Opioid Induced Bowel Dysfunction
Conditions
Keywords
Chronic pain, Opioid physical dependence
Brief summary
The primary objective of the study is to evaluate the safety of single doses of oral naldemedine in adults physically dependent on opioids.
Detailed description
A single dose of naldemedine or matching placebo will be administered orally to each cohort of 12 participants (9 treatments, 3 placebos) in the morning of Day 15 under fasted conditions. The first cohort will receive a 0.1 mg dose. Cohorts will continue to be enrolled at the next higher dose level until the highest dose level (3 mg) has been achieved or until the study is discontinued due to adverse events or Clinical Opioid Withdrawal Score of \>8. A 0.03 mg dose will also be tested. A 0.01 mg dose will be tested if 4 or more subjects experience 1 or more bowel movements within the 24 hour period post dose in the 0.03 mg dosing cohort.
Interventions
DRUGNaldemedine
Tablets or solution for oral administration
DRUGPlacebo
Tablets or solution for oral administration
Sponsors
Shionogi
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Understand and sign an informed consent form * Males will agree to use an approved double-barrier method of contraception from Day 1 until 1 month after study completion * Subject tests negative on urine drug test unless the subject has a prescription for the drug(s) that test positive
Exclusion criteria
* Subjects under opioid therapy for cancer-related pain or for the management of drug addiction * Fecal incontinence, irritable bowel syndrome, inflammatory bowel disease, or other active medical disorders associated with diarrhea, intermittent loose stools, or constipation * Subjects who have participated in any other investigational drug study within 30 days prior to Day 1 * Prior exposure to S-297995
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | From the first dose of study drug on Day 15 up to Day 24. | Severity of adverse events (AEs) was graded according to the following definitions: * Mild: The subject experiences awareness of symptoms but these are easily tolerated or managed without specific treatment * Moderate: The subject experiences discomfort enough to cause interference with usual activity, and/or the condition requires specific treatment * Severe: The subject is incapacitated with inability to work or do usual activity, and/or the event requires significant treatment measures. The relationship of the event to the study drug was determined by the investigator. A serious adverse event (SAE) is defined as any AE occurring at any dose that resulted in any of the following outcomes: death, life-threatening AE, hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to 48 Hours Post-dose in the Number of SBMs Per Day | Baseline (Day 1 to Day 15) and Day 15 to Day 17 (0 to 48 hours post-dose) | Participants completed a bowel function assessment daily diary to record information about bowel movements and constipation. A spontaneous bowel movement was defined as a bowel movement where no laxative or enema was used in the 24 hours preceding the bowel movement. Baseline was defined as the average number of SBMs per day during the 2 weeks prior to receiving study drug (Day 1 to Day 15). Forty-eight hours post-dose was defined as the average number of SBMs per day from 0 to 48 hours post-dose. |
| Change From Baseline to 24 Hours Post-dose in Number of Bowel Movements (BM) Per Day | Baseline and 24 hours post-dose | Participants completed a bowel function assessment daily diary to record information about bowel movements and constipation. Baseline was defined as the average number of BMs per day during the 2 weeks prior to receiving study drug (Day 1 to Day 15). |
| Change From Baseline to 48 Hours Post-dose in Number of Bowel Movements Per Day | Baseline and 48 hours post-dose | Participants completed a bowel function assessment daily diary to record information about bowel movements and constipation. Baseline was defined as the average number of BMs per day during the 2 weeks prior to receiving study drug (Day 1 to Day 15). Forty-eight hours post-dose was defined as the average number of BMs per day from 0 to 48 hours post-dose. |
| Change From Baseline to 24 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | Baseline and 24 hours post-dose | Participants completed a bowel function assessment daily diary to record information about bowel movements and constipation. A complete spontaneous bowel movement was defined as a bowel movement where no laxative or enema was used and the bowel movement resulted in a sensation of complete evacuation (based on the question of having a feeling of complete emptying after the bowel movement). Baseline was defined as the average number of CSBMs per day during the 2 weeks prior to receiving study drug (Day 1 to Day 15). |
| Change From Baseline to 48 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | Baseline and 48 hours post-dose | Participants completed a bowel function assessment daily diary to record information about bowel movements and constipation. A complete spontaneous bowel movement was defined as a bowel movement where no laxative or enema was used and the bowel movement resulted in a sensation of complete evacuation (based on the question of having a feeling of complete emptying after the bowel movement). Baseline was defined as the average number of CSBMs per day during the 2 weeks prior to receiving study drug (Day 1 to Day 15). Forty-eight hours post-dose was defined as the average number of CSBMs per day from 0 to 48 hours post-dose. |
| Time to First Spontaneous Bowel Movement | From first dose on Day 15 through Day 17 | The time to first SBM during the Study Drug Administration Period was summarized using Kaplan-Meier estimates. Each participant's first SBM was counted as an event and the time to first SBM after dosing was calculated from the date and time of first dosing until the date and time of first SBM. Participants who dropped out or were lost to follow-up before the first SBM were censored. |
| Time to First Bowel Movement | From first dose on Day 15 through Day 17 | The time to first BM during the Study Drug Administration Period was summarized using Kaplan-Meier estimates. Each participant's first BM was counted as an event and the time to first BM after dosing was calculated from the date and time of first dosing until the date and time of first BM. Participants who dropped out or were lost to follow-up before the first BM were censored. |
| Time to First Complete Spontaneous Bowel Movement | From first dose on Day 15 through Day 17 | The time to first CSBM during the Study Drug Administration Period was summarized using Kaplan-Meier estimates. Each participant's first CSBM was counted as an event and the time to first CSBM after dosing was calculated from the date and time of first dosing until the date and time of first CSBM. Participants who dropped out or were lost to follow-up before the first CSBM were censored. |
| Change From Baseline in Straining During Bowel Movements | Baseline, 24 hours post-dose and 48 hours post-dose | Straining during BMs was graded using the following scale: 0 = Absent; 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Very Severe. Baseline was defined as the average straining score of all BMs prior to receiving study drug (Day 1 to Day 15). The straining score at 24 and 48 hours post-dose was calculated as the average straining score from all bowel movements from 0 to 24 and 0 to 48 hours post-dose, respectively. |
| Change From Baseline to 24 Hours Post-dose in Number of Complete Bowel Movements Per Day | Baseline and 24 hours post-dose | A complete bowel movement (CBM) was defined as a bowel movement that resulted in a sensation of complete evacuation based on the question Did you have a feeling of complete emptying after the bowel movement? Baseline was defined as the average number of CBMs per day prior to receiving study drug (Day 1 to Day 15). |
| Change From Baseline to 48 Hours Post-dose in Number of Complete Bowel Movements Per Day | Baseline and 48 hours post-dose | A complete bowel movement (CBM) was defined as a bowel movement that resulted in a sensation of complete evacuation based on the question Did you have a feeling of complete emptying after the bowel movement? Baseline was defined as the average number of CBMs per day prior to receiving study drug (Day 1 to 15). Forty-eight hours post-dose was calculated as the average number of CBMs per day from 0 to 48 hours post-dose. |
| Change From Baseline in Abdominal Bloating | Baseline, 24 hours post-dose and 48 hours post-dose | Participants were asked to rate their abdominal bloating for the past 24 hours using the following scale: 0 = Absent; 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Very Severe. Baseline was defined as the average abdominal bloating score prior to receiving study drug (Day 1 to Day 15). Abdominal bloating at 24 hours and 48 hours post-dose was calculated as the mean score from 0 to 24 and 0 to 48 hours post-dose respectively. |
| Change From Baseline to 24 Hours Post-dose in Number of Spontaneous Bowel Movements (SBMs) Per Day | Baseline (Day 1 to Day 15) and Day 15 to 16 (0 to 24 hours post-dose) | Participants completed a bowel function assessment daily diary to record information about bowel movements and constipation. A spontaneous bowel movement was defined as a bowel movement where no laxative or enema was used in the 24 hours preceding the bowel movement. Baseline was defined as the average number of SBMs per day during the 2 weeks prior to receiving study drug (Day 1 to Day 15). |
| Change From Baseline in Number of Rescue Medications Used Per Day | Baseline, 24 hours post-dose and 48 hours post-dose | Baseline was defined as the average number of rescue medications used per day prior to receiving study drug (Day 1 to Day 15). The number of rescue medications used per day at 24 hours and 48 hours post-dose was calculated as the average number of rescue medications used per day from 0 to 24 hours and 0 to 48 hours post-dose, respectively. |
| Change From Baseline in BM Consistency | Baseline, 24 hours post-dose and 48 hours post-dose | Consistency of BMs was measured using the Bristol Stool Scale, as follows: 1 = separate hard lumps like nuts; 2 = sausage shaped but lumpy; 3 = like a sausage, but with cracks on its surface; 4 = like a sausage or a snake, smooth and soft; 5 = soft blobs and with clear-cut edges; 6 = floppy pieces with ragged edges/mushy stool; 7 = watery, no solid pieces, entirely liquid. Baseline was defined as the average consistency of BMs prior to receiving study drug (Day 1 to Day 15). BM consistency at 24 hours and 48 hours post-dose was calculated as the average scores from all bowel movements from 0 to 24 and 0 to 48 hours post-dose, respectively. |
| Change From Baseline in Number of False Start Bowel Movements Per Day | Baseline, 24 hours post-dose and 48 hours post-dose | A false start was defined as any attempted, but unsuccessful bowel movement (no solid or liquid fecal material was excreted) based on the question In the past 24 hours, how many times did you try to have a bowel movement but were unsuccessful? Baseline was defined as the average number of false start BMs per day prior to receiving study drug (Day 1 to Day 15). The number of false start BMs per day at 24 hours and 48 hours post-dose was calculated as is the average number of false start BMs per day from 0 to 24 and 0 to 48 hours post-dose, respectively. |
| Change From Baseline in the Number of Bowel Movements With No Straining Per Day | Baseline, 24 hours post-dose and 48 hours post-dose | Straining during BMs was graded using the following scale: 0 = Absent; 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Very Severe. A BM without straining was defined as a BM with a straining score = 0. Baseline was defined as the average number of BMs without straining per day prior to receiving study drug (Day 1 to Day 15). The number of BMs without straining per day at 24 hours and 48 hours post-dose was calculated as the average number of BMs with no straining per day from 0 to 24 hours and 0 to 48 hours post-dose, respectively. |
| Percentage of Participants With Clinical Opiate Withdrawal Scale (COWS) Score > 8 at Any Time During the Study | The COWS assessments were performed at Screening, on Day 14, Day 15 (pre-dose and 1, 2, 3, 4, 5, 6 and 8 hours post-dose, and at unscheduled times as signs or symptoms indicate), on Days 16 and 17, and on Day 24/End of Study. | The COWS assessment consisted of 11 questions which rated the severity of opiate withdrawal symptoms, including resting pulse rate, gastrointestinal upset, sweating, restlessness, pupil size, tremor, anxiety or irritability, bone or joint aches, gooseflesh skin, yawning, and runny nose or tearing. Each symptom was rated on a scale from 0 (not present) to 4 or 5 (most severe). The total score was calculated by summing the 11 individual scores and ranged from 0 (no withdrawal symptoms) to 48 (worst symptoms). |
| Percentage of Participants With Webster Opiate Withdrawal Scale (WOWS) Score > 8 at Any Time During the Study | The WOWS assessment was performed at Screening, Day 14, Day 15 at pre-dose , and 24 and 48 hours post-dose and at the Follow-up/End of Study visit (Day 24). | The Webster Opiate Withdrawal Scale (WOWS) assessment consisted of 7 questions which rate the severity of opiate withdrawal symptoms, including sweating, sleep, bone or joint aches, runny nose or tearing, gastrointestinal upset, anxiety or irritability and gooseflesh skin. Each symptom was rated on a scale from 0 (not present/no issues) to 4 or 5 (severe). The total score was calculated by summing the 7 individual scores and ranged from 0 (no withdrawal symptoms) to 29 (worst symptoms). |
| Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995 | Blood samples were collected predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post-dose. | The plasma concentration of naldemedine and its metabolite Nor-S-297995 were measured by liquid chromatography/tandem mass spectrometry (LC/MS/MS) method. |
| Time to Maximum Observed Plasma Concentration of Naldemedine and Metabolite Nor-S-297995 | Blood samples were collected predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post-dose. | The plasma concentration of naldemedine and its metabolite Nor-S-297995 were measured by liquid chromatography/tandem mass spectrometry (LC/MS/MS) method. |
| Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable Concentration of Naldemedine and Metabolite Nor-S-297995 | Blood samples were collected predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post-dose. | The plasma concentration of naldemedine and its metabolite Nor-S-297995 were measured by liquid chromatography/tandem mass spectrometry (LC/MS/MS) method. Area under the plasma concentration versus time curve from time zero to the last sampling time at which concentrations were at or above the limit of quantitation, calculated using the linear trapezoidal rule for increasing concentrations and the logarithmic rule for decreasing concentrations (Linear Up/ Log Down). |
| Area Under the Plasma Concentration-time Curve From Time Zero to Infinity for Naldemedine and Metabolite Nor-S-297995 | Blood samples were collected predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post-dose. | The plasma concentration of naldemedine and its metabolite Nor-S-297995 were measured by liquid chromatography/tandem mass spectrometry (LC/MS/MS) method. Area under the plasma concentration versus time curve from time zero to infinity, calculated using the formula: AUC0-inf = AUC0-t + Ct/λZ where Ct was the last measurable concentration and λZ was the apparent terminal elimination rate constant. |
| Apparent Elimination Half-life of Naldemedine and Metabolite Nor-S-297995 | Blood samples were collected predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post-dose. | The plasma concentration of naldemedine and its metabolite Nor-S-297995 were measured by liquid chromatography/tandem mass spectrometry (LC/MS/MS) method. The apparent elimination half-life was calculated using the formula t1/2,z = (ln2)/λZ |
| Change From Baseline in Abdominal Discomfort | Baseline, 24 hours post-dose and 48 hours post-dose | Participants were asked to rate their abdominal discomfort for the past 24 hours using the following scale: 0 = Absent; 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Very Severe. Baseline was defined as the average abdominal discomfort score prior to receiving study drug (Day 1 to Day 15). Abdominal discomfort at 24 hours and 48 hours post-dose was calculated as the mean score from 0 to 24 and 0 to 48 hours post-dose respectively. |
Countries
United States
Participant flow
Recruitment details
The study was conducted at a single study center in the United States.
Pre-assignment details
Participants were randomized to naldemedine or placebo, screened for 13 days (Days 1-13), and admitted to the clinic on Day 14 for pre-admission assessments. Six cohorts were sequentially enrolled from Cohort 1 (0.1 mg) to Cohort 2 (0.3 mg), Cohort 3 (1 mg), and Cohort 4 (3 mg), and subsequent de-escalation in Cohorts 5 (0.03 mg) and 6 (0.01 mg).
Participants by arm
| Arm | Count |
|---|---|
| Pooled Placebo Participants received a single dose of matching placebo administered orally on Day 15 under fasted conditions. | 18 |
| Naldemedine 0.01 mg Participants received a single dose of 0.01 mg naldemedine oral solution administered on Day 15 under fasted conditions. | 9 |
| Naldemedine 0.03 mg Participants received a single dose of 0.03 mg naldemedine oral solution administered on Day 15 under fasted conditions. | 9 |
| Naldemedine 0.1 mg Participants received one 0.1 mg naldemedine tablet administered on Day 15 under fasted conditions. | 9 |
| Naldemedine 0.3 mg Participants received a single dose of 0.3 mg naldemedine tablets administered on Day 15 under fasted conditions. | 9 |
| Naldemedine 1 mg Participants received a single dose of 1 mg naldemedine tablets administered on Day 15 under fasted conditions. | 9 |
| Naldemedine 3 mg Participants received a single dose of 3 mg naldemedine tablets administered on Day 15 under fasted conditions. | 9 |
| Total | 72 |
Baseline characteristics
| Characteristic | Total | Pooled Placebo | Naldemedine 0.01 mg | Naldemedine 0.03 mg | Naldemedine 0.1 mg | Naldemedine 0.3 mg | Naldemedine 1 mg | Naldemedine 3 mg |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 43.3 years STANDARD_DEVIATION 10.3 | 46.7 years STANDARD_DEVIATION 8.55 | 41.4 years STANDARD_DEVIATION 12.99 | 45.2 years STANDARD_DEVIATION 13.13 | 45.6 years STANDARD_DEVIATION 6.02 | 39.7 years STANDARD_DEVIATION 10.64 | 36.6 years STANDARD_DEVIATION 10.19 | 44.8 years STANDARD_DEVIATION 9.09 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 67 Participants | 16 Participants | 8 Participants | 8 Participants | 9 Participants | 8 Participants | 9 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 70 Participants | 18 Participants | 8 Participants | 9 Participants | 9 Participants | 8 Participants | 9 Participants | 9 Participants |
| Sex: Female, Male Female | 38 Participants | 7 Participants | 7 Participants | 7 Participants | 5 Participants | 6 Participants | 4 Participants | 2 Participants |
| Sex: Female, Male Male | 34 Participants | 11 Participants | 2 Participants | 2 Participants | 4 Participants | 3 Participants | 5 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 18 | 6 / 9 | 6 / 9 | 5 / 9 | 9 / 9 | 9 / 9 | 9 / 9 |
| serious Total, serious adverse events | 0 / 18 | 0 / 9 | 0 / 9 | 0 / 9 | 0 / 9 | 0 / 9 | 0 / 9 |
Outcome results
Primary
Number of Participants With Adverse Events
Severity of adverse events (AEs) was graded according to the following definitions: * Mild: The subject experiences awareness of symptoms but these are easily tolerated or managed without specific treatment * Moderate: The subject experiences discomfort enough to cause interference with usual activity, and/or the condition requires specific treatment * Severe: The subject is incapacitated with inability to work or do usual activity, and/or the event requires significant treatment measures. The relationship of the event to the study drug was determined by the investigator. A serious adverse event (SAE) is defined as any AE occurring at any dose that resulted in any of the following outcomes: death, life-threatening AE, hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect.
Time frame: From the first dose of study drug on Day 15 up to Day 24.
Population: All participants who received any amount of study drug (safety population).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pooled Placebo | Number of Participants With Adverse Events | Moderate adverse events | 0 participants |
| Pooled Placebo | Number of Participants With Adverse Events | Any adverse event | 9 participants |
| Pooled Placebo | Number of Participants With Adverse Events | Severe adverse events | 0 participants |
| Pooled Placebo | Number of Participants With Adverse Events | Treatment-related adverse events | 6 participants |
| Pooled Placebo | Number of Participants With Adverse Events | Serious adverse events | 0 participants |
| Pooled Placebo | Number of Participants With Adverse Events | Adverse events leading to discontinuation | 0 participants |
| Pooled Placebo | Number of Participants With Adverse Events | Deaths | 0 participants |
| Pooled Placebo | Number of Participants With Adverse Events | Mild adverse events | 9 participants |
| Naldemedine 0.01 mg | Number of Participants With Adverse Events | Deaths | 0 participants |
| Naldemedine 0.01 mg | Number of Participants With Adverse Events | Treatment-related adverse events | 5 participants |
| Naldemedine 0.01 mg | Number of Participants With Adverse Events | Severe adverse events | 0 participants |
| Naldemedine 0.01 mg | Number of Participants With Adverse Events | Moderate adverse events | 0 participants |
| Naldemedine 0.01 mg | Number of Participants With Adverse Events | Mild adverse events | 6 participants |
| Naldemedine 0.01 mg | Number of Participants With Adverse Events | Any adverse event | 6 participants |
| Naldemedine 0.01 mg | Number of Participants With Adverse Events | Adverse events leading to discontinuation | 0 participants |
| Naldemedine 0.01 mg | Number of Participants With Adverse Events | Serious adverse events | 0 participants |
| Naldemedine 0.03 mg | Number of Participants With Adverse Events | Moderate adverse events | 0 participants |
| Naldemedine 0.03 mg | Number of Participants With Adverse Events | Deaths | 0 participants |
| Naldemedine 0.03 mg | Number of Participants With Adverse Events | Serious adverse events | 0 participants |
| Naldemedine 0.03 mg | Number of Participants With Adverse Events | Adverse events leading to discontinuation | 0 participants |
| Naldemedine 0.03 mg | Number of Participants With Adverse Events | Any adverse event | 6 participants |
| Naldemedine 0.03 mg | Number of Participants With Adverse Events | Mild adverse events | 6 participants |
| Naldemedine 0.03 mg | Number of Participants With Adverse Events | Severe adverse events | 0 participants |
| Naldemedine 0.03 mg | Number of Participants With Adverse Events | Treatment-related adverse events | 3 participants |
| Naldemedine 0.1 mg | Number of Participants With Adverse Events | Severe adverse events | 0 participants |
| Naldemedine 0.1 mg | Number of Participants With Adverse Events | Moderate adverse events | 1 participants |
| Naldemedine 0.1 mg | Number of Participants With Adverse Events | Any adverse event | 5 participants |
| Naldemedine 0.1 mg | Number of Participants With Adverse Events | Treatment-related adverse events | 1 participants |
| Naldemedine 0.1 mg | Number of Participants With Adverse Events | Mild adverse events | 4 participants |
| Naldemedine 0.1 mg | Number of Participants With Adverse Events | Adverse events leading to discontinuation | 0 participants |
| Naldemedine 0.1 mg | Number of Participants With Adverse Events | Serious adverse events | 0 participants |
| Naldemedine 0.1 mg | Number of Participants With Adverse Events | Deaths | 0 participants |
| Naldemedine 0.3 mg | Number of Participants With Adverse Events | Mild adverse events | 6 participants |
| Naldemedine 0.3 mg | Number of Participants With Adverse Events | Treatment-related adverse events | 9 participants |
| Naldemedine 0.3 mg | Number of Participants With Adverse Events | Adverse events leading to discontinuation | 0 participants |
| Naldemedine 0.3 mg | Number of Participants With Adverse Events | Any adverse event | 9 participants |
| Naldemedine 0.3 mg | Number of Participants With Adverse Events | Serious adverse events | 0 participants |
| Naldemedine 0.3 mg | Number of Participants With Adverse Events | Moderate adverse events | 3 participants |
| Naldemedine 0.3 mg | Number of Participants With Adverse Events | Severe adverse events | 0 participants |
| Naldemedine 0.3 mg | Number of Participants With Adverse Events | Deaths | 0 participants |
| Naldemedine 1 mg | Number of Participants With Adverse Events | Severe adverse events | 1 participants |
| Naldemedine 1 mg | Number of Participants With Adverse Events | Adverse events leading to discontinuation | 0 participants |
| Naldemedine 1 mg | Number of Participants With Adverse Events | Mild adverse events | 5 participants |
| Naldemedine 1 mg | Number of Participants With Adverse Events | Treatment-related adverse events | 8 participants |
| Naldemedine 1 mg | Number of Participants With Adverse Events | Serious adverse events | 0 participants |
| Naldemedine 1 mg | Number of Participants With Adverse Events | Any adverse event | 9 participants |
| Naldemedine 1 mg | Number of Participants With Adverse Events | Moderate adverse events | 3 participants |
| Naldemedine 1 mg | Number of Participants With Adverse Events | Deaths | 0 participants |
| Naldemedine 3 mg | Number of Participants With Adverse Events | Treatment-related adverse events | 9 participants |
| Naldemedine 3 mg | Number of Participants With Adverse Events | Moderate adverse events | 2 participants |
| Naldemedine 3 mg | Number of Participants With Adverse Events | Mild adverse events | 1 participants |
| Naldemedine 3 mg | Number of Participants With Adverse Events | Any adverse event | 9 participants |
| Naldemedine 3 mg | Number of Participants With Adverse Events | Adverse events leading to discontinuation | 0 participants |
| Naldemedine 3 mg | Number of Participants With Adverse Events | Severe adverse events | 6 participants |
| Naldemedine 3 mg | Number of Participants With Adverse Events | Deaths | 0 participants |
| Naldemedine 3 mg | Number of Participants With Adverse Events | Serious adverse events | 0 participants |
Secondary
Apparent Elimination Half-life of Naldemedine and Metabolite Nor-S-297995
The plasma concentration of naldemedine and its metabolite Nor-S-297995 were measured by liquid chromatography/tandem mass spectrometry (LC/MS/MS) method. The apparent elimination half-life was calculated using the formula t1/2,z = (ln2)/λZ
Time frame: Blood samples were collected predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post-dose.
Population: PK population
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Pooled Placebo | Apparent Elimination Half-life of Naldemedine and Metabolite Nor-S-297995 | Naldemedine | 8.13 hours | Geometric Coefficient of Variation 58.3 |
| Pooled Placebo | Apparent Elimination Half-life of Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 | NA hours | — |
| Naldemedine 0.01 mg | Apparent Elimination Half-life of Naldemedine and Metabolite Nor-S-297995 | Naldemedine | 7.46 hours | Geometric Coefficient of Variation 38.5 |
| Naldemedine 0.01 mg | Apparent Elimination Half-life of Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 | NA hours | — |
| Naldemedine 0.03 mg | Apparent Elimination Half-life of Naldemedine and Metabolite Nor-S-297995 | Naldemedine | 12.6 hours | Geometric Coefficient of Variation 35.6 |
| Naldemedine 0.03 mg | Apparent Elimination Half-life of Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 | 24.6 hours | Geometric Coefficient of Variation 52.7 |
| Naldemedine 0.1 mg | Apparent Elimination Half-life of Naldemedine and Metabolite Nor-S-297995 | Naldemedine | 12.2 hours | Geometric Coefficient of Variation 34.6 |
| Naldemedine 0.1 mg | Apparent Elimination Half-life of Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 | 25.7 hours | Geometric Coefficient of Variation 61.8 |
| Naldemedine 0.3 mg | Apparent Elimination Half-life of Naldemedine and Metabolite Nor-S-297995 | Naldemedine | 10.8 hours | Geometric Coefficient of Variation 20.9 |
| Naldemedine 0.3 mg | Apparent Elimination Half-life of Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 | 16.0 hours | Geometric Coefficient of Variation 24.8 |
| Naldemedine 1 mg | Apparent Elimination Half-life of Naldemedine and Metabolite Nor-S-297995 | Naldemedine | 11.6 hours | Geometric Coefficient of Variation 20.8 |
| Naldemedine 1 mg | Apparent Elimination Half-life of Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 | 17.0 hours | Geometric Coefficient of Variation 18.1 |
Secondary
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity for Naldemedine and Metabolite Nor-S-297995
The plasma concentration of naldemedine and its metabolite Nor-S-297995 were measured by liquid chromatography/tandem mass spectrometry (LC/MS/MS) method. Area under the plasma concentration versus time curve from time zero to infinity, calculated using the formula: AUC0-inf = AUC0-t + Ct/λZ where Ct was the last measurable concentration and λZ was the apparent terminal elimination rate constant.
Time frame: Blood samples were collected predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post-dose.
Population: PK population
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Pooled Placebo | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity for Naldemedine and Metabolite Nor-S-297995 | Naldemedine | 0.8023 ng*hr/mL | Geometric Coefficient of Variation 33.8 |
| Pooled Placebo | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity for Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 | NA ng*hr/mL | — |
| Naldemedine 0.01 mg | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity for Naldemedine and Metabolite Nor-S-297995 | Naldemedine | 2.294 ng*hr/mL | Geometric Coefficient of Variation 30.2 |
| Naldemedine 0.01 mg | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity for Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 | NA ng*hr/mL | — |
| Naldemedine 0.03 mg | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity for Naldemedine and Metabolite Nor-S-297995 | Naldemedine | 12.04 ng*hr/mL | Geometric Coefficient of Variation 21.7 |
| Naldemedine 0.03 mg | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity for Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 | 3.046 ng*hr/mL | Geometric Coefficient of Variation 63 |
| Naldemedine 0.1 mg | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity for Naldemedine and Metabolite Nor-S-297995 | Naldemedine | 31.87 ng*hr/mL | Geometric Coefficient of Variation 29.9 |
| Naldemedine 0.1 mg | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity for Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 | 4.515 ng*hr/mL | Geometric Coefficient of Variation 58.8 |
| Naldemedine 0.3 mg | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity for Naldemedine and Metabolite Nor-S-297995 | Naldemedine | 94.53 ng*hr/mL | Geometric Coefficient of Variation 34.8 |
| Naldemedine 0.3 mg | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity for Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 | 17.10 ng*hr/mL | Geometric Coefficient of Variation 73.4 |
| Naldemedine 1 mg | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity for Naldemedine and Metabolite Nor-S-297995 | Naldemedine | 219.9 ng*hr/mL | Geometric Coefficient of Variation 37.8 |
| Naldemedine 1 mg | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity for Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 | 44.91 ng*hr/mL | Geometric Coefficient of Variation 63.6 |
Secondary
Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable Concentration of Naldemedine and Metabolite Nor-S-297995
The plasma concentration of naldemedine and its metabolite Nor-S-297995 were measured by liquid chromatography/tandem mass spectrometry (LC/MS/MS) method. Area under the plasma concentration versus time curve from time zero to the last sampling time at which concentrations were at or above the limit of quantitation, calculated using the linear trapezoidal rule for increasing concentrations and the logarithmic rule for decreasing concentrations (Linear Up/ Log Down).
Time frame: Blood samples were collected predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post-dose.
Population: PK population
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Pooled Placebo | Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable Concentration of Naldemedine and Metabolite Nor-S-297995 | Naldemedine | 0.5863 ng*hr/mL) | Geometric Coefficient of Variation 34.3 |
| Pooled Placebo | Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable Concentration of Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 | NA ng*hr/mL) | — |
| Naldemedine 0.01 mg | Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable Concentration of Naldemedine and Metabolite Nor-S-297995 | Naldemedine | 2.111 ng*hr/mL) | Geometric Coefficient of Variation 31.4 |
| Naldemedine 0.01 mg | Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable Concentration of Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 | NA ng*hr/mL) | — |
| Naldemedine 0.03 mg | Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable Concentration of Naldemedine and Metabolite Nor-S-297995 | Naldemedine | 11.71 ng*hr/mL) | Geometric Coefficient of Variation 21.4 |
| Naldemedine 0.03 mg | Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable Concentration of Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 | 0.5856 ng*hr/mL) | Geometric Coefficient of Variation 232.7 |
| Naldemedine 0.1 mg | Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable Concentration of Naldemedine and Metabolite Nor-S-297995 | Naldemedine | 31.29 ng*hr/mL) | Geometric Coefficient of Variation 30.5 |
| Naldemedine 0.1 mg | Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable Concentration of Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 | 1.869 ng*hr/mL) | Geometric Coefficient of Variation 68.3 |
| Naldemedine 0.3 mg | Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable Concentration of Naldemedine and Metabolite Nor-S-297995 | Naldemedine | 93.60 ng*hr/mL) | Geometric Coefficient of Variation 34.6 |
| Naldemedine 0.3 mg | Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable Concentration of Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 | 14.97 ng*hr/mL) | Geometric Coefficient of Variation 76.3 |
| Naldemedine 1 mg | Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable Concentration of Naldemedine and Metabolite Nor-S-297995 | Naldemedine | 218.2 ng*hr/mL) | Geometric Coefficient of Variation 37.6 |
| Naldemedine 1 mg | Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable Concentration of Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 | 41.94 ng*hr/mL) | Geometric Coefficient of Variation 63.3 |
Secondary
Change From Baseline in Abdominal Bloating
Participants were asked to rate their abdominal bloating for the past 24 hours using the following scale: 0 = Absent; 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Very Severe. Baseline was defined as the average abdominal bloating score prior to receiving study drug (Day 1 to Day 15). Abdominal bloating at 24 hours and 48 hours post-dose was calculated as the mean score from 0 to 24 and 0 to 48 hours post-dose respectively.
Time frame: Baseline, 24 hours post-dose and 48 hours post-dose
Population: Intent-to-treat population with available data at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pooled Placebo | Change From Baseline in Abdominal Bloating | Change from Baseline to 48 hours post-dose | -0.5 units on a scale | Standard Deviation 0.54 |
| Pooled Placebo | Change From Baseline in Abdominal Bloating | Change from Baseline to 24 hours post-dose | 0.0 units on a scale | Standard Deviation 0.83 |
| Pooled Placebo | Change From Baseline in Abdominal Bloating | Baseline | 2.0 units on a scale | Standard Deviation 0.65 |
| Naldemedine 0.01 mg | Change From Baseline in Abdominal Bloating | Change from Baseline to 24 hours post-dose | 0.0 units on a scale | — |
| Naldemedine 0.01 mg | Change From Baseline in Abdominal Bloating | Baseline | 1.4 units on a scale | Standard Deviation 0.95 |
| Naldemedine 0.01 mg | Change From Baseline in Abdominal Bloating | Change from Baseline to 48 hours post-dose | 0.1 units on a scale | Standard Deviation 0.86 |
| Naldemedine 0.03 mg | Change From Baseline in Abdominal Bloating | Change from Baseline to 48 hours post-dose | 0.2 units on a scale | Standard Deviation 1.17 |
| Naldemedine 0.03 mg | Change From Baseline in Abdominal Bloating | Baseline | 1.5 units on a scale | Standard Deviation 0.69 |
| Naldemedine 0.03 mg | Change From Baseline in Abdominal Bloating | Change from Baseline to 24 hours post-dose | 0.2 units on a scale | Standard Deviation 1.09 |
| Naldemedine 0.1 mg | Change From Baseline in Abdominal Bloating | Change from Baseline to 24 hours post-dose | -0.2 units on a scale | Standard Deviation 1.03 |
| Naldemedine 0.1 mg | Change From Baseline in Abdominal Bloating | Baseline | 1.7 units on a scale | Standard Deviation 0.87 |
| Naldemedine 0.1 mg | Change From Baseline in Abdominal Bloating | Change from Baseline to 48 hours post-dose | 0.1 units on a scale | Standard Deviation 0.89 |
| Naldemedine 0.3 mg | Change From Baseline in Abdominal Bloating | Change from Baseline to 24 hours post-dose | 0.3 units on a scale | Standard Deviation 0.69 |
| Naldemedine 0.3 mg | Change From Baseline in Abdominal Bloating | Baseline | 1.7 units on a scale | Standard Deviation 0.66 |
| Naldemedine 0.3 mg | Change From Baseline in Abdominal Bloating | Change from Baseline to 48 hours post-dose | 0.4 units on a scale | — |
| Naldemedine 1 mg | Change From Baseline in Abdominal Bloating | Baseline | 2.5 units on a scale | Standard Deviation 0.64 |
| Naldemedine 1 mg | Change From Baseline in Abdominal Bloating | Change from Baseline to 48 hours post-dose | -0.8 units on a scale | Standard Deviation 0.5 |
| Naldemedine 1 mg | Change From Baseline in Abdominal Bloating | Change from Baseline to 24 hours post-dose | -0.5 units on a scale | Standard Deviation 0.91 |
| Naldemedine 3 mg | Change From Baseline in Abdominal Bloating | Change from Baseline to 48 hours post-dose | -0.2 units on a scale | Standard Deviation 1.95 |
| Naldemedine 3 mg | Change From Baseline in Abdominal Bloating | Change from Baseline to 24 hours post-dose | 0.7 units on a scale | Standard Deviation 1.53 |
| Naldemedine 3 mg | Change From Baseline in Abdominal Bloating | Baseline | 1.3 units on a scale | Standard Deviation 0.65 |
Secondary
Change From Baseline in Abdominal Discomfort
Participants were asked to rate their abdominal discomfort for the past 24 hours using the following scale: 0 = Absent; 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Very Severe. Baseline was defined as the average abdominal discomfort score prior to receiving study drug (Day 1 to Day 15). Abdominal discomfort at 24 hours and 48 hours post-dose was calculated as the mean score from 0 to 24 and 0 to 48 hours post-dose respectively.
Time frame: Baseline, 24 hours post-dose and 48 hours post-dose
Population: Intent-to-treat population with available data at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pooled Placebo | Change From Baseline in Abdominal Discomfort | Change from Baseline to 48 hours post-dose | -0.4 units on a scale | Standard Deviation 0.67 |
| Pooled Placebo | Change From Baseline in Abdominal Discomfort | Change from Baseline to 24 hours post-dose | -0.2 units on a scale | Standard Deviation 0.78 |
| Pooled Placebo | Change From Baseline in Abdominal Discomfort | Baseline | 2.1 units on a scale | Standard Deviation 0.63 |
| Naldemedine 0.01 mg | Change From Baseline in Abdominal Discomfort | Change from Baseline to 24 hours post-dose | -0.8 units on a scale | — |
| Naldemedine 0.01 mg | Change From Baseline in Abdominal Discomfort | Baseline | 1.5 units on a scale | Standard Deviation 0.98 |
| Naldemedine 0.01 mg | Change From Baseline in Abdominal Discomfort | Change from Baseline to 48 hours post-dose | -0.3 units on a scale | Standard Deviation 1 |
| Naldemedine 0.03 mg | Change From Baseline in Abdominal Discomfort | Change from Baseline to 48 hours post-dose | -0.2 units on a scale | Standard Deviation 1 |
| Naldemedine 0.03 mg | Change From Baseline in Abdominal Discomfort | Baseline | 2.0 units on a scale | Standard Deviation 0.75 |
| Naldemedine 0.03 mg | Change From Baseline in Abdominal Discomfort | Change from Baseline to 24 hours post-dose | -0.5 units on a scale | Standard Deviation 0.8 |
| Naldemedine 0.1 mg | Change From Baseline in Abdominal Discomfort | Change from Baseline to 24 hours post-dose | -0.7 units on a scale | Standard Deviation 1.3 |
| Naldemedine 0.1 mg | Change From Baseline in Abdominal Discomfort | Baseline | 2.0 units on a scale | Standard Deviation 0.74 |
| Naldemedine 0.1 mg | Change From Baseline in Abdominal Discomfort | Change from Baseline to 48 hours post-dose | -0.4 units on a scale | Standard Deviation 0.44 |
| Naldemedine 0.3 mg | Change From Baseline in Abdominal Discomfort | Change from Baseline to 24 hours post-dose | 0.3 units on a scale | Standard Deviation 0.6 |
| Naldemedine 0.3 mg | Change From Baseline in Abdominal Discomfort | Baseline | 1.9 units on a scale | Standard Deviation 0.81 |
| Naldemedine 0.3 mg | Change From Baseline in Abdominal Discomfort | Change from Baseline to 48 hours post-dose | 1.1 units on a scale | — |
| Naldemedine 1 mg | Change From Baseline in Abdominal Discomfort | Baseline | 2.6 units on a scale | Standard Deviation 0.77 |
| Naldemedine 1 mg | Change From Baseline in Abdominal Discomfort | Change from Baseline to 48 hours post-dose | -1.1 units on a scale | Standard Deviation 1.07 |
| Naldemedine 1 mg | Change From Baseline in Abdominal Discomfort | Change from Baseline to 24 hours post-dose | -0.1 units on a scale | Standard Deviation 0.96 |
| Naldemedine 3 mg | Change From Baseline in Abdominal Discomfort | Change from Baseline to 48 hours post-dose | -0.1 units on a scale | Standard Deviation 1.59 |
| Naldemedine 3 mg | Change From Baseline in Abdominal Discomfort | Change from Baseline to 24 hours post-dose | 1.3 units on a scale | Standard Deviation 0.9 |
| Naldemedine 3 mg | Change From Baseline in Abdominal Discomfort | Baseline | 1.7 units on a scale | Standard Deviation 0.77 |
Secondary
Change From Baseline in BM Consistency
Consistency of BMs was measured using the Bristol Stool Scale, as follows: 1 = separate hard lumps like nuts; 2 = sausage shaped but lumpy; 3 = like a sausage, but with cracks on its surface; 4 = like a sausage or a snake, smooth and soft; 5 = soft blobs and with clear-cut edges; 6 = floppy pieces with ragged edges/mushy stool; 7 = watery, no solid pieces, entirely liquid. Baseline was defined as the average consistency of BMs prior to receiving study drug (Day 1 to Day 15). BM consistency at 24 hours and 48 hours post-dose was calculated as the average scores from all bowel movements from 0 to 24 and 0 to 48 hours post-dose, respectively.
Time frame: Baseline, 24 hours post-dose and 48 hours post-dose
Population: Intent-to-treat population with available data at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pooled Placebo | Change From Baseline in BM Consistency | Change from Baseline to 48 hours post-dose | -1.0 units on a scale | Standard Deviation 1.45 |
| Pooled Placebo | Change From Baseline in BM Consistency | Change from Baseline to 24 hours post-dose | -1.4 units on a scale | Standard Deviation 1.09 |
| Pooled Placebo | Change From Baseline in BM Consistency | Baseline | 2.9 units on a scale | Standard Deviation 1.24 |
| Naldemedine 0.01 mg | Change From Baseline in BM Consistency | Change from Baseline to 24 hours post-dose | -3.0 units on a scale | — |
| Naldemedine 0.01 mg | Change From Baseline in BM Consistency | Baseline | 3.2 units on a scale | Standard Deviation 1.13 |
| Naldemedine 0.01 mg | Change From Baseline in BM Consistency | Change from Baseline to 48 hours post-dose | 0.2 units on a scale | Standard Deviation 2.45 |
| Naldemedine 0.03 mg | Change From Baseline in BM Consistency | Change from Baseline to 48 hours post-dose | -0.3 units on a scale | Standard Deviation 1.43 |
| Naldemedine 0.03 mg | Change From Baseline in BM Consistency | Baseline | 2.2 units on a scale | Standard Deviation 1.12 |
| Naldemedine 0.03 mg | Change From Baseline in BM Consistency | Change from Baseline to 24 hours post-dose | -0.0 units on a scale | Standard Deviation 0.24 |
| Naldemedine 0.1 mg | Change From Baseline in BM Consistency | Change from Baseline to 24 hours post-dose | -1.4 units on a scale | Standard Deviation 1.56 |
| Naldemedine 0.1 mg | Change From Baseline in BM Consistency | Baseline | 3.0 units on a scale | Standard Deviation 1.71 |
| Naldemedine 0.1 mg | Change From Baseline in BM Consistency | Change from Baseline to 48 hours post-dose | -1.0 units on a scale | Standard Deviation 2 |
| Naldemedine 0.3 mg | Change From Baseline in BM Consistency | Change from Baseline to 24 hours post-dose | 1.5 units on a scale | Standard Deviation 1.44 |
| Naldemedine 0.3 mg | Change From Baseline in BM Consistency | Baseline | 3.2 units on a scale | Standard Deviation 1.33 |
| Naldemedine 0.3 mg | Change From Baseline in BM Consistency | Change from Baseline to 48 hours post-dose | 0.6 units on a scale | — |
| Naldemedine 1 mg | Change From Baseline in BM Consistency | Baseline | 3.2 units on a scale | Standard Deviation 2.06 |
| Naldemedine 1 mg | Change From Baseline in BM Consistency | Change from Baseline to 48 hours post-dose | 0.7 units on a scale | Standard Deviation 3.66 |
| Naldemedine 1 mg | Change From Baseline in BM Consistency | Change from Baseline to 24 hours post-dose | 1.9 units on a scale | Standard Deviation 3.27 |
| Naldemedine 3 mg | Change From Baseline in BM Consistency | Change from Baseline to 48 hours post-dose | 2.5 units on a scale | Standard Deviation 1.88 |
| Naldemedine 3 mg | Change From Baseline in BM Consistency | Change from Baseline to 24 hours post-dose | 4.1 units on a scale | Standard Deviation 1.07 |
| Naldemedine 3 mg | Change From Baseline in BM Consistency | Baseline | 2.2 units on a scale | Standard Deviation 0.81 |
Secondary
Change From Baseline in Number of False Start Bowel Movements Per Day
A false start was defined as any attempted, but unsuccessful bowel movement (no solid or liquid fecal material was excreted) based on the question In the past 24 hours, how many times did you try to have a bowel movement but were unsuccessful? Baseline was defined as the average number of false start BMs per day prior to receiving study drug (Day 1 to Day 15). The number of false start BMs per day at 24 hours and 48 hours post-dose was calculated as is the average number of false start BMs per day from 0 to 24 and 0 to 48 hours post-dose, respectively.
Time frame: Baseline, 24 hours post-dose and 48 hours post-dose
Population: Intent-to-treat population; LOCF imputation was used
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pooled Placebo | Change From Baseline in Number of False Start Bowel Movements Per Day | Change from Baseline to 48 hours post-dose | 0.25 false start bowel movements / day | Standard Deviation 0.69 |
| Pooled Placebo | Change From Baseline in Number of False Start Bowel Movements Per Day | Change from Baseline to 24 hours post-dose | 0.28 false start bowel movements / day | Standard Deviation 0.89 |
| Pooled Placebo | Change From Baseline in Number of False Start Bowel Movements Per Day | Baseline | 0.56 false start bowel movements / day | Standard Deviation 0.86 |
| Naldemedine 0.01 mg | Change From Baseline in Number of False Start Bowel Movements Per Day | Change from Baseline to 24 hours post-dose | 0.44 false start bowel movements / day | Standard Deviation 1.33 |
| Naldemedine 0.01 mg | Change From Baseline in Number of False Start Bowel Movements Per Day | Baseline | 0.67 false start bowel movements / day | Standard Deviation 1 |
| Naldemedine 0.01 mg | Change From Baseline in Number of False Start Bowel Movements Per Day | Change from Baseline to 48 hours post-dose | 0.28 false start bowel movements / day | Standard Deviation 1.18 |
| Naldemedine 0.03 mg | Change From Baseline in Number of False Start Bowel Movements Per Day | Change from Baseline to 48 hours post-dose | 0.22 false start bowel movements / day | Standard Deviation 1.48 |
| Naldemedine 0.03 mg | Change From Baseline in Number of False Start Bowel Movements Per Day | Baseline | 0.67 false start bowel movements / day | Standard Deviation 1.12 |
| Naldemedine 0.03 mg | Change From Baseline in Number of False Start Bowel Movements Per Day | Change from Baseline to 24 hours post-dose | -0.11 false start bowel movements / day | Standard Deviation 1.17 |
| Naldemedine 0.1 mg | Change From Baseline in Number of False Start Bowel Movements Per Day | Change from Baseline to 24 hours post-dose | 0.00 false start bowel movements / day | Standard Deviation 0.5 |
| Naldemedine 0.1 mg | Change From Baseline in Number of False Start Bowel Movements Per Day | Baseline | 0.22 false start bowel movements / day | Standard Deviation 0.44 |
| Naldemedine 0.1 mg | Change From Baseline in Number of False Start Bowel Movements Per Day | Change from Baseline to 48 hours post-dose | 0.00 false start bowel movements / day | Standard Deviation 0.5 |
| Naldemedine 0.3 mg | Change From Baseline in Number of False Start Bowel Movements Per Day | Change from Baseline to 24 hours post-dose | -0.11 false start bowel movements / day | Standard Deviation 0.6 |
| Naldemedine 0.3 mg | Change From Baseline in Number of False Start Bowel Movements Per Day | Baseline | 0.56 false start bowel movements / day | Standard Deviation 1.01 |
| Naldemedine 0.3 mg | Change From Baseline in Number of False Start Bowel Movements Per Day | Change from Baseline to 48 hours post-dose | -0.06 false start bowel movements / day | Standard Deviation 0.58 |
| Naldemedine 1 mg | Change From Baseline in Number of False Start Bowel Movements Per Day | Baseline | 0.00 false start bowel movements / day | Standard Deviation 0 |
| Naldemedine 1 mg | Change From Baseline in Number of False Start Bowel Movements Per Day | Change from Baseline to 48 hours post-dose | 1.61 false start bowel movements / day | Standard Deviation 2.42 |
| Naldemedine 1 mg | Change From Baseline in Number of False Start Bowel Movements Per Day | Change from Baseline to 24 hours post-dose | 2.56 false start bowel movements / day | Standard Deviation 3.81 |
| Naldemedine 3 mg | Change From Baseline in Number of False Start Bowel Movements Per Day | Change from Baseline to 48 hours post-dose | 0.44 false start bowel movements / day | Standard Deviation 0.77 |
| Naldemedine 3 mg | Change From Baseline in Number of False Start Bowel Movements Per Day | Change from Baseline to 24 hours post-dose | 0.78 false start bowel movements / day | Standard Deviation 1.79 |
| Naldemedine 3 mg | Change From Baseline in Number of False Start Bowel Movements Per Day | Baseline | 0.33 false start bowel movements / day | Standard Deviation 0.5 |
Secondary
Change From Baseline in Number of Rescue Medications Used Per Day
Baseline was defined as the average number of rescue medications used per day prior to receiving study drug (Day 1 to Day 15). The number of rescue medications used per day at 24 hours and 48 hours post-dose was calculated as the average number of rescue medications used per day from 0 to 24 hours and 0 to 48 hours post-dose, respectively.
Time frame: Baseline, 24 hours post-dose and 48 hours post-dose
Population: Intent-to-treat population; LOCF imputation was used
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pooled Placebo | Change From Baseline in Number of Rescue Medications Used Per Day | Change from Baseline to 48 hours post-dose | -0.04 rescue medications / day | Standard Deviation 0.51 |
| Pooled Placebo | Change From Baseline in Number of Rescue Medications Used Per Day | Change from Baseline to 24 hours post-dose | -0.04 rescue medications / day | Standard Deviation 0.7 |
| Pooled Placebo | Change From Baseline in Number of Rescue Medications Used Per Day | Baseline | 0.31 rescue medications / day | Standard Deviation 0.36 |
| Naldemedine 0.01 mg | Change From Baseline in Number of Rescue Medications Used Per Day | Change from Baseline to 24 hours post-dose | -0.18 rescue medications / day | Standard Deviation 0.21 |
| Naldemedine 0.01 mg | Change From Baseline in Number of Rescue Medications Used Per Day | Baseline | 0.18 rescue medications / day | Standard Deviation 0.21 |
| Naldemedine 0.01 mg | Change From Baseline in Number of Rescue Medications Used Per Day | Change from Baseline to 48 hours post-dose | -0.01 rescue medications / day | Standard Deviation 0.36 |
| Naldemedine 0.03 mg | Change From Baseline in Number of Rescue Medications Used Per Day | Change from Baseline to 48 hours post-dose | -0.25 rescue medications / day | Standard Deviation 0.37 |
| Naldemedine 0.03 mg | Change From Baseline in Number of Rescue Medications Used Per Day | Baseline | 0.36 rescue medications / day | Standard Deviation 0.43 |
| Naldemedine 0.03 mg | Change From Baseline in Number of Rescue Medications Used Per Day | Change from Baseline to 24 hours post-dose | -0.36 rescue medications / day | Standard Deviation 0.43 |
| Naldemedine 0.1 mg | Change From Baseline in Number of Rescue Medications Used Per Day | Change from Baseline to 24 hours post-dose | 0.02 rescue medications / day | Standard Deviation 1.13 |
| Naldemedine 0.1 mg | Change From Baseline in Number of Rescue Medications Used Per Day | Baseline | 0.53 rescue medications / day | Standard Deviation 0.68 |
| Naldemedine 0.1 mg | Change From Baseline in Number of Rescue Medications Used Per Day | Change from Baseline to 48 hours post-dose | 0.08 rescue medications / day | Standard Deviation 0.8 |
| Naldemedine 0.3 mg | Change From Baseline in Number of Rescue Medications Used Per Day | Change from Baseline to 24 hours post-dose | -0.52 rescue medications / day | Standard Deviation 0.84 |
| Naldemedine 0.3 mg | Change From Baseline in Number of Rescue Medications Used Per Day | Baseline | 0.52 rescue medications / day | Standard Deviation 0.84 |
| Naldemedine 0.3 mg | Change From Baseline in Number of Rescue Medications Used Per Day | Change from Baseline to 48 hours post-dose | -0.52 rescue medications / day | Standard Deviation 0.84 |
| Naldemedine 1 mg | Change From Baseline in Number of Rescue Medications Used Per Day | Baseline | 0.28 rescue medications / day | Standard Deviation 0.36 |
| Naldemedine 1 mg | Change From Baseline in Number of Rescue Medications Used Per Day | Change from Baseline to 48 hours post-dose | -0.23 rescue medications / day | Standard Deviation 0.38 |
| Naldemedine 1 mg | Change From Baseline in Number of Rescue Medications Used Per Day | Change from Baseline to 24 hours post-dose | -0.28 rescue medications / day | Standard Deviation 0.36 |
| Naldemedine 3 mg | Change From Baseline in Number of Rescue Medications Used Per Day | Change from Baseline to 48 hours post-dose | -0.20 rescue medications / day | Standard Deviation 0.24 |
| Naldemedine 3 mg | Change From Baseline in Number of Rescue Medications Used Per Day | Change from Baseline to 24 hours post-dose | -0.20 rescue medications / day | Standard Deviation 0.24 |
| Naldemedine 3 mg | Change From Baseline in Number of Rescue Medications Used Per Day | Baseline | 0.20 rescue medications / day | Standard Deviation 0.24 |
Secondary
Change From Baseline in Straining During Bowel Movements
Straining during BMs was graded using the following scale: 0 = Absent; 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Very Severe. Baseline was defined as the average straining score of all BMs prior to receiving study drug (Day 1 to Day 15). The straining score at 24 and 48 hours post-dose was calculated as the average straining score from all bowel movements from 0 to 24 and 0 to 48 hours post-dose, respectively.
Time frame: Baseline, 24 hours post-dose and 48 hours post-dose
Population: Intent-to-treat population with available data at each time point
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pooled Placebo | Change From Baseline in Straining During Bowel Movements | Change from Baseline to 48 hours post-dose | 0.5 units on a scale | Standard Deviation 0.87 |
| Pooled Placebo | Change From Baseline in Straining During Bowel Movements | Change from Baseline to 24 hours post-dose | 0.8 units on a scale | Standard Deviation 0.76 |
| Pooled Placebo | Change From Baseline in Straining During Bowel Movements | Baseline | 2.2 units on a scale | Standard Deviation 0.71 |
| Naldemedine 0.01 mg | Change From Baseline in Straining During Bowel Movements | Change from Baseline to 24 hours post-dose | -0.8 units on a scale | — |
| Naldemedine 0.01 mg | Change From Baseline in Straining During Bowel Movements | Baseline | 2.0 units on a scale | Standard Deviation 0.78 |
| Naldemedine 0.01 mg | Change From Baseline in Straining During Bowel Movements | Change from Baseline to 48 hours post-dose | 0.2 units on a scale | Standard Deviation 0.74 |
| Naldemedine 0.03 mg | Change From Baseline in Straining During Bowel Movements | Change from Baseline to 48 hours post-dose | 0.4 units on a scale | Standard Deviation 0.8 |
| Naldemedine 0.03 mg | Change From Baseline in Straining During Bowel Movements | Baseline | 2.2 units on a scale | Standard Deviation 0.68 |
| Naldemedine 0.03 mg | Change From Baseline in Straining During Bowel Movements | Change from Baseline to 24 hours post-dose | -0.2 units on a scale | Standard Deviation 0.88 |
| Naldemedine 0.1 mg | Change From Baseline in Straining During Bowel Movements | Change from Baseline to 24 hours post-dose | -0.7 units on a scale | Standard Deviation 0.43 |
| Naldemedine 0.1 mg | Change From Baseline in Straining During Bowel Movements | Baseline | 1.9 units on a scale | Standard Deviation 0.9 |
| Naldemedine 0.1 mg | Change From Baseline in Straining During Bowel Movements | Change from Baseline to 48 hours post-dose | -0.6 units on a scale | Standard Deviation 0.67 |
| Naldemedine 0.3 mg | Change From Baseline in Straining During Bowel Movements | Change from Baseline to 24 hours post-dose | -0.1 units on a scale | Standard Deviation 0.89 |
| Naldemedine 0.3 mg | Change From Baseline in Straining During Bowel Movements | Baseline | 2.0 units on a scale | Standard Deviation 1.08 |
| Naldemedine 0.3 mg | Change From Baseline in Straining During Bowel Movements | Change from Baseline to 48 hours post-dose | 0.1 units on a scale | — |
| Naldemedine 1 mg | Change From Baseline in Straining During Bowel Movements | Baseline | 2.5 units on a scale | Standard Deviation 0.97 |
| Naldemedine 1 mg | Change From Baseline in Straining During Bowel Movements | Change from Baseline to 48 hours post-dose | -0.4 units on a scale | Standard Deviation 0.42 |
| Naldemedine 1 mg | Change From Baseline in Straining During Bowel Movements | Change from Baseline to 24 hours post-dose | -0.5 units on a scale | Standard Deviation 1.37 |
| Naldemedine 3 mg | Change From Baseline in Straining During Bowel Movements | Change from Baseline to 48 hours post-dose | -1.4 units on a scale | Standard Deviation 1.4 |
| Naldemedine 3 mg | Change From Baseline in Straining During Bowel Movements | Change from Baseline to 24 hours post-dose | -0.9 units on a scale | Standard Deviation 1.64 |
| Naldemedine 3 mg | Change From Baseline in Straining During Bowel Movements | Baseline | 1.7 units on a scale | Standard Deviation 0.99 |
Secondary
Change From Baseline in the Number of Bowel Movements With No Straining Per Day
Straining during BMs was graded using the following scale: 0 = Absent; 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Very Severe. A BM without straining was defined as a BM with a straining score = 0. Baseline was defined as the average number of BMs without straining per day prior to receiving study drug (Day 1 to Day 15). The number of BMs without straining per day at 24 hours and 48 hours post-dose was calculated as the average number of BMs with no straining per day from 0 to 24 hours and 0 to 48 hours post-dose, respectively.
Time frame: Baseline, 24 hours post-dose and 48 hours post-dose
Population: Intent-to-treat population; LOCF imputation was used
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pooled Placebo | Change From Baseline in the Number of Bowel Movements With No Straining Per Day | Change from Baseline to 48 hours post-dose | -0.01 bowel movements with no straining / day | Standard Deviation 0.14 |
| Pooled Placebo | Change From Baseline in the Number of Bowel Movements With No Straining Per Day | Change from Baseline to 24 hours post-dose | -0.03 bowel movements with no straining / day | Standard Deviation 0.07 |
| Pooled Placebo | Change From Baseline in the Number of Bowel Movements With No Straining Per Day | Baseline | 0.03 bowel movements with no straining / day | Standard Deviation 0.07 |
| Naldemedine 0.01 mg | Change From Baseline in the Number of Bowel Movements With No Straining Per Day | Change from Baseline to 24 hours post-dose | -0.09 bowel movements with no straining / day | Standard Deviation 0.11 |
| Naldemedine 0.01 mg | Change From Baseline in the Number of Bowel Movements With No Straining Per Day | Baseline | 0.09 bowel movements with no straining / day | Standard Deviation 0.11 |
| Naldemedine 0.01 mg | Change From Baseline in the Number of Bowel Movements With No Straining Per Day | Change from Baseline to 48 hours post-dose | -0.03 bowel movements with no straining / day | Standard Deviation 0.13 |
| Naldemedine 0.03 mg | Change From Baseline in the Number of Bowel Movements With No Straining Per Day | Change from Baseline to 24 hours post-dose | 0.06 bowel movements with no straining / day | Standard Deviation 0.36 |
| Naldemedine 0.03 mg | Change From Baseline in the Number of Bowel Movements With No Straining Per Day | Baseline | 0.05 bowel movements with no straining / day | Standard Deviation 0.09 |
| Naldemedine 0.03 mg | Change From Baseline in the Number of Bowel Movements With No Straining Per Day | Change from Baseline to 48 hours post-dose | 0.01 bowel movements with no straining / day | Standard Deviation 0.21 |
| Naldemedine 0.1 mg | Change From Baseline in the Number of Bowel Movements With No Straining Per Day | Baseline | 0.03 bowel movements with no straining / day | Standard Deviation 0.07 |
| Naldemedine 0.1 mg | Change From Baseline in the Number of Bowel Movements With No Straining Per Day | Change from Baseline to 24 hours post-dose | -0.03 bowel movements with no straining / day | Standard Deviation 0.07 |
| Naldemedine 0.1 mg | Change From Baseline in the Number of Bowel Movements With No Straining Per Day | Change from Baseline to 48 hours post-dose | -0.03 bowel movements with no straining / day | Standard Deviation 0.07 |
| Naldemedine 0.3 mg | Change From Baseline in the Number of Bowel Movements With No Straining Per Day | Change from Baseline to 24 hours post-dose | 0.28 bowel movements with no straining / day | Standard Deviation 0.71 |
| Naldemedine 0.3 mg | Change From Baseline in the Number of Bowel Movements With No Straining Per Day | Baseline | 0.05 bowel movements with no straining / day | Standard Deviation 0.07 |
| Naldemedine 0.3 mg | Change From Baseline in the Number of Bowel Movements With No Straining Per Day | Change from Baseline to 48 hours post-dose | 0.12 bowel movements with no straining / day | Standard Deviation 0.36 |
| Naldemedine 1 mg | Change From Baseline in the Number of Bowel Movements With No Straining Per Day | Baseline | 0.03 bowel movements with no straining / day | Standard Deviation 0.05 |
| Naldemedine 1 mg | Change From Baseline in the Number of Bowel Movements With No Straining Per Day | Change from Baseline to 24 hours post-dose | 0.41 bowel movements with no straining / day | Standard Deviation 0.74 |
| Naldemedine 1 mg | Change From Baseline in the Number of Bowel Movements With No Straining Per Day | Change from Baseline to 48 hours post-dose | 0.19 bowel movements with no straining / day | Standard Deviation 0.38 |
| Naldemedine 3 mg | Change From Baseline in the Number of Bowel Movements With No Straining Per Day | Baseline | 0.07 bowel movements with no straining / day | Standard Deviation 0.11 |
| Naldemedine 3 mg | Change From Baseline in the Number of Bowel Movements With No Straining Per Day | Change from Baseline to 48 hours post-dose | 1.76 bowel movements with no straining / day | Standard Deviation 1.02 |
| Naldemedine 3 mg | Change From Baseline in the Number of Bowel Movements With No Straining Per Day | Change from Baseline to 24 hours post-dose | 3.37 bowel movements with no straining / day | Standard Deviation 2.16 |
Secondary
Change From Baseline to 24 Hours Post-dose in Number of Bowel Movements (BM) Per Day
Participants completed a bowel function assessment daily diary to record information about bowel movements and constipation. Baseline was defined as the average number of BMs per day during the 2 weeks prior to receiving study drug (Day 1 to Day 15).
Time frame: Baseline and 24 hours post-dose
Population: Intent-to-treat; LOCF imputation was used
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pooled Placebo | Change From Baseline to 24 Hours Post-dose in Number of Bowel Movements (BM) Per Day | Change from Baseline to 24 hours post-dose | 0.15 bowel movements / day | Standard Deviation 0.65 |
| Pooled Placebo | Change From Baseline to 24 Hours Post-dose in Number of Bowel Movements (BM) Per Day | 24 hours post-dose | 0.50 bowel movements / day | Standard Deviation 0.62 |
| Pooled Placebo | Change From Baseline to 24 Hours Post-dose in Number of Bowel Movements (BM) Per Day | Baseline | 0.35 bowel movements / day | Standard Deviation 0.18 |
| Naldemedine 0.01 mg | Change From Baseline to 24 Hours Post-dose in Number of Bowel Movements (BM) Per Day | 24 hours post-dose | 0.11 bowel movements / day | Standard Deviation 0.33 |
| Naldemedine 0.01 mg | Change From Baseline to 24 Hours Post-dose in Number of Bowel Movements (BM) Per Day | Baseline | 0.34 bowel movements / day | Standard Deviation 0.1 |
| Naldemedine 0.01 mg | Change From Baseline to 24 Hours Post-dose in Number of Bowel Movements (BM) Per Day | Change from Baseline to 24 hours post-dose | -0.23 bowel movements / day | Standard Deviation 0.36 |
| Naldemedine 0.03 mg | Change From Baseline to 24 Hours Post-dose in Number of Bowel Movements (BM) Per Day | Change from Baseline to 24 hours post-dose | 0.25 bowel movements / day | Standard Deviation 0.75 |
| Naldemedine 0.03 mg | Change From Baseline to 24 Hours Post-dose in Number of Bowel Movements (BM) Per Day | Baseline | 0.41 bowel movements / day | Standard Deviation 0.22 |
| Naldemedine 0.03 mg | Change From Baseline to 24 Hours Post-dose in Number of Bowel Movements (BM) Per Day | 24 hours post-dose | 0.67 bowel movements / day | Standard Deviation 0.71 |
| Naldemedine 0.1 mg | Change From Baseline to 24 Hours Post-dose in Number of Bowel Movements (BM) Per Day | 24 hours post-dose | 0.56 bowel movements / day | Standard Deviation 0.73 |
| Naldemedine 0.1 mg | Change From Baseline to 24 Hours Post-dose in Number of Bowel Movements (BM) Per Day | Baseline | 0.35 bowel movements / day | Standard Deviation 0.17 |
| Naldemedine 0.1 mg | Change From Baseline to 24 Hours Post-dose in Number of Bowel Movements (BM) Per Day | Change from Baseline to 24 hours post-dose | 0.21 bowel movements / day | Standard Deviation 0.76 |
| Naldemedine 0.3 mg | Change From Baseline to 24 Hours Post-dose in Number of Bowel Movements (BM) Per Day | 24 hours post-dose | 2.00 bowel movements / day | Standard Deviation 1.32 |
| Naldemedine 0.3 mg | Change From Baseline to 24 Hours Post-dose in Number of Bowel Movements (BM) Per Day | Baseline | 0.33 bowel movements / day | Standard Deviation 0.12 |
| Naldemedine 0.3 mg | Change From Baseline to 24 Hours Post-dose in Number of Bowel Movements (BM) Per Day | Change from Baseline to 24 hours post-dose | 1.67 bowel movements / day | Standard Deviation 1.35 |
| Naldemedine 1 mg | Change From Baseline to 24 Hours Post-dose in Number of Bowel Movements (BM) Per Day | Baseline | 0.29 bowel movements / day | Standard Deviation 0.09 |
| Naldemedine 1 mg | Change From Baseline to 24 Hours Post-dose in Number of Bowel Movements (BM) Per Day | Change from Baseline to 24 hours post-dose | 3.60 bowel movements / day | Standard Deviation 3.1 |
| Naldemedine 1 mg | Change From Baseline to 24 Hours Post-dose in Number of Bowel Movements (BM) Per Day | 24 hours post-dose | 3.89 bowel movements / day | Standard Deviation 3.06 |
| Naldemedine 3 mg | Change From Baseline to 24 Hours Post-dose in Number of Bowel Movements (BM) Per Day | Change from Baseline to 24 hours post-dose | 4.62 bowel movements / day | Standard Deviation 2.06 |
| Naldemedine 3 mg | Change From Baseline to 24 Hours Post-dose in Number of Bowel Movements (BM) Per Day | 24 hours post-dose | 5.00 bowel movements / day | Standard Deviation 2.12 |
| Naldemedine 3 mg | Change From Baseline to 24 Hours Post-dose in Number of Bowel Movements (BM) Per Day | Baseline | 0.38 bowel movements / day | Standard Deviation 0.19 |
p-value: 0.1334ANCOVA
p-value: 0.332ANCOVA
p-value: 0.9371ANCOVA
p-value: 0.0002ANCOVA
p-value: <0.0001ANCOVA
p-value: <0.0001ANCOVA
Secondary
Change From Baseline to 24 Hours Post-dose in Number of Complete Bowel Movements Per Day
A complete bowel movement (CBM) was defined as a bowel movement that resulted in a sensation of complete evacuation based on the question Did you have a feeling of complete emptying after the bowel movement? Baseline was defined as the average number of CBMs per day prior to receiving study drug (Day 1 to Day 15).
Time frame: Baseline and 24 hours post-dose
Population: Intent-to-treat population; LOCF imputation was used
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pooled Placebo | Change From Baseline to 24 Hours Post-dose in Number of Complete Bowel Movements Per Day | Change from baseline to 24 hours post-dose | -0.07 complete bowel movements / day | Standard Deviation 0.2 |
| Pooled Placebo | Change From Baseline to 24 Hours Post-dose in Number of Complete Bowel Movements Per Day | 24 hours post-dose | 0.06 complete bowel movements / day | Standard Deviation 0.24 |
| Pooled Placebo | Change From Baseline to 24 Hours Post-dose in Number of Complete Bowel Movements Per Day | Baseline | 0.13 complete bowel movements / day | Standard Deviation 0.16 |
| Naldemedine 0.01 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Bowel Movements Per Day | Change from baseline to 24 hours post-dose | -0.13 complete bowel movements / day | Standard Deviation 0.14 |
| Naldemedine 0.01 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Bowel Movements Per Day | 24 hours post-dose | 0.00 complete bowel movements / day | Standard Deviation 0 |
| Naldemedine 0.01 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Bowel Movements Per Day | Baseline | 0.13 complete bowel movements / day | Standard Deviation 0.14 |
| Naldemedine 0.03 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Bowel Movements Per Day | Change from baseline to 24 hours post-dose | 0.01 complete bowel movements / day | Standard Deviation 0.31 |
| Naldemedine 0.03 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Bowel Movements Per Day | 24 hours post-dose | 0.11 complete bowel movements / day | Standard Deviation 0.33 |
| Naldemedine 0.03 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Bowel Movements Per Day | Baseline | 0.11 complete bowel movements / day | Standard Deviation 0.09 |
| Naldemedine 0.1 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Bowel Movements Per Day | Change from baseline to 24 hours post-dose | 0.09 complete bowel movements / day | Standard Deviation 0.45 |
| Naldemedine 0.1 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Bowel Movements Per Day | Baseline | 0.14 complete bowel movements / day | Standard Deviation 0.12 |
| Naldemedine 0.1 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Bowel Movements Per Day | 24 hours post-dose | 0.22 complete bowel movements / day | Standard Deviation 0.44 |
| Naldemedine 0.3 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Bowel Movements Per Day | 24 hours post-dose | 0.11 complete bowel movements / day | Standard Deviation 0.33 |
| Naldemedine 0.3 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Bowel Movements Per Day | Change from baseline to 24 hours post-dose | 0.07 complete bowel movements / day | Standard Deviation 0.35 |
| Naldemedine 0.3 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Bowel Movements Per Day | Baseline | 0.04 complete bowel movements / day | Standard Deviation 0.06 |
| Naldemedine 1 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Bowel Movements Per Day | Change from baseline to 24 hours post-dose | 2.32 complete bowel movements / day | Standard Deviation 2.61 |
| Naldemedine 1 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Bowel Movements Per Day | Baseline | 0.12 complete bowel movements / day | Standard Deviation 0.15 |
| Naldemedine 1 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Bowel Movements Per Day | 24 hours post-dose | 2.44 complete bowel movements / day | Standard Deviation 2.55 |
| Naldemedine 3 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Bowel Movements Per Day | 24 hours post-dose | 3.00 complete bowel movements / day | Standard Deviation 3.2 |
| Naldemedine 3 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Bowel Movements Per Day | Baseline | 0.19 complete bowel movements / day | Standard Deviation 0.15 |
| Naldemedine 3 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Bowel Movements Per Day | Change from baseline to 24 hours post-dose | 2.81 complete bowel movements / day | Standard Deviation 3.21 |
p-value: 0.5054ANCOVA
p-value: 0.9688ANCOVA
p-value: 0.6963ANCOVA
p-value: 0.9599ANCOVA
p-value: 0.0001ANCOVA
p-value: 0.0006ANCOVA
Secondary
Change From Baseline to 24 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day
Participants completed a bowel function assessment daily diary to record information about bowel movements and constipation. A complete spontaneous bowel movement was defined as a bowel movement where no laxative or enema was used and the bowel movement resulted in a sensation of complete evacuation (based on the question of having a feeling of complete emptying after the bowel movement). Baseline was defined as the average number of CSBMs per day during the 2 weeks prior to receiving study drug (Day 1 to Day 15).
Time frame: Baseline and 24 hours post-dose
Population: Intent-to-treat population; LOCF imputation was used
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pooled Placebo | Change From Baseline to 24 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | Change from Baseline to 24 hours post-dose | 0.02 complete spontaneous bowel movements/day | Standard Deviation 0.25 |
| Pooled Placebo | Change From Baseline to 24 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | 24 hours post-dose | 0.06 complete spontaneous bowel movements/day | Standard Deviation 0.24 |
| Pooled Placebo | Change From Baseline to 24 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | Baseline | 0.03 complete spontaneous bowel movements/day | Standard Deviation 0.06 |
| Naldemedine 0.01 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | 24 hours post-dose | 0.00 complete spontaneous bowel movements/day | Standard Deviation 0 |
| Naldemedine 0.01 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | Baseline | 0.07 complete spontaneous bowel movements/day | Standard Deviation 0.09 |
| Naldemedine 0.01 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | Change from Baseline to 24 hours post-dose | -0.07 complete spontaneous bowel movements/day | Standard Deviation 0.09 |
| Naldemedine 0.03 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | Change from Baseline to 24 hours post-dose | 0.04 complete spontaneous bowel movements/day | Standard Deviation 0.29 |
| Naldemedine 0.03 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | Baseline | 0.07 complete spontaneous bowel movements/day | Standard Deviation 0.08 |
| Naldemedine 0.03 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | 24 hours post-dose | 0.11 complete spontaneous bowel movements/day | Standard Deviation 0.33 |
| Naldemedine 0.1 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | 24 hours post-dose | 0.22 complete spontaneous bowel movements/day | Standard Deviation 0.44 |
| Naldemedine 0.1 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | Baseline | 0.06 complete spontaneous bowel movements/day | Standard Deviation 0.1 |
| Naldemedine 0.1 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | Change from Baseline to 24 hours post-dose | 0.16 complete spontaneous bowel movements/day | Standard Deviation 0.44 |
| Naldemedine 0.3 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | 24 hours post-dose | 0.11 complete spontaneous bowel movements/day | Standard Deviation 0.33 |
| Naldemedine 0.3 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | Baseline | 0.01 complete spontaneous bowel movements/day | Standard Deviation 0.03 |
| Naldemedine 0.3 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | Change from Baseline to 24 hours post-dose | 0.10 complete spontaneous bowel movements/day | Standard Deviation 0.34 |
| Naldemedine 1 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | Change from Baseline to 24 hours post-dose | 2.42 complete spontaneous bowel movements/day | Standard Deviation 2.55 |
| Naldemedine 1 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | 24 hours post-dose | 2.44 complete spontaneous bowel movements/day | Standard Deviation 2.55 |
| Naldemedine 1 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | Baseline | 0.03 complete spontaneous bowel movements/day | Standard Deviation 0.04 |
| Naldemedine 3 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | 24 hours post-dose | 3.00 complete spontaneous bowel movements/day | Standard Deviation 3.2 |
| Naldemedine 3 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | Change from Baseline to 24 hours post-dose | 2.90 complete spontaneous bowel movements/day | Standard Deviation 3.24 |
| Naldemedine 3 mg | Change From Baseline to 24 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | Baseline | 0.10 complete spontaneous bowel movements/day | Standard Deviation 0.07 |
p-value: 0.6269ANCOVA
p-value: 0.7456ANCOVA
p-value: 0.1968ANCOVA
p-value: 0.8708ANCOVA
p-value: <0.0001ANCOVA
p-value: 0.0002ANCOVA
Secondary
Change From Baseline to 24 Hours Post-dose in Number of Spontaneous Bowel Movements (SBMs) Per Day
Participants completed a bowel function assessment daily diary to record information about bowel movements and constipation. A spontaneous bowel movement was defined as a bowel movement where no laxative or enema was used in the 24 hours preceding the bowel movement. Baseline was defined as the average number of SBMs per day during the 2 weeks prior to receiving study drug (Day 1 to Day 15).
Time frame: Baseline (Day 1 to Day 15) and Day 15 to 16 (0 to 24 hours post-dose)
Population: All randomized participants who received study drug and had at least 1 post-dose efficacy assessment completed (intent-to-treat population). Last observation carried forward (LOCF) imputation was used.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pooled Placebo | Change From Baseline to 24 Hours Post-dose in Number of Spontaneous Bowel Movements (SBMs) Per Day | Baseline | 0.15 spontaneous bowel movements / day | Standard Deviation 0.13 |
| Pooled Placebo | Change From Baseline to 24 Hours Post-dose in Number of Spontaneous Bowel Movements (SBMs) Per Day | Change from Baseline to 24 hours post-dose | 0.29 spontaneous bowel movements / day | Standard Deviation 0.48 |
| Pooled Placebo | Change From Baseline to 24 Hours Post-dose in Number of Spontaneous Bowel Movements (SBMs) Per Day | 24 hours post-dose | 0.44 spontaneous bowel movements / day | Standard Deviation 0.51 |
| Naldemedine 0.01 mg | Change From Baseline to 24 Hours Post-dose in Number of Spontaneous Bowel Movements (SBMs) Per Day | Change from Baseline to 24 hours post-dose | -0.09 spontaneous bowel movements / day | Standard Deviation 0.41 |
| Naldemedine 0.01 mg | Change From Baseline to 24 Hours Post-dose in Number of Spontaneous Bowel Movements (SBMs) Per Day | 24 hours post-dose | 0.11 spontaneous bowel movements / day | Standard Deviation 0.33 |
| Naldemedine 0.01 mg | Change From Baseline to 24 Hours Post-dose in Number of Spontaneous Bowel Movements (SBMs) Per Day | Baseline | 0.20 spontaneous bowel movements / day | Standard Deviation 0.14 |
| Naldemedine 0.03 mg | Change From Baseline to 24 Hours Post-dose in Number of Spontaneous Bowel Movements (SBMs) Per Day | 24 hours post-dose | 0.67 spontaneous bowel movements / day | Standard Deviation 0.71 |
| Naldemedine 0.03 mg | Change From Baseline to 24 Hours Post-dose in Number of Spontaneous Bowel Movements (SBMs) Per Day | Baseline | 0.24 spontaneous bowel movements / day | Standard Deviation 0.09 |
| Naldemedine 0.03 mg | Change From Baseline to 24 Hours Post-dose in Number of Spontaneous Bowel Movements (SBMs) Per Day | Change from Baseline to 24 hours post-dose | 0.42 spontaneous bowel movements / day | Standard Deviation 0.72 |
| Naldemedine 0.1 mg | Change From Baseline to 24 Hours Post-dose in Number of Spontaneous Bowel Movements (SBMs) Per Day | Change from Baseline to 24 hours post-dose | 0.43 spontaneous bowel movements / day | Standard Deviation 0.68 |
| Naldemedine 0.1 mg | Change From Baseline to 24 Hours Post-dose in Number of Spontaneous Bowel Movements (SBMs) Per Day | Baseline | 0.13 spontaneous bowel movements / day | Standard Deviation 0.13 |
| Naldemedine 0.1 mg | Change From Baseline to 24 Hours Post-dose in Number of Spontaneous Bowel Movements (SBMs) Per Day | 24 hours post-dose | 0.56 spontaneous bowel movements / day | Standard Deviation 0.73 |
| Naldemedine 0.3 mg | Change From Baseline to 24 Hours Post-dose in Number of Spontaneous Bowel Movements (SBMs) Per Day | 24 hours post-dose | 2.00 spontaneous bowel movements / day | Standard Deviation 1.32 |
| Naldemedine 0.3 mg | Change From Baseline to 24 Hours Post-dose in Number of Spontaneous Bowel Movements (SBMs) Per Day | Baseline | 0.17 spontaneous bowel movements / day | Standard Deviation 0.12 |
| Naldemedine 0.3 mg | Change From Baseline to 24 Hours Post-dose in Number of Spontaneous Bowel Movements (SBMs) Per Day | Change from Baseline to 24 hours post-dose | 1.83 spontaneous bowel movements / day | Standard Deviation 1.34 |
| Naldemedine 1 mg | Change From Baseline to 24 Hours Post-dose in Number of Spontaneous Bowel Movements (SBMs) Per Day | Change from Baseline to 24 hours post-dose | 3.76 spontaneous bowel movements / day | Standard Deviation 3.06 |
| Naldemedine 1 mg | Change From Baseline to 24 Hours Post-dose in Number of Spontaneous Bowel Movements (SBMs) Per Day | 24 hours post-dose | 3.89 spontaneous bowel movements / day | Standard Deviation 3.06 |
| Naldemedine 1 mg | Change From Baseline to 24 Hours Post-dose in Number of Spontaneous Bowel Movements (SBMs) Per Day | Baseline | 0.13 spontaneous bowel movements / day | Standard Deviation 0.09 |
| Naldemedine 3 mg | Change From Baseline to 24 Hours Post-dose in Number of Spontaneous Bowel Movements (SBMs) Per Day | Baseline | 0.23 spontaneous bowel movements / day | Standard Deviation 0.11 |
| Naldemedine 3 mg | Change From Baseline to 24 Hours Post-dose in Number of Spontaneous Bowel Movements (SBMs) Per Day | 24 hours post-dose | 5.00 spontaneous bowel movements / day | Standard Deviation 2.12 |
| Naldemedine 3 mg | Change From Baseline to 24 Hours Post-dose in Number of Spontaneous Bowel Movements (SBMs) Per Day | Change from Baseline to 24 hours post-dose | 4.77 spontaneous bowel movements / day | Standard Deviation 2.15 |
p-value: 0.0767ANCOVA
p-value: 0.8727ANCOVA
p-value: 0.6373ANCOVA
p-value: <0.0001ANCOVA
p-value: <0.0001ANCOVA
p-value: <0.0001ANCOVA
Secondary
Change From Baseline to 48 Hours Post-dose in Number of Bowel Movements Per Day
Participants completed a bowel function assessment daily diary to record information about bowel movements and constipation. Baseline was defined as the average number of BMs per day during the 2 weeks prior to receiving study drug (Day 1 to Day 15). Forty-eight hours post-dose was defined as the average number of BMs per day from 0 to 48 hours post-dose.
Time frame: Baseline and 48 hours post-dose
Population: Intent-to-treat population; LOCF imputation was used
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pooled Placebo | Change From Baseline to 48 Hours Post-dose in Number of Bowel Movements Per Day | Change from baseline to 48 hours post-dose | 0.15 bowel movements / day | Standard Deviation 0.53 |
| Pooled Placebo | Change From Baseline to 48 Hours Post-dose in Number of Bowel Movements Per Day | 48 hours post-dose | 0.50 bowel movements / day | Standard Deviation 0.51 |
| Pooled Placebo | Change From Baseline to 48 Hours Post-dose in Number of Bowel Movements Per Day | Baseline | 0.35 bowel movements / day | Standard Deviation 0.18 |
| Naldemedine 0.01 mg | Change From Baseline to 48 Hours Post-dose in Number of Bowel Movements Per Day | Change from baseline to 48 hours post-dose | 0.27 bowel movements / day | Standard Deviation 0.51 |
| Naldemedine 0.01 mg | Change From Baseline to 48 Hours Post-dose in Number of Bowel Movements Per Day | Baseline | 0.34 bowel movements / day | Standard Deviation 0.1 |
| Naldemedine 0.01 mg | Change From Baseline to 48 Hours Post-dose in Number of Bowel Movements Per Day | 48 hours post-dose | 0.61 bowel movements / day | Standard Deviation 0.49 |
| Naldemedine 0.03 mg | Change From Baseline to 48 Hours Post-dose in Number of Bowel Movements Per Day | 48 hours post-dose | 0.72 bowel movements / day | Standard Deviation 0.71 |
| Naldemedine 0.03 mg | Change From Baseline to 48 Hours Post-dose in Number of Bowel Movements Per Day | Baseline | 0.41 bowel movements / day | Standard Deviation 0.22 |
| Naldemedine 0.03 mg | Change From Baseline to 48 Hours Post-dose in Number of Bowel Movements Per Day | Change from baseline to 48 hours post-dose | 0.31 bowel movements / day | Standard Deviation 0.67 |
| Naldemedine 0.1 mg | Change From Baseline to 48 Hours Post-dose in Number of Bowel Movements Per Day | Change from baseline to 48 hours post-dose | 0.21 bowel movements / day | Standard Deviation 0.52 |
| Naldemedine 0.1 mg | Change From Baseline to 48 Hours Post-dose in Number of Bowel Movements Per Day | Baseline | 0.35 bowel movements / day | Standard Deviation 0.17 |
| Naldemedine 0.1 mg | Change From Baseline to 48 Hours Post-dose in Number of Bowel Movements Per Day | 48 hours post-dose | 0.56 bowel movements / day | Standard Deviation 0.46 |
| Naldemedine 0.3 mg | Change From Baseline to 48 Hours Post-dose in Number of Bowel Movements Per Day | Baseline | 0.33 bowel movements / day | Standard Deviation 0.12 |
| Naldemedine 0.3 mg | Change From Baseline to 48 Hours Post-dose in Number of Bowel Movements Per Day | 48 hours post-dose | 1.06 bowel movements / day | Standard Deviation 0.68 |
| Naldemedine 0.3 mg | Change From Baseline to 48 Hours Post-dose in Number of Bowel Movements Per Day | Change from baseline to 48 hours post-dose | 0.72 bowel movements / day | Standard Deviation 0.7 |
| Naldemedine 1 mg | Change From Baseline to 48 Hours Post-dose in Number of Bowel Movements Per Day | Baseline | 0.29 bowel movements / day | Standard Deviation 0.09 |
| Naldemedine 1 mg | Change From Baseline to 48 Hours Post-dose in Number of Bowel Movements Per Day | 48 hours post-dose | 2.28 bowel movements / day | Standard Deviation 1.8 |
| Naldemedine 1 mg | Change From Baseline to 48 Hours Post-dose in Number of Bowel Movements Per Day | Change from baseline to 48 hours post-dose | 1.99 bowel movements / day | Standard Deviation 1.82 |
| Naldemedine 3 mg | Change From Baseline to 48 Hours Post-dose in Number of Bowel Movements Per Day | 48 hours post-dose | 2.67 bowel movements / day | Standard Deviation 1.03 |
| Naldemedine 3 mg | Change From Baseline to 48 Hours Post-dose in Number of Bowel Movements Per Day | Change from baseline to 48 hours post-dose | 2.29 bowel movements / day | Standard Deviation 0.98 |
| Naldemedine 3 mg | Change From Baseline to 48 Hours Post-dose in Number of Bowel Movements Per Day | Baseline | 0.38 bowel movements / day | Standard Deviation 0.19 |
p-value: 0.7978ANCOVA
p-value: 0.7143ANCOVA
p-value: 0.7531ANCOVA
p-value: 0.0283ANCOVA
p-value: <0.0001ANCOVA
p-value: <0.0001ANCOVA
Secondary
Change From Baseline to 48 Hours Post-dose in Number of Complete Bowel Movements Per Day
A complete bowel movement (CBM) was defined as a bowel movement that resulted in a sensation of complete evacuation based on the question Did you have a feeling of complete emptying after the bowel movement? Baseline was defined as the average number of CBMs per day prior to receiving study drug (Day 1 to 15). Forty-eight hours post-dose was calculated as the average number of CBMs per day from 0 to 48 hours post-dose.
Time frame: Baseline and 48 hours post-dose
Population: Intent-to-treat population; LOCF imputation was used
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pooled Placebo | Change From Baseline to 48 Hours Post-dose in Number of Complete Bowel Movements Per Day | 48 hours post-dose | 0.08 complete bowel movements / day | Standard Deviation 0.19 |
| Pooled Placebo | Change From Baseline to 48 Hours Post-dose in Number of Complete Bowel Movements Per Day | Baseline | 0.13 complete bowel movements / day | Standard Deviation 0.16 |
| Pooled Placebo | Change From Baseline to 48 Hours Post-dose in Number of Complete Bowel Movements Per Day | Change from Baseline to 48 hours post-dose | -0.04 complete bowel movements / day | Standard Deviation 0.17 |
| Naldemedine 0.01 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Bowel Movements Per Day | 48 hours post-dose | 0.17 complete bowel movements / day | Standard Deviation 0.25 |
| Naldemedine 0.01 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Bowel Movements Per Day | Change from Baseline to 48 hours post-dose | 0.04 complete bowel movements / day | Standard Deviation 0.15 |
| Naldemedine 0.01 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Bowel Movements Per Day | Baseline | 0.13 complete bowel movements / day | Standard Deviation 0.14 |
| Naldemedine 0.03 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Bowel Movements Per Day | Baseline | 0.11 complete bowel movements / day | Standard Deviation 0.09 |
| Naldemedine 0.03 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Bowel Movements Per Day | Change from Baseline to 48 hours post-dose | 0.06 complete bowel movements / day | Standard Deviation 0.28 |
| Naldemedine 0.03 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Bowel Movements Per Day | 48 hours post-dose | 0.17 complete bowel movements / day | Standard Deviation 0.25 |
| Naldemedine 0.1 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Bowel Movements Per Day | 48 hours post-dose | 0.22 complete bowel movements / day | Standard Deviation 0.36 |
| Naldemedine 0.1 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Bowel Movements Per Day | Baseline | 0.14 complete bowel movements / day | Standard Deviation 0.12 |
| Naldemedine 0.1 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Bowel Movements Per Day | Change from Baseline to 48 hours post-dose | 0.09 complete bowel movements / day | Standard Deviation 0.38 |
| Naldemedine 0.3 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Bowel Movements Per Day | 48 hours post-dose | 0.06 complete bowel movements / day | Standard Deviation 0.17 |
| Naldemedine 0.3 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Bowel Movements Per Day | Baseline | 0.04 complete bowel movements / day | Standard Deviation 0.06 |
| Naldemedine 0.3 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Bowel Movements Per Day | Change from Baseline to 48 hours post-dose | 0.01 complete bowel movements / day | Standard Deviation 0.19 |
| Naldemedine 1 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Bowel Movements Per Day | Baseline | 0.12 complete bowel movements / day | Standard Deviation 0.15 |
| Naldemedine 1 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Bowel Movements Per Day | Change from Baseline to 48 hours post-dose | 1.27 complete bowel movements / day | Standard Deviation 1.38 |
| Naldemedine 1 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Bowel Movements Per Day | 48 hours post-dose | 1.39 complete bowel movements / day | Standard Deviation 1.34 |
| Naldemedine 3 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Bowel Movements Per Day | Change from Baseline to 48 hours post-dose | 1.42 complete bowel movements / day | Standard Deviation 1.53 |
| Naldemedine 3 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Bowel Movements Per Day | 48 hours post-dose | 1.61 complete bowel movements / day | Standard Deviation 1.52 |
| Naldemedine 3 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Bowel Movements Per Day | Baseline | 0.19 complete bowel movements / day | Standard Deviation 0.15 |
p-value: 0.3441ANCOVA
p-value: 0.7159ANCOVA
p-value: 0.7342ANCOVA
p-value: 0.8714ANCOVA
p-value: <0.0001ANCOVA
p-value: 0.0006ANCOVA
Secondary
Change From Baseline to 48 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day
Participants completed a bowel function assessment daily diary to record information about bowel movements and constipation. A complete spontaneous bowel movement was defined as a bowel movement where no laxative or enema was used and the bowel movement resulted in a sensation of complete evacuation (based on the question of having a feeling of complete emptying after the bowel movement). Baseline was defined as the average number of CSBMs per day during the 2 weeks prior to receiving study drug (Day 1 to Day 15). Forty-eight hours post-dose was defined as the average number of CSBMs per day from 0 to 48 hours post-dose.
Time frame: Baseline and 48 hours post-dose
Population: Intent-to-treat population; LOCF imputation was used
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pooled Placebo | Change From Baseline to 48 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | 48 hours post-dose | 0.08 complete spontaneous bowel movements/day | Standard Deviation 0.19 |
| Pooled Placebo | Change From Baseline to 48 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | Baseline | 0.03 complete spontaneous bowel movements/day | Standard Deviation 0.06 |
| Pooled Placebo | Change From Baseline to 48 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | Change from baseline to 48 hours post-dose | 0.05 complete spontaneous bowel movements/day | Standard Deviation 0.16 |
| Naldemedine 0.01 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | Change from baseline to 48 hours post-dose | 0.10 complete spontaneous bowel movements/day | Standard Deviation 0.18 |
| Naldemedine 0.01 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | Baseline | 0.07 complete spontaneous bowel movements/day | Standard Deviation 0.09 |
| Naldemedine 0.01 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | 48 hours post-dose | 0.17 complete spontaneous bowel movements/day | Standard Deviation 0.25 |
| Naldemedine 0.03 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | Change from baseline to 48 hours post-dose | 0.10 complete spontaneous bowel movements/day | Standard Deviation 0.25 |
| Naldemedine 0.03 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | 48 hours post-dose | 0.17 complete spontaneous bowel movements/day | Standard Deviation 0.25 |
| Naldemedine 0.03 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | Baseline | 0.07 complete spontaneous bowel movements/day | Standard Deviation 0.08 |
| Naldemedine 0.1 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | Baseline | 0.06 complete spontaneous bowel movements/day | Standard Deviation 0.1 |
| Naldemedine 0.1 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | 48 hours post-dose | 0.17 complete spontaneous bowel movements/day | Standard Deviation 0.35 |
| Naldemedine 0.1 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | Change from baseline to 48 hours post-dose | 0.10 complete spontaneous bowel movements/day | Standard Deviation 0.34 |
| Naldemedine 0.3 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | 48 hours post-dose | 0.06 complete spontaneous bowel movements/day | Standard Deviation 0.17 |
| Naldemedine 0.3 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | Change from baseline to 48 hours post-dose | 0.04 complete spontaneous bowel movements/day | Standard Deviation 0.17 |
| Naldemedine 0.3 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | Baseline | 0.01 complete spontaneous bowel movements/day | Standard Deviation 0.03 |
| Naldemedine 1 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | 48 hours post-dose | 1.39 complete spontaneous bowel movements/day | Standard Deviation 1.34 |
| Naldemedine 1 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | Baseline | 0.03 complete spontaneous bowel movements/day | Standard Deviation 0.04 |
| Naldemedine 1 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | Change from baseline to 48 hours post-dose | 1.36 complete spontaneous bowel movements/day | Standard Deviation 1.34 |
| Naldemedine 3 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | Baseline | 0.10 complete spontaneous bowel movements/day | Standard Deviation 0.07 |
| Naldemedine 3 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | Change from baseline to 48 hours post-dose | 1.51 complete spontaneous bowel movements/day | Standard Deviation 1.56 |
| Naldemedine 3 mg | Change From Baseline to 48 Hours Post-dose in Number of Complete Spontaneous Bowel Movements (CSBMs) Per Day | 48 hours post-dose | 1.61 complete spontaneous bowel movements/day | Standard Deviation 1.52 |
p-value: 0.6131ANCOVA
p-value: 0.9293ANCOVA
p-value: 0.799ANCOVA
p-value: 0.7674ANCOVA
p-value: <0.0001ANCOVA
p-value: 0.0018ANCOVA
Secondary
Change From Baseline to 48 Hours Post-dose in the Number of SBMs Per Day
Participants completed a bowel function assessment daily diary to record information about bowel movements and constipation. A spontaneous bowel movement was defined as a bowel movement where no laxative or enema was used in the 24 hours preceding the bowel movement. Baseline was defined as the average number of SBMs per day during the 2 weeks prior to receiving study drug (Day 1 to Day 15). Forty-eight hours post-dose was defined as the average number of SBMs per day from 0 to 48 hours post-dose.
Time frame: Baseline (Day 1 to Day 15) and Day 15 to Day 17 (0 to 48 hours post-dose)
Population: Intent-to-treat population; LOCF imputation was used
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pooled Placebo | Change From Baseline to 48 Hours Post-dose in the Number of SBMs Per Day | Change from Baseline to 48 hours post-dose | 0.21 Spontaneous bowel movements / day | Standard Deviation 0.32 |
| Pooled Placebo | Change From Baseline to 48 Hours Post-dose in the Number of SBMs Per Day | 48 hours post-dose | 0.36 Spontaneous bowel movements / day | Standard Deviation 0.33 |
| Pooled Placebo | Change From Baseline to 48 Hours Post-dose in the Number of SBMs Per Day | Baseline | 0.15 Spontaneous bowel movements / day | Standard Deviation 0.13 |
| Naldemedine 0.01 mg | Change From Baseline to 48 Hours Post-dose in the Number of SBMs Per Day | 48 hours post-dose | 0.44 Spontaneous bowel movements / day | Standard Deviation 0.39 |
| Naldemedine 0.01 mg | Change From Baseline to 48 Hours Post-dose in the Number of SBMs Per Day | Baseline | 0.20 Spontaneous bowel movements / day | Standard Deviation 0.14 |
| Naldemedine 0.01 mg | Change From Baseline to 48 Hours Post-dose in the Number of SBMs Per Day | Change from Baseline to 48 hours post-dose | 0.24 Spontaneous bowel movements / day | Standard Deviation 0.39 |
| Naldemedine 0.03 mg | Change From Baseline to 48 Hours Post-dose in the Number of SBMs Per Day | Change from Baseline to 48 hours post-dose | 0.42 Spontaneous bowel movements / day | Standard Deviation 0.65 |
| Naldemedine 0.03 mg | Change From Baseline to 48 Hours Post-dose in the Number of SBMs Per Day | Baseline | 0.24 Spontaneous bowel movements / day | Standard Deviation 0.09 |
| Naldemedine 0.03 mg | Change From Baseline to 48 Hours Post-dose in the Number of SBMs Per Day | 48 hours post-dose | 0.67 Spontaneous bowel movements / day | Standard Deviation 0.61 |
| Naldemedine 0.1 mg | Change From Baseline to 48 Hours Post-dose in the Number of SBMs Per Day | 48 hours post-dose | 0.39 Spontaneous bowel movements / day | Standard Deviation 0.49 |
| Naldemedine 0.1 mg | Change From Baseline to 48 Hours Post-dose in the Number of SBMs Per Day | Baseline | 0.13 Spontaneous bowel movements / day | Standard Deviation 0.13 |
| Naldemedine 0.1 mg | Change From Baseline to 48 Hours Post-dose in the Number of SBMs Per Day | Change from Baseline to 48 hours post-dose | 0.26 Spontaneous bowel movements / day | Standard Deviation 0.45 |
| Naldemedine 0.3 mg | Change From Baseline to 48 Hours Post-dose in the Number of SBMs Per Day | 48 hours post-dose | 1.06 Spontaneous bowel movements / day | Standard Deviation 0.68 |
| Naldemedine 0.3 mg | Change From Baseline to 48 Hours Post-dose in the Number of SBMs Per Day | Baseline | 0.17 Spontaneous bowel movements / day | Standard Deviation 0.12 |
| Naldemedine 0.3 mg | Change From Baseline to 48 Hours Post-dose in the Number of SBMs Per Day | Change from Baseline to 48 hours post-dose | 0.88 Spontaneous bowel movements / day | Standard Deviation 0.68 |
| Naldemedine 1 mg | Change From Baseline to 48 Hours Post-dose in the Number of SBMs Per Day | Baseline | 0.13 Spontaneous bowel movements / day | Standard Deviation 0.09 |
| Naldemedine 1 mg | Change From Baseline to 48 Hours Post-dose in the Number of SBMs Per Day | Change from Baseline to 48 hours post-dose | 2.15 Spontaneous bowel movements / day | Standard Deviation 1.81 |
| Naldemedine 1 mg | Change From Baseline to 48 Hours Post-dose in the Number of SBMs Per Day | 48 hours post-dose | 2.28 Spontaneous bowel movements / day | Standard Deviation 1.8 |
| Naldemedine 3 mg | Change From Baseline to 48 Hours Post-dose in the Number of SBMs Per Day | Change from Baseline to 48 hours post-dose | 2.44 Spontaneous bowel movements / day | Standard Deviation 1.05 |
| Naldemedine 3 mg | Change From Baseline to 48 Hours Post-dose in the Number of SBMs Per Day | 48 hours post-dose | 2.67 Spontaneous bowel movements / day | Standard Deviation 1.03 |
| Naldemedine 3 mg | Change From Baseline to 48 Hours Post-dose in the Number of SBMs Per Day | Baseline | 0.23 Spontaneous bowel movements / day | Standard Deviation 0.11 |
p-value: 0.8982ANCOVA
p-value: 0.4946ANCOVA
p-value: 0.9301ANCOVA
p-value: 0.0047ANCOVA
p-value: <0.0001ANCOVA
p-value: <0.0001ANCOVA
Secondary
Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995
The plasma concentration of naldemedine and its metabolite Nor-S-297995 were measured by liquid chromatography/tandem mass spectrometry (LC/MS/MS) method.
Time frame: Blood samples were collected predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post-dose.
Population: The pharmacokinetic (PK) analysis population included all randomized participants who received study drug and had at least one post-dose PK assessment completed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Pooled Placebo | Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995 | Naldemedine | 0.0837 ng/mL | Geometric Coefficient of Variation 29.6 |
| Pooled Placebo | Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 | NA ng/mL | — |
| Naldemedine 0.01 mg | Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995 | Naldemedine | 0.290 ng/mL | Geometric Coefficient of Variation 28.9 |
| Naldemedine 0.01 mg | Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 | NA ng/mL | — |
| Naldemedine 0.03 mg | Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995 | Naldemedine | 1.00 ng/mL | Geometric Coefficient of Variation 28.4 |
| Naldemedine 0.03 mg | Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 | 0.0713 ng/mL | Geometric Coefficient of Variation 31.8 |
| Naldemedine 0.1 mg | Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995 | Naldemedine | 3.12 ng/mL | Geometric Coefficient of Variation 30.2 |
| Naldemedine 0.1 mg | Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 | 0.134 ng/mL | Geometric Coefficient of Variation 27.6 |
| Naldemedine 0.3 mg | Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995 | Naldemedine | 9.68 ng/mL | Geometric Coefficient of Variation 31.3 |
| Naldemedine 0.3 mg | Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 | 0.526 ng/mL | Geometric Coefficient of Variation 49.4 |
| Naldemedine 1 mg | Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995 | Naldemedine | 30.9 ng/mL | Geometric Coefficient of Variation 44.2 |
| Naldemedine 1 mg | Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 | 1.50 ng/mL | Geometric Coefficient of Variation 53.3 |
Secondary
Percentage of Participants With Clinical Opiate Withdrawal Scale (COWS) Score > 8 at Any Time During the Study
The COWS assessment consisted of 11 questions which rated the severity of opiate withdrawal symptoms, including resting pulse rate, gastrointestinal upset, sweating, restlessness, pupil size, tremor, anxiety or irritability, bone or joint aches, gooseflesh skin, yawning, and runny nose or tearing. Each symptom was rated on a scale from 0 (not present) to 4 or 5 (most severe). The total score was calculated by summing the 11 individual scores and ranged from 0 (no withdrawal symptoms) to 48 (worst symptoms).
Time frame: The COWS assessments were performed at Screening, on Day 14, Day 15 (pre-dose and 1, 2, 3, 4, 5, 6 and 8 hours post-dose, and at unscheduled times as signs or symptoms indicate), on Days 16 and 17, and on Day 24/End of Study.
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pooled Placebo | Percentage of Participants With Clinical Opiate Withdrawal Scale (COWS) Score > 8 at Any Time During the Study | 0.0 percentage of participants |
| Naldemedine 0.01 mg | Percentage of Participants With Clinical Opiate Withdrawal Scale (COWS) Score > 8 at Any Time During the Study | 0.0 percentage of participants |
| Naldemedine 0.03 mg | Percentage of Participants With Clinical Opiate Withdrawal Scale (COWS) Score > 8 at Any Time During the Study | 0.0 percentage of participants |
| Naldemedine 0.1 mg | Percentage of Participants With Clinical Opiate Withdrawal Scale (COWS) Score > 8 at Any Time During the Study | 0.0 percentage of participants |
| Naldemedine 0.3 mg | Percentage of Participants With Clinical Opiate Withdrawal Scale (COWS) Score > 8 at Any Time During the Study | 0.0 percentage of participants |
| Naldemedine 1 mg | Percentage of Participants With Clinical Opiate Withdrawal Scale (COWS) Score > 8 at Any Time During the Study | 11.1 percentage of participants |
| Naldemedine 3 mg | Percentage of Participants With Clinical Opiate Withdrawal Scale (COWS) Score > 8 at Any Time During the Study | 66.7 percentage of participants |
Secondary
Percentage of Participants With Webster Opiate Withdrawal Scale (WOWS) Score > 8 at Any Time During the Study
The Webster Opiate Withdrawal Scale (WOWS) assessment consisted of 7 questions which rate the severity of opiate withdrawal symptoms, including sweating, sleep, bone or joint aches, runny nose or tearing, gastrointestinal upset, anxiety or irritability and gooseflesh skin. Each symptom was rated on a scale from 0 (not present/no issues) to 4 or 5 (severe). The total score was calculated by summing the 7 individual scores and ranged from 0 (no withdrawal symptoms) to 29 (worst symptoms).
Time frame: The WOWS assessment was performed at Screening, Day 14, Day 15 at pre-dose , and 24 and 48 hours post-dose and at the Follow-up/End of Study visit (Day 24).
Population: Safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pooled Placebo | Percentage of Participants With Webster Opiate Withdrawal Scale (WOWS) Score > 8 at Any Time During the Study | 0.0 percentage of participants |
| Naldemedine 0.01 mg | Percentage of Participants With Webster Opiate Withdrawal Scale (WOWS) Score > 8 at Any Time During the Study | 0.0 percentage of participants |
| Naldemedine 0.03 mg | Percentage of Participants With Webster Opiate Withdrawal Scale (WOWS) Score > 8 at Any Time During the Study | 0.0 percentage of participants |
| Naldemedine 0.1 mg | Percentage of Participants With Webster Opiate Withdrawal Scale (WOWS) Score > 8 at Any Time During the Study | 0.0 percentage of participants |
| Naldemedine 0.3 mg | Percentage of Participants With Webster Opiate Withdrawal Scale (WOWS) Score > 8 at Any Time During the Study | 11.1 percentage of participants |
| Naldemedine 1 mg | Percentage of Participants With Webster Opiate Withdrawal Scale (WOWS) Score > 8 at Any Time During the Study | 0.0 percentage of participants |
| Naldemedine 3 mg | Percentage of Participants With Webster Opiate Withdrawal Scale (WOWS) Score > 8 at Any Time During the Study | 0.0 percentage of participants |
Secondary
Time to First Bowel Movement
The time to first BM during the Study Drug Administration Period was summarized using Kaplan-Meier estimates. Each participant's first BM was counted as an event and the time to first BM after dosing was calculated from the date and time of first dosing until the date and time of first BM. Participants who dropped out or were lost to follow-up before the first BM were censored.
Time frame: From first dose on Day 15 through Day 17
Population: Intent-to-treat population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pooled Placebo | Time to First Bowel Movement | 27.2 hours |
| Naldemedine 0.01 mg | Time to First Bowel Movement | 28.4 hours |
| Naldemedine 0.03 mg | Time to First Bowel Movement | 13.9 hours |
| Naldemedine 0.1 mg | Time to First Bowel Movement | 25.1 hours |
| Naldemedine 0.3 mg | Time to First Bowel Movement | 4.7 hours |
| Naldemedine 1 mg | Time to First Bowel Movement | 1.4 hours |
| Naldemedine 3 mg | Time to First Bowel Movement | 0.7 hours |
p-value: 0.492395% CI: [0.53, 4.28]Log Rank
p-value: 0.547995% CI: [0.52, 4.06]Log Rank
p-value: 0.50695% CI: [0.56, 3.67]Log Rank
p-value: 0.000595% CI: [2.27, 23.9]Log Rank
p-value: <0.000195% CI: [3, 30.35]Log Rank
p-value: <0.0001Log Rank
Secondary
Time to First Complete Spontaneous Bowel Movement
The time to first CSBM during the Study Drug Administration Period was summarized using Kaplan-Meier estimates. Each participant's first CSBM was counted as an event and the time to first CSBM after dosing was calculated from the date and time of first dosing until the date and time of first CSBM. Participants who dropped out or were lost to follow-up before the first CSBM were censored.
Time frame: From first dose on Day 15 through Day 17
Population: Intent-to-treat population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pooled Placebo | Time to First Complete Spontaneous Bowel Movement | NA hours |
| Naldemedine 0.01 mg | Time to First Complete Spontaneous Bowel Movement | NA hours |
| Naldemedine 0.03 mg | Time to First Complete Spontaneous Bowel Movement | NA hours |
| Naldemedine 0.1 mg | Time to First Complete Spontaneous Bowel Movement | NA hours |
| Naldemedine 0.3 mg | Time to First Complete Spontaneous Bowel Movement | NA hours |
| Naldemedine 1 mg | Time to First Complete Spontaneous Bowel Movement | 1.7 hours |
| Naldemedine 3 mg | Time to First Complete Spontaneous Bowel Movement | 0.8 hours |
p-value: 0.152395% CI: [0.62, 19.35]Log Rank
p-value: 0.085695% CI: [0.76, 27.07]Log Rank
p-value: 0.528495% CI: [0.3, 10.98]Log Rank
p-value: 0.859495% CI: [0.09, 8.66]Log Rank
p-value: <0.000195% CI: [6.55, 537.38]Log Rank
p-value: 0.000795% CI: [2.3, 52.57]Log Rank
Secondary
Time to First Spontaneous Bowel Movement
The time to first SBM during the Study Drug Administration Period was summarized using Kaplan-Meier estimates. Each participant's first SBM was counted as an event and the time to first SBM after dosing was calculated from the date and time of first dosing until the date and time of first SBM. Participants who dropped out or were lost to follow-up before the first SBM were censored.
Time frame: From first dose on Day 15 through Day 17
Population: Intent-to-treat population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pooled Placebo | Time to First Spontaneous Bowel Movement | 27.2 hours |
| Naldemedine 0.01 mg | Time to First Spontaneous Bowel Movement | 37.0 hours |
| Naldemedine 0.03 mg | Time to First Spontaneous Bowel Movement | 13.9 hours |
| Naldemedine 0.1 mg | Time to First Spontaneous Bowel Movement | NA hours |
| Naldemedine 0.3 mg | Time to First Spontaneous Bowel Movement | 4.7 hours |
| Naldemedine 1 mg | Time to First Spontaneous Bowel Movement | 1.4 hours |
| Naldemedine 3 mg | Time to First Spontaneous Bowel Movement | 0.7 hours |
p-value: 0.812995% CI: [0.27, 2.72]Log Rank
p-value: 0.000595% CI: [2.29, 24.72]Log Rank
p-value: 0.743495% CI: [0.42, 3.92]Log Rank
p-value: 0.444995% CI: [0.54, 4.42]Log Rank
p-value: <0.000195% CI: [3.09, 31.89]Log Rank
p-value: <0.0001Log Rank
Secondary
Time to Maximum Observed Plasma Concentration of Naldemedine and Metabolite Nor-S-297995
The plasma concentration of naldemedine and its metabolite Nor-S-297995 were measured by liquid chromatography/tandem mass spectrometry (LC/MS/MS) method.
Time frame: Blood samples were collected predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, 36, 48, and 72 hours post-dose.
Population: PK population
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pooled Placebo | Time to Maximum Observed Plasma Concentration of Naldemedine and Metabolite Nor-S-297995 | Naldemedine | 0.75 hours |
| Pooled Placebo | Time to Maximum Observed Plasma Concentration of Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 | NA hours |
| Naldemedine 0.01 mg | Time to Maximum Observed Plasma Concentration of Naldemedine and Metabolite Nor-S-297995 | Naldemedine | 1.0 hours |
| Naldemedine 0.01 mg | Time to Maximum Observed Plasma Concentration of Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 | NA hours |
| Naldemedine 0.03 mg | Time to Maximum Observed Plasma Concentration of Naldemedine and Metabolite Nor-S-297995 | Naldemedine | 2.5 hours |
| Naldemedine 0.03 mg | Time to Maximum Observed Plasma Concentration of Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 | 5.0 hours |
| Naldemedine 0.1 mg | Time to Maximum Observed Plasma Concentration of Naldemedine and Metabolite Nor-S-297995 | Naldemedine | 1.0 hours |
| Naldemedine 0.1 mg | Time to Maximum Observed Plasma Concentration of Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 | 4.1 hours |
| Naldemedine 0.3 mg | Time to Maximum Observed Plasma Concentration of Naldemedine and Metabolite Nor-S-297995 | Naldemedine | 1.0 hours |
| Naldemedine 0.3 mg | Time to Maximum Observed Plasma Concentration of Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 | 8.0 hours |
| Naldemedine 1 mg | Time to Maximum Observed Plasma Concentration of Naldemedine and Metabolite Nor-S-297995 | Naldemedine | 0.75 hours |
| Naldemedine 1 mg | Time to Maximum Observed Plasma Concentration of Naldemedine and Metabolite Nor-S-297995 | Nor-S-297995 | 5.0 hours |