| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Opioid-induced constipation in subjects with advanced illness |
|
| E.1.1.1 | Medical condition in easily understood language |
| Constipation caused by opioid (pain medication) used in subjects with an advanced disease. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 13.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10010774 |
| E.1.2 | Term | Constipation |
| E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Primary: The primary objective of this study is to evaluate the efficacy and safety of a fixed dose of SC methylnaltrexone in inducing laxation over a 7-day period in subjects with advanced illness and OIC. |
|
| E.2.2 | Secondary objectives of the trial |
| Secondary: The secondary objectives of this study are to assess the effect of SC methylnaltrexone on patient-reported constipation symptoms and constipation-related quality of life and to assess the efficacy of SC methylnaltrexone beyond 7 days in individuals with advanced illness and OIC. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
The subject:
1.Is a man or woman aged 18 years or older.
2.Has a diagnosis of advanced illness (ie, a terminal illness such as incurable cancer or other end-stage disease).
3.Has a life expectancy of ≥ 1 month.
4.In the opinion of the investigator, has sufficient cognitive function to answer patient-reported outcomes (PRO) questions.
5.Is receiving opioids, both
a.On a regular schedule, not just as-needed (PRN) or rescue doses, for the control of pain or discomfort for at least 2 weeks before the first dose of test article, and
b.On a stable opioid regimen for at least 3 days before the first dose of test article. “Stable” is defined as no reduction in dose of ≥50%. Increases to the opioid regimen are permitted.
6.Has a diagnosis of constipation, defined as either
a.Fewer than 3 bowel movements during the previous week by history, and no clinically notable laxation in the 24 hours before the first dose of test article, or
b.No clinically notable laxation in the 48 hours before the first dose of test article. Note: Small amounts of “leakage” of liquid stool or “pellets” may or may not be considered clinically notable, at the discretion of the investigator.
7.Has constipation further defined as opioid induced, as determined by the investigator.
8.Is on a stable laxative regimen for at least 3 days before the first dose of test article administration (eg, stool softener and senna or equivalent). This means that there must be a standing laxative order (not PRN).
a.A subject who meets inclusion criterion 6a and uses or used a rescue laxative (or enema/suppository) that produces a notable bowel movement within the 24 hours before the first dose of test article must wait to be laxation free for 24 hours in order to receive test article.
b.A subject who meets inclusion criterion 6b and receives or received a rescue laxative (or enema/suppository) that produces a notable bowel movement within the 24 hours before the first dose of test article must wait to be laxation free for 48 hours in order to receive test article.
Note: Rescue medications or rescue procedures for constipation may not be used within 4 hours before or 4 hours after test article administration.
9.Has stable vital signs, as determined by the investigator.
10.Has had an electrocardiogram (ECG) performed during the screening visit or within the 2 months before the screening visit. If an ECG is not performed specifically for this study, a copy of the previously recorded tracing must be obtained and stored in the source documents.
11.Has a negative urine pregnancy test result at screening (for women of presumed childbearing potential).
12.Must be surgically sterile, or must agree to use a medically acceptable method of birth control or practice sexual abstinence for the duration of the study and for 15 days after the last dose of test article (unless female and postmenopausal, ie, > 12 months since the last menstrual period). |
|
| E.4 | Principal exclusion criteria |
The subject:
1.Has received treatment with methylnaltrexone at any time during the 7 days before the first dose of test article.
2.Has a known or suspected mechanical gastrointestinal obstruction; or a known/suspected lesion of the gastrointestinal tract that, in the opinion of the investigator, might be associated with an increased risk of gastrointestinal perforation.
3.Has any potential nonopioid cause of bowel dysfunction that in the opinion of the investigator might be a major contributor to the constipation.
4.Has clinically significant active diverticular disease as determined by the investigator.
5.Has evidence of current fecal impaction by physical examination or previously performed x-ray examination.
6.Has physical evidence of peritonitis.
7.Has a history of bowel surgery within 10 days before test article administration.
8.Has a fecal ostomy.
9.Has used vinca alkaloids (eg, vincristine, vinblastine, or vinorelbine) at any time during the 4 months before screening.
10.Has a body weight less than 38 kg.
11.Requires dialysis.
12.Has a known or suspected allergy to methylnaltrexone or other similar compounds (ie, naltrexone or naloxone).
13. Is participating or participated in studies involving investigational products (e.g, products in which the safety profile is not yet established) within the 30 days before screening.
14.Is a woman who is pregnant and/or nursing.
15.Has any other clinically important abnormalities as determined by the investigator that may interfere with his or her participation in or compliance with the study.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of subjects who have a laxation response within 4 hours after at least 2 of the first 4 doses (the first week of treatment). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Bowel Movements and Study Medications records are available every day through out the 14 day trial and are either captured on an eDiary or paper diary. |
|
| E.5.2 | Secondary end point(s) |
· Time to first recue-free laxation.
· Proportion of subjects with rescue-free laxation within 4 hours after the first dose of
study drug.
· Proportion of subjects with rescue-free laxation within 4 or 24 hours after each dose.
· Proportion of subjects with rescue-free laxation within 4 hours after at least 4 of the
maximum 7 doses.
· Number of laxations per week.
· Number of rescue-free laxations per week.
· Time to first rescue-free laxation within 4 hours
· Time to first rescue-free laxation within 24 hours
· Time to first rescue-free laxation after each dose
· Proportion of subjects using Doses of rescue laxatives required per week during the
double-blind period.
· Proportion of subjects using Number of enemas during the double-blind period required
per week.
· Proportion of subjects having Number of manual disimpaction procedures performed
during the double-blind period per week. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 100 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Belgium |
| Brazil |
| Canada |
| Finland |
| France |
| Germany |
| Italy |
| Mexico |
| Netherlands |
| Norway |
| Portugal |
| Spain |
| Sweden |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 45 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 45 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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