fecal material was excreted).

Outcome measures

Measure	Placebo n=60 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=58 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=57 Participants Participants received 0.4 mg naldemedine orally once daily for 28 days.
Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of False Start BMs Per Week	-2.71 false start BMs Standard Deviation 5.105	-3.06 false start BMs Standard Deviation 4.568	-3.75 false start BMs Standard Deviation 5.673	-2.80 false start BMs Standard Deviation 5.353

SECONDARY outcome

Timeframe: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)

Population: mITT population

Participants were asked how many doses of rescue laxative medication they had taken within the past 24 hours as part of the Bowel Movement and Constipation Assessment Diary (BMCA).

Outcome measures

Measure	Placebo n=61 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=59 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=57 Participants Participants received 0.4 mg naldemedine orally once daily for 28 days.
Change From Baseline to the Last 2 Weeks of the Treatment Period in Rescue Use of Laxative Agents Per Week	0.94 doses/week Standard Deviation 6.068	-0.47 doses/week Standard Deviation 1.691	0.15 doses/week Standard Deviation 07.211	-1.24 doses/week Standard Deviation 2.847

SECONDARY outcome

Timeframe: Weeks 1 to 4

Population: mITT population

Participants were asked how many doses of rescue laxative medication they had taken within the past 24 hours as part of the Bowel Movement and Constipation Assessment Diary (BMCA).

Outcome measures

Measure	Placebo n=61 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=59 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=57 Participants Participants received 0.4 mg naldemedine orally once daily for 28 days.
Mean Rescue Laxative Use Per Week During the Treatment Period	2.9 doses/week Standard Deviation 6.98	0.9 doses/week Standard Deviation 1.81	2.9 doses/week Standard Deviation 7.64	1.8 doses/week Standard Deviation 4.86

SECONDARY outcome

Timeframe: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)

Population: mITT population with a value at both baseline and the last 2 weeks of treatment.

Participants were asked to rate their abdominal bloating for the past 24 hours on a scale of 0 to 4, where 0 = Absent; 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Very Severe.

Outcome measures

Measure	Placebo n=60 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=58 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=57 Participants Participants received 0.4 mg naldemedine orally once daily for 28 days.
Change From Baseline to the Last 2 Weeks of the Treatment Period in Abdominal Bloating	-0.40 units on a scale Standard Deviation 0.689	-0.46 units on a scale Standard Deviation 0.759	-0.54 units on a scale Standard Deviation 0.719	-0.57 units on a scale Standard Deviation 0.773

SECONDARY outcome

Timeframe: Baseline and Weeks 1, 2, 3, and 4

Population: mITT population with a value at both baseline and the specified time point.

Participants were asked to rate their abdominal bloating for the past 24 hours on a scale of 0 to 4, where 0 = Absent; 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Very Severe.

Outcome measures

Measure	Placebo n=61 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=59 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=57 Participants Participants received 0.4 mg naldemedine orally once daily for 28 days.
Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Bloating Week 1 (n = 61, 61, 59, 57)	-0.20 units on a scale Standard Deviation 0.592	-0.30 units on a scale Standard Deviation 0.621	-0.34 units on a scale Standard Deviation 0.760	-0.48 units on a scale Standard Deviation 0.692
Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Bloating Week 2 (n = 61, 61, 59, 56)	-0.36 units on a scale Standard Deviation 0.654	-0.45 units on a scale Standard Deviation 0.812	-0.40 units on a scale Standard Deviation 0.839	-0.68 units on a scale Standard Deviation 0.745
Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Bloating Week 3 (n = 61, 61, 59, 57)	-0.33 units on a scale Standard Deviation 0.666	-0.40 units on a scale Standard Deviation 0.874	-0.44 units on a scale Standard Deviation 0.933	-0.57 units on a scale Standard Deviation 0.818
Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Bloating Week 4 (n = 61, 61, 59, 57)	-0.41 units on a scale Standard Deviation 0.652	-0.51 units on a scale Standard Deviation 0.769	-0.47 units on a scale Standard Deviation 0.903	-0.63 units on a scale Standard Deviation 0.784

SECONDARY outcome

Timeframe: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)

Population: mITT population with a value at both baseline and the last 2 weeks of treatment.

Participants were asked to rate their abdominal discomfort for the past 24 hours on a scale from 0 to 4, where 0 = Absent; 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Very Severe.

Outcome measures

Measure	Placebo n=60 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=58 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=57 Participants Participants received 0.4 mg naldemedine orally once daily for 28 days.
Change From Baseline to the Last 2 Weeks of the Treatment Period in Abdominal Discomfort	-0.42 units on a scale Standard Deviation 0.730	-0.51 units on a scale Standard Deviation 0.787	-0.50 units on a scale Standard Deviation 0.703	-0.42 units on a scale Standard Deviation 0.991

SECONDARY outcome

Timeframe: Baseline and Weeks 1, 2, 3, and 4

Population: mITT population with a value at both baseline and the specified time point.

Participants were asked to rate their abdominal discomfort for the past 24 hours on a scale from 0 to 4, where 0 = Absent; 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Very Severe.

Outcome measures

Measure	Placebo n=61 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=59 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=57 Participants Participants received 0.4 mg naldemedine orally once daily for 28 days.
Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Discomfort Week 1 (n = 61, 61, 59, 57)	-0.22 units on a scale Standard Deviation 0.652	-0.35 units on a scale Standard Deviation 0.609	-0.24 units on a scale Standard Deviation 0.755	-0.23 units on a scale Standard Deviation 0.652
Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Discomfort Week 2 (n = 61, 61, 59, 56)	-0.27 units on a scale Standard Deviation 0.705	-0.48 units on a scale Standard Deviation 0.752	-0.39 units on a scale Standard Deviation 0.825	-0.49 units on a scale Standard Deviation 0.713
Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Discomfort Week 3 (n = 61, 61, 59, 57)	-0.36 units on a scale Standard Deviation 0.741	-0.43 units on a scale Standard Deviation 0.859	-0.42 units on a scale Standard Deviation 0.884	-0.45 units on a scale Standard Deviation 1.001
Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Discomfort Week 4 (n = 61, 61, 59, 57)	-0.40 units on a scale Standard Deviation 0.684	-0.51 units on a scale Standard Deviation 0.787	-0.50 units on a scale Standard Deviation 0.703	-0.42 units on a scale Standard Deviation 0.991

SECONDARY outcome

Timeframe: Day 29, or at early termination

Population: mITT population

On day 29 (or at early termination), participants were asked about their degree of satisfaction with constipation and abdominal symptoms from the start of study drug dosing to Day 28 (or early termination visit). The grades were as follows: 1, markedly worsened; 2, moderately worsened; 3, slightly worsened; 4, unchanged; 5, slightly improved; 6, moderately improved; and 7, markedly improved.

Outcome measures

Measure	Placebo n=61 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=59 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=57 Participants Participants received 0.4 mg naldemedine orally once daily for 28 days.
Subject Global Satisfaction at End of Treatment Unchanged	23 participants	12 participants	4 participants	6 participants
Subject Global Satisfaction at End of Treatment Markedly worsened	1 participants	0 participants	0 participants	1 participants
Subject Global Satisfaction at End of Treatment Moderately worsened	2 participants	2 participants	0 participants	2 participants
Subject Global Satisfaction at End of Treatment Slightly worsened	3 participants	2 participants	1 participants	0 participants
Subject Global Satisfaction at End of Treatment Slightly improved	12 participants	18 participants	17 participants	8 participants
Subject Global Satisfaction at End of Treatment Moderately improved	14 participants	17 participants	21 participants	13 participants
Subject Global Satisfaction at End of Treatment Markedly improved	3 participants	7 participants	14 participants	23 participants
Subject Global Satisfaction at End of Treatment Missing	3 participants	3 participants	2 participants	4 participants

SECONDARY outcome

Timeframe: Day 1 and Day 28 predose and 1, 2, 4, 8, and 24 hours postdose

Population: The PK parameter population (PK population) includes all participants who received study drug with at least one PK parameter estimated adequately on Day 1 or Day 28

Pharmacokinetic blood samples for naldemedine (S-297995) and its metabolite, Nor-S-297995, were collected from a subset of participants at selected study sites on Day 1 and in a further subset on Day 28.

Outcome measures

Measure	Placebo n=9 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=9 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=10 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg Participants received 0.4 mg naldemedine orally once daily for 28 days.
Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995 Naldemedine Day 1 (n = 9, 9, 10)	0.987 ng/mL Geometric Coefficient of Variation 41.1	1.89 ng/mL Geometric Coefficient of Variation 48.2	3.67 ng/mL Geometric Coefficient of Variation 41.3	—
Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995 Naldemedine Day 28 (n = 4, 4, 4)	1.15 ng/mL Geometric Coefficient of Variation 25.8	2.00 ng/mL Geometric Coefficient of Variation 22.7	4.03 ng/mL Geometric Coefficient of Variation 32.3	—
Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995 Nor-S-297995 Day 1 (n = 9, 9, 10)	NA ng/mL Geometric Coefficient of Variation NA Not calculable as plasma concentrations of Nor-S-297995 on Day 1 were below the limit of quantification.	0.107 ng/mL Geometric Coefficient of Variation 7.8	0.184 ng/mL Geometric Coefficient of Variation 30.9	—
Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995 Nor-S-297995 Day 28 (n = 4, 4, 4)	0.111 ng/mL Geometric Coefficient of Variation 27.1	0.148 ng/mL Geometric Coefficient of Variation 59.9	0.218 ng/mL Geometric Coefficient of Variation 58.3	—

SECONDARY outcome

Timeframe: Day 1 and Day 28 predose and 1, 2 , 4, 8, and 24 hours postdose

Population: PK population with available data

Pharmacokinetic blood samples for naldemedine (S-297995) and its metabolite, Nor-S-297995, were collected from a subset of participants at selected study sites on Day 1 and in a further subset on Day 28.

Outcome measures

Measure	Placebo n=9 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=9 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=10 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg Participants received 0.4 mg naldemedine orally once daily for 28 days.
Time to Maximum Concentration (Tmax) of Naldemedine and Metabolite Nor-S-297995 Naldemedine Day 1 (n = 9, 9, 10)	1.00 hours Interval 0.97 to 2.27	1.03 hours Interval 0.97 to 4.02	1.03 hours Interval 0.95 to 4.0	—
Time to Maximum Concentration (Tmax) of Naldemedine and Metabolite Nor-S-297995 Naldemedine Day 28 (n = 4, 4, 4)	1.03 hours Interval 1.0 to 1.97	1.00 hours Interval 1.0 to 1.03	1.00 hours Interval 1.0 to 1.08	—
Time to Maximum Concentration (Tmax) of Naldemedine and Metabolite Nor-S-297995 Nor-S-297995 Day 1 (n = 9, 5, 9)	NA hours Not calculable as plasma concentrations of Nor-S-297995 on Day 1 were below the limit of quantification.	4.00 hours Interval 2.0 to 8.0	4.03 hours Interval 2.0 to 8.0	—
Time to Maximum Concentration (Tmax) of Naldemedine and Metabolite Nor-S-297995 Nor-S-297995 Day 28 (n = 3, 4, 4)	2.02 hours Interval 2.0 to 4.0	4.00 hours Interval 3.97 to 8.03	3.00 hours Interval 2.0 to 4.0	—

SECONDARY outcome

Timeframe: Day 1 and Day 28 predose and 1, 2 , 4, 8, and 24 hours postdose

Population: PK population with available data

Pharmacokinetic blood samples for naldemedine (S-297995) and its metabolite, Nor-S-297995, were collected from a subset of participants at selected study sites on Day 1 and in a further subset on Day 28.

Outcome measures

Measure	Placebo n=9 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=9 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=10 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg Participants received 0.4 mg naldemedine orally once daily for 28 days.
Area Under the Concentration-time Curve From Hour 0 to the Time Point of the Last Measurable Concentration Within the Dose Interval (AUC0-τ) Naldemedine Day 1 (n = 6, 8, 7)	8.491 ng*hr/mL Geometric Coefficient of Variation 24.5	15.95 ng*hr/mL Geometric Coefficient of Variation 42.6	30.58 ng*hr/mL Geometric Coefficient of Variation 26.9	—
Area Under the Concentration-time Curve From Hour 0 to the Time Point of the Last Measurable Concentration Within the Dose Interval (AUC0-τ) Naldemedine Day 28 (n = 3, 4, 3)	9.677 ng*hr/mL Geometric Coefficient of Variation 33.7	16.94 ng*hr/mL Geometric Coefficient of Variation 46.6	31.72 ng*hr/mL Geometric Coefficient of Variation 11.4	—
Area Under the Concentration-time Curve From Hour 0 to the Time Point of the Last Measurable Concentration Within the Dose Interval (AUC0-τ) Nor-S-297995 Day 1 (n = 9, 8, 7)	NA ng*hr/mL Geometric Coefficient of Variation NA Not calculable as plasma concentrations of Nor-S-297995 on Day 1 were below the limit of quantification.	0.5106 ng*hr/mL Geometric Coefficient of Variation 55.5	2.950 ng*hr/mL Geometric Coefficient of Variation 53.8	—
Area Under the Concentration-time Curve From Hour 0 to the Time Point of the Last Measurable Concentration Within the Dose Interval (AUC0-τ) Nor-S-297995 Day 28 (n = 3, 4, 3)	0.3522 ng*hr/mL Geometric Coefficient of Variation 896.9	0.8158 ng*hr/mL Geometric Coefficient of Variation 463.1	2.256 ng*hr/mL Geometric Coefficient of Variation 140.0	—

SECONDARY outcome

Timeframe: From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days).

Population: Adverse events were assessed using the safety population. The safety population included all participants who received study drug. This population was analyzed as treated.

Treatment-emergent adverse events (TEAEs) were adverse events that occurred after the first dose of study drug.

Treatment-related TEAEs were defined as TEAEs that were considered by the Investigator to be definitely, probably, or possibly related to study drug.

Outcome measures

Measure	Placebo n=61 Participants Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 Participants Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=60 Participants Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=61 Participants Participants received 0.4 mg naldemedine orally once daily for 28 days.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) TEAEs	31 participants	25 participants	30 participants	34 participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Treatment-related TEAEs	10 participants	10 participants	15 participants	24 participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Serious TEAEs	0 participants	2 participants	0 participants	1 participants

Adverse Events

Placebo

Serious events: 0 serious events

Other events: 19 other events

Deaths: 0 deaths

Naldemedine 0.1 mg

Serious events: 2 serious events

Other events: 15 other events

Deaths: 0 deaths

Naldemedine 0.2 mg

Serious events: 0 serious events

Other events: 19 other events

Deaths: 0 deaths

Naldemedine 0.4 mg

Serious events: 1 serious events

Other events: 28 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo n=61 participants at risk Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 participants at risk Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=60 participants at risk Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=61 participants at risk Participants received 0.4 mg naldemedine orally once daily for 28 days.
Cardiac disorders Chest pain	0.00% 0/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	1.6% 1/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	0.00% 0/60 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	0.00% 0/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.
Cardiac disorders Left ventricular dysfunction	0.00% 0/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	0.00% 0/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	0.00% 0/60 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	1.6% 1/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.
Gastrointestinal disorders Appendicitis	0.00% 0/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	1.6% 1/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	0.00% 0/60 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	0.00% 0/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.

Other adverse events

Measure	Placebo n=61 participants at risk Participants received placebo orally once daily for 28 days.	Naldemedine 0.1 mg n=61 participants at risk Participants received 0.1 mg naldemedine orally once daily for 28 days.	Naldemedine 0.2 mg n=60 participants at risk Participants received 0.2 mg naldemedine orally once daily for 28 days.	Naldemedine 0.4 mg n=61 participants at risk Participants received 0.4 mg naldemedine orally once daily for 28 days.
Gastrointestinal disorders Anorectal discomfort	0.00% 0/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	3.3% 2/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	0.00% 0/60 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	0.00% 0/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.
Gastrointestinal disorders Abdominal pain lower	3.3% 2/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	0.00% 0/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	0.00% 0/60 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	0.00% 0/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.
Infections and infestations Urinary tract infection	1.6% 1/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	1.6% 1/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	5.0% 3/60 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	6.6% 4/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.
Infections and infestations Influenza	3.3% 2/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	1.6% 1/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	1.7% 1/60 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	0.00% 0/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.
Infections and infestations Nasopharyngitis	3.3% 2/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	0.00% 0/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	0.00% 0/60 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	3.3% 2/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.
Musculoskeletal and connective tissue disorders Arthralgia	6.6% 4/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	1.6% 1/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	1.7% 1/60 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	1.6% 1/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.
Musculoskeletal and connective tissue disorders Back pain	6.6% 4/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	1.6% 1/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	0.00% 0/60 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	1.6% 1/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.
General disorders Influenza like illness	0.00% 0/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	3.3% 2/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	0.00% 0/60 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	1.6% 1/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.
Gastrointestinal disorders Abdominal pain	1.6% 1/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	4.9% 3/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	8.3% 5/60 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	14.8% 9/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.
Gastrointestinal disorders Diarrhea	4.9% 3/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	4.9% 3/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	5.0% 3/60 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	18.0% 11/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.
Gastrointestinal disorders Flatulence	3.3% 2/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	4.9% 3/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	5.0% 3/60 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	3.3% 2/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.
Gastrointestinal disorders Nausea	1.6% 1/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	1.6% 1/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	6.7% 4/60 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	4.9% 3/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	1.6% 1/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	3.3% 2/60 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	6.6% 4/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.
Gastrointestinal disorders Abdominal distension	1.6% 1/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	3.3% 2/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	3.3% 2/60 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	0.00% 0/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.
Gastrointestinal disorders Vomiting	0.00% 0/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	0.00% 0/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	0.00% 0/60 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	3.3% 2/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.
General disorders Fatigue	0.00% 0/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	0.00% 0/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	0.00% 0/60 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	3.3% 2/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.
Nervous system disorders Headache	0.00% 0/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	1.6% 1/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	3.3% 2/60 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	4.9% 3/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.
Respiratory, thoracic and mediastinal disorders Dyspnea	1.6% 1/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	0.00% 0/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	0.00% 0/60 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	3.3% 2/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.
Investigations Gamma-glutamyltransferase increased	3.3% 2/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	0.00% 0/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	0.00% 0/60 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	0.00% 0/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.
Skin and subcutaneous tissue disorders Hyperhidrosis	0.00% 0/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	0.00% 0/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	1.7% 1/60 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	3.3% 2/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.
Vascular disorders Hot flush	0.00% 0/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	0.00% 0/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	3.3% 2/60 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.	0.00% 0/61 • From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). The safety population included all participants who received study drug.

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