Opioid-induced Constipation
Conditions
Keywords
Opioid Therapy, Non-Malignant Chronic Pain, Opioid-Induced Constipation
Brief summary
The purpose of this study is to determine efficacy and safety of naldemedine for the treatment of opioid-induced constipation in adults with non-malignant chronic pain receiving opioid therapy for ≥ 3 months.
Interventions
DRUGPlacebo
Matching placebo tablets administered orally once a day.
DRUGNaldemedine
Naldemedine tablets administered orally once a day.
Sponsors
Shionogi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects aged 18 years or older at time of informed consent with non-malignant chronic pain experiencing opioid-induced constipation * Subjects with \< 3 spontaneous bowel movements a week and experiencing bowel symptoms * Subjects receiving chronic opioid therapy due to non-malignant pain for ≥ 3 months
Exclusion criteria
* Evidence of clinically significant gastrointestinal disease * History of chronic constipation prior to starting analgesic medication or any potential non-opioid cause of bowel dysfunction that may be a major contributor to the constipation * Severe constipation that has not been appropriately managed such that the subject is at immediate risk of developing serious complications of constipation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Last 2 Weeks of the Treatment Period in the Number of Spontaneous Bowel Movements Per Week | 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) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Spontaneous Bowel Movements Per Week | Baseline and Weeks 1, 2, 3, and 4 | 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. |
| Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Bowel Movements (BMs) Per Week | Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) | 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. |
| Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Bowel Movements Per Week | Baseline and Weeks 1, 2, 3, and 4 | 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. |
| Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Complete Bowel Movements (CBMs) Per Week | Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) | 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?' |
| Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Complete Bowel Movements Per Week | Baseline and Weeks 1, 2, 3, and 4 | 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?' |
| Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Complete Spontaneous Bowel Movements (CSBMs) Per Week | Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) | 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. |
| Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Complete Spontaneous Bowel Movements Per Week | Baseline and Weeks 1, 2, 3, and 4 | 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. |
| Percentage of Participants With an SBM Response in the Last 2 Weeks of the Treatment Period | Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) | 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. |
| Percentage of Participants With an SBM Response at Weeks 1, 2, 3 and 4 | Baseline and Weeks 1, 2, 3, and 4 | 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. |
| Percentage of Participants With a CSBM Response in the Last 2 Weeks of the Treatment Period | Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) | 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. |
| Percentage of Participants With a CSBM Response at Weeks 1, 2, 3, and 4 | Baseline and Weeks 1, 2, 3, and 4 | 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. |
| Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of Days Per Week With SBMs | Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) | 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. |
| Change From Baseline to Weeks 1, 2, 3 and 4 in Number of Days Per Week With SBMs | Baseline and Weeks 1, 2, 3, and 4 | 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. |
| Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of Days Per Week With CSBMs | Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) | 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. |
| Change From Baseline to Weeks 1, 2, 3 and 4 in Number of Days Per Week With CSBMs | Baseline and Weeks 1, 2, 3, and 4 | 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. |
| Time to the First Spontaneous Bowel Movement | 28 days | 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. |
| Time to the First Complete Spontaneous Bowel Movement | 28 days | 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. |
| Percentage of Participants With SBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug | 4, 8, 12, and 24 hours | 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. |
| Percentage of Participants With CSBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug | 4, 8, 12, and 24 hours | 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. |
| 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 | Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) | 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. |
| 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 | Baseline and Weeks 1, 2, 3, and 4 | 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. |
| Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of SBMs Per Week With no Straining | Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) | 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. |
| Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of SBMs Per Week Without Straining | Baseline and Weeks 1, 2, 3, and 4 | 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. |
| Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of False Start BMs Per Week | Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day 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). |
| Change From Baseline to the Last 2 Weeks of the Treatment Period in Rescue Use of Laxative Agents Per Week | Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) | 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). |
| Mean Rescue Laxative Use Per Week During the Treatment Period | Weeks 1 to 4 | 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). |
| Change From Baseline to the Last 2 Weeks of the Treatment Period in Abdominal Bloating | Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) | 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. |
| Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Bloating | Baseline and Weeks 1, 2, 3, and 4 | 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. |
| Change From Baseline to the Last 2 Weeks of the Treatment Period in Abdominal Discomfort | Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) | 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. |
| Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Discomfort | Baseline and Weeks 1, 2, 3, and 4 | 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. |
| Subject Global Satisfaction at End of Treatment | Day 29, or at early termination | 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. |
| Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995 | Day 1 and Day 28 predose and 1, 2, 4, 8, and 24 hours postdose | 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. |
| Time to Maximum Concentration (Tmax) of Naldemedine and Metabolite Nor-S-297995 | Day 1 and Day 28 predose and 1, 2 , 4, 8, and 24 hours postdose | 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. |
| Area Under the Concentration-time Curve From Hour 0 to the Time Point of the Last Measurable Concentration Within the Dose Interval (AUC0-τ) | Day 1 and Day 28 predose and 1, 2 , 4, 8, and 24 hours postdose | 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. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). | 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. |
Countries
United States
Participant flow
Recruitment details
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.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo orally once daily for 28 days. | 61 |
| Naldemedine 0.1 mg Participants received 0.1 mg naldemedine orally once daily for 28 days. | 61 |
| Naldemedine 0.2 mg Participants received 0.2 mg naldemedine orally once daily for 28 days. | 59 |
| Naldemedine 0.4 mg Participants received 0.4 mg naldemedine orally once daily for 28 days. | 57 |
| Total | 238 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 4 | 5 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 1 |
| Overall Study | Other - Miscellaneous | 1 | 0 | 0 | 1 |
| Overall Study | Protocol Violation | 2 | 1 | 1 | 1 |
| Overall Study | Use of Prohibited Treatment | 2 | 3 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 2 | 1 |
Baseline characteristics
| Characteristic | Total | Naldemedine 0.1 mg | Placebo | Naldemedine 0.2 mg | Naldemedine 0.4 mg |
|---|---|---|---|---|---|
| Age, Continuous | 51.9 Years STANDARD_DEVIATION 10.8 | 49.5 Years STANDARD_DEVIATION 9.71 | 53.1 Years STANDARD_DEVIATION 10.88 | 50.7 Years STANDARD_DEVIATION 11.4 | 54.1 Years STANDARD_DEVIATION 11.19 |
| Age, Customized ≥ 18 - < 40 years | 36 participants | 10 participants | 6 participants | 13 participants | 7 participants |
| Age, Customized ≥ 40 - < 50 years | 52 participants | 18 participants | 14 participants | 8 participants | 12 participants |
| Age, Customized ≥ 50 - < 65 years | 127 participants | 31 participants | 33 participants | 34 participants | 29 participants |
| Age, Customized ≥ 65 - < 75 years | 19 participants | 2 participants | 6 participants | 3 participants | 8 participants |
| Age, Customized ≥ 75 years | 4 participants | 0 participants | 2 participants | 1 participants | 1 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 16 Participants | 6 Participants | 4 Participants | 2 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 222 Participants | 55 Participants | 57 Participants | 57 Participants | 53 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Naive | 2 participants | 0 participants | 2 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Asian | 1 participants | 0 participants | 1 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Black or African American | 38 participants | 11 participants | 9 participants | 12 participants | 6 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Other | 1 participants | 1 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized White | 196 participants | 49 participants | 49 participants | 47 participants | 51 participants |
| Sex: Female, Male Female | 167 Participants | 47 Participants | 45 Participants | 38 Participants | 37 Participants |
| Sex: Female, Male Male | 71 Participants | 14 Participants | 16 Participants | 21 Participants | 20 Participants |
| Spontaneous Bowel Movement (SBM) Frequency per Week | 1.36 SBMs/week STANDARD_DEVIATION 0.851 | 1.51 SBMs/week STANDARD_DEVIATION 0.82 | 1.22 SBMs/week STANDARD_DEVIATION 0.72 | 1.52 SBMs/week STANDARD_DEVIATION 0.916 | 1.20 SBMs/week STANDARD_DEVIATION 0.948 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 19 / 61 | 15 / 61 | 19 / 60 | 28 / 61 |
| serious Total, serious adverse events | 0 / 61 | 2 / 61 | 0 / 60 | 1 / 61 |
Outcome results
Primary
Change From Baseline to Last 2 Weeks of the Treatment Period in the Number of Spontaneous Bowel Movements Per Week
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.
Time frame: 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
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | 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 |
| Naldemedine 0.1 mg | Change From Baseline to Last 2 Weeks of the Treatment Period in the Number of Spontaneous Bowel Movements Per Week | 1.98 spontaneous bowel movements per week | Standard Error 0.422 |
| Naldemedine 0.2 mg | Change From Baseline to Last 2 Weeks of the Treatment Period in the Number of Spontaneous Bowel Movements Per Week | 3.37 spontaneous bowel movements per week | Standard Error 0.429 |
| Naldemedine 0.4 mg | Change From Baseline to Last 2 Weeks of the Treatment Period in the Number of Spontaneous Bowel Movements Per Week | 3.64 spontaneous bowel movements per week | Standard Error 0.437 |
p-value: 0.000395% CI: [1.02, 3.41]ANCOVA
p-value: 0.001495% CI: [0.76, 3.14]ANCOVA
p-value: 0.350495% CI: [-0.62, 1.74]ANCOVA
Secondary
Area Under the Concentration-time Curve From Hour 0 to the Time Point of the Last Measurable Concentration Within the Dose Interval (AUC0-τ)
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.
Time frame: Day 1 and Day 28 predose and 1, 2 , 4, 8, and 24 hours postdose
Population: PK population with available data
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 | — |
| Placebo | 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 |
| Naldemedine 0.1 mg | 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) | 0.8158 ng*hr/mL | Geometric Coefficient of Variation 463.1 |
| Naldemedine 0.1 mg | 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) | 15.95 ng*hr/mL | Geometric Coefficient of Variation 42.6 |
| Naldemedine 0.1 mg | 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) | 0.5106 ng*hr/mL | Geometric Coefficient of Variation 55.5 |
| Naldemedine 0.1 mg | 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) | 16.94 ng*hr/mL | Geometric Coefficient of Variation 46.6 |
| Naldemedine 0.2 mg | 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) | 2.256 ng*hr/mL | Geometric Coefficient of Variation 140 |
| Naldemedine 0.2 mg | 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) | 31.72 ng*hr/mL | Geometric Coefficient of Variation 11.4 |
| Naldemedine 0.2 mg | 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) | 2.950 ng*hr/mL | Geometric Coefficient of Variation 53.8 |
| Naldemedine 0.2 mg | 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) | 30.58 ng*hr/mL | Geometric Coefficient of Variation 26.9 |
Secondary
Change From Baseline to the Last 2 Weeks of the Treatment Period in Abdominal Bloating
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | 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 |
| Naldemedine 0.1 mg | Change From Baseline to the Last 2 Weeks of the Treatment Period in Abdominal Bloating | -0.46 units on a scale | Standard Deviation 0.759 |
| Naldemedine 0.2 mg | Change From Baseline to the Last 2 Weeks of the Treatment Period in Abdominal Bloating | -0.54 units on a scale | Standard Deviation 0.719 |
| Naldemedine 0.4 mg | Change From Baseline to the Last 2 Weeks of the Treatment Period in Abdominal Bloating | -0.57 units on a scale | Standard Deviation 0.773 |
p-value: 0.2126Welch's t-test
p-value: 0.2799Welch's t-test
p-value: 0.6466Welch's t-test
Secondary
Change From Baseline to the Last 2 Weeks of the Treatment Period in Abdominal Discomfort
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to the Last 2 Weeks of the Treatment Period in Abdominal Discomfort | -0.42 units on a scale | Standard Deviation 0.73 |
| Naldemedine 0.1 mg | Change From Baseline to the Last 2 Weeks of the Treatment Period in Abdominal Discomfort | -0.51 units on a scale | Standard Deviation 0.787 |
| Naldemedine 0.2 mg | Change From Baseline to the Last 2 Weeks of the Treatment Period in Abdominal Discomfort | -0.50 units on a scale | Standard Deviation 0.703 |
| Naldemedine 0.4 mg | Change From Baseline to the Last 2 Weeks of the Treatment Period in Abdominal Discomfort | -0.42 units on a scale | Standard Deviation 0.991 |
p-value: 0.9826Welch's t-test
p-value: 0.5188Welch's t-test
p-value: 0.5029Welch's t-test
Secondary
Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of Days Per Week With CSBMs
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.
Time frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)
Population: mITT population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | 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 |
| Naldemedine 0.1 mg | Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of Days Per Week With CSBMs | 1.25 days/week | Standard Error 0.213 |
| Naldemedine 0.2 mg | Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of Days Per Week With CSBMs | 1.93 days/week | Standard Error 0.217 |
| Naldemedine 0.4 mg | Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of Days Per Week With CSBMs | 2.02 days/week | Standard Error 0.221 |
p-value: 0.000495% CI: [0.49, 1.7]ANCOVA
p-value: 0.000195% CI: [0.58, 1.79]ANCOVA
p-value: 0.164895% CI: [-0.17, 1.02]ANCOVA
Secondary
Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of Days Per Week With SBMs
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.
Time frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)
Population: mITT population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | 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 |
| Naldemedine 0.1 mg | Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of Days Per Week With SBMs | 1.46 days/week | Standard Error 0.223 |
| Naldemedine 0.2 mg | Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of Days Per Week With SBMs | 2.10 days/week | Standard Error 0.227 |
| Naldemedine 0.4 mg | Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of Days Per Week With SBMs | 2.42 days/week | Standard Error 0.232 |
p-value: <0.000195% CI: [0.9, 2.17]ANCOVA
p-value: 0.000295% CI: [0.59, 1.85]ANCOVA
p-value: 0.069895% CI: [-0.05, 1.2]ANCOVA
Secondary
Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of False Start BMs Per Week
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).
Time frame: 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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | 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 |
| Naldemedine 0.1 mg | Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of False Start BMs Per Week | -3.06 false start BMs | Standard Deviation 4.568 |
| Naldemedine 0.2 mg | Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of False Start BMs Per Week | -3.75 false start BMs | Standard Deviation 5.673 |
| Naldemedine 0.4 mg | Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of False Start BMs Per Week | -2.80 false start BMs | Standard Deviation 5.353 |
Secondary
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
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.
Time frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)
Population: mITT population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | 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 |
| Naldemedine 0.1 mg | 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 | 1.08 spontaneous bowel movements/week | Standard Error 0.249 |
| Naldemedine 0.2 mg | 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 | 2.05 spontaneous bowel movements/week | Standard Error 0.256 |
| Naldemedine 0.4 mg | 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 | 1.87 spontaneous bowel movements/week | Standard Error 0.259 |
p-value: 0.000395% CI: [0.62, 2.03]ANCOVA
p-value: <0.000195% CI: [0.8, 2.22]ANCOVA
p-value: 0.121195% CI: [-0.15, 1.24]ANCOVA
Secondary
Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of SBMs Per Week With no Straining
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.
Time frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)
Population: mITT population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | 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 |
| Naldemedine 0.1 mg | Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of SBMs Per Week With no Straining | 1.54 bowel movements/week | Standard Error 0.383 |
| Naldemedine 0.2 mg | Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of SBMs Per Week With no Straining | 2.92 bowel movements/week | Standard Error 0.391 |
| Naldemedine 0.4 mg | Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of SBMs Per Week With no Straining | 3.21 bowel movements/week | Standard Error 0.396 |
p-value: <0.000195% CI: [1.28, 3.45]ANCOVA
p-value: 0.000295% CI: [0.99, 3.15]ANCOVA
p-value: 0.202295% CI: [-0.37, 1.76]ANCOVA
Secondary
Change From Baseline to the Last 2 Weeks of the Treatment Period in Rescue Use of Laxative Agents Per Week
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).
Time frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)
Population: mITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | 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 |
| Naldemedine 0.1 mg | Change From Baseline to the Last 2 Weeks of the Treatment Period in Rescue Use of Laxative Agents Per Week | -0.47 doses/week | Standard Deviation 1.691 |
| Naldemedine 0.2 mg | Change From Baseline to the Last 2 Weeks of the Treatment Period in Rescue Use of Laxative Agents Per Week | 0.15 doses/week | Standard Deviation 7.211 |
| Naldemedine 0.4 mg | Change From Baseline to the Last 2 Weeks of the Treatment Period in Rescue Use of Laxative Agents Per Week | -1.24 doses/week | Standard Deviation 2.847 |
p-value: 0.0272Wilcoxon (Mann-Whitney)
p-value: 0.1355Wilcoxon (Mann-Whitney)
p-value: 0.3689Wilcoxon (Mann-Whitney)
Secondary
Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Bowel Movements (BMs) Per Week
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.
Time frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)
Population: mITT population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | 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 |
| Naldemedine 0.1 mg | Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Bowel Movements (BMs) Per Week | 2.07 bowel movements per week | Standard Error 0.394 |
| Naldemedine 0.2 mg | Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Bowel Movements (BMs) Per Week | 3.35 bowel movements per week | Standard Error 0.404 |
| Naldemedine 0.4 mg | Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Bowel Movements (BMs) Per Week | 3.36 bowel movements per week | Standard Error 0.408 |
p-value: 0.000895% CI: [0.81, 3.05]ANCOVA
p-value: 0.000995% CI: [0.79, 3.04]ANCOVA
p-value: 0.257295% CI: [-0.47, 1.73]ANCOVA
Secondary
Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Complete Bowel Movements (CBMs) Per Week
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?'
Time frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)
Population: mITT population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | 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 |
| Naldemedine 0.1 mg | Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Complete Bowel Movements (CBMs) Per Week | 1.58 complete bowel movements per week | Standard Error 0.336 |
| Naldemedine 0.2 mg | Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Complete Bowel Movements (CBMs) Per Week | 2.71 complete bowel movements per week | Standard Error 0.344 |
| Naldemedine 0.4 mg | Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Complete Bowel Movements (CBMs) Per Week | 2.41 complete bowel movements per week | Standard Error 0.348 |
p-value: 0.006595% CI: [0.38, 2.28]ANCOVA
p-value: 0.000895% CI: [0.69, 2.58]ANCOVA
p-value: 0.292195% CI: [-0.43, 1.44]ANCOVA
Secondary
Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Complete Spontaneous Bowel Movements (CSBMs) Per Week
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.
Time frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)
Population: mITT population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | 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 |
| Naldemedine 0.1 mg | Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Complete Spontaneous Bowel Movements (CSBMs) Per Week | 1.49 complete spontaneous BMs per week | Standard Error 0.344 |
| Naldemedine 0.2 mg | Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Complete Spontaneous Bowel Movements (CSBMs) Per Week | 2.69 complete spontaneous BMs per week | Standard Error 0.351 |
| Naldemedine 0.4 mg | Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Complete Spontaneous Bowel Movements (CSBMs) Per Week | 2.44 complete spontaneous BMs per week | Standard Error 0.356 |
p-value: 0.003995% CI: [0.47, 2.42]ANCOVA
p-value: 0.000795% CI: [0.73, 2.67]ANCOVA
p-value: 0.307795% CI: [-0.46, 1.46]ANCOVA
Secondary
Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Bloating
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.
Time frame: Baseline and Weeks 1, 2, 3, and 4
Population: mITT population with a value at both baseline and the specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Naldemedine 0.1 mg | Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Bloating | Week 2 (n = 61, 61, 59, 56) | -0.45 units on a scale | Standard Deviation 0.812 |
| Naldemedine 0.1 mg | Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Bloating | Week 3 (n = 61, 61, 59, 57) | -0.40 units on a scale | Standard Deviation 0.874 |
| Naldemedine 0.1 mg | Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Bloating | Week 4 (n = 61, 61, 59, 57) | -0.51 units on a scale | Standard Deviation 0.769 |
| Naldemedine 0.1 mg | Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Bloating | Week 1 (n = 61, 61, 59, 57) | -0.30 units on a scale | Standard Deviation 0.621 |
| Naldemedine 0.2 mg | Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Bloating | Week 3 (n = 61, 61, 59, 57) | -0.44 units on a scale | Standard Deviation 0.933 |
| Naldemedine 0.2 mg | Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Bloating | Week 2 (n = 61, 61, 59, 56) | -0.40 units on a scale | Standard Deviation 0.839 |
| Naldemedine 0.2 mg | Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Bloating | Week 4 (n = 61, 61, 59, 57) | -0.47 units on a scale | Standard Deviation 0.903 |
| Naldemedine 0.2 mg | Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Bloating | Week 1 (n = 61, 61, 59, 57) | -0.34 units on a scale | Standard Deviation 0.76 |
| Naldemedine 0.4 mg | Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Bloating | Week 4 (n = 61, 61, 59, 57) | -0.63 units on a scale | Standard Deviation 0.784 |
| Naldemedine 0.4 mg | Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Bloating | Week 2 (n = 61, 61, 59, 56) | -0.68 units on a scale | Standard Deviation 0.745 |
| Naldemedine 0.4 mg | Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Bloating | Week 1 (n = 61, 61, 59, 57) | -0.48 units on a scale | Standard Deviation 0.692 |
| Naldemedine 0.4 mg | Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Bloating | Week 3 (n = 61, 61, 59, 57) | -0.57 units on a scale | Standard Deviation 0.818 |
Secondary
Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Discomfort
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.
Time frame: Baseline and Weeks 1, 2, 3, and 4
Population: mITT population with a value at both baseline and the specified time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Naldemedine 0.1 mg | Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Discomfort | Week 2 (n = 61, 61, 59, 56) | -0.48 units on a scale | Standard Deviation 0.752 |
| Naldemedine 0.1 mg | Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Discomfort | Week 3 (n = 61, 61, 59, 57) | -0.43 units on a scale | Standard Deviation 0.859 |
| Naldemedine 0.1 mg | Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Discomfort | Week 4 (n = 61, 61, 59, 57) | -0.51 units on a scale | Standard Deviation 0.787 |
| Naldemedine 0.1 mg | Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Discomfort | Week 1 (n = 61, 61, 59, 57) | -0.35 units on a scale | Standard Deviation 0.609 |
| Naldemedine 0.2 mg | Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Discomfort | Week 3 (n = 61, 61, 59, 57) | -0.42 units on a scale | Standard Deviation 0.884 |
| Naldemedine 0.2 mg | Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Discomfort | Week 2 (n = 61, 61, 59, 56) | -0.39 units on a scale | Standard Deviation 0.825 |
| Naldemedine 0.2 mg | Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Discomfort | Week 4 (n = 61, 61, 59, 57) | -0.50 units on a scale | Standard Deviation 0.703 |
| Naldemedine 0.2 mg | Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Discomfort | Week 1 (n = 61, 61, 59, 57) | -0.24 units on a scale | Standard Deviation 0.755 |
| Naldemedine 0.4 mg | Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Discomfort | Week 4 (n = 61, 61, 59, 57) | -0.42 units on a scale | Standard Deviation 0.991 |
| Naldemedine 0.4 mg | Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Discomfort | Week 2 (n = 61, 61, 59, 56) | -0.49 units on a scale | Standard Deviation 0.713 |
| Naldemedine 0.4 mg | Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Discomfort | Week 1 (n = 61, 61, 59, 57) | -0.23 units on a scale | Standard Deviation 0.652 |
| Naldemedine 0.4 mg | Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Discomfort | Week 3 (n = 61, 61, 59, 57) | -0.45 units on a scale | Standard Deviation 1.001 |
Secondary
Change From Baseline to Weeks 1, 2, 3 and 4 in Number of Days Per Week With CSBMs
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.
Time frame: Baseline and Weeks 1, 2, 3, and 4
Population: mITT population with values at both baseline and the specified time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Naldemedine 0.1 mg | 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) | 1.18 days/week | Standard Error 0.226 |
| Naldemedine 0.1 mg | 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) | 1.26 days/week | Standard Error 0.223 |
| Naldemedine 0.1 mg | 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) | 1.31 days/week | Standard Error 0.256 |
| Naldemedine 0.1 mg | 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) | 1.17 days/week | Standard Error 0.234 |
| Naldemedine 0.2 mg | 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) | 1.71 days/week | Standard Error 0.228 |
| Naldemedine 0.2 mg | 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) | 1.65 days/week | Standard Error 0.23 |
| Naldemedine 0.2 mg | 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) | 2.17 days/week | Standard Error 0.26 |
| Naldemedine 0.2 mg | 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) | 1.74 days/week | Standard Error 0.238 |
| Naldemedine 0.4 mg | 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) | 2.10 days/week | Standard Error 0.262 |
| Naldemedine 0.4 mg | 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) | 1.93 days/week | Standard Error 0.234 |
| Naldemedine 0.4 mg | 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) | 2.14 days/week | Standard Error 0.242 |
| Naldemedine 0.4 mg | 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) | 1.98 days/week | Standard Error 0.23 |
Secondary
Change From Baseline to Weeks 1, 2, 3 and 4 in Number of Days Per Week With SBMs
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.
Time frame: Baseline and Weeks 1, 2, 3, and 4
Population: mITT population with values at both baseline and the specified time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 0.25 |
| Placebo | 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 0.24 |
| Placebo | 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 |
| Placebo | 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 |
| Naldemedine 0.1 mg | 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) | 1.56 days/week | Standard Error 0.24 |
| Naldemedine 0.1 mg | 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) | 1.57 days/week | Standard Error 0.232 |
| Naldemedine 0.1 mg | 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) | 1.27 days/week | Standard Error 0.274 |
| Naldemedine 0.1 mg | 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) | 1.62 days/week | Standard Error 0.251 |
| Naldemedine 0.2 mg | 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) | 2.07 days/week | Standard Error 0.237 |
| Naldemedine 0.2 mg | 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) | 2.03 days/week | Standard Error 0.245 |
| Naldemedine 0.2 mg | 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) | 2.20 days/week | Standard Error 0.278 |
| Naldemedine 0.2 mg | 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) | 2.35 days/week | Standard Error 0.255 |
| Naldemedine 0.4 mg | 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) | 2.52 days/week | Standard Error 0.281 |
| Naldemedine 0.4 mg | 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) | 2.45 days/week | Standard Error 0.25 |
| Naldemedine 0.4 mg | 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) | 2.38 days/week | Standard Error 0.26 |
| Naldemedine 0.4 mg | 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) | 2.37 days/week | Standard Error 0.24 |
Secondary
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
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.
Time frame: Baseline and Weeks 1, 2, 3, and 4
Population: mITT population with values at both baseline and the specified time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Naldemedine 0.1 mg | 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) | 1.19 spontaneous bowel movements/week | Standard Error 0.27 |
| Naldemedine 0.1 mg | 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) | 1.08 spontaneous bowel movements/week | Standard Error 0.261 |
| Naldemedine 0.1 mg | 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) | 1.10 spontaneous bowel movements/week | Standard Error 0.307 |
| Naldemedine 0.1 mg | 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) | 0.97 spontaneous bowel movements/week | Standard Error 0.278 |
| Naldemedine 0.2 mg | 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) | 2.03 spontaneous bowel movements/week | Standard Error 0.268 |
| Naldemedine 0.2 mg | 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) | 2.03 spontaneous bowel movements/week | Standard Error 0.278 |
| Naldemedine 0.2 mg | 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) | 2.01 spontaneous bowel movements/week | Standard Error 0.313 |
| Naldemedine 0.2 mg | 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) | 2.16 spontaneous bowel movements/week | Standard Error 0.285 |
| Naldemedine 0.4 mg | 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) | 1.94 spontaneous bowel movements/week | Standard Error 0.315 |
| Naldemedine 0.4 mg | 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) | 1.98 spontaneous bowel movements/week | Standard Error 0.281 |
| Naldemedine 0.4 mg | 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) | 1.76 spontaneous bowel movements/week | Standard Error 0.288 |
| Naldemedine 0.4 mg | 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) | 1.91 spontaneous bowel movements/week | Standard Error 0.27 |
Secondary
Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Bowel Movements Per Week
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.
Time frame: Baseline and Weeks 1, 2, 3, and 4
Population: mITT population with values at both baseline and the specified time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Naldemedine 0.1 mg | 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) | 1.97 bowel movements per week | Standard Error 0.36 |
| Naldemedine 0.1 mg | 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) | 2.36 bowel movements per week | Standard Error 0.344 |
| Naldemedine 0.1 mg | 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) | 1.68 bowel movements per week | Standard Error 0.372 |
| Naldemedine 0.1 mg | 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) | 2.27 bowel movements per week | Standard Error 0.456 |
| Naldemedine 0.2 mg | 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) | 3.02 bowel movements per week | Standard Error 0.352 |
| Naldemedine 0.2 mg | 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) | 2.96 bowel movements per week | Standard Error 0.369 |
| Naldemedine 0.2 mg | 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) | 3.06 bowel movements per week | Standard Error 0.379 |
| Naldemedine 0.2 mg | 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) | 4.25 bowel movements per week | Standard Error 0.466 |
| Naldemedine 0.4 mg | 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) | 3.16 bowel movements per week | Standard Error 0.381 |
| Naldemedine 0.4 mg | 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) | 3.75 bowel movements per week | Standard Error 0.373 |
| Naldemedine 0.4 mg | 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) | 4.60 bowel movements per week | Standard Error 0.472 |
| Naldemedine 0.4 mg | 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) | 2.93 bowel movements per week | Standard Error 0.354 |
Secondary
Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Complete Bowel Movements Per Week
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?'
Time frame: Baseline and Weeks 1, 2, 3, and 4
Population: mITT population with values at both baseline and the specified time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Naldemedine 0.1 mg | 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) | 1.54 complete bowel movements per week | Standard Error 0.324 |
| Naldemedine 0.1 mg | 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) | 1.62 complete bowel movements per week | Standard Error 0.296 |
| Naldemedine 0.1 mg | 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) | 1.60 complete bowel movements per week | Standard Error 0.333 |
| Naldemedine 0.1 mg | 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) | 1.38 complete bowel movements per week | Standard Error 0.38 |
| Naldemedine 0.2 mg | 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) | 2.29 complete bowel movements per week | Standard Error 0.302 |
| Naldemedine 0.2 mg | 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) | 1.99 complete bowel movements per week | Standard Error 0.331 |
| Naldemedine 0.2 mg | 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) | 2.77 complete bowel movements per week | Standard Error 0.339 |
| Naldemedine 0.2 mg | 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) | 2.88 complete bowel movements per week | Standard Error 0.388 |
| Naldemedine 0.4 mg | 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) | 2.56 complete bowel movements per week | Standard Error 0.342 |
| Naldemedine 0.4 mg | 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) | 2.50 complete bowel movements per week | Standard Error 0.336 |
| Naldemedine 0.4 mg | 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) | 3.14 complete bowel movements per week | Standard Error 0.394 |
| Naldemedine 0.4 mg | 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) | 2.12 complete bowel movements per week | Standard Error 0.305 |
Secondary
Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Complete Spontaneous Bowel Movements Per Week
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.
Time frame: Baseline and Weeks 1, 2, 3, and 4
Population: mITT population with values at both baseline and the specified time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 0.34 |
| Naldemedine 0.1 mg | 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) | 1.41 complete spontaneous BMs per week | Standard Error 0.326 |
| Naldemedine 0.1 mg | 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) | 1.53 complete spontaneous BMs per week | Standard Error 0.301 |
| Naldemedine 0.1 mg | 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) | 1.51 complete spontaneous BMs per week | Standard Error 0.34 |
| Naldemedine 0.1 mg | 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) | 1.31 complete spontaneous BMs per week | Standard Error 0.386 |
| Naldemedine 0.2 mg | 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) | 2.28 complete spontaneous BMs per week | Standard Error 0.307 |
| Naldemedine 0.2 mg | 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) | 2.08 complete spontaneous BMs per week | Standard Error 0.332 |
| Naldemedine 0.2 mg | 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) | 2.77 complete spontaneous BMs per week | Standard Error 0.345 |
| Naldemedine 0.2 mg | 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) | 2.63 complete spontaneous BMs per week | Standard Error 0.393 |
| Naldemedine 0.4 mg | 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) | 2.58 complete spontaneous BMs per week | Standard Error 0.349 |
| Naldemedine 0.4 mg | 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) | 2.50 complete spontaneous BMs per week | Standard Error 0.337 |
| Naldemedine 0.4 mg | 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) | 2.99 complete spontaneous BMs per week | Standard Error 0.399 |
| Naldemedine 0.4 mg | 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) | 2.21 complete spontaneous BMs per week | Standard Error 0.311 |
Secondary
Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of SBMs Per Week Without Straining
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.
Time frame: Baseline and Weeks 1, 2, 3, and 4
Population: mITT population with values at both baseline and the specified time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Naldemedine 0.1 mg | 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) | 1.39 bowel movements/week | Standard Error 0.358 |
| Naldemedine 0.1 mg | 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) | 1.42 bowel movements/week | Standard Error 0.442 |
| Naldemedine 0.1 mg | 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) | 1.43 bowel movements/week | Standard Error 0.382 |
| Naldemedine 0.1 mg | 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) | 1.70 bowel movements/week | Standard Error 0.369 |
| Naldemedine 0.2 mg | 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) | 3.23 bowel movements/week | Standard Error 0.451 |
| Naldemedine 0.2 mg | 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) | 2.82 bowel movements/week | Standard Error 0.365 |
| Naldemedine 0.2 mg | 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) | 2.54 bowel movements/week | Standard Error 0.39 |
| Naldemedine 0.2 mg | 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) | 2.67 bowel movements/week | Standard Error 0.377 |
| Naldemedine 0.4 mg | 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) | 3.27 bowel movements/week | Standard Error 0.394 |
| Naldemedine 0.4 mg | 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) | 2.84 bowel movements/week | Standard Error 0.368 |
| Naldemedine 0.4 mg | 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) | 3.06 bowel movements/week | Standard Error 0.381 |
| Naldemedine 0.4 mg | 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) | 3.46 bowel movements/week | Standard Error 0.457 |
Secondary
Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Spontaneous Bowel Movements Per Week
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.
Time frame: Baseline and Weeks 1, 2, 3, and 4
Population: mITT population with values at both baseline and the specified time point.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Naldemedine 0.1 mg | 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) | 2.06 spontaneous bowel movements per week | Standard Error 0.402 |
| Naldemedine 0.1 mg | 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) | 2.27 spontaneous bowel movements per week | Standard Error 0.372 |
| Naldemedine 0.1 mg | 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) | 1.69 spontaneous bowel movements per week | Standard Error 0.409 |
| Naldemedine 0.1 mg | 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) | 2.21 spontaneous bowel movements per week | Standard Error 0.507 |
| Naldemedine 0.2 mg | 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) | 3.07 spontaneous bowel movements per week | Standard Error 0.38 |
| Naldemedine 0.2 mg | 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) | 2.99 spontaneous bowel movements per week | Standard Error 0.41 |
| Naldemedine 0.2 mg | 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) | 3.30 spontaneous bowel movements per week | Standard Error 0.415 |
| Naldemedine 0.2 mg | 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) | 4.05 spontaneous bowel movements per week | Standard Error 0.516 |
| Naldemedine 0.4 mg | 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) | 3.41 spontaneous bowel movements per week | Standard Error 0.42 |
| Naldemedine 0.4 mg | 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) | 3.87 spontaneous bowel movements per week | Standard Error 0.416 |
| Naldemedine 0.4 mg | 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) | 4.52 spontaneous bowel movements per week | Standard Error 0.525 |
| Naldemedine 0.4 mg | 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) | 3.33 spontaneous bowel movements per week | Standard Error 0.384 |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995
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.
Time frame: 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
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | 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 |
| Placebo | 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 |
| Placebo | Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 Day 1 (n = 9, 9, 10) | NA ng/mL | — |
| Placebo | 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 |
| Naldemedine 0.1 mg | Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 Day 28 (n = 4, 4, 4) | 0.148 ng/mL | Geometric Coefficient of Variation 59.9 |
| Naldemedine 0.1 mg | Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995 | Naldemedine Day 1 (n = 9, 9, 10) | 1.89 ng/mL | Geometric Coefficient of Variation 48.2 |
| Naldemedine 0.1 mg | Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 Day 1 (n = 9, 9, 10) | 0.107 ng/mL | Geometric Coefficient of Variation 7.8 |
| Naldemedine 0.1 mg | Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995 | Naldemedine Day 28 (n = 4, 4, 4) | 2.00 ng/mL | Geometric Coefficient of Variation 22.7 |
| Naldemedine 0.2 mg | Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 Day 28 (n = 4, 4, 4) | 0.218 ng/mL | Geometric Coefficient of Variation 58.3 |
| Naldemedine 0.2 mg | Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995 | Naldemedine Day 28 (n = 4, 4, 4) | 4.03 ng/mL | Geometric Coefficient of Variation 32.3 |
| Naldemedine 0.2 mg | Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 Day 1 (n = 9, 9, 10) | 0.184 ng/mL | Geometric Coefficient of Variation 30.9 |
| Naldemedine 0.2 mg | Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995 | Naldemedine Day 1 (n = 9, 9, 10) | 3.67 ng/mL | Geometric Coefficient of Variation 41.3 |
Secondary
Mean Rescue Laxative Use Per Week During the Treatment Period
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).
Time frame: Weeks 1 to 4
Population: mITT population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Rescue Laxative Use Per Week During the Treatment Period | 2.9 doses/week | Standard Deviation 6.98 |
| Naldemedine 0.1 mg | Mean Rescue Laxative Use Per Week During the Treatment Period | 0.9 doses/week | Standard Deviation 1.81 |
| Naldemedine 0.2 mg | Mean Rescue Laxative Use Per Week During the Treatment Period | 2.9 doses/week | Standard Deviation 7.64 |
| Naldemedine 0.4 mg | Mean Rescue Laxative Use Per Week During the Treatment Period | 1.8 doses/week | Standard Deviation 4.86 |
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
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.
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAEs | 31 participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Serious TEAEs | 0 participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related TEAEs | 10 participants |
| Naldemedine 0.1 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAEs | 25 participants |
| Naldemedine 0.1 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Serious TEAEs | 2 participants |
| Naldemedine 0.1 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related TEAEs | 10 participants |
| Naldemedine 0.2 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related TEAEs | 15 participants |
| Naldemedine 0.2 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAEs | 30 participants |
| Naldemedine 0.2 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Serious TEAEs | 0 participants |
| Naldemedine 0.4 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAEs | 34 participants |
| Naldemedine 0.4 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Serious TEAEs | 1 participants |
| Naldemedine 0.4 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Treatment-related TEAEs | 24 participants |
Secondary
Percentage of Participants With a CSBM Response at Weeks 1, 2, 3, and 4
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.
Time frame: Baseline and Weeks 1, 2, 3, and 4
Population: mITT population; missing data were imputed using last observation carried forward (LOCF).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Participants With a CSBM Response at Weeks 1, 2, 3, and 4 | Week 4 | 21.3 percentage of participants |
| Placebo | Percentage of Participants With a CSBM Response at Weeks 1, 2, 3, and 4 | Week 1 | 21.3 percentage of participants |
| Placebo | Percentage of Participants With a CSBM Response at Weeks 1, 2, 3, and 4 | Week 3 | 24.6 percentage of participants |
| Placebo | Percentage of Participants With a CSBM Response at Weeks 1, 2, 3, and 4 | Week 2 | 23.0 percentage of participants |
| Naldemedine 0.1 mg | Percentage of Participants With a CSBM Response at Weeks 1, 2, 3, and 4 | Week 4 | 27.9 percentage of participants |
| Naldemedine 0.1 mg | Percentage of Participants With a CSBM Response at Weeks 1, 2, 3, and 4 | Week 1 | 31.1 percentage of participants |
| Naldemedine 0.1 mg | Percentage of Participants With a CSBM Response at Weeks 1, 2, 3, and 4 | Week 3 | 37.7 percentage of participants |
| Naldemedine 0.1 mg | Percentage of Participants With a CSBM Response at Weeks 1, 2, 3, and 4 | Week 2 | 29.5 percentage of participants |
| Naldemedine 0.2 mg | Percentage of Participants With a CSBM Response at Weeks 1, 2, 3, and 4 | Week 2 | 42.4 percentage of participants |
| Naldemedine 0.2 mg | Percentage of Participants With a CSBM Response at Weeks 1, 2, 3, and 4 | Week 3 | 44.1 percentage of participants |
| Naldemedine 0.2 mg | Percentage of Participants With a CSBM Response at Weeks 1, 2, 3, and 4 | Week 1 | 42.4 percentage of participants |
| Naldemedine 0.2 mg | Percentage of Participants With a CSBM Response at Weeks 1, 2, 3, and 4 | Week 4 | 45.8 percentage of participants |
| Naldemedine 0.4 mg | Percentage of Participants With a CSBM Response at Weeks 1, 2, 3, and 4 | Week 3 | 45.6 percentage of participants |
| Naldemedine 0.4 mg | Percentage of Participants With a CSBM Response at Weeks 1, 2, 3, and 4 | Week 2 | 40.4 percentage of participants |
| Naldemedine 0.4 mg | Percentage of Participants With a CSBM Response at Weeks 1, 2, 3, and 4 | Week 4 | 43.9 percentage of participants |
| Naldemedine 0.4 mg | Percentage of Participants With a CSBM Response at Weeks 1, 2, 3, and 4 | Week 1 | 50.9 percentage of participants |
Secondary
Percentage of Participants With a CSBM Response in 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 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.
Time frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)
Population: mITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With a CSBM Response in the Last 2 Weeks of the Treatment Period | 21.3 percentage of participants |
| Naldemedine 0.1 mg | Percentage of Participants With a CSBM Response in the Last 2 Weeks of the Treatment Period | 29.5 percentage of participants |
| Naldemedine 0.2 mg | Percentage of Participants With a CSBM Response in the Last 2 Weeks of the Treatment Period | 45.8 percentage of participants |
| Naldemedine 0.4 mg | Percentage of Participants With a CSBM Response in the Last 2 Weeks of the Treatment Period | 45.6 percentage of participants |
p-value: 0.00595% CI: [7.8, 40.8]Chi-squared
p-value: 0.004595% CI: [8.1, 40.8]Chi-squared
p-value: 0.298495% CI: [-7.2, 23.6]Chi-squared
Secondary
Percentage of Participants With an SBM Response at Weeks 1, 2, 3 and 4
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.
Time frame: Baseline and Weeks 1, 2, 3, and 4
Population: mITT population; missing data were imputed using last observation carried forward (LOCF).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Participants With an SBM Response at Weeks 1, 2, 3 and 4 | Week1 | 45.9 percentage of participants |
| Placebo | Percentage of Participants With an SBM Response at Weeks 1, 2, 3 and 4 | Week 2 | 45.9 percentage of participants |
| Placebo | Percentage of Participants With an SBM Response at Weeks 1, 2, 3 and 4 | Week 3 | 45.9 percentage of participants |
| Placebo | Percentage of Participants With an SBM Response at Weeks 1, 2, 3 and 4 | Week 4 | 39.3 percentage of participants |
| Naldemedine 0.1 mg | Percentage of Participants With an SBM Response at Weeks 1, 2, 3 and 4 | Week 2 | 55.7 percentage of participants |
| Naldemedine 0.1 mg | Percentage of Participants With an SBM Response at Weeks 1, 2, 3 and 4 | Week 3 | 55.7 percentage of participants |
| Naldemedine 0.1 mg | Percentage of Participants With an SBM Response at Weeks 1, 2, 3 and 4 | Week 4 | 42.6 percentage of participants |
| Naldemedine 0.1 mg | Percentage of Participants With an SBM Response at Weeks 1, 2, 3 and 4 | Week1 | 62.3 percentage of participants |
| Naldemedine 0.2 mg | Percentage of Participants With an SBM Response at Weeks 1, 2, 3 and 4 | Week 3 | 74.6 percentage of participants |
| Naldemedine 0.2 mg | Percentage of Participants With an SBM Response at Weeks 1, 2, 3 and 4 | Week 2 | 69.5 percentage of participants |
| Naldemedine 0.2 mg | Percentage of Participants With an SBM Response at Weeks 1, 2, 3 and 4 | Week 4 | 64.4 percentage of participants |
| Naldemedine 0.2 mg | Percentage of Participants With an SBM Response at Weeks 1, 2, 3 and 4 | Week1 | 72.9 percentage of participants |
| Naldemedine 0.4 mg | Percentage of Participants With an SBM Response at Weeks 1, 2, 3 and 4 | Week 4 | 64.9 percentage of participants |
| Naldemedine 0.4 mg | Percentage of Participants With an SBM Response at Weeks 1, 2, 3 and 4 | Week 2 | 70.2 percentage of participants |
| Naldemedine 0.4 mg | Percentage of Participants With an SBM Response at Weeks 1, 2, 3 and 4 | Week1 | 70.2 percentage of participants |
| Naldemedine 0.4 mg | Percentage of Participants With an SBM Response at Weeks 1, 2, 3 and 4 | Week 3 | 73.7 percentage of participants |
Secondary
Percentage of Participants With an SBM Response in 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. 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.
Time frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)
Population: mITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With an SBM Response in the Last 2 Weeks of the Treatment Period | 39.3 percentage of participants |
| Naldemedine 0.1 mg | Percentage of Participants With an SBM Response in the Last 2 Weeks of the Treatment Period | 52.5 percentage of participants |
| Naldemedine 0.2 mg | Percentage of Participants With an SBM Response in the Last 2 Weeks of the Treatment Period | 71.2 percentage of participants |
| Naldemedine 0.4 mg | Percentage of Participants With an SBM Response in the Last 2 Weeks of the Treatment Period | 66.7 percentage of participants |
p-value: 0.00395% CI: [10, 44.6]Chi-squared
p-value: 0.000595% CI: [15, 48.7]Chi-squared
p-value: 0.146195% CI: [-4.4, 30.6]Chi-squared
Secondary
Percentage of Participants With CSBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug
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.
Time frame: 4, 8, 12, and 24 hours
Population: mITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Naldemedine 0.1 mg | Percentage of Participants With CSBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug | Up to 8 hours | 16.4 percentage of participants |
| Naldemedine 0.1 mg | Percentage of Participants With CSBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug | Up to 12 hours | 21.3 percentage of participants |
| Naldemedine 0.1 mg | Percentage of Participants With CSBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug | Up to 24 hours | 27.9 percentage of participants |
| Naldemedine 0.1 mg | Percentage of Participants With CSBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug | Up to 4 hours | 11.5 percentage of participants |
| Naldemedine 0.2 mg | Percentage of Participants With CSBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug | Up to 12 hours | 23.7 percentage of participants |
| Naldemedine 0.2 mg | Percentage of Participants With CSBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug | Up to 8 hours | 20.3 percentage of participants |
| Naldemedine 0.2 mg | Percentage of Participants With CSBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug | Up to 24 hours | 30.5 percentage of participants |
| Naldemedine 0.2 mg | Percentage of Participants With CSBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug | Up to 4 hours | 18.6 percentage of participants |
| Naldemedine 0.4 mg | Percentage of Participants With CSBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug | Up to 24 hours | 43.9 percentage of participants |
| Naldemedine 0.4 mg | Percentage of Participants With CSBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug | Up to 8 hours | 24.6 percentage of participants |
| Naldemedine 0.4 mg | Percentage of Participants With CSBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug | Up to 4 hours | 12.3 percentage of participants |
| Naldemedine 0.4 mg | Percentage of Participants With CSBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug | Up to 12 hours | 33.3 percentage of participants |
Secondary
Percentage of Participants With SBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug
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.
Time frame: 4, 8, 12, and 24 hours
Population: mITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Placebo | 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 |
| Naldemedine 0.1 mg | Percentage of Participants With SBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug | Up to 8 hours | 29.5 percentage of participants |
| Naldemedine 0.1 mg | Percentage of Participants With SBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug | Up to 12 hours | 34.4 percentage of participants |
| Naldemedine 0.1 mg | Percentage of Participants With SBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug | Up to 24 hours | 44.3 percentage of participants |
| Naldemedine 0.1 mg | Percentage of Participants With SBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug | Up to 4 hours | 18.0 percentage of participants |
| Naldemedine 0.2 mg | Percentage of Participants With SBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug | Up to 12 hours | 50.8 percentage of participants |
| Naldemedine 0.2 mg | Percentage of Participants With SBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug | Up to 8 hours | 47.5 percentage of participants |
| Naldemedine 0.2 mg | Percentage of Participants With SBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug | Up to 24 hours | 59.3 percentage of participants |
| Naldemedine 0.2 mg | Percentage of Participants With SBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug | Up to 4 hours | 35.6 percentage of participants |
| Naldemedine 0.4 mg | Percentage of Participants With SBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug | Up to 24 hours | 59.6 percentage of participants |
| Naldemedine 0.4 mg | Percentage of Participants With SBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug | Up to 8 hours | 42.1 percentage of participants |
| Naldemedine 0.4 mg | Percentage of Participants With SBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug | Up to 4 hours | 31.6 percentage of participants |
| Naldemedine 0.4 mg | Percentage of Participants With SBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug | Up to 12 hours | 43.9 percentage of participants |
Secondary
Subject Global Satisfaction at End of Treatment
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.
Time frame: Day 29, or at early termination
Population: mITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Subject Global Satisfaction at End of Treatment | Markedly improved | 3 participants |
| Placebo | Subject Global Satisfaction at End of Treatment | Missing | 3 participants |
| Placebo | Subject Global Satisfaction at End of Treatment | Moderately worsened | 2 participants |
| Placebo | Subject Global Satisfaction at End of Treatment | Slightly worsened | 3 participants |
| Placebo | Subject Global Satisfaction at End of Treatment | Unchanged | 23 participants |
| Placebo | Subject Global Satisfaction at End of Treatment | Markedly worsened | 1 participants |
| Placebo | Subject Global Satisfaction at End of Treatment | Slightly improved | 12 participants |
| Placebo | Subject Global Satisfaction at End of Treatment | Moderately improved | 14 participants |
| Naldemedine 0.1 mg | Subject Global Satisfaction at End of Treatment | Markedly improved | 7 participants |
| Naldemedine 0.1 mg | Subject Global Satisfaction at End of Treatment | Slightly worsened | 2 participants |
| Naldemedine 0.1 mg | Subject Global Satisfaction at End of Treatment | Moderately worsened | 2 participants |
| Naldemedine 0.1 mg | Subject Global Satisfaction at End of Treatment | Unchanged | 12 participants |
| Naldemedine 0.1 mg | Subject Global Satisfaction at End of Treatment | Markedly worsened | 0 participants |
| Naldemedine 0.1 mg | Subject Global Satisfaction at End of Treatment | Moderately improved | 17 participants |
| Naldemedine 0.1 mg | Subject Global Satisfaction at End of Treatment | Missing | 3 participants |
| Naldemedine 0.1 mg | Subject Global Satisfaction at End of Treatment | Slightly improved | 18 participants |
| Naldemedine 0.2 mg | Subject Global Satisfaction at End of Treatment | Moderately improved | 21 participants |
| Naldemedine 0.2 mg | Subject Global Satisfaction at End of Treatment | Unchanged | 4 participants |
| Naldemedine 0.2 mg | Subject Global Satisfaction at End of Treatment | Missing | 2 participants |
| Naldemedine 0.2 mg | Subject Global Satisfaction at End of Treatment | Markedly improved | 14 participants |
| Naldemedine 0.2 mg | Subject Global Satisfaction at End of Treatment | Slightly improved | 17 participants |
| Naldemedine 0.2 mg | Subject Global Satisfaction at End of Treatment | Markedly worsened | 0 participants |
| Naldemedine 0.2 mg | Subject Global Satisfaction at End of Treatment | Moderately worsened | 0 participants |
| Naldemedine 0.2 mg | Subject Global Satisfaction at End of Treatment | Slightly worsened | 1 participants |
| Naldemedine 0.4 mg | Subject Global Satisfaction at End of Treatment | Moderately worsened | 2 participants |
| Naldemedine 0.4 mg | Subject Global Satisfaction at End of Treatment | Slightly worsened | 0 participants |
| Naldemedine 0.4 mg | Subject Global Satisfaction at End of Treatment | Markedly worsened | 1 participants |
| Naldemedine 0.4 mg | Subject Global Satisfaction at End of Treatment | Unchanged | 6 participants |
| Naldemedine 0.4 mg | Subject Global Satisfaction at End of Treatment | Moderately improved | 13 participants |
| Naldemedine 0.4 mg | Subject Global Satisfaction at End of Treatment | Missing | 4 participants |
| Naldemedine 0.4 mg | Subject Global Satisfaction at End of Treatment | Markedly improved | 23 participants |
| Naldemedine 0.4 mg | Subject Global Satisfaction at End of Treatment | Slightly improved | 8 participants |
Secondary
Time to Maximum Concentration (Tmax) of Naldemedine and Metabolite Nor-S-297995
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.
Time frame: Day 1 and Day 28 predose and 1, 2 , 4, 8, and 24 hours postdose
Population: PK population with available data
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Time to Maximum Concentration (Tmax) of Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 Day 28 (n = 3, 4, 4) | 2.02 hours |
| Placebo | Time to Maximum Concentration (Tmax) of Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 Day 1 (n = 9, 5, 9) | NA hours |
| Placebo | Time to Maximum Concentration (Tmax) of Naldemedine and Metabolite Nor-S-297995 | Naldemedine Day 28 (n = 4, 4, 4) | 1.03 hours |
| Placebo | Time to Maximum Concentration (Tmax) of Naldemedine and Metabolite Nor-S-297995 | Naldemedine Day 1 (n = 9, 9, 10) | 1.00 hours |
| Naldemedine 0.1 mg | Time to Maximum Concentration (Tmax) of Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 Day 1 (n = 9, 5, 9) | 4.00 hours |
| Naldemedine 0.1 mg | Time to Maximum Concentration (Tmax) of Naldemedine and Metabolite Nor-S-297995 | Naldemedine Day 28 (n = 4, 4, 4) | 1.00 hours |
| Naldemedine 0.1 mg | Time to Maximum Concentration (Tmax) of Naldemedine and Metabolite Nor-S-297995 | Naldemedine Day 1 (n = 9, 9, 10) | 1.03 hours |
| Naldemedine 0.1 mg | Time to Maximum Concentration (Tmax) of Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 Day 28 (n = 3, 4, 4) | 4.00 hours |
| Naldemedine 0.2 mg | Time to Maximum Concentration (Tmax) of Naldemedine and Metabolite Nor-S-297995 | Naldemedine Day 28 (n = 4, 4, 4) | 1.00 hours |
| Naldemedine 0.2 mg | Time to Maximum Concentration (Tmax) of Naldemedine and Metabolite Nor-S-297995 | Naldemedine Day 1 (n = 9, 9, 10) | 1.03 hours |
| Naldemedine 0.2 mg | Time to Maximum Concentration (Tmax) of Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 Day 28 (n = 3, 4, 4) | 3.00 hours |
| Naldemedine 0.2 mg | Time to Maximum Concentration (Tmax) of Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 Day 1 (n = 9, 5, 9) | 4.03 hours |
Secondary
Time to the First Complete Spontaneous Bowel Movement
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.
Time frame: 28 days
Population: mITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to the First Complete Spontaneous Bowel Movement | 223.92 hours |
| Naldemedine 0.1 mg | Time to the First Complete Spontaneous Bowel Movement | 82.50 hours |
| Naldemedine 0.2 mg | Time to the First Complete Spontaneous Bowel Movement | 44.83 hours |
| Naldemedine 0.4 mg | Time to the First Complete Spontaneous Bowel Movement | 32.93 hours |
p-value: <0.0001Wilcoxon (Mann-Whitney)
p-value: 0.0011Wilcoxon (Mann-Whitney)
p-value: 0.0079Wilcoxon (Mann-Whitney)
Secondary
Time to the First Spontaneous Bowel Movement
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.
Time frame: 28 days
Population: mITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to the First Spontaneous Bowel Movement | 49.57 hours |
| Naldemedine 0.1 mg | Time to the First Spontaneous Bowel Movement | 28.15 hours |
| Naldemedine 0.2 mg | Time to the First Spontaneous Bowel Movement | 11.08 hours |
| Naldemedine 0.4 mg | Time to the First Spontaneous Bowel Movement | 21.33 hours |
p-value: 0.0004Wilcoxon (Mann-Whitney)
p-value: <0.0001Wilcoxon (Mann-Whitney)
p-value: 0.0118Wilcoxon (Mann-Whitney)