Trial Outcomes & Findings for Efficacy and Safety of Naldemedine in the Treatment of Opioid-induced Constipation (NCT NCT01965158)
NCT ID: NCT01965158
Last Updated: 2017-05-30
Results Overview
A bowel movement and constipation assessment (BMCA) was completed by participants every day during the screening and treatment periods to record information about bowel movements (BMs) and constipation. An SBM was defined as a bowel movement that occurred without the use of rescue laxative therapy during the 24 hours prior to the BM. A responder was defined as a participant having 9 or more positive response weeks out of the 12-week Treatment Period and 3 positive response weeks out of last 4 weeks of the 12-week Treatment Period. A positive response week was defined as ≥ 3 SBMs per week and an increase from baseline of ≥ 1 SBM per week for that week. If a participant had less than 4 days of diary entries for a week, that week was treated as a "non-response" week. Any participant with insufficient primary endpoint data (data for less than 9 out of 12 weeks of the Treatment Period or less than 3 out of the last 4 weeks of the 12-week Treatment Period) was treated as a non-responder.
Recruitment status
COMPLETED
Study phase
PHASE3
Target enrollment
547 participants
Primary outcome timeframe
12-week treatment period
Results posted on
2017-05-30
Participant Flow
This study was conducted at 68 sites in North America and Europe, including Austria, Czech Republic, Germany, Poland, Spain, United Kingdom, and the United States.
Participants were randomized in a 1:1 ratio to 0.2 mg of naldemedine or placebo. Participants were stratified based on their documented opioid use (average total daily dose (TDD) during the 14-consecutive-day qualifying period) as follows: * 30 to 100 mg equivalents of oral morphine sulfate * \> 100 mg equivalents of oral morphine sulfate
Participant milestones
| Measure |
Naldemedine
Participants received 0.2 mg naldemedine orally once daily for 12 weeks.
|
Placebo
Participants received placebo orally once daily for 12 weeks.
|
|---|---|---|
|
Overall Study
STARTED
|
274
|
273
|
|
Overall Study
Received Treatment
|
272
|
273
|
|
Overall Study
COMPLETED
|
233
|
238
|
|
Overall Study
NOT COMPLETED
|
41
|
35
|
Reasons for withdrawal
| Measure |
Naldemedine
Participants received 0.2 mg naldemedine orally once daily for 12 weeks.
|
Placebo
Participants received placebo orally once daily for 12 weeks.
|
|---|---|---|
|
Overall Study
Adverse Event
|
14
|
5
|
|
Overall Study
Withdrawal by Subject
|
16
|
24
|
|
Overall Study
Lost to Follow-up
|
7
|
5
|
|
Overall Study
Protocol Violation
|
1
|
1
|
|
Overall Study
Other - Miscellaneous
|
3
|
0
|
Baseline Characteristics
Efficacy and Safety of Naldemedine in the Treatment of Opioid-induced Constipation
Baseline characteristics by cohort
| Measure |
Naldemedine
n=273 Participants
Participants received 0.2 mg naldemedine orally once daily for 12 weeks.
|
Placebo
n=272 Participants
Participants received placebo orally once daily for 12 weeks.
|
Total
n=545 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Continuous
|
53.3 years
STANDARD_DEVIATION 10.44 • n=5 Participants
|
53.4 years
STANDARD_DEVIATION 11.03 • n=7 Participants
|
53.4 years
STANDARD_DEVIATION 10.73 • n=5 Participants
|
|
Age, Customized
< 40 years
|
25 participants
n=5 Participants
|
26 participants
n=7 Participants
|
51 participants
n=5 Participants
|
|
Age, Customized
≥ 40 to < 65 years
|
209 participants
n=5 Participants
|
199 participants
n=7 Participants
|
408 participants
n=5 Participants
|
|
Age, Customized
≥ 65 years
|
39 participants
n=5 Participants
|
47 participants
n=7 Participants
|
86 participants
n=5 Participants
|
|
Sex: Female, Male
Female
|
161 Participants
n=5 Participants
|
168 Participants
n=7 Participants
|
329 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
112 Participants
n=5 Participants
|
104 Participants
n=7 Participants
|
216 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Hispanic or Latino
|
26 Participants
n=5 Participants
|
27 Participants
n=7 Participants
|
53 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Not Hispanic or Latino
|
247 Participants
n=5 Participants
|
245 Participants
n=7 Participants
|
492 Participants
n=5 Participants
|
|
Ethnicity (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Race/Ethnicity, Customized
American Indian or Alaska Native
|
1 participants
n=5 Participants
|
1 participants
n=7 Participants
|
2 participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Asian
|
2 participants
n=5 Participants
|
1 participants
n=7 Participants
|
3 participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Black or African American
|
53 participants
n=5 Participants
|
48 participants
n=7 Participants
|
101 participants
n=5 Participants
|
|
Race/Ethnicity, Customized
Native Hawaiian or Other Pacific Islander
|
1 participants
n=5 Participants
|
2 participants
n=7 Participants
|
3 participants
n=5 Participants
|
|
Race/Ethnicity, Customized
White
|
216 participants
n=5 Participants
|
220 participants
n=7 Participants
|
436 participants
n=5 Participants
|
|
Stratification by Opioid Dose
30-100 mg
|
155 participants
n=5 Participants
|
153 participants
n=7 Participants
|
308 participants
n=5 Participants
|
|
Stratification by Opioid Dose
> 100 mg
|
118 participants
n=5 Participants
|
119 participants
n=7 Participants
|
237 participants
n=5 Participants
|
|
Spontaneous Bowel Movements per Week
|
1.31 spontaneous bowel movements
STANDARD_DEVIATION 0.746 • n=5 Participants
|
1.30 spontaneous bowel movements
STANDARD_DEVIATION 0.713 • n=7 Participants
|
1.31 spontaneous bowel movements
STANDARD_DEVIATION 0.729 • n=5 Participants
|
PRIMARY outcome
Timeframe: 12-week treatment periodPopulation: Intent-to-treat population
A bowel movement and constipation assessment (BMCA) was completed by participants every day during the screening and treatment periods to record information about bowel movements (BMs) and constipation. An SBM was defined as a bowel movement that occurred without the use of rescue laxative therapy during the 24 hours prior to the BM. A responder was defined as a participant having 9 or more positive response weeks out of the 12-week Treatment Period and 3 positive response weeks out of last 4 weeks of the 12-week Treatment Period. A positive response week was defined as ≥ 3 SBMs per week and an increase from baseline of ≥ 1 SBM per week for that week. If a participant had less than 4 days of diary entries for a week, that week was treated as a "non-response" week. Any participant with insufficient primary endpoint data (data for less than 9 out of 12 weeks of the Treatment Period or less than 3 out of the last 4 weeks of the 12-week Treatment Period) was treated as a non-responder.
Outcome measures
| Measure |
Naldemedine
n=273 Participants
Participants received 0.2 mg naldemedine orally once daily for 12 weeks.
|
Placebo
n=272 Participants
Participants received placebo orally once daily for 12 weeks.
|
|---|---|---|
|
Percentage of Participants With a Spontaneous Bowel Movement (SBM) Response
|
47.6 percentage of participants
Interval 41.6 to 53.7
|
34.6 percentage of participants
Interval 28.9 to 40.5
|
SECONDARY outcome
Timeframe: Baseline and the last 2 weeks of the treatment period (Weeks 11 and 12 for participants who completed 12 weeks of treatment)Population: Intent-to-treat population
A bowel movement and constipation assessment (BMCA) was completed by participants every day during the screening and treatment periods to record information about bowel movements (BMs) and constipation. An SBM was defined as a bowel movement that occurred without the use of a rescue laxative therapy during the 24 hours prior to the BM. Baseline was defined as the 14 days in the screening period prior to study drug administration.
Outcome measures
| Measure |
Naldemedine
n=273 Participants
Participants received 0.2 mg naldemedine orally once daily for 12 weeks.
|
Placebo
n=272 Participants
Participants received placebo orally once daily for 12 weeks.
|
|---|---|---|
|
Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Spontaneous Bowel Movements Per Week
|
3.42 spontaneous bowel movements / week
Standard Error 0.193
|
2.12 spontaneous bowel movements / week
Standard Error 0.192
|
SECONDARY outcome
Timeframe: Baseline and Week 1Population: Intent-to-treat population
A bowel movement and constipation assessment (BMCA) was completed by participants every day during the screening and treatment periods to record information about bowel movements (BMs) and constipation. An SBM was defined as a bowel movement that occurred without the use of a rescue laxative therapy during the 24 hours prior to the BM. Baseline was defined as the 14 days in the screening period prior to study drug administration.
Outcome measures
| Measure |
Naldemedine
n=273 Participants
Participants received 0.2 mg naldemedine orally once daily for 12 weeks.
|
Placebo
n=272 Participants
Participants received placebo orally once daily for 12 weeks.
|
|---|---|---|
|
Change From Baseline to Week 1 in the Number of Spontaneous Bowel Movements Per Week
|
3.48 spontaneous bowel movements / week
Standard Error 0.185
|
1.36 spontaneous bowel movements / week
Standard Error 0.184
|
SECONDARY outcome
Timeframe: Baseline and the last 2 weeks of the treatment period (Weeks 11 and 12 for participants who completed 12 weeks of treatment)Population: Intent-to-treat population
A bowel movement and constipation assessment (BMCA) was completed by participants every day during the screening and treatment periods to record information about bowel movements (BMs) and constipation. A complete spontaneous bowel movement (CSBM) was defined as an SBM which was accompanied by the feeling of complete evacuation.
Outcome measures
| Measure |
Naldemedine
n=273 Participants
Participants received 0.2 mg naldemedine orally once daily for 12 weeks.
|
Placebo
n=272 Participants
Participants received placebo orally once daily for 12 weeks.
|
|---|---|---|
|
Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Complete Spontaneous Bowel Movements Per Week
|
2.58 complete spontaneous BMs / week
Standard Error 0.170
|
1.57 complete spontaneous BMs / week
Standard Error 0.170
|
SECONDARY outcome
Timeframe: Baseline and the last 2 weeks of the treatment period (Weeks 11 and 12 for participants who completed 12 weeks of treatment)Population: Intent-to-treat population
A bowel movement and constipation assessment (BMCA) was completed by participants every day during the screening and treatment periods to record information about bowel movements (BMs) and constipation. The severity of straining with each bowel movement was assessed on the following scale: 0=no straining, 1=mild straining, 2=moderate straining, 3=severe straining, 4=very severe straining. SBMs without straining were defined as SBMs with a straining score of 0.
Outcome measures
| Measure |
Naldemedine
n=273 Participants
Participants received 0.2 mg naldemedine orally once daily for 12 weeks.
|
Placebo
n=272 Participants
Participants received placebo orally once daily for 12 weeks.
|
|---|---|---|
|
Change From Baseline to the Last 2 Weeks of the Treatment Period in the Number of Spontaneous Bowel Movements With No Straining Per Week
|
1.46 SBMs with no straining / week
Standard Error 0.141
|
0.73 SBMs with no straining / week
Standard Error 0.140
|
Adverse Events
Naldemedine
Serious events: 14 serious events
Other events: 29 other events
Deaths: 0 deaths
Placebo
Serious events: 5 serious events
Other events: 11 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
Naldemedine
n=271 participants at risk
Participants received 0.2 mg naldemedine orally once daily for 12 weeks.
|
Placebo
n=272 participants at risk
Participants received placebo orally once daily for 12 weeks.
|
|---|---|---|
|
Infections and infestations
Appendicitis
|
0.37%
1/271 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
0.00%
0/272 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
|
Infections and infestations
Pneumonia
|
0.00%
0/271 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
0.37%
1/272 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
|
Immune system disorders
Hypersensitivity
|
0.37%
1/271 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
0.00%
0/272 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
|
Metabolism and nutrition disorders
Dehydration
|
0.37%
1/271 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
0.00%
0/272 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
|
Nervous system disorders
Transient ischaemic attack
|
0.37%
1/271 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
0.00%
0/272 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
|
Cardiac disorders
Angina pectoris
|
0.00%
0/271 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
0.37%
1/272 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
|
Cardiac disorders
Supraventricular tachycardia
|
0.37%
1/271 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
0.00%
0/272 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
|
Cardiac disorders
Ventricular extrasystoles
|
0.37%
1/271 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
0.00%
0/272 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
|
Vascular disorders
Deep vein thrombosis
|
0.37%
1/271 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
0.00%
0/272 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
|
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
|
0.37%
1/271 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
0.00%
0/272 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
|
Gastrointestinal disorders
Abdominal pain
|
0.37%
1/271 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
0.00%
0/272 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
|
Musculoskeletal and connective tissue disorders
Back pain
|
0.37%
1/271 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
0.00%
0/272 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
|
Musculoskeletal and connective tissue disorders
Muscular weakness
|
0.37%
1/271 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
0.00%
0/272 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
|
Musculoskeletal and connective tissue disorders
Osteoarthritis
|
0.00%
0/271 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
0.37%
1/272 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
|
Musculoskeletal and connective tissue disorders
Pain in extremity
|
0.37%
1/271 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
0.00%
0/272 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
|
Congenital, familial and genetic disorders
Patent ductus arteriosus
|
0.37%
1/271 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
0.00%
0/272 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
|
General disorders
Device failure
|
0.00%
0/271 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
0.37%
1/272 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
|
Injury, poisoning and procedural complications
Ligament sprain
|
0.37%
1/271 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
0.00%
0/272 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
|
Injury, poisoning and procedural complications
Overdose
|
0.00%
0/271 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
0.37%
1/272 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
Other adverse events
| Measure |
Naldemedine
n=271 participants at risk
Participants received 0.2 mg naldemedine orally once daily for 12 weeks.
|
Placebo
n=272 participants at risk
Participants received placebo orally once daily for 12 weeks.
|
|---|---|---|
|
Gastrointestinal disorders
Abdominal pain
|
5.9%
16/271 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
1.8%
5/272 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
|
Gastrointestinal disorders
Diarrhoea
|
6.6%
18/271 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
2.9%
8/272 • From the first dose of study drug to 28 days after the last dose of study drug (16 weeks).
The Safety Population included all randomized participants who received at least 1 dose of study drug. One participant was excluded from each arm due to simultaneous enrollment at 2 different sites.
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee The sponsor can embargo results from a PI's center until the combined results from the completed study have been published in full or the sponsor confirms there will be no multicenter study publication. Results communications must be provided to the sponsor for review at least 60 days before submission for publication. By written request, the sponsor can extend the embargo up to an additional 60 days. The sponsor cannot require changes to scientific content and cannot further extend the embargo.
- Publication restrictions are in place
Restriction type: OTHER