Opioid-induced Constipation
Conditions
Keywords
Opioid Induced Constipation
Brief summary
The purpose of this study is to evaluate the long-term safety of naldemedine for the treatment of constipation due to opioid therapy.
Interventions
DRUGNaldemedine
Naldemedine 0.2 mg tablet taken orally once a day
DRUGPlacebo
Placebo tablet taken orally once a day
Sponsors
Shionogi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Subjects aged 18 to 80 years inclusive at the time of informed consent 2. Subjects must have non-malignant chronic pain treated and must have opioid induced constipation (OIC) 3. Subjects must be treated with a stable opioid regimen at a total daily dose on average of ≥ 30 mg equivalents of oral morphine sulfate 4. Subjects may or may not be on a routine laxative regimen at the time of Screening
Exclusion criteria
1. Evidence of significant structural abnormalities of the gastrointestinal (GI) tract 2. Evidence of active medical diseases affecting bowel transit 3. History of pelvic disorders that may be a cause of constipation 4. Surgery (except for minor procedures) within 60 days of Screening 5. History of chronic constipation prior to starting analgesic medication or any potential non-opioid cause of bowel dysfunction that may be a major contributor to the constipation (e.g. mechanical GI obstruction) 6. Subjects who have never taken laxatives for the treatment of OIC 7. Current use of any prohibited medication including opioid antagonists, partial or mixed agonists/antagonists
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | From the first dose of study drug up to 14 days after the last dose of study drug (54 weeks). | A serious adverse event was defined as any adverse event (AE) 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. Important medical events that may not result in death, be life threatening, or require hospitalization were considered an SAE when, based upon appropriate medical judgment, they jeopardized the patient or required medical or surgical intervention to prevent one of the outcomes listed above. Adverse drug reactions (ADRs) were defined as adverse events that were considered by the investigator to be definitely, probably, or possibly related to study drug. Serious ADRs were defined as serious AEs considered by the investigator to be definitely, probably, or possibly related to study drug. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Meeting Each Criterion of Laxative Use | From 28 days prior to screening until the end of the treatment period (total of 56 weeks) | Participants who were taking stable routine/regular laxatives at Screening were to continue taking the same regimen throughout the study. The percentage of participants meeting each of the criteria below are reported: 1\. Participants not on stable laxatives, defined as participants who did not use laxatives from 28 days prior to the Screening Period to the final dose of study drug or who received only rescue laxative. Rescue is defined as any laxative taken for the first time during the Treatment Period. 1a. Out of participants who were not on stable laxatives, participants who received rescue laxatives. 2\. Participants on stable laxatives, defined as participants who may have had at least one/any stable laxative use reported from 28 days prior to Screening Period to the final dose of study drug. 2a. Out of participants who were on stable laxatives, participants who received rescue laxatives. 3\. Participants who did not meet criteria 1 or 2. |
| Change From Baseline in the Overall Score for Patient Assessment of Constipation Symptoms | Baseline and Weeks 2, 12, 24, 36, and 52 | The Patient Assessment of Constipation Symptom Questionnaire (PAC-SYM) asked participants to rate the severity of 12 constipation symptoms in the last 2 weeks on a scale from 0 (absent) to 4 (very severe). The overall score was calculated as the mean of all 12 items and ranges from 0 (best) to 4 (worst). A negative change from baseline value indicates improvement. |
| Change From Baseline in the PAC-SYM Abdominal-symptoms Domain Score | Baseline and Weeks 2, 12, 24, 36, and 52 | The Patient Assessment of Constipation Symptom Questionnaire (PAC-SYM) asked participants to rate the severity of 12 constipation symptoms in the last 2 weeks on a scale from 0 (absent) to 4 (very severe). The abdominal-symptom domain score was calculated as the mean of the following 4 items: abdominal discomfort, abdominal pain, abdominal bloating and stomach cramps. A negative change from baseline value indicates improvement in symptoms. |
| Change From Baseline in the PAC-SYM Rectal-symptoms Domain Score | Baseline and Weeks 2, 12, 24, 36, and 52 | The Patient Assessment of Constipation Symptom Questionnaire (PAC-SYM) asked participants to rate the severity of 12 constipation symptoms in the last 2 weeks on a scale from 0 (absent) to 4 (very severe). The abdominal-symptom domain score was calculated as the mean of the following 3 items: painful bowel movements, rectal burning during or after a bowel movement, and rectal bleeding or tearing during or after a bowel movement. A negative change from baseline value indicates improvement in symptoms. |
| Change From Baseline in the PAC-SYM Stool-symptoms Domain Score | Baseline and Weeks 2, 12, 24, 36, and 52 | The Patient Assessment of Constipation Symptom Questionnaire (PAC-SYM) asked participants to rate the severity of 12 constipation symptoms in the last 2 weeks on a scale from 0 (absent) to 4 (very severe). The stool-symptom domain score was calculated as the mean of the following 5 items: incomplete bowel movements, bowel movements that were too hard, bowel movements that were too small, straining or squeezing to try to pass bowel movements, and false-alarm bowel movements. A negative change from baseline value indicates improvement in symptoms. |
| Change From Baseline in the Number of Bowel Movements Per Week | Baseline and Weeks 12, 24, 36, and 52 | Participants monitored their bowel movements and completed a daily bowel habits diary the week prior to study visits (i.e. during Weeks 11, 23, 35, and 51). |
| Change From Baseline in the Physical Discomfort Domain of PAC-QOL | Baseline and Weeks 2, 12, 24, 36, and 52 | The Patient Assessment of Constipation Quality of Life Questionnaire (PAC-QOL) consists of 28 questions designed to measure the impact constipation has had on participants' daily life during the past 2 weeks. Each question was evaluated by the participant on a five-point scale ranging from 0 (not at all or none of the time) to 4 (extremely or all of the time), where higher scores represent poorer quality of life. The physical discomfort domain consists of 4 questions related to bloating, feeling heavy, how much of the time participants felt any physical discomfort and how much time they felt the need to open their bowel but were not able to. The physical discomfort score was calculated as the mean of the 4 individual scores. A negative change from baseline value indicates improvement. |
| Change From Baseline in the Psychosocial Discomfort Domain of PAC-QOL | Baseline and Weeks 2, 12, 24, 36, and 52 | The Patient Assessment of Constipation Quality of Life Questionnaire (PAC-QOL) consists of 28 questions designed to measure the impact constipation has had on participants' daily life during the past 2 weeks. Each question was evaluated by the participant on a five-point scale ranging from 0 (not at all or none of the time) to 4 (extremely or all of the time), where higher scores represent poorer quality of life. The psychosocial discomfort domain consists of 8 questions related to participants' embarrassment regarding their constipation and effects of constipation on eating habits and appetite. The psychosocial discomfort score was calculated as the mean of the 8 individual scores. A negative change from baseline value indicates improvement. |
| Change From Baseline in the Worries and Concerns Domain of PAC-QOL | Baseline and Weeks 2, 12, 24, 36, and 52 | The Patient Assessment of Constipation Quality of Life Questionnaire (PAC-QOL) consists of 28 questions designed to measure the impact constipation has had on participants' daily life during the past 2 weeks. Each question was evaluated by the participant on a five-point scale ranging from 0 (not at all or none of the time) to 4 (extremely or all of the time), where higher scores represent poorer quality of life. The worries and concerns domain consists of 11 questions related to participants' feelings and concerns about their constipation. The worries and concerns domain score was calculated as the mean of the 11 individual scores. A negative change from baseline value indicates improvement. |
| Change From Baseline in the Satisfaction Domain of PAC-QOL | Baseline and Weeks 2, 12, 24, 36, and 52 | The Patient Assessment of Constipation Quality of Life Questionnaire (PAC-QOL) consists of 28 questions designed to measure the impact constipation has had on participants' daily life during the past 2 weeks. Each question was evaluated by the participant on a five-point scale ranging from 0 (not at all or none of the time) to 4 (extremely or all of the time), where higher scores represent poorer quality of life. The satisfaction domain consists of 5 questions related to participants' feelings of satisfaction with their bowel function. The satisfaction domain score was calculated as the mean of the 5 individual scores. A negative change from baseline value indicates improvement. |
| Participant Global Satisfaction | Week 52 or early termination visit | Participants were asked to rate their degree of satisfaction of constipation and abdominal symptoms from the start of study drug dosing to Week 52 (or early termination). Satisfaction was rated based on the following seven grades: * Grade 1 = markedly worsened * Grade 2 = moderately worsened * Grade 3 = slightly worsened * Grade 4 = unchanged * Grade 5 = slightly improved * Grade 6 = moderately improved * Grade 7 = markedly improved |
| Change From Baseline in the Patient Assessment of Constipation Quality of Life Overall Score | Baseline and Weeks 2, 12, 24, 36, and 52 | The Patient Assessment of Constipation Quality of Life Questionnaire (PAC-QOL) consists of 28 questions designed to measure the impact constipation has had on participants' daily life during the past 2 weeks. Each question was evaluated by the participant on a five-point scale ranging from 0 (not at all or none of the time) to 4 (extremely or all of the time), where higher scores represent poorer quality of life. The overall score was calculated as the mean of all 28 item scores. A negative change from baseline value indicates improvement. |
Countries
Australia, Austria, Canada, Czechia, Denmark, France, Germany, Hungary, Israel, Italy, Poland, South Africa, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
This study was conducted at 195 clinical sites in North America (Canada and the United States), Europe (Belgium, Denmark, Estonia, France, Germany, Hungary, Poland, Spain, Sweden, and the United Kingdom), and Africa/Asia Pacific (Australia and South Africa)
Pre-assignment details
Participants were randomized in a 1:1 ratio to receive naldemedine or placebo for 52 weeks. Randomization was stratified based on documented opioid use (average total daily dose \[TDD\] during the 14-consecutive-day qualifying period) as follows: * 30 - 100 mg equivalents of oral morphine sulfate. * \> 100 mg equivalents of oral morphine sulfate.
Participants by arm
| Arm | Count |
|---|---|
| Naldemedine Participants received 0.2 mg naldemedine tablets orally once daily for 52 weeks. | 621 |
| Placebo Participants received placebo tablets orally once daily for 52 weeks. | 619 |
| Total | 1,240 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 40 | 37 |
| Overall Study | Death | 3 | 4 |
| Overall Study | Lost to Follow-up | 53 | 40 |
| Overall Study | Other - Miscellaneous | 18 | 21 |
| Overall Study | Pregnancy | 0 | 1 |
| Overall Study | Protocol Violation | 34 | 38 |
| Overall Study | Withdrawal by Subject | 62 | 69 |
Baseline characteristics
| Characteristic | Naldemedine | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 53.4 Years STANDARD_DEVIATION 11.68 | 52.7 Years STANDARD_DEVIATION 10.55 | 53.0 Years STANDARD_DEVIATION 11.13 |
| Age, Customized ≥ 40 to < 65 years | 445 participants | 475 participants | 920 participants |
| Age, Customized < 40 years | 75 participants | 68 participants | 143 participants |
| Age, Customized ≥ 65 years | 101 participants | 76 participants | 177 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 47 Participants | 42 Participants | 89 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 574 Participants | 577 Participants | 1151 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 2 participants | 7 participants | 9 participants |
| Race/Ethnicity, Customized Asian | 5 participants | 7 participants | 12 participants |
| Race/Ethnicity, Customized Black or African American | 120 participants | 108 participants | 228 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 2 participants | 1 participants | 3 participants |
| Race/Ethnicity, Customized White | 492 participants | 496 participants | 988 participants |
| Sex: Female, Male Female | 383 Participants | 402 Participants | 785 Participants |
| Sex: Female, Male Male | 238 Participants | 217 Participants | 455 Participants |
| Stratification by Opioid Dose > 100 mg | 225 participants | 227 participants | 452 participants |
| Stratification by Opioid Dose 30-100 mg | 396 participants | 392 participants | 788 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 225 / 621 | 179 / 619 |
| serious Total, serious adverse events | 60 / 621 | 73 / 619 |
Outcome results
Primary
Number of Participants With Adverse Events
A serious adverse event was defined as any adverse event (AE) 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. Important medical events that may not result in death, be life threatening, or require hospitalization were considered an SAE when, based upon appropriate medical judgment, they jeopardized the patient or required medical or surgical intervention to prevent one of the outcomes listed above. Adverse drug reactions (ADRs) were defined as adverse events that were considered by the investigator to be definitely, probably, or possibly related to study drug. Serious ADRs were defined as serious AEs considered by the investigator to be definitely, probably, or possibly related to study drug.
Time frame: From the first dose of study drug up to 14 days after the last dose of study drug (54 weeks).
Population: Safety population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Naldemedine | Number of Participants With Adverse Events | AEs leading to discontinuation of study drug | 39 participants |
| Naldemedine | Number of Participants With Adverse Events | Serious adverse drug reactions | 3 participants |
| Naldemedine | Number of Participants With Adverse Events | Adverse drug reactions | 149 participants |
| Naldemedine | Number of Participants With Adverse Events | SAEs leading to discontinuation of study drug | 7 participants |
| Naldemedine | Number of Participants With Adverse Events | Serious adverse events | 60 participants |
| Naldemedine | Number of Participants With Adverse Events | Deaths | 1 participants |
| Naldemedine | Number of Participants With Adverse Events | Adverse events | 425 participants |
| Placebo | Number of Participants With Adverse Events | Deaths | 3 participants |
| Placebo | Number of Participants With Adverse Events | Adverse events | 446 participants |
| Placebo | Number of Participants With Adverse Events | Adverse drug reactions | 121 participants |
| Placebo | Number of Participants With Adverse Events | AEs leading to discontinuation of study drug | 36 participants |
| Placebo | Number of Participants With Adverse Events | Serious adverse events | 73 participants |
| Placebo | Number of Participants With Adverse Events | Serious adverse drug reactions | 6 participants |
| Placebo | Number of Participants With Adverse Events | SAEs leading to discontinuation of study drug | 12 participants |
Secondary
Change From Baseline in the Number of Bowel Movements Per Week
Participants monitored their bowel movements and completed a daily bowel habits diary the week prior to study visits (i.e. during Weeks 11, 23, 35, and 51).
Time frame: Baseline and Weeks 12, 24, 36, and 52
Population: The intent-to-treat population includes all randomized participants. Five participants were excluded due to double enrollment at different sites.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Naldemedine | Change From Baseline in the Number of Bowel Movements Per Week | Week 12 | 3.70 bowel movements / week | Standard Error 0.163 |
| Naldemedine | Change From Baseline in the Number of Bowel Movements Per Week | Week 24 | 3.77 bowel movements / week | Standard Error 0.172 |
| Naldemedine | Change From Baseline in the Number of Bowel Movements Per Week | Week 36 | 3.88 bowel movements / week | Standard Error 0.18 |
| Naldemedine | Change From Baseline in the Number of Bowel Movements Per Week | Week 52 | 3.92 bowel movements / week | Standard Error 0.184 |
| Placebo | Change From Baseline in the Number of Bowel Movements Per Week | Week 52 | 2.92 bowel movements / week | Standard Error 0.187 |
| Placebo | Change From Baseline in the Number of Bowel Movements Per Week | Week 12 | 2.42 bowel movements / week | Standard Error 0.162 |
| Placebo | Change From Baseline in the Number of Bowel Movements Per Week | Week 36 | 2.88 bowel movements / week | Standard Error 0.177 |
| Placebo | Change From Baseline in the Number of Bowel Movements Per Week | Week 24 | 2.77 bowel movements / week | Standard Error 0.172 |
Comparison: Week 12 Analysisp-value: <0.000195% CI: [0.83, 1.72]Mixed-effects model repeated measures
Comparison: Week 24 Analysisp-value: <0.000195% CI: [0.53, 1.47]Mixed-effects model repeated measures
Comparison: Week 36 Analysisp-value: <0.000195% CI: [0.52, 1.5]Mixed-effects model repeated measures
Comparison: Week 52 Analysisp-value: 0.000195% CI: [0.49, 1.51]Mixed-effects model repeated measures
Secondary
Change From Baseline in the Overall Score for Patient Assessment of Constipation Symptoms
The Patient Assessment of Constipation Symptom Questionnaire (PAC-SYM) asked participants to rate the severity of 12 constipation symptoms in the last 2 weeks on a scale from 0 (absent) to 4 (very severe). The overall score was calculated as the mean of all 12 items and ranges from 0 (best) to 4 (worst). A negative change from baseline value indicates improvement.
Time frame: Baseline and Weeks 2, 12, 24, 36, and 52
Population: The intent-to-treat population includes all randomized participants. Five participants were excluded due to double enrollment at different sites.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Naldemedine | Change From Baseline in the Overall Score for Patient Assessment of Constipation Symptoms | Week 2 | -1.15 units on a scale | Standard Error 0.036 |
| Naldemedine | Change From Baseline in the Overall Score for Patient Assessment of Constipation Symptoms | Week 36 | -1.21 units on a scale | Standard Error 0.04 |
| Naldemedine | Change From Baseline in the Overall Score for Patient Assessment of Constipation Symptoms | Week 24 | -1.16 units on a scale | Standard Error 0.039 |
| Naldemedine | Change From Baseline in the Overall Score for Patient Assessment of Constipation Symptoms | Week 52 | -1.22 units on a scale | Standard Error 0.041 |
| Naldemedine | Change From Baseline in the Overall Score for Patient Assessment of Constipation Symptoms | Week 12 | -1.11 units on a scale | Standard Error 0.039 |
| Placebo | Change From Baseline in the Overall Score for Patient Assessment of Constipation Symptoms | Week 52 | -0.98 units on a scale | Standard Error 0.042 |
| Placebo | Change From Baseline in the Overall Score for Patient Assessment of Constipation Symptoms | Week 2 | -0.81 units on a scale | Standard Error 0.036 |
| Placebo | Change From Baseline in the Overall Score for Patient Assessment of Constipation Symptoms | Week 12 | -0.86 units on a scale | Standard Error 0.039 |
| Placebo | Change From Baseline in the Overall Score for Patient Assessment of Constipation Symptoms | Week 24 | -0.87 units on a scale | Standard Error 0.039 |
| Placebo | Change From Baseline in the Overall Score for Patient Assessment of Constipation Symptoms | Week 36 | -0.85 units on a scale | Standard Error 0.04 |
Comparison: Week 2 Analysisp-value: <0.000195% CI: [-0.44, -0.25]Mixed-effects model repeated measures
Comparison: Week 12 Analysisp-value: <0.000195% CI: [-0.36, -0.14]Mixed-effects model repeated measures
Comparison: Week 24 Analysisp-value: <0.000195% CI: [-0.4, -0.18]Mixed-effects model repeated measures
Comparison: Week 36 Analysisp-value: <0.000195% CI: [-0.47, -0.24]Mixed-effects model repeated measures
Comparison: Week 52 Analysisp-value: <0.000195% CI: [-0.35, -0.12]Mixed-effects model repeated measures
Secondary
Change From Baseline in the PAC-SYM Abdominal-symptoms Domain Score
The Patient Assessment of Constipation Symptom Questionnaire (PAC-SYM) asked participants to rate the severity of 12 constipation symptoms in the last 2 weeks on a scale from 0 (absent) to 4 (very severe). The abdominal-symptom domain score was calculated as the mean of the following 4 items: abdominal discomfort, abdominal pain, abdominal bloating and stomach cramps. A negative change from baseline value indicates improvement in symptoms.
Time frame: Baseline and Weeks 2, 12, 24, 36, and 52
Population: Intent-to-treat population
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Naldemedine | Change From Baseline in the PAC-SYM Abdominal-symptoms Domain Score | Week 12 | -0.93 units on a scale | Standard Error 0.042 |
| Naldemedine | Change From Baseline in the PAC-SYM Abdominal-symptoms Domain Score | Week 36 | -1.06 units on a scale | Standard Error 0.043 |
| Naldemedine | Change From Baseline in the PAC-SYM Abdominal-symptoms Domain Score | Week 24 | -0.99 units on a scale | Standard Error 0.043 |
| Naldemedine | Change From Baseline in the PAC-SYM Abdominal-symptoms Domain Score | Week 52 | -1.07 units on a scale | Standard Error 0.045 |
| Naldemedine | Change From Baseline in the PAC-SYM Abdominal-symptoms Domain Score | Week 2 | -0.99 units on a scale | Standard Error 0.038 |
| Placebo | Change From Baseline in the PAC-SYM Abdominal-symptoms Domain Score | Week 52 | -0.94 units on a scale | Standard Error 0.045 |
| Placebo | Change From Baseline in the PAC-SYM Abdominal-symptoms Domain Score | Week 2 | -0.79 units on a scale | Standard Error 0.038 |
| Placebo | Change From Baseline in the PAC-SYM Abdominal-symptoms Domain Score | Week 12 | -0.78 units on a scale | Standard Error 0.043 |
| Placebo | Change From Baseline in the PAC-SYM Abdominal-symptoms Domain Score | Week 24 | -0.81 units on a scale | Standard Error 0.043 |
| Placebo | Change From Baseline in the PAC-SYM Abdominal-symptoms Domain Score | Week 36 | -0.78 units on a scale | Standard Error 0.043 |
Comparison: Week 36 Analysisp-value: <0.000195% CI: [-0.4, -0.16]Mixed-effects model repeated measures
Comparison: Week 2 Analysisp-value: 0.000295% CI: [-0.31, -0.1]Mixed-effects model repeated measures
Comparison: Week 12 Analysisp-value: 0.017395% CI: [-0.26, -0.03]Mixed-effects model repeated meaures
Comparison: Week 24 Analysisp-value: 0.003595% CI: [-0.3, -0.06]Mixed-effects model repeated measures
Comparison: Week 52 Analysisp-value: 0.033695% CI: [-0.26, -0.01]Mixed-effects model repeated measures
Secondary
Change From Baseline in the PAC-SYM Rectal-symptoms Domain Score
The Patient Assessment of Constipation Symptom Questionnaire (PAC-SYM) asked participants to rate the severity of 12 constipation symptoms in the last 2 weeks on a scale from 0 (absent) to 4 (very severe). The abdominal-symptom domain score was calculated as the mean of the following 3 items: painful bowel movements, rectal burning during or after a bowel movement, and rectal bleeding or tearing during or after a bowel movement. A negative change from baseline value indicates improvement in symptoms.
Time frame: Baseline and Weeks 2, 12, 24, 36, and 52
Population: Intent-to-treat population
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Naldemedine | Change From Baseline in the PAC-SYM Rectal-symptoms Domain Score | Week 12 | -0.97 units on a scale | Standard Error 0.044 |
| Naldemedine | Change From Baseline in the PAC-SYM Rectal-symptoms Domain Score | Week 36 | -1.02 units on a scale | Standard Error 0.045 |
| Naldemedine | Change From Baseline in the PAC-SYM Rectal-symptoms Domain Score | Week 24 | -1.02 units on a scale | Standard Error 0.046 |
| Naldemedine | Change From Baseline in the PAC-SYM Rectal-symptoms Domain Score | Week 52 | -1.03 units on a scale | Standard Error 0.046 |
| Naldemedine | Change From Baseline in the PAC-SYM Rectal-symptoms Domain Score | Week 2 | -1.00 units on a scale | Standard Error 0.04 |
| Placebo | Change From Baseline in the PAC-SYM Rectal-symptoms Domain Score | Week 52 | -0.87 units on a scale | Standard Error 0.047 |
| Placebo | Change From Baseline in the PAC-SYM Rectal-symptoms Domain Score | Week 2 | -0.75 units on a scale | Standard Error 0.04 |
| Placebo | Change From Baseline in the PAC-SYM Rectal-symptoms Domain Score | Week 12 | -0.81 units on a scale | Standard Error 0.045 |
| Placebo | Change From Baseline in the PAC-SYM Rectal-symptoms Domain Score | Week 24 | -0.79 units on a scale | Standard Error 0.046 |
| Placebo | Change From Baseline in the PAC-SYM Rectal-symptoms Domain Score | Week 36 | -0.76 units on a scale | Standard Error 0.045 |
Comparison: Week 2 Analysisp-value: <0.000195% CI: [-0.37, -0.14]Mixed-effects model repeated measures
Comparison: Week 12 Analysisp-value: 0.011495% CI: [-0.28, -0.04]Mixed-effects model repeated measures
Comparison: Week 24 Analysisp-value: 0.000395% CI: [-0.36, -0.11]Mixed-effects model repeated measures
Comparison: Week 36 Analysisp-value: <0.000195% CI: [-0.38, -0.13]Mixed-effects model repeated measures
Comparison: Week 52 Analysisp-value: 0.011995% CI: [-0.29, -0.04]Mixed-effects model repeated measures
Secondary
Change From Baseline in the PAC-SYM Stool-symptoms Domain Score
The Patient Assessment of Constipation Symptom Questionnaire (PAC-SYM) asked participants to rate the severity of 12 constipation symptoms in the last 2 weeks on a scale from 0 (absent) to 4 (very severe). The stool-symptom domain score was calculated as the mean of the following 5 items: incomplete bowel movements, bowel movements that were too hard, bowel movements that were too small, straining or squeezing to try to pass bowel movements, and false-alarm bowel movements. A negative change from baseline value indicates improvement in symptoms.
Time frame: Baseline and Weeks 2, 12, 24, 36, and 52
Population: Intent-to-treat population
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Naldemedine | Change From Baseline in the PAC-SYM Stool-symptoms Domain Score | Week 12 | -1.34 units on a scale | Standard Error 0.046 |
| Naldemedine | Change From Baseline in the PAC-SYM Stool-symptoms Domain Score | Week 36 | -1.44 units on a scale | Standard Error 0.05 |
| Naldemedine | Change From Baseline in the PAC-SYM Stool-symptoms Domain Score | Week 24 | -1.37 units on a scale | Standard Error 0.048 |
| Naldemedine | Change From Baseline in the PAC-SYM Stool-symptoms Domain Score | Week 52 | -1.45 units on a scale | Standard Error 0.051 |
| Naldemedine | Change From Baseline in the PAC-SYM Stool-symptoms Domain Score | Week 2 | -1.37 units on a scale | Standard Error 0.045 |
| Placebo | Change From Baseline in the PAC-SYM Stool-symptoms Domain Score | Week 52 | -1.08 units on a scale | Standard Error 0.051 |
| Placebo | Change From Baseline in the PAC-SYM Stool-symptoms Domain Score | Week 2 | -0.86 units on a scale | Standard Error 0.045 |
| Placebo | Change From Baseline in the PAC-SYM Stool-symptoms Domain Score | Week 12 | -0.96 units on a scale | Standard Error 0.047 |
| Placebo | Change From Baseline in the PAC-SYM Stool-symptoms Domain Score | Week 24 | -0.97 units on a scale | Standard Error 0.048 |
| Placebo | Change From Baseline in the PAC-SYM Stool-symptoms Domain Score | Week 36 | -0.96 units on a scale | Standard Error 0.05 |
Comparison: Week 2 Analysisp-value: <0.000195% CI: [-0.64, -0.39]Mixed-effects model repeated measures
Comparison: Week 12 Analysisp-value: <0.000195% CI: [-0.51, -0.26]Mixed-effects model repeated measures
Comparison: Week 24 Analysisp-value: <0.000195% CI: [-0.54, -0.27]Mixed-effects model repeated measures
Comparison: Week 36 Analysisp-value: <0.000195% CI: [-0.62, -0.34]Mixed-effects model repeated measures
Comparison: Week 52 Analysisp-value: <0.000195% CI: [-0.52, -0.23]Mixed-effects model repeated measures
Secondary
Change From Baseline in the Patient Assessment of Constipation Quality of Life Overall Score
The Patient Assessment of Constipation Quality of Life Questionnaire (PAC-QOL) consists of 28 questions designed to measure the impact constipation has had on participants' daily life during the past 2 weeks. Each question was evaluated by the participant on a five-point scale ranging from 0 (not at all or none of the time) to 4 (extremely or all of the time), where higher scores represent poorer quality of life. The overall score was calculated as the mean of all 28 item scores. A negative change from baseline value indicates improvement.
Time frame: Baseline and Weeks 2, 12, 24, 36, and 52
Population: Intent-to-treat
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Naldemedine | Change From Baseline in the Patient Assessment of Constipation Quality of Life Overall Score | Week 12 | -1.19 units on a scale | Standard Error 0.036 |
| Naldemedine | Change From Baseline in the Patient Assessment of Constipation Quality of Life Overall Score | Week 36 | -1.22 units on a scale | Standard Error 0.039 |
| Naldemedine | Change From Baseline in the Patient Assessment of Constipation Quality of Life Overall Score | Week 2 | -1.14 units on a scale | Standard Error 0.033 |
| Naldemedine | Change From Baseline in the Patient Assessment of Constipation Quality of Life Overall Score | Week 52 | -1.24 units on a scale | Standard Error 0.039 |
| Naldemedine | Change From Baseline in the Patient Assessment of Constipation Quality of Life Overall Score | Week 24 | -1.19 units on a scale | Standard Error 0.038 |
| Placebo | Change From Baseline in the Patient Assessment of Constipation Quality of Life Overall Score | Week 52 | -0.94 units on a scale | Standard Error 0.04 |
| Placebo | Change From Baseline in the Patient Assessment of Constipation Quality of Life Overall Score | Week 2 | -0.75 units on a scale | Standard Error 0.033 |
| Placebo | Change From Baseline in the Patient Assessment of Constipation Quality of Life Overall Score | Week 12 | -0.83 units on a scale | Standard Error 0.037 |
| Placebo | Change From Baseline in the Patient Assessment of Constipation Quality of Life Overall Score | Week 24 | -0.86 units on a scale | Standard Error 0.038 |
| Placebo | Change From Baseline in the Patient Assessment of Constipation Quality of Life Overall Score | Week 36 | -0.82 units on a scale | Standard Error 0.039 |
Comparison: Week 2 Analysisp-value: <0.000195% CI: [-0.49, -0.3]Mixed-effects model repeated measures
Comparison: Week 12 Analysisp-value: <0.000195% CI: [-0.46, -0.26]Mixed-effects model repeated measures
Comparison: Week 24 Analysisp-value: <0.000195% CI: [-0.43, -0.22]Mixed-effects model repeated measures
Comparison: Week 36 Analysisp-value: <0.000195% CI: [-0.5, -0.29]Mixed-effects model repeated measures
Comparison: Week 52 Analysisp-value: <0.000195% CI: [-0.42, -0.2]Mixed-effects model repeated measures
Secondary
Change From Baseline in the Physical Discomfort Domain of PAC-QOL
The Patient Assessment of Constipation Quality of Life Questionnaire (PAC-QOL) consists of 28 questions designed to measure the impact constipation has had on participants' daily life during the past 2 weeks. Each question was evaluated by the participant on a five-point scale ranging from 0 (not at all or none of the time) to 4 (extremely or all of the time), where higher scores represent poorer quality of life. The physical discomfort domain consists of 4 questions related to bloating, feeling heavy, how much of the time participants felt any physical discomfort and how much time they felt the need to open their bowel but were not able to. The physical discomfort score was calculated as the mean of the 4 individual scores. A negative change from baseline value indicates improvement.
Time frame: Baseline and Weeks 2, 12, 24, 36, and 52
Population: Intent-to-treat population
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Naldemedine | Change From Baseline in the Physical Discomfort Domain of PAC-QOL | Week 52 | -1.38 units on a scale | Standard Error 0.047 |
| Naldemedine | Change From Baseline in the Physical Discomfort Domain of PAC-QOL | Week 2 | -1.33 units on a scale | Standard Error 0.04 |
| Naldemedine | Change From Baseline in the Physical Discomfort Domain of PAC-QOL | Week 12 | -1.27 units on a scale | Standard Error 0.044 |
| Naldemedine | Change From Baseline in the Physical Discomfort Domain of PAC-QOL | Week 24 | -1.26 units on a scale | Standard Error 0.046 |
| Naldemedine | Change From Baseline in the Physical Discomfort Domain of PAC-QOL | Week 36 | -1.28 units on a scale | Standard Error 0.048 |
| Placebo | Change From Baseline in the Physical Discomfort Domain of PAC-QOL | Week 36 | -0.94 units on a scale | Standard Error 0.048 |
| Placebo | Change From Baseline in the Physical Discomfort Domain of PAC-QOL | Week 24 | -0.98 units on a scale | Standard Error 0.046 |
| Placebo | Change From Baseline in the Physical Discomfort Domain of PAC-QOL | Week 2 | -0.94 units on a scale | Standard Error 0.04 |
| Placebo | Change From Baseline in the Physical Discomfort Domain of PAC-QOL | Week 52 | -1.09 units on a scale | Standard Error 0.047 |
| Placebo | Change From Baseline in the Physical Discomfort Domain of PAC-QOL | Week 12 | -0.95 units on a scale | Standard Error 0.045 |
Comparison: Week 2 Analysisp-value: <0.000195% CI: [-0.5, -0.28]Mixed-effects model repeated measures
Comparison: Week 12 Anaysisp-value: <0.000195% CI: [-0.44, -0.2]Mixed-effects model repeated measures
Comparison: Week 24 Analysisp-value: <0.000195% CI: [-0.4, -0.15]Mixed-effects model repeated measures
Comparison: Week 36 Analysisp-value: <0.000195% CI: [-0.48, -0.21]Mixed-effects model repeated measures
Comparison: Week 52 Analysisp-value: <0.000195% CI: [-0.41, -0.15]Mixed-effects model repeated measures
Secondary
Change From Baseline in the Psychosocial Discomfort Domain of PAC-QOL
The Patient Assessment of Constipation Quality of Life Questionnaire (PAC-QOL) consists of 28 questions designed to measure the impact constipation has had on participants' daily life during the past 2 weeks. Each question was evaluated by the participant on a five-point scale ranging from 0 (not at all or none of the time) to 4 (extremely or all of the time), where higher scores represent poorer quality of life. The psychosocial discomfort domain consists of 8 questions related to participants' embarrassment regarding their constipation and effects of constipation on eating habits and appetite. The psychosocial discomfort score was calculated as the mean of the 8 individual scores. A negative change from baseline value indicates improvement.
Time frame: Baseline and Weeks 2, 12, 24, 36, and 52
Population: Intent-to-treat population
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Naldemedine | Change From Baseline in the Psychosocial Discomfort Domain of PAC-QOL | Week 12 | -0.96 units on a scale | Standard Error 0.039 |
| Naldemedine | Change From Baseline in the Psychosocial Discomfort Domain of PAC-QOL | Week 36 | -0.99 units on a scale | Standard Error 0.042 |
| Naldemedine | Change From Baseline in the Psychosocial Discomfort Domain of PAC-QOL | Week 24 | -0.97 units on a scale | Standard Error 0.04 |
| Naldemedine | Change From Baseline in the Psychosocial Discomfort Domain of PAC-QOL | Week 52 | -1.00 units on a scale | Standard Error 0.043 |
| Naldemedine | Change From Baseline in the Psychosocial Discomfort Domain of PAC-QOL | Week 2 | -0.92 units on a scale | Standard Error 0.036 |
| Placebo | Change From Baseline in the Psychosocial Discomfort Domain of PAC-QOL | Week 52 | -0.80 units on a scale | Standard Error 0.043 |
| Placebo | Change From Baseline in the Psychosocial Discomfort Domain of PAC-QOL | Week 2 | -0.69 units on a scale | Standard Error 0.036 |
| Placebo | Change From Baseline in the Psychosocial Discomfort Domain of PAC-QOL | Week 12 | -0.72 units on a scale | Standard Error 0.039 |
| Placebo | Change From Baseline in the Psychosocial Discomfort Domain of PAC-QOL | Week 24 | -0.72 units on a scale | Standard Error 0.04 |
| Placebo | Change From Baseline in the Psychosocial Discomfort Domain of PAC-QOL | Week 36 | -0.68 units on a scale | Standard Error 0.042 |
Comparison: Week 2 Analysisp-value: <0.000195% CI: [-0.34, -0.14]Mixed-effects model repeated measures
Comparison: Week 12 Analysisp-value: <0.000195% CI: [-0.35, -0.14]Mixed-effects model repeated measures
Comparison: Week 24 Analysisp-value: <0.000195% CI: [-0.36, -0.14]Mixed-effects model repeated measures
Comparison: Week 36 Analysisp-value: <0.000195% CI: [-0.43, -0.19]Mixed-effects model repeated measures
Comparison: Week 52 Analysisp-value: 0.000695% CI: [-0.33, -0.09]Mixed-effects model repeated measures
Secondary
Change From Baseline in the Satisfaction Domain of PAC-QOL
The Patient Assessment of Constipation Quality of Life Questionnaire (PAC-QOL) consists of 28 questions designed to measure the impact constipation has had on participants' daily life during the past 2 weeks. Each question was evaluated by the participant on a five-point scale ranging from 0 (not at all or none of the time) to 4 (extremely or all of the time), where higher scores represent poorer quality of life. The satisfaction domain consists of 5 questions related to participants' feelings of satisfaction with their bowel function. The satisfaction domain score was calculated as the mean of the 5 individual scores. A negative change from baseline value indicates improvement.
Time frame: Baseline and Weeks 2, 12, 24, 36, and 52
Population: Intent-to-treat population
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Naldemedine | Change From Baseline in the Satisfaction Domain of PAC-QOL | Week 52 | -1.54 units on a scale | Standard Error 0.059 |
| Naldemedine | Change From Baseline in the Satisfaction Domain of PAC-QOL | Week 2 | -1.37 units on a scale | Standard Error 0.05 |
| Naldemedine | Change From Baseline in the Satisfaction Domain of PAC-QOL | Week 12 | -1.45 units on a scale | Standard Error 0.053 |
| Naldemedine | Change From Baseline in the Satisfaction Domain of PAC-QOL | Week 24 | -1.50 units on a scale | Standard Error 0.054 |
| Naldemedine | Change From Baseline in the Satisfaction Domain of PAC-QOL | Week 36 | -1.53 units on a scale | Standard Error 0.056 |
| Placebo | Change From Baseline in the Satisfaction Domain of PAC-QOL | Week 36 | -1.00 units on a scale | Standard Error 0.056 |
| Placebo | Change From Baseline in the Satisfaction Domain of PAC-QOL | Week 24 | -0.99 units on a scale | Standard Error 0.054 |
| Placebo | Change From Baseline in the Satisfaction Domain of PAC-QOL | Week 2 | -0.70 units on a scale | Standard Error 0.05 |
| Placebo | Change From Baseline in the Satisfaction Domain of PAC-QOL | Week 52 | -1.07 units on a scale | Standard Error 0.059 |
| Placebo | Change From Baseline in the Satisfaction Domain of PAC-QOL | Week 12 | -0.87 units on a scale | Standard Error 0.053 |
Comparison: Week 2 Analysisp-value: <0.000195% CI: [-0.81, -0.53]Mixed-effects model repeated measures
Comparison: Week 12 Analysisp-value: <0.000195% CI: [-0.73, -0.43]Mixed-effects model repeated measures
Comparison: Week 24 Analysisp-value: <0.000195% CI: [-0.66, -0.36]Mixed-effects model repeated measures
Comparison: Week 36 Analysisp-value: <0.000195% CI: [-0.69, -0.38]Mixed-effects model repeated measures
Comparison: Week 52 Analysisp-value: <0.000195% CI: [-0.64, -0.32]Mixed-effects model repeated measures
Secondary
Change From Baseline in the Worries and Concerns Domain of PAC-QOL
The Patient Assessment of Constipation Quality of Life Questionnaire (PAC-QOL) consists of 28 questions designed to measure the impact constipation has had on participants' daily life during the past 2 weeks. Each question was evaluated by the participant on a five-point scale ranging from 0 (not at all or none of the time) to 4 (extremely or all of the time), where higher scores represent poorer quality of life. The worries and concerns domain consists of 11 questions related to participants' feelings and concerns about their constipation. The worries and concerns domain score was calculated as the mean of the 11 individual scores. A negative change from baseline value indicates improvement.
Time frame: Baseline and Weeks 2, 12, 24, 36, and 52
Population: Intent-to-treat population
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Naldemedine | Change From Baseline in the Worries and Concerns Domain of PAC-QOL | Week 12 | -1.21 units on a scale | Standard Error 0.042 |
| Naldemedine | Change From Baseline in the Worries and Concerns Domain of PAC-QOL | Week 36 | -1.23 units on a scale | Standard Error 0.044 |
| Naldemedine | Change From Baseline in the Worries and Concerns Domain of PAC-QOL | Week 2 | -1.14 units on a scale | Standard Error 0.038 |
| Naldemedine | Change From Baseline in the Worries and Concerns Domain of PAC-QOL | Week 52 | -1.24 units on a scale | Standard Error 0.045 |
| Naldemedine | Change From Baseline in the Worries and Concerns Domain of PAC-QOL | Week 24 | -1.19 units on a scale | Standard Error 0.043 |
| Placebo | Change From Baseline in the Worries and Concerns Domain of PAC-QOL | Week 52 | -0.92 units on a scale | Standard Error 0.045 |
| Placebo | Change From Baseline in the Worries and Concerns Domain of PAC-QOL | Week 24 | -0.87 units on a scale | Standard Error 0.043 |
| Placebo | Change From Baseline in the Worries and Concerns Domain of PAC-QOL | Week 2 | -0.74 units on a scale | Standard Error 0.038 |
| Placebo | Change From Baseline in the Worries and Concerns Domain of PAC-QOL | Week 36 | -0.81 units on a scale | Standard Error 0.044 |
| Placebo | Change From Baseline in the Worries and Concerns Domain of PAC-QOL | Week 12 | -0.85 units on a scale | Standard Error 0.042 |
Comparison: Week 2 Analysisp-value: <0.000195% CI: [-0.5, -0.29]Mixed-effects model repeated measures
Comparison: Week 12 Analysisp-value: <0.000195% CI: [-0.48, -0.24]Mixed-effects model repeated measures
Comparison: Week 24 Analysisp-value: <0.000195% CI: [-0.45, -0.21]Mixed-effects model repeated measures
Comparison: Week 36 Analysisp-value: <0.000195% CI: [-0.54, -0.3]Mixed-effects model repeated measures
Comparison: Week 52 Analysisp-value: <0.000195% CI: [-0.44, -0.19]Mixed-effects model repeated measures
Secondary
Participant Global Satisfaction
Participants were asked to rate their degree of satisfaction of constipation and abdominal symptoms from the start of study drug dosing to Week 52 (or early termination). Satisfaction was rated based on the following seven grades: * Grade 1 = markedly worsened * Grade 2 = moderately worsened * Grade 3 = slightly worsened * Grade 4 = unchanged * Grade 5 = slightly improved * Grade 6 = moderately improved * Grade 7 = markedly improved
Time frame: Week 52 or early termination visit
Population: Intent-to-treat population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Naldemedine | Participant Global Satisfaction | Moderately worsened | 0.6 percentage of participants |
| Naldemedine | Participant Global Satisfaction | Unchanged | 14.9 percentage of participants |
| Naldemedine | Participant Global Satisfaction | Markedly improved | 35.0 percentage of participants |
| Naldemedine | Participant Global Satisfaction | Slightly improved | 20.1 percentage of participants |
| Naldemedine | Participant Global Satisfaction | Slightly worsened | 1.0 percentage of participants |
| Naldemedine | Participant Global Satisfaction | Moderately improved | 26.0 percentage of participants |
| Naldemedine | Participant Global Satisfaction | Markedly worsened | 2.4 percentage of participants |
| Placebo | Participant Global Satisfaction | Markedly improved | 18.8 percentage of participants |
| Placebo | Participant Global Satisfaction | Moderately improved | 17.7 percentage of participants |
| Placebo | Participant Global Satisfaction | Markedly worsened | 2.0 percentage of participants |
| Placebo | Participant Global Satisfaction | Moderately worsened | 2.8 percentage of participants |
| Placebo | Participant Global Satisfaction | Slightly worsened | 2.2 percentage of participants |
| Placebo | Participant Global Satisfaction | Unchanged | 33.5 percentage of participants |
| Placebo | Participant Global Satisfaction | Slightly improved | 23.0 percentage of participants |
p-value: <0.0001Wilcoxon (Mann-Whitney)
Secondary
Percentage of Participants Meeting Each Criterion of Laxative Use
Participants who were taking stable routine/regular laxatives at Screening were to continue taking the same regimen throughout the study. The percentage of participants meeting each of the criteria below are reported: 1\. Participants not on stable laxatives, defined as participants who did not use laxatives from 28 days prior to the Screening Period to the final dose of study drug or who received only rescue laxative. Rescue is defined as any laxative taken for the first time during the Treatment Period. 1a. Out of participants who were not on stable laxatives, participants who received rescue laxatives. 2\. Participants on stable laxatives, defined as participants who may have had at least one/any stable laxative use reported from 28 days prior to Screening Period to the final dose of study drug. 2a. Out of participants who were on stable laxatives, participants who received rescue laxatives. 3\. Participants who did not meet criteria 1 or 2.
Time frame: From 28 days prior to screening until the end of the treatment period (total of 56 weeks)
Population: Intent-to-treat population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Naldemedine | Percentage of Participants Meeting Each Criterion of Laxative Use | 2. Participants on stable laxatives | 50.2 percentage of participants |
| Naldemedine | Percentage of Participants Meeting Each Criterion of Laxative Use | 2a. Who received rescue laxative | 8.0 percentage of participants |
| Naldemedine | Percentage of Participants Meeting Each Criterion of Laxative Use | 1a. Who received rescue laxative | 7.0 percentage of participants |
| Naldemedine | Percentage of Participants Meeting Each Criterion of Laxative Use | 3. Other participants | 19.8 percentage of participants |
| Naldemedine | Percentage of Participants Meeting Each Criterion of Laxative Use | 1. Participants not on stable laxatives | 30.0 percentage of participants |
| Placebo | Percentage of Participants Meeting Each Criterion of Laxative Use | 3. Other participants | 16.5 percentage of participants |
| Placebo | Percentage of Participants Meeting Each Criterion of Laxative Use | 1. Participants not on stable laxatives | 29.5 percentage of participants |
| Placebo | Percentage of Participants Meeting Each Criterion of Laxative Use | 1a. Who received rescue laxative | 13.1 percentage of participants |
| Placebo | Percentage of Participants Meeting Each Criterion of Laxative Use | 2a. Who received rescue laxative | 14.0 percentage of participants |
| Placebo | Percentage of Participants Meeting Each Criterion of Laxative Use | 2. Participants on stable laxatives | 54.0 percentage of participants |