Constipation
Conditions
Keywords
Opioid Induced Constipation
Brief summary
The primary purpose of this study is to evaluate the safety, efficacy, and tolerability of subcutaneous (injection beneath the skin) MOA-728 versus placebo in adult Asian subjects with opioid-induced constipation associated with advanced illness (ie, a terminal illness such as incurable cancer or other end-stage disease) or chronic nonmalignant pain.
Detailed description
Subjects received subcutaneous methylnaltrexone (also referred to as MOA-728 or MNTX) or placebo every other day beginning on Day 1 up to a maximum of 7 doses during the 2-week double-blind period. Inclusion criteria for this study included subjects with advanced illness or subjects with chronic nonmalignant pain. The actual study population included only subjects with cancer-related advanced illness. All subjects who completed the double-blind treatment phase of this study could elect to receive methylnaltrexone during a 12-week open-label extension study, provided eligibility criteria were met. Subjects who did not continue in the open-label extension study had a follow-up visit 2 weeks after their last dose of test article.
Interventions
DRUGMethylnaltrexone
Subjects received 0.6 mL (12 mg) every other day if weight ≥ 62kg; 0.4 mL (8 mg) every other day if weight between 38 and \< 62 kg; or 0.0075 mL/kg (0.15 mg/kg) every other day if weight between 27 and \<38 kg. Study duration: 2 weeks double-blind period (MNTX treatments) followed by 12 weeks open-label extension period (MNTX treatments).
DRUGPlacebo
Subjects received matching placebo injections. Study duration: 2 weeks double-blind period (placebo treatments) followed by 12 weeks open-label extension period (MNTX treatments).
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
* Men and women who are at least 18 years of age, and who have a diagnosis of advanced illness with anticipated life expectancy \>= 1 month; * Is receiving a regular dose of opioids for the control of pain; * Has a diagnosis of opioid induced constipation; * Is on a stable laxative regimen.
Exclusion criteria
* Has a known or suspected mechanical gastrointestinal obstruction, or any potential non-opioid cause of bowel dysfunction contributed to constipation; * Has evidence of current fecal impaction; * Has evidence of active diverticulitis, or peritonitis, or a history of bowel surgery within 30 days before test article administration; * Has a body weight less than 27 kg * Has any major illness/condition that, in the investigator's judgment, will substantially increase the risk associated with the subject's participation in and completion of the study, or could preclude the evaluation of the subject's response.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Proportion of Subjects Having a Rescue-free Bowel Movement (RFBM) Within 4 Hours After the First Injection. | Up to 4 hours after the first injection | There were 2 co-primary endpoints for this study. This measurement is the first of the 2 co-primary endpoints. This endpoint measures the percentage of patients who had an RFBM within 4 hours after the first dose of test article during the double-blind period; data are expressed as percentages of patients for the MNTX and placebo groups. To qualify as rescue free, the bowel movement could not occur within 6 hours after a rectal intervention (ie, rectal suppository, enema, manual disimpaction). Note that efficacy results (primary and secondary outcomes) are presented for the double-blind period only. Therefore, no efficacy results are presented for the open-label period. |
| The Proportion of Subjects Having a Rescue-free Bowel Movement (RFBM) Within 4 Hours After Each Dose During Double-blind Period. | Within 4 Hours After Each Dose During the 2 weeks Double-Blind Period | This measurement is the second of the 2 co-primary endpoints. This endpoint measures the percentage of patients who had an RFBM within 4 hours after each dose of test article during the double-blind period; data are expressed as percentages of patients by dose (first, second, third, fourth, etc.) for the MNTX and placebo groups. The definition of RFBM is described above (see first co-primary endpoint). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Injections Resulting in RFBM Within 4 Hours After Test Article Administration. | Within 4 Hours After Each Dose During the 2 weeks Double-Blind Period | This endpoint measures the percentage of injections resulting in RFBMs within 4 hours after test article administration during the double-blind period. The percentage of injections resulting in RFBMs is calculated for each patient and then data are expressed as the mean (± standard deviation) percentage for the MNTX and placebo groups. The definition of RFBM is described above (see first co-primary endpoint). |
Countries
South Korea, Taiwan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Methylnaltrexone Double-blind Methylnaltrexone once every other day.
Subjects received 0.6 mL (12 mg) every other day if weight ≥ 62kg; 0.4 mL (8 mg) every other day if weight between 38 and \< 62 kg; or 0.0075 mL/kg (0.15 mg/kg) every other day if weight between 27 and \<38 kg. | 25 |
| Placebo Placebo once every other day.
Subjects received matching placebo injections. | 25 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Double-blind | Adverse Event | 1 | 0 | 0 |
| Double-blind | Death | 2 | 1 | 0 |
| Double-blind | Did not receive study drug | 0 | 1 | 0 |
| Double-blind | Lack of Efficacy | 1 | 1 | 0 |
| Double-blind | No post baseline diary entry | 1 | 0 | 0 |
| Double-blind | Physician Decision | 1 | 0 | 0 |
| Double-blind | Withdrawal by Subject | 6 | 4 | 0 |
Baseline characteristics
| Characteristic | Methylnaltrexone Double-blind | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 7 Participants | 12 Participants | 19 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants | 13 Participants | 31 Participants |
| Age, Continuous | 58.5 years STANDARD_DEVIATION 11.68 | 62.1 years STANDARD_DEVIATION 14.23 | 60.3 years STANDARD_DEVIATION 13.01 |
| Eastern Cooperative Oncology Group Score 0 - Fully active | 0 Participants | 1 Participants | 1 Participants |
| Eastern Cooperative Oncology Group Score 1 - Restricted in strenuous activity | 3 Participants | 4 Participants | 7 Participants |
| Eastern Cooperative Oncology Group Score 2 - Unable to work | 6 Participants | 5 Participants | 11 Participants |
| Eastern Cooperative Oncology Group Score 3 - Limited self-care | 16 Participants | 15 Participants | 31 Participants |
| Hospitalization Status at Screening Period No | 13 participants | 17 participants | 30 participants |
| Hospitalization Status at Screening Period Yes | 12 participants | 8 participants | 20 participants |
| Sex: Female, Male Female | 14 Participants | 11 Participants | 25 Participants |
| Sex: Female, Male Male | 11 Participants | 14 Participants | 25 Participants |
| Underlying Advanced Illness - Cancer-related illness | 25 Participants | 25 Participants | 50 Participants |
| Weight 38 - < 62 kg | 17 Participants | 20 Participants | 37 Participants |
| Weight < 38 kg | 2 Participants | 0 Participants | 2 Participants |
| Weight ≥62 kg | 6 Participants | 4 Participants | 10 Participants |
| Weight Missing | 0 Participants | 1 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 16 / 25 | 18 / 24 | 25 / 31 |
| serious Total, serious adverse events | 12 / 25 | 8 / 24 | 21 / 31 |
Outcome results
Primary
The Proportion of Subjects Having a Rescue-free Bowel Movement (RFBM) Within 4 Hours After Each Dose During Double-blind Period.
This measurement is the second of the 2 co-primary endpoints. This endpoint measures the percentage of patients who had an RFBM within 4 hours after each dose of test article during the double-blind period; data are expressed as percentages of patients by dose (first, second, third, fourth, etc.) for the MNTX and placebo groups. The definition of RFBM is described above (see first co-primary endpoint).
Time frame: Within 4 Hours After Each Dose During the 2 weeks Double-Blind Period
Population: Although 25 patients in the MNTX group and 24 in the placebo group received study drug, 24 and 23 patients, respectively, had ≥ 1 post baseline diary assessment and were analyzed for efficacy.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Methylnaltrexone Double-blind | The Proportion of Subjects Having a Rescue-free Bowel Movement (RFBM) Within 4 Hours After Each Dose During Double-blind Period. | RFBM post eighth DB injection | 57.1 percentage of participants |
| Methylnaltrexone Double-blind | The Proportion of Subjects Having a Rescue-free Bowel Movement (RFBM) Within 4 Hours After Each Dose During Double-blind Period. | RFBM post second DB injection | 61.9 percentage of participants |
| Methylnaltrexone Double-blind | The Proportion of Subjects Having a Rescue-free Bowel Movement (RFBM) Within 4 Hours After Each Dose During Double-blind Period. | RFBM post third DB injection | 52.6 percentage of participants |
| Methylnaltrexone Double-blind | The Proportion of Subjects Having a Rescue-free Bowel Movement (RFBM) Within 4 Hours After Each Dose During Double-blind Period. | RFBM post fourth DB injection | 38.9 percentage of participants |
| Methylnaltrexone Double-blind | The Proportion of Subjects Having a Rescue-free Bowel Movement (RFBM) Within 4 Hours After Each Dose During Double-blind Period. | RFBM post fifth DB injection | 56.3 percentage of participants |
| Methylnaltrexone Double-blind | The Proportion of Subjects Having a Rescue-free Bowel Movement (RFBM) Within 4 Hours After Each Dose During Double-blind Period. | RFBM post sixth DB injection | 43.8 percentage of participants |
| Methylnaltrexone Double-blind | The Proportion of Subjects Having a Rescue-free Bowel Movement (RFBM) Within 4 Hours After Each Dose During Double-blind Period. | RFBM post seventh DB injection | 43.8 percentage of participants |
| Placebo | The Proportion of Subjects Having a Rescue-free Bowel Movement (RFBM) Within 4 Hours After Each Dose During Double-blind Period. | RFBM post eighth DB injection | 7.7 percentage of participants |
| Placebo | The Proportion of Subjects Having a Rescue-free Bowel Movement (RFBM) Within 4 Hours After Each Dose During Double-blind Period. | RFBM post fifth DB injection | 4.5 percentage of participants |
| Placebo | The Proportion of Subjects Having a Rescue-free Bowel Movement (RFBM) Within 4 Hours After Each Dose During Double-blind Period. | RFBM post second DB injection | 8.7 percentage of participants |
| Placebo | The Proportion of Subjects Having a Rescue-free Bowel Movement (RFBM) Within 4 Hours After Each Dose During Double-blind Period. | RFBM post seventh DB injection | 0 percentage of participants |
| Placebo | The Proportion of Subjects Having a Rescue-free Bowel Movement (RFBM) Within 4 Hours After Each Dose During Double-blind Period. | RFBM post third DB injection | 8.7 percentage of participants |
| Placebo | The Proportion of Subjects Having a Rescue-free Bowel Movement (RFBM) Within 4 Hours After Each Dose During Double-blind Period. | RFBM post sixth DB injection | 0 percentage of participants |
| Placebo | The Proportion of Subjects Having a Rescue-free Bowel Movement (RFBM) Within 4 Hours After Each Dose During Double-blind Period. | RFBM post fourth DB injection | 8.7 percentage of participants |
p-value: <0.000197.5% CI: [10.91, 50.14]Chi-squared
Primary
The Proportion of Subjects Having a Rescue-free Bowel Movement (RFBM) Within 4 Hours After the First Injection.
There were 2 co-primary endpoints for this study. This measurement is the first of the 2 co-primary endpoints. This endpoint measures the percentage of patients who had an RFBM within 4 hours after the first dose of test article during the double-blind period; data are expressed as percentages of patients for the MNTX and placebo groups. To qualify as rescue free, the bowel movement could not occur within 6 hours after a rectal intervention (ie, rectal suppository, enema, manual disimpaction). Note that efficacy results (primary and secondary outcomes) are presented for the double-blind period only. Therefore, no efficacy results are presented for the open-label period.
Time frame: Up to 4 hours after the first injection
Population: Although 25 patients in the MNTX group and 24 in the placebo group received study drug, 24 and 23 patients, respectively, had ≥ 1 post baseline diary assessment and were analyzed for efficacy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Methylnaltrexone Double-blind | The Proportion of Subjects Having a Rescue-free Bowel Movement (RFBM) Within 4 Hours After the First Injection. | 79.2 percentage of participants |
| Placebo | The Proportion of Subjects Having a Rescue-free Bowel Movement (RFBM) Within 4 Hours After the First Injection. | 4.3 percentage of participants |
p-value: <0.000197.5% CI: [6.5, 1074.7]Chi-squared
Secondary
Percentage of Injections Resulting in RFBM Within 4 Hours After Test Article Administration.
This endpoint measures the percentage of injections resulting in RFBMs within 4 hours after test article administration during the double-blind period. The percentage of injections resulting in RFBMs is calculated for each patient and then data are expressed as the mean (± standard deviation) percentage for the MNTX and placebo groups. The definition of RFBM is described above (see first co-primary endpoint).
Time frame: Within 4 Hours After Each Dose During the 2 weeks Double-Blind Period
Population: Although 25 patients in the MNTX group and 24 in the placebo group received study drug, 24 and 23 patients, respectively, had ≥ 1 post baseline diary assessment and were analyzed for efficacy.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Methylnaltrexone Double-blind | Percentage of Injections Resulting in RFBM Within 4 Hours After Test Article Administration. | 61.61 percentage of injections | Standard Deviation 36.52 |
| Placebo | Percentage of Injections Resulting in RFBM Within 4 Hours After Test Article Administration. | 4.97 percentage of injections | Standard Deviation 22.203 |
p-value: <0.000197.5% CI: [40.62, 72.66]ANOVA