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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Shionogi Inc. ( Shionogi )
ClinicalTrials.gov Identifier:
NCT01443403
First received: September 20, 2011
Last updated: April 19, 2017
Last verified: April 2013
  Purpose
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.

Condition Intervention Phase
Opioid-induced Constipation Drug: Placebo Drug: Naldemedine Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Participant, Care Provider, Investigator, Outcomes Assessor
Primary Purpose: Treatment
Official Title: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study of S-297995 for the Treatment of Opioid-Induced Constipation in Subjects With Non-Malignant Chronic Pain Receiving Opioid Therapy

Resource links provided by NLM:


Further study details as provided by Shionogi Inc. ( Shionogi ):

Primary Outcome Measures:
  • Change From Baseline to Last 2 Weeks of the Treatment Period in the Number of Spontaneous Bowel Movements Per Week [ 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) ]

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

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



Secondary Outcome Measures:
  • Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Spontaneous Bowel Movements Per Week [ Time Frame: Baseline and Weeks 1, 2, 3, and 4 ]

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

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


  • Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Bowel Movements (BMs) Per Week [ Time Frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) ]

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

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


  • Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Bowel Movements Per Week [ Time Frame: Baseline and Weeks 1, 2, 3, and 4 ]

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

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


  • Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Complete Bowel Movements (CBMs) Per Week [ Time Frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) ]

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

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


  • Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Complete Bowel Movements Per Week [ Time Frame: Baseline and Weeks 1, 2, 3, and 4 ]

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

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


  • Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Complete Spontaneous Bowel Movements (CSBMs) Per Week [ Time Frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) ]

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

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


  • Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of Complete Spontaneous Bowel Movements Per Week [ Time Frame: Baseline and Weeks 1, 2, 3, and 4 ]

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

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


  • Percentage of Participants With an SBM Response in the Last 2 Weeks of the Treatment Period [ Time Frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) ]

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

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


  • Percentage of Participants With an SBM Response at Weeks 1, 2, 3 and 4 [ Time Frame: Baseline and Weeks 1, 2, 3, and 4 ]

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

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


  • Percentage of Participants With a CSBM Response in the Last 2 Weeks of the Treatment Period [ Time Frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) ]

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

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


  • Percentage of Participants With a CSBM Response at Weeks 1, 2, 3, and 4 [ Time Frame: Baseline and Weeks 1, 2, 3, and 4 ]

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

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


  • Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of Days Per Week With SBMs [ Time Frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) ]

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

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


  • Change From Baseline to Weeks 1, 2, 3 and 4 in Number of Days Per Week With SBMs [ Time Frame: Baseline and Weeks 1, 2, 3, and 4 ]

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

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


  • Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of Days Per Week With CSBMs [ Time Frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) ]

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

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


  • Change From Baseline to Weeks 1, 2, 3 and 4 in Number of Days Per Week With CSBMs [ Time Frame: Baseline and Weeks 1, 2, 3, and 4 ]

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

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


  • Time to the First Spontaneous Bowel Movement [ Time Frame: 28 days ]
    Time to the first SBM was defined as the time to the first SBM after the initial administration of study drug. Participants who withdrew from the study before an SBM was observed or had no SBM during the treatment period were treated as censored.

  • Time to the First Complete Spontaneous Bowel Movement [ Time Frame: 28 days ]
    Time to the first CSBM was defined as the time to the first CSBM after the initial administration of study drug. Participants who withdrew from the study before a CSBM was observed or had no CSBM during the treatment period were treated as censored.

  • Percentage of Participants With SBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug [ Time Frame: 4, 8, 12, and 24 hours ]
    The percentage of participants who experienced at least one SBM within 4, 8, 12, and 24 hours after the initial administration of study drug and before the second administration.

  • Percentage of Participants With CSBMs Within 4, 8, 12, and 24 Hours After the Initial Administration of Study Drug [ Time Frame: 4, 8, 12, and 24 hours ]
    The percentage of participants who experienced at least one CSBM within 4, 8, 12, and 24 hours after the initial administration of study drug and before the second administration.

  • Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of SBMs Per Week Rated as 3 or 4 on the Bristol Stool Scale [ Time Frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) ]
    Consistency of BMs was measured using the Bristol Stool Scale, according to the following: 1 = separate hard lumps like nuts; 2 = sausage shaped but lumpy; 3 = like a sausage, but with cracks on its surface; 4 = like a sausage or a snake, smooth and soft; 5 = soft blobs and with clear-cut edges; 6 = floppy pieces with ragged edges/mushy stool; 7 = watery, no solid pieces, entirely liquid.

  • Change From Baseline to Weeks 1, 2, 3, and 4 in Number of SBMs Rated as 3 or 4 on the Bristol Stool Scale Per Week [ Time Frame: Baseline and Weeks 1, 2, 3, and 4 ]
    Consistency of BMs was measured using the Bristol Stool Scale, according to the following: 1 = separate hard lumps like nuts; 2 = sausage shaped but lumpy; 3 = like a sausage, but with cracks on its surface; 4 = like a sausage or a snake, smooth and soft; 5 = soft blobs and with clear-cut edges; 6 = floppy pieces with ragged edges/mushy stool; 7 = watery, no solid pieces, entirely liquid.

  • Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of SBMs Per Week With no Straining [ Time Frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) ]
    Straining during BMs was graded using the following scale: 0 = No straining; 1 = Mild straining; 2 = Moderate; 3 = Severe; 4 = Very Severe. A BM without straining was defined as a BM with a straining score of 0 or 1.

  • Change From Baseline to Weeks 1, 2, 3, and 4 in the Number of SBMs Per Week Without Straining [ Time Frame: Baseline and Weeks 1, 2, 3, and 4 ]
    Straining during BMs was graded using the following scale: 0 = No straining; 1 = Mild straining; 2 = Moderate; 3 = Severe; 4 = Very Severe. A BM without straining is defined as a BM with a straining score of 0 or 1.

  • Change From Baseline to the Last 2 Weeks of the Treatment Period in Number of False Start BMs Per Week [ Time Frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) ]

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

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


  • Change From Baseline to the Last 2 Weeks of the Treatment Period in Rescue Use of Laxative Agents Per Week [ Time Frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) ]
    Participants were asked how many doses of rescue laxative medication they had taken within the past 24 hours as part of the Bowel Movement and Constipation Assessment Diary (BMCA).

  • Mean Rescue Laxative Use Per Week During the Treatment Period [ Time Frame: Weeks 1 to 4 ]
    Participants were asked how many doses of rescue laxative medication they had taken within the past 24 hours as part of the Bowel Movement and Constipation Assessment Diary (BMCA).

  • Change From Baseline to the Last 2 Weeks of the Treatment Period in Abdominal Bloating [ Time Frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) ]
    Participants were asked to rate their abdominal bloating for the past 24 hours on a scale of 0 to 4, where 0 = Absent; 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Very Severe.

  • Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Bloating [ Time Frame: Baseline and Weeks 1, 2, 3, and 4 ]
    Participants were asked to rate their abdominal bloating for the past 24 hours on a scale of 0 to 4, where 0 = Absent; 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Very Severe.

  • Change From Baseline to the Last 2 Weeks of the Treatment Period in Abdominal Discomfort [ Time Frame: Baseline and the last 2 weeks of treatment (Weeks 3 to 4 for participants who completed the 28-day treatment period) ]
    Participants were asked to rate their abdominal discomfort for the past 24 hours on a scale from 0 to 4, where 0 = Absent; 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Very Severe.

  • Change From Baseline to Weeks 1, 2, 3, and 4 in Abdominal Discomfort [ Time Frame: Baseline and Weeks 1, 2, 3, and 4 ]
    Participants were asked to rate their abdominal discomfort for the past 24 hours on a scale from 0 to 4, where 0 = Absent; 1 = Mild; 2 = Moderate; 3 = Severe; 4 = Very Severe.

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

  • Maximum Observed Plasma Concentration (Cmax) of Naldemedine and Metabolite Nor-S-297995 [ Time Frame: Day 1 and Day 28 predose and 1, 2, 4, 8, and 24 hours postdose ]
    Pharmacokinetic blood samples for naldemedine (S-297995) and its metabolite, Nor-S-297995, were collected from a subset of participants at selected study sites on Day 1 and in a further subset on Day 28.

  • Time to Maximum Concentration (Tmax) of Naldemedine and Metabolite Nor-S-297995 [ Time Frame: Day 1 and Day 28 predose and 1, 2 , 4, 8, and 24 hours postdose ]
    Pharmacokinetic blood samples for naldemedine (S-297995) and its metabolite, Nor-S-297995, were collected from a subset of participants at selected study sites on Day 1 and in a further subset on Day 28.

  • Area Under the Concentration-time Curve From Hour 0 to the Time Point of the Last Measurable Concentration Within the Dose Interval (AUC0-τ) [ Time Frame: Day 1 and Day 28 predose and 1, 2 , 4, 8, and 24 hours postdose ]
    Pharmacokinetic blood samples for naldemedine (S-297995) and its metabolite, Nor-S-297995, were collected from a subset of participants at selected study sites on Day 1 and in a further subset on Day 28.

  • Number of Participants With Treatment-emergent Adverse Events (TEAEs) [ Time Frame: From first dose of study drug through 28 days after the last dose of study treatment (up to 57 days). ]

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

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



Enrollment: 244
Actual Study Start Date: August 17, 2011
Study Completion Date: August 22, 2012
Primary Completion Date: August 22, 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Placebo
Participants received placebo orally once daily for 28 days.
Drug: Placebo
Matching placebo tablets administered orally once a day.
Experimental: Naldemedine 0.1 mg
Participants received 0.1 mg naldemedine orally once daily for 28 days.
Drug: Naldemedine
Naldemedine tablets administered orally once a day.
Other Names:
  • S 297995
  • Symproic®
Experimental: Naldemedine 0.2 mg
Participants received 0.2 mg naldemedine orally once daily for 28 days.
Drug: Naldemedine
Naldemedine tablets administered orally once a day.
Other Names:
  • S 297995
  • Symproic®
Experimental: Naldemedine 0.4 mg
Participants received 0.4 mg naldemedine orally once daily for 28 days.
Drug: Naldemedine
Naldemedine tablets administered orally once a day.
Other Names:
  • S 297995
  • Symproic®

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subjects aged 18 years or older at time of informed consent with non-malignant chronic pain experiencing opioid-induced constipation
  • Subjects with < 3 spontaneous bowel movements a week and experiencing bowel symptoms
  • Subjects receiving chronic opioid therapy due to non-malignant pain for ≥ 3 months

Exclusion Criteria:

  • Evidence of clinically significant gastrointestinal disease
  • History of chronic constipation prior to starting analgesic medication or any potential non-opioid cause of bowel dysfunction that may be a major contributor to the constipation
  • Severe constipation that has not been appropriately managed such that the subject is at immediate risk of developing serious complications of constipation
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01443403

  Show 49 Study Locations
Sponsors and Collaborators
Shionogi
Investigators
Study Director: Shionogi Clinical Trials Administrator Clinical Support Help Line Shionogi
  More Information

Publications:
Responsible Party: Shionogi
ClinicalTrials.gov Identifier: NCT01443403     History of Changes
Other Study ID Numbers: 1107V9221
Study First Received: September 20, 2011
Results First Received: April 19, 2017
Last Updated: April 19, 2017

Keywords provided by Shionogi Inc. ( Shionogi ):
Opioid Therapy
Non-Malignant Chronic Pain
Opioid-Induced Constipation

Additional relevant MeSH terms:
Chronic Pain
Constipation
Pain
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Signs and Symptoms, Digestive
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents

ClinicalTrials.gov processed this record on June 22, 2017