Long Term Safety of Naldemedine

Opioid-induced Constipation Clinical Trial

Official title:

A Randomized Double-blind, Placebo-controlled, Parallel-group, Multicenter, Phase 3 Study to Evaluate the Long-term Safety of Naldemedine for the Treatment of Opioid-induced Constipation in Subjects With Non-malignant Chronic Pain Receiving Opioid Therapy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01965652
• Other study ID #: 1326V9235
• Status: Completed
• Phase: Phase 3
• First received: October 15, 2013
• Last updated: April 16, 2018
• Start date: September 24, 2013
• Est. completion date: January 12, 2016

Study information

• Verified date: April 2018
• Source: Shionogi Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate the long-term safety of naldemedine for the treatment of constipation due to opioid therapy.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1246
• Est. completion date: January 12, 2016
• Est. primary completion date: January 12, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Constipation
• Opioid-induced Constipation

Intervention

Drug:
• Naldemedine
Naldemedine 0.2 mg tablet taken orally once a day
• Placebo
Placebo tablet taken orally once a day

Locations

Country	Name	City	State
Australia	Shionogi Research Site	Adelaide
Australia	Shionogi Research Site	Bedford Park
Australia	Shionogi Research Site	Camperdown
Australia	Shionogi Research Site	Carina Heights
Australia	Shionogi Research Site	Caulfield South
Australia	Shionogi Research Site	Malvern East
Australia	Shionogi Research Site	Nambour
Australia	Shionogi Research Site	Sherwood
Australia	Shionogi Research Site	St Leonards
Austria	Shionogi Research Site	Linz
Austria	Shionogi Research Site	Vienna
Austria	Shionogi Research Site	Zams
Canada	Shionogi Research Site	London
Canada	Shionogi Research Site	Mirabel
Canada	Shionogi Research Site	Sarnia
Canada	Shionogi Research Site	Sherbrooke
Canada	Shionogi Research Site	Toronto
Canada	Shionogi Research Site	Vancouver
Czechia	Shionogi Research Site	Benesov
Czechia	Shionogi Research Site	Olomouc
Czechia	Shionogi Research Site	Ostrava
Czechia	Shionogi Research Site	Pardubice
Czechia	Shionogi Research Site	Pribram V- Zdabor
Denmark	Shionogi Research Site	Glostrup
Denmark	Shionogi Research Site	Hellerup
Denmark	Shionogi Research Site	Odense
France	Shionogi Research Site	Soulaine Sur Aubance
Germany	Shionogi Research Site	Berlin
Germany	Shionogi Research Site	Dresden
Germany	Shionogi Research Site	Halle
Germany	Shionogi Research Site	Hamburg
Germany	Shionogi Research Site	Hannover
Germany	Shionogi Research Site	Kassel
Germany	Shionogi Research Site	Leipzig
Germany	Shionogi Research Site	Luenen
Germany	Shionogi Research Site	Mainz
Germany	Shionogi Research Site	Muenster
Germany	Shionogi Research Site	Stadtroda
Hungary	Shionogi Research Site	Balatonfuered
Hungary	Shionogi Research Site	Budapest
Hungary	Shionogi Research Site	Debrecen
Hungary	Shionogi Research Site	Hatvan
Hungary	Shionogi Research Site	Szikszo
Israel	Shionogi Research Site	Beer Sheva
Israel	Shionogi Research Site	Haifa
Israel	Shionogi Research Site	Tel Aviv
Israel	Shionogi Research Site	Tel Hashomer
Italy	Shionogi Research Site	Asti
Italy	Shionogi Research Site	Catania
Italy	Shionogi Research Site	Chieti
Italy	Shionogi Research Site	Firenze
Italy	Shionogi Research Site	Napoli
Italy	Shionogi Research Site	Rionero in Vulture
Italy	Shionogi Research Site	Roma
Italy	Shionogi Research Site	Rome
Poland	Shionogi Research Site	Chorzów
Poland	Shionogi Research Site	Gdansk
Poland	Shionogi Research Site	Katowice
Poland	Shionogi Research Site	Lublin
South Africa	Shionogi Research Site	Alberton
South Africa	Shionogi Research Site	Lyttelton Centurion
South Africa	Shionogi Research Site	Muckleneuk Pretoria
South Africa	Shionogi Research Site	Pretoria West Pretoria
South Africa	Shionogi Research Site	Worcester
Spain	Shionogi Research Site	Barcelona
Spain	Shionogi Research Site	Girona
Spain	Shionogi Research Site	Sevilla
Sweden	Shionogi Research Site	Skene
Sweden	Shionogi Research Site	Stockholm
United Kingdom	Shionogi Research Site	Bath
United Kingdom	Shionogi Research Site	Belfast
United Kingdom	Shionogi Research Site	Bexhill On Sea East Sussex
United Kingdom	Shionogi Research Site	Chesterfield
United Kingdom	Shionogi Research Site	Chestfield Kent
United Kingdom	Shionogi Research Site	Daventry Northants
United Kingdom	Shionogi Research Site	Devon
United Kingdom	Shionogi Research Site	Epworth Doncaster
United Kingdom	Shionogi Research Site	Harrogate
United Kingdom	Shionogi Research Site	Hinckley
United Kingdom	Shionogi Research Site	Liverpool
United Kingdom	Shionogi Research Site	Norwich
United Kingdom	Shionogi Research Site	Oldham
United Kingdom	Shionogi Research Site	Peterborough
United Kingdom	Shionogi Research Site	Randalstown, County Antrim
United Kingdom	Shionogi Research Site	Spiro Close, Pulborough West Sussex
United Kingdom	Shionogi Research Site	Wellingborough Northamptonshire
United Kingdom	Shionogi Research Site	York
United States	Shionogi Research Site	Akron	Ohio
United States	Shionogi Research Site	Albuquerque	New Mexico
United States	Shionogi Research Site	Atlanta	Georgia
United States	Shionogi Research Site	Augusta	Kansas
United States	Shionogi Research Site	Aurora	Illinois
United States	Shionogi Research Site	Austin	Texas
United States	Shionogi Research Site	Bellevue	Washington
United States	Shionogi Research Site	Biloxi	Mississippi
United States	Shionogi Research Site	Birmingham	Alabama
United States	Shionogi Research Site	Bloomington	Illinois
United States	Shionogi Research Site	Blue Ridge	Georgia
United States	Shionogi Research Site	Boise	Idaho
United States	Shionogi Research Site	Bountiful	Utah
United States	Shionogi Research Site	Boynton Beach	Florida
United States	Shionogi Research Site	Brandon	Florida
United States	Shionogi Research Site	Bristol	Tennessee
United States	Shionogi Research Site	Brockton	Massachusetts
United States	Shionogi Research Site	Brooksville	Florida
United States	Shionogi Research Site	Canton	Ohio
United States	Shionogi Research Site	Chandler	Arizona
United States	Shionogi Research Site	Charleston	South Carolina
United States	Shionogi Research Site	Clearwater	Florida
United States	Shionogi Research Site	Colorado Springs	Colorado
United States	Shionogi Research Site	Columbus	Ohio
United States	Shionogi Research Site	Dallas	Texas
United States	Shionogi Research Site	Decatur	Illinois
United States	Shionogi Research Site	Decatur	Georgia
United States	Shionogi Research Site	Edmonds	Washington
United States	Shionogi Research Site	Eunice	Louisiana
United States	Shionogi Research Site	Evansville	Indiana
United States	Shionogi Research Site	Fall River	Massachusetts
United States	Shionogi Research Site	Fort Myers	Florida
United States	Shionogi Research Site	Fountain Valley	California
United States	Shionogi Research Site	Fremont	Nebraska
United States	Shionogi Research Site	Garden Grove	California
United States	Shionogi Research Site	Glendale	California
United States	Shionogi Research Site	Glendale	Arizona
United States	Shionogi Research Site	Goodyear	Arizona
United States	Shionogi Research Site	Greensboro	North Carolina
United States	Shionogi Research Site	Greer	South Carolina
United States	Shionogi Research Site	Groveport	Ohio
United States	Shionogi Research Site	Hartford	Kentucky
United States	Shionogi Research Site	Henderson	Nevada
United States	Shionogi Research Site	Houston	Texas
United States	Shionogi Research Site	Huntingdon Valley	Pennsylvania
United States	Shionogi Research Site	Hurst	Texas
United States	Shionogi Research Site	Jacksonville	Florida
United States	Shionogi Research Site	Jenkintown	Pennsylvania
United States	Shionogi Research Site	Kettering	Ohio
United States	Shionogi Research Site	Lafayette	Indiana
United States	Shionogi Research Site	Lake Charles	Louisiana
United States	Shionogi Research Site	Lake City	Florida
United States	Shionogi Research Site	Lakeland	Florida
United States	Shionogi Research Site	Lansdale	Pennsylvania
United States	Shionogi Research Site	Las Vegas	Nevada
United States	Shionogi Research Site	Lebanon	Ohio
United States	Shionogi Research Site	Long Beach	California
United States	Shionogi Research Site	Los Angeles	California
United States	Shionogi Research Site	Mandeville	Louisiana
United States	Shionogi Research Site	Marion	Ohio
United States	Shionogi Research Site	Mesa	Arizona
United States	Shionogi Research Site	Milan	Tennessee
United States	Shionogi Research Site	Mobile	Alabama
United States	Shionogi Research Site	Munroe Falls	Ohio
United States	Shionogi Research Site	Myrtle Beach	South Carolina
United States	Shionogi Research Site	Nashville	Tennessee
United States	Shionogi Research Site	New Bedford	Massachusetts
United States	Shionogi Research Site	New York	New York
United States	Shionogi Research Site	Newton	Kansas
United States	Shionogi Research Site	Oceanside	California
United States	Shionogi Research Site	Oklahoma City	Oklahoma
United States	Shionogi Research Site	Omaha	Nebraska
United States	Shionogi Research Site	Orlando	Florida
United States	Shionogi Research Site	Phoenix	Arizona
United States	Shionogi Research Site	Portland	Oregon
United States	Shionogi Research Site	Richmond	Virginia
United States	Shionogi Research Site	Rochester	Michigan
United States	Shionogi Research Site	Rockford	Illinois
United States	Shionogi Research Site	Sacramento	California
United States	Shionogi Research Site	Saginaw	Michigan
United States	Shionogi Research Site	Saint Petersburg	Florida
United States	Shionogi Research Site	Salt Lake City	Utah
United States	Shionogi Research Site	Santa Ana	California
United States	Shionogi Research Site	Savannah	Georgia
United States	Shionogi Research Site	Schaumburg	Illinois
United States	Shionogi Research Site	South Miami	Florida
United States	Shionogi Research Site	South Ogden	Utah
United States	Shionogi Research Site	Sugar Land	Texas
United States	Shionogi Research Site	Summerville	South Carolina
United States	Shionogi Research Site	Tampa	Florida
United States	Shionogi Research Site	Traverse City	Michigan
United States	Shionogi Research Site	Trenton	New Jersey
United States	Shionogi Research Site	Tucson	Arizona
United States	Shionogi Research Site	Tulsa	Oklahoma
United States	Shionogi Research Site	Upland	California
United States	Shionogi Research Site	Valparaiso	Indiana
United States	Shionogi Research Site	Wichita	Kansas
United States	Shionogi Research Site	Wilmington	North Carolina
United States	Shionogi Research Site	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Shionogi

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Canada,  Czechia,  Denmark,  France,  Germany,  Hungary,  Israel,  Italy,  Poland,  South Africa,  Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	From the first dose of study drug up to 14 days after the last dose of study drug (54 weeks).
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).	Baseline and Weeks 12, 24, 36, and 52
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.	From 28 days prior to screening until the end of the treatment period (total of 56 weeks)
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.	Baseline and Weeks 2, 12, 24, 36, and 52
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.	Baseline and Weeks 2, 12, 24, 36, and 52
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.	Baseline and Weeks 2, 12, 24, 36, and 52
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.	Baseline and Weeks 2, 12, 24, 36, and 52
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.	Baseline and Weeks 2, 12, 24, 36, and 52
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.	Baseline and Weeks 2, 12, 24, 36, and 52
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.	Baseline and Weeks 2, 12, 24, 36, and 52
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.	Baseline and Weeks 2, 12, 24, 36, and 52
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.	Baseline and Weeks 2, 12, 24, 36, and 52
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	Week 52 or early termination visit