Opioid-Induced Constipation
Conditions
Keywords
Treatment of Opioid-Induced Constipation in Participants with Chronic, Non-Malignant Pain
Brief summary
MNTX 3201 is a Phase 3, international, multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the safety and efficacy of oral MNTX for the treatment of opioid induced constipation in participants with chronic, non-malignant pain.
Interventions
DRUGMethylnaltrexone
Methylnaltrexone will be administered as per the dose and schedule specified in the respective arms.
DRUGPlacebo
Placebo matching to methylnaltrexone will be administered as per the schedule specified in the respective arms.
Sponsors
Progenics Pharmaceuticals, Inc.
Bausch Health Americas, Inc.
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 No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. History of chronic non-malignant pain (originating from a non-malignant source) with condition(s) underlying the chronic pain of greater than or equal to (≥) 2 months' duration before the screening visit. 2. Taking oral, transdermal, intravenous (IV), or subcutaneous (SC) opioids for chronic non-malignant pain for ≥1 month. 3. No known history of chronic constipation prior to the initiation of opioid therapy. 4. Currently taking laxative therapy for ≥30 days and willing to discontinue all laxative therapy at the start of screening period and use only study-permitted rescue laxatives throughout the screening and double-blind treatment periods.. Key
Exclusion criteria
1. Prior treatment with oral MNTX. 2. Prior treatment with SC MNTX within 30 days of screening. 3. Women who are pregnant, breastfeeding, or plan to become pregnant during the study. 4. Fecal incontinence, rectal prolapse, fecal ostomy or other clinically significant gastrointestinal disorders such as inflammatory bowel disease or clinically significant irritable bowel syndrome that would have made bowel movement assessment inaccurate. 5. Current treatment with partial opioid agonists (for example; buprenorphine) or combination agonists/antagonists.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Average Percentage of Dosing Days That Resulted in Rescue-Free Bowel Movements (RFBMs) Within 4 Hours of Dosing During Weeks 1 to 4 | Weeks 1 to 4 | RFBM was defined as a bowel movement without laxative use within 24 hours prior to bowel movement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Responded (Responder) to Study Drug During Weeks 1 to 4 | Weeks 1 to 4 | A responder was defined as at least 3 RFBMs/week, with an increase of at least 1 RFBM/week over baseline, for at least 3 out of the first 4 weeks of the treatment period. Weekly number of RFBMs were calculated as follows: 7 \* total number of RFBMs in a week/all non-missing assessment days in the given week. Weekly number of RFBMs was set to missing for any week when a participant completed less than (\<) 4 diary days in a week. A RFBM was a bowel movement without laxative use within 24 hrs prior to the bowel movement. |
| Change in Weekly Number of RFBMs From Baseline Over the Entire First 4 Weeks (28 Days) of Dosing | Baseline, Weeks 1 to 4 | Weekly number of RFBMs were calculated as follows: 7 \* total number of RFBMs in a week/all non-missing assessment days in the given week. Weekly number of RFBMs was set to missing for any week when a participant completed less than (\<) 4 diary days in a week. A RFBM was a bowel movement without laxative use within 24 hrs prior to the bowel movement. |
Countries
United States
Participant flow
Pre-assignment details
A total of 804 participants met inclusion/exclusion criteria and randomized in 1:1:1:1 ratio to either MNTX 150 mg, MNTX 300 mg, MNTX 450 mg, or placebo treatment groups.
Participants by arm
| Arm | Count |
|---|---|
| MNTX 150 mg Participants received MNTX 150 mg (1 tablet of MNTX 150 mg and 2 matching placebo tablets) orally QD for 28 days (4 weeks), then MNTX tablets at a dose PRN for remaining 56 days (8 weeks). | 201 |
| MNTX 300 mg Participants received MNTX 300 mg (2 tablets of MNTX 150 mg each and 1 matching placebo tablet) orally QD for 28 days (4 weeks), then MNTX tablets at a dose PRN for remaining 56 days (8 weeks). | 201 |
| MNTX 450 mg Participants received MNTX 450 mg (3 tablets of MNTX 150 mg each) orally QD for 28 days (4 weeks), then MNTX tablets at a dose PRN for remaining 56 days (8 weeks). | 200 |
| Placebo Participants received 3 tablets of placebo matched to MNTX orally QD for 84 days (12 weeks). | 201 |
| Total | 803 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 9 | 7 | 9 |
| Overall Study | Ineligibility | 0 | 0 | 2 | 0 |
| Overall Study | Insufficient response to treatment | 7 | 8 | 5 | 7 |
| Overall Study | Lost to Follow-up | 10 | 6 | 14 | 9 |
| Overall Study | Other than specified | 0 | 1 | 1 | 2 |
| Overall Study | Protocol Violation | 7 | 9 | 12 | 14 |
| Overall Study | Withdrawal by Subject | 15 | 13 | 11 | 17 |
Baseline characteristics
| Characteristic | MNTX 450 mg | MNTX 150 mg | MNTX 300 mg | Placebo | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Age, Categorical >=65 years | 19 Participants | 15 Participants | 19 Participants | 22 Participants | 75 Participants |
| Age, Categorical Between 18 and 65 years | 181 Participants | 185 Participants | 182 Participants | 179 Participants | 727 Participants |
| Age, Continuous | 51.4 years STANDARD_DEVIATION 10.5 | 50.9 years STANDARD_DEVIATION 10.32 | 51.5 years STANDARD_DEVIATION 10.54 | 52.6 years STANDARD_DEVIATION 10.33 | 51.6 years STANDARD_DEVIATION 10.38 |
| Primary pain condition requiring opioid medication Arthritis | 19 Participants | 20 Participants | 15 Participants | 12 Participants | 66 Participants |
| Primary pain condition requiring opioid medication Back pain | 135 Participants | 132 Participants | 136 Participants | 145 Participants | 548 Participants |
| Primary pain condition requiring opioid medication Fibromyalgia | 11 Participants | 15 Participants | 8 Participants | 12 Participants | 46 Participants |
| Primary pain condition requiring opioid medication Joint/extremity pain | 11 Participants | 13 Participants | 16 Participants | 10 Participants | 50 Participants |
| Primary pain condition requiring opioid medication Neurologic/neuropathic pain | 16 Participants | 16 Participants | 13 Participants | 11 Participants | 56 Participants |
| Primary pain condition requiring opioid medication Other pain condition requiring opioids | 8 Participants | 5 Participants | 13 Participants | 11 Participants | 37 Participants |
| Sex: Female, Male Female | 128 Participants | 133 Participants | 114 Participants | 130 Participants | 505 Participants |
| Sex: Female, Male Male | 72 Participants | 68 Participants | 87 Participants | 71 Participants | 298 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 38 / 201 | 35 / 201 | 42 / 200 | 32 / 201 |
| serious Total, serious adverse events | 5 / 201 | 6 / 201 | 4 / 200 | 8 / 201 |
Outcome results
Primary
Average Percentage of Dosing Days That Resulted in Rescue-Free Bowel Movements (RFBMs) Within 4 Hours of Dosing During Weeks 1 to 4
RFBM was defined as a bowel movement without laxative use within 24 hours prior to bowel movement.
Time frame: Weeks 1 to 4
Population: ITT population included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MNTX 150 mg | Average Percentage of Dosing Days That Resulted in Rescue-Free Bowel Movements (RFBMs) Within 4 Hours of Dosing During Weeks 1 to 4 | 21.05 percentage of days | Standard Deviation 20.116 |
| MNTX 300 mg | Average Percentage of Dosing Days That Resulted in Rescue-Free Bowel Movements (RFBMs) Within 4 Hours of Dosing During Weeks 1 to 4 | 24.64 percentage of days | Standard Deviation 21.311 |
| MNTX 450 mg | Average Percentage of Dosing Days That Resulted in Rescue-Free Bowel Movements (RFBMs) Within 4 Hours of Dosing During Weeks 1 to 4 | 27.40 percentage of days | Standard Deviation 23.453 |
| Placebo | Average Percentage of Dosing Days That Resulted in Rescue-Free Bowel Movements (RFBMs) Within 4 Hours of Dosing During Weeks 1 to 4 | 18.18 percentage of days | Standard Deviation 16.995 |
Comparison: Analysis was performed using analysis of covariance (ANCOVA) with treatment as effect and analysis region as covariate.p-value: 0.169295% CI: [-1.21, 6.86]ANCOVA
Comparison: Analysis was performed using ANCOVA with treatment as effect and analysis region as covariate.p-value: 0.001695% CI: [2.47, 10.55]ANCOVA
Comparison: Analysis was performed using ANCOVA with treatment as effect and analysis region as covariate.p-value: <0.000195% CI: [5.09, 13.18]ANCOVA
Secondary
Change in Weekly Number of RFBMs From Baseline Over the Entire First 4 Weeks (28 Days) of Dosing
Weekly number of RFBMs were calculated as follows: 7 \* total number of RFBMs in a week/all non-missing assessment days in the given week. Weekly number of RFBMs was set to missing for any week when a participant completed less than (\<) 4 diary days in a week. A RFBM was a bowel movement without laxative use within 24 hrs prior to the bowel movement.
Time frame: Baseline, Weeks 1 to 4
Population: ITT population included all randomized participants who received at least 1 dose of study drug. Missing data was imputed using LOCF method.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MNTX 150 mg | Change in Weekly Number of RFBMs From Baseline Over the Entire First 4 Weeks (28 Days) of Dosing | Baseline | 1.46 RFBMs | Standard Deviation 0.911 |
| MNTX 150 mg | Change in Weekly Number of RFBMs From Baseline Over the Entire First 4 Weeks (28 Days) of Dosing | Change during Weeks 1-4 | 1.98 RFBMs | Standard Deviation 2.139 |
| MNTX 300 mg | Change in Weekly Number of RFBMs From Baseline Over the Entire First 4 Weeks (28 Days) of Dosing | Change during Weeks 1-4 | 2.43 RFBMs | Standard Deviation 2.616 |
| MNTX 300 mg | Change in Weekly Number of RFBMs From Baseline Over the Entire First 4 Weeks (28 Days) of Dosing | Baseline | 1.35 RFBMs | Standard Deviation 0.891 |
| MNTX 450 mg | Change in Weekly Number of RFBMs From Baseline Over the Entire First 4 Weeks (28 Days) of Dosing | Baseline | 1.37 RFBMs | Standard Deviation 0.789 |
| MNTX 450 mg | Change in Weekly Number of RFBMs From Baseline Over the Entire First 4 Weeks (28 Days) of Dosing | Change during Weeks 1-4 | 2.44 RFBMs | Standard Deviation 2.515 |
| Placebo | Change in Weekly Number of RFBMs From Baseline Over the Entire First 4 Weeks (28 Days) of Dosing | Baseline | 1.49 RFBMs | Standard Deviation 1.045 |
| Placebo | Change in Weekly Number of RFBMs From Baseline Over the Entire First 4 Weeks (28 Days) of Dosing | Change during Weeks 1-4 | 1.87 RFBMs | Standard Deviation 2.052 |
Comparison: Analysis was performed using ANCOVA model with treatment as effect and analysis region and baseline as covariates.p-value: 0.69295% CI: [-0.36, 0.55]ANCOVA
Comparison: Analysis was performed using ANCOVA model with treatment as effect and analysis region and baseline as covariates.p-value: 0.027495% CI: [0.06, 0.97]ANCOVA
Comparison: Analysis was performed using ANCOVA model with treatment as effect and analysis region and baseline as covariates.p-value: 0.023795% CI: [0.07, 0.98]ANCOVA
Secondary
Percentage of Participants Who Responded (Responder) to Study Drug During Weeks 1 to 4
A responder was defined as at least 3 RFBMs/week, with an increase of at least 1 RFBM/week over baseline, for at least 3 out of the first 4 weeks of the treatment period. Weekly number of RFBMs were calculated as follows: 7 \* total number of RFBMs in a week/all non-missing assessment days in the given week. Weekly number of RFBMs was set to missing for any week when a participant completed less than (\<) 4 diary days in a week. A RFBM was a bowel movement without laxative use within 24 hrs prior to the bowel movement.
Time frame: Weeks 1 to 4
Population: ITT population included all randomized participants who received at least 1 dose of study drug. Missing data was imputed using last observation carried forward (LOCF) method.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MNTX 150 mg | Percentage of Participants Who Responded (Responder) to Study Drug During Weeks 1 to 4 | 45.3 percentage of participants |
| MNTX 300 mg | Percentage of Participants Who Responded (Responder) to Study Drug During Weeks 1 to 4 | 51.7 percentage of participants |
| MNTX 450 mg | Percentage of Participants Who Responded (Responder) to Study Drug During Weeks 1 to 4 | 54.5 percentage of participants |
| Placebo | Percentage of Participants Who Responded (Responder) to Study Drug During Weeks 1 to 4 | 40.8 percentage of participants |
Comparison: Analysis was performed using logistic regression model with treatment as effect and analysis region as covariate.p-value: 0.307695% CI: [0.82, 1.84]Regression, Logistic
Comparison: Analysis was performed using logistic regression model with treatment as effect and analysis region as covariate.p-value: 0.033995% CI: [1.03, 2.29]Regression, Logistic
Comparison: Analysis was performed using logistic regression model with treatment as effect and analysis region as covariate.p-value: 0.004395% CI: [1.2, 2.66]Regression, Logistic