The purpose of this study is to determine efficacy and safety of naldemedine for the treatment of opioid-induced constipation in adults with non-malignant chronic pain receiving opioid therapy for ≥ 3 months.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
244
Matching placebo tablets administered orally once a day.
Naldemedine tablets administered orally once a day.
Change From Baseline to Last 2 Weeks of the Treatment Period in the Number of Spontaneous Bowel Movements Per Week
Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation. A spontaneous bowel movement was defined as a bowel movement unassisted by rescue medication (laxative or enema) taken within the 24 hours preceding the bowel movement. Baseline was defined as the average number of SBMs per week during the 2 weeks prior to randomization. The number of SBMs per week in the last 2 weeks of treatment is defined as the average number of SBMs per week recorded in the diary for the 14 days prior to the last dose of study drug.
Time frame: Baseline (2 weeks prior to randomization) and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)
Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Spontaneous Bowel Movements Per Week
Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation. A spontaneous bowel movement was defined as a bowel movement unassisted by rescue medication (laxative or enema) taken within the 24 hours preceding the bowel movement. Baseline was defined as the average number of SBMs per day during the 2 weeks prior to randomization.
Time frame: Baseline and Weeks 1, 2, 3, and 4
Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Bowel Movements (BMs) Per Week
Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation. A BM was defined as all bowel movements observed irrespective of the use of a laxative agent.
Time frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)
Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Bowel Movements Per Week
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Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation. A BM was defined as all bowel movements observed irrespective of the use of a laxative agent.
Time frame: Baseline and Weeks 1, 2, 3, and 4
Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Complete Bowel Movements (CBMs) Per Week
Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation. A complete BM (CBM) was defined as a BM where the participant answered 'Yes' to the following question: 'Did you have a feeling of complete emptying after the bowel movement?'
Time frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)
Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Complete Bowel Movements Per Week
Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation. A complete BM (CBM) was defined as a BM where the participant answered 'Yes' to the following question: 'Did you have a feeling of complete emptying after the bowel movement?'
Time frame: Baseline and Weeks 1, 2, 3, and 4
Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Complete Spontaneous Bowel Movements (CSBMs) Per Week
Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation. A CSBM was defined as a spontaneous BM which was accompanied by the feeling of complete evacuation.
Time frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)
Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Complete Spontaneous Bowel Movements Per Week
Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation. A CSBM was defined as a spontaneous BM which was accompanied by the feeling of complete evacuation.
Time frame: Baseline and Weeks 1, 2, 3, and 4
Percentage of Participants With an SBM Response in the Last 2 Weeks of the Treatment Period
Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation. An SBM responder was defined as a participant whose frequency of SBMs within the last 2 weeks of the treatment period was 3 times or more per week and who had an average increase in the frequency of SBMs from baseline of 1 or more per week.
Time frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)
Percentage of Participants With an SBM Response at Weeks 1, 2, 3 and 4
Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation. An SBM responder was defined as any participant whose frequency of SBM per week during the treatment period was 3 times or more per week, and who had an average increase from baseline of 1 or more per week.
Time frame: Baseline and Weeks 1, 2, 3, and 4
Percentage of Participants With a CSBM Response in the Last 2 Weeks of the Treatment Period
Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation. A CSBM responder was defined as a participant whose frequency of CSBMs within the last 2 weeks of the treatment period was 3 times or more per week and who had an average increase in the frequency of CSBMs from baseline of 1 or more per week.
Time frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)
Percentage of Participants With a CSBM Response at Weeks 1, 2, 3, and 4
Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation. A CSBM responder was defined as a participant whose frequency of CSBMs during the treatment period was 3 times or more per week and who had an average increase in the frequency of CSBMs from baseline of 1 or more per week.
Time frame: Baseline and Weeks 1, 2, 3, and 4
Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of Days Per Week With SBMs
Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation. An SBM is defined as a bowel movement unassisted by rescue medication (laxative or enema) taken within the 24 hours preceding the bowel movement.
Time frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)
Change From Baseline to Weeks 1, 2, 3 and 4 in Number of Days Per Week With SBMs
Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation. An SBM is defined as a bowel movement unassisted by rescue medication (laxative or enema) taken within the 24 hours preceding the bowel movement.
Time frame: Baseline and Weeks 1, 2, 3, and 4
Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of Days Per Week With CSBMs
Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation. A CSBM was defined as a spontaneous BM which was accompanied by the feeling of complete evacuation.
Time frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)
Change From Baseline to Weeks 1, 2, 3 and 4 in Number of Days Per Week With CSBMs
Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation. A CSBM was defined as a spontaneous BM which was accompanied by the feeling of complete evacuation.
Time frame: Baseline and Weeks 1, 2, 3, and 4
Time to the First Spontaneous Bowel Movement
Time to the first SBM was defined as the time to the first SBM after the initial administration of study drug. Participants who withdrew from the study before an SBM was observed or had no SBM during the treatment period were treated as censored.
Time frame: 28 days
Time to the First Complete Spontaneous Bowel Movement
Time to the first CSBM was defined as the time to the first CSBM after the initial administration of study drug. Participants who withdrew from the study before a CSBM was observed or had no CSBM during the treatment period were treated as censored.
Time frame: 28 days
Percentage of Participants With SBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug
The percentage of participants who experienced at least one SBM within 4, 8, 12, and 24 hours after the initial administration of study drug and before the second administration.
Time frame: 4, 8, 12, and 24 hours
Percentage of Participants With CSBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug
The percentage of participants who experienced at least one CSBM within 4, 8, 12, and 24 hours after the initial administration of study drug and before the second administration.
Time frame: 4, 8, 12, and 24 hours
Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of SBMs Per Week Rated as 3 or 4 on the Bristol Stool Scale
Consistency of BMs was measured using the Bristol Stool Scale, according to the following: 1 = separate hard lumps like nuts; 2 = sausage shaped but lumpy; 3 = like a sausage, but with cracks on its surface; 4 = like a sausage or a snake, smooth and soft; 5 = soft blobs and with clear-cut edges; 6 = floppy pieces with ragged edges/mushy stool; 7 = watery, no solid pieces, entirely liquid.
Time frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)
Change From Baseline to Weeks 1, 2, 3, and 4 in Number of SBMs Rated as 3 or 4 on the Bristol Stool Scale Per Week
Consistency of BMs was measured using the Bristol Stool Scale, according to the following: 1 = separate hard lumps like nuts; 2 = sausage shaped but lumpy; 3 = like a sausage, but with cracks on its surface; 4 = like a sausage or a snake, smooth and soft; 5 = soft blobs and with clear-cut edges; 6 = floppy pieces with ragged edges/mushy stool; 7 = watery, no solid pieces, entirely liquid.
Time frame: Baseline and Weeks 1, 2, 3, and 4
Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of SBMs Per Week With no Straining
Straining during BMs was graded using the following scale: 0 = No straining; 1 = Mild straining; 2 = Moderate; 3 = Severe; 4 = Very Severe. A BM without straining was defined as a BM with a straining score of 0 or 1.
Time frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)
Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of SBMs Per Week Without Straining
Straining during BMs was graded using the following scale: 0 = No straining; 1 = Mild straining; 2 = Moderate; 3 = Severe; 4 = Very Severe. A BM without straining is defined as a BM with a straining score of 0 or 1.
Time frame: Baseline and Weeks 1, 2, 3, and 4
Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of False Start BMs Per Week
Participants completed a daily Bowel Movement and Constipation Assessment Diary to record information about bowel movements and constipation. A false start was defined as any attempted, but unsuccessful bowel movement (no solid or liquid fecal material was excreted).
Time frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)
Change From Baseline to the Last 2 Weeks of the Treatment Period in Rescue Use of Laxative Agents Per Week
Participants were asked how many doses of rescue laxative medication they had taken within the past 24 hours as part of the Bowel Movement and Constipation Assessment Diary (BMCA).
Time frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)
Mean Rescue Laxative Use Per Week During the Treatment Period
Participants were asked how many doses of rescue laxative medication they had taken within the past 24 hours as part of the Bowel Movement and Constipation Assessment Diary (BMCA).
Time frame: Weeks 1 to 4
Change From Baseline to the Last 2 Weeks of the Treatment Period in Abdominal Bloating
Participants were asked to rate their abdominal bloating for the past 24 hours on a scale of 0 to 4, where 0 = Absent; 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Very Severe.
Time frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)
Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Bloating
Participants were asked to rate their abdominal bloating for the past 24 hours on a scale of 0 to 4, where 0 = Absent; 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Very Severe.
Time frame: Baseline and Weeks 1, 2, 3, and 4
Change From Baseline to the Last 2 Weeks of the Treatment Period in Abdominal Discomfort
Participants were asked to rate their abdominal discomfort for the past 24 hours on a scale from 0 to 4, where 0 = Absent; 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Very Severe.
Time frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period)
Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Discomfort
Participants were asked to rate their abdominal discomfort for the past 24 hours on a scale from 0 to 4, where 0 = Absent; 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Very Severe.
Time frame: Baseline and Weeks 1, 2, 3, and 4
Subject Global Satisfaction at End of Treatment
On day 29 (or at early termination), participants were asked about their degree of satisfaction with constipation and abdominal symptoms from the start of study drug dosing to Day 28 (or early termination visit). The grades were as follows: 1, markedly worsened; 2, moderately worsened; 3, slightly worsened; 4, unchanged; 5, slightly improved; 6, moderately improved; and 7, markedly improved.
Time frame: Day 29, or at early termination
Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995
Pharmacokinetic blood samples for naldemedine (S-297995) and its metabolite, Nor-S-297995, were collected from a subset of participants at selected study sites on Day 1 and in a further subset on Day 28.
Time frame: Day 1 and Day 28 predose and 1, 2, 4, 8, and 24 hours postdose
Time to Maximum Concentration (Tmax) of Naldemedine and Metabolite Nor-S-297995
Pharmacokinetic blood samples for naldemedine (S-297995) and its metabolite, Nor-S-297995, were collected from a subset of participants at selected study sites on Day 1 and in a further subset on Day 28.
Time frame: Day 1 and Day 28 predose and 1, 2 , 4, 8, and 24 hours postdose
Area Under the Concentration-time Curve From Hour 0 to the Time Point of the Last Measurable Concentration Within the Dose Interval (AUC0-τ)
Pharmacokinetic blood samples for naldemedine (S-297995) and its metabolite, Nor-S-297995, were collected from a subset of participants at selected study sites on Day 1 and in a further subset on Day 28.
Time frame: Day 1 and Day 28 predose and 1, 2 , 4, 8, and 24 hours postdose
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Treatment-emergent adverse events (TEAEs) were adverse events that occurred after the first dose of study drug. Treatment-related TEAEs were defined as TEAEs that were considered by the Investigator to be definitely, probably, or possibly related to study drug.
Time frame: From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days).