E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
patients receiving palliative care suffering from opioid induced constipation |
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E.1.1.1 | Medical condition in easily understood language |
patients receiving palliative care suffering from constipation caused by opioids |
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E.1.1.2 | Therapeutic area | Body processes [G] - Digestive System and Oral Physiological Phenomena [G10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10059513 |
E.1.2 | Term | Palliative care |
E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
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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 |
To compare the efficacy of a fixed dose of subcutaneous methylnaltrexone to induce laxation in patients receiving palliative care who suffer from constipation due to either fentanyl, oxycodone or morphine sulphate (opioids with different mechanisms of action). |
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E.2.2 | Secondary objectives of the trial |
1) To determine size, phenotype, and function of various leukocyte subsets as well as serum cytokine levels during treatment with the µ-opioid receptor antagonist methylnaltrexone.
2) To determine whether systemic antagonistic treatment with methylnaltrexone will modify systemic biomarkers of angiogenesis.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age ≥ 18 years
2. Receiving palliative care
3. Life expectancy ≥ 2 weeks
4. Able to give informed consent
5. Receiving opioid treatment with either morphine sulphate, oxycodone or fentanyl
6. Opioid treatment, both
o On a regular schedule (not just as needed or rescue doses) for the control of pain or dyspnea for at least 2 weeks before the first dose of methylnaltrexone, and
o On a stable opioid regimen for at least 3 days before the first dose of methylnaltrexone. This is defined as no dose reduction of ≥ 50%, dose increases are permitted. If rescue medication is prescribed of a different type of opioid than the regular dosed opioid, the rescue medication should be switched to the same type as the regular dosed opioid for at least 3 days before the first dose of methylnaltrexone.
7. Has diagnosis of constipation, defined as either
o < 3 bowel movements during the previous week by history and no clinically notable laxation* in the 24 hours before the first dose of methylnaltrexone, or
o No clinically notable laxation* in the 48 hours before the first dose of methylnaltrexone.
8. Constipation is defined as opioid induced, determined by investigator
9. On stable laxative regimen for ≥ 3 days before the first dose of methylnaltrexone. This is defined as at least one type of laxative in an adequate dosing regimen, (e.g. macrogol 2 packets daily, magnesium(hydr)oxide 500 mg three times daily, bisacodyl 10 mg daily or sennoside A+B 10 ml daily) or at least two types of laxatives in a suboptimal dose with patient characteristics hampering optimal treatment.
10. If the subject is a woman with presumed child bearing potential; negative urine pregnancy test at screening
11. Surgically sterile or agrees to use a medically acceptable method of birth control or practice sexual abstinence for the duration of the methylnaltrexone treatment and the following 15 days. ~
* including laxation after rescue laxative or enema
~ not necessary for postmenopausal women
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E.4 | Principal exclusion criteria |
1. Previous treatment with methylnaltrexone
2. Known or suspected mechanical gastrointestinal obstruction
3. Presence of an other cause of bowel dysfunction that is considered to be a major contribution to the constipation according to investigator
4. Presence of a peritoneal catheter for intraperitoneal chemotherapy or dialysis
5. Clinically relevant active diverticular disease
6. History of bowel surgery within 10 days before first dose of methylnaltrexone
7. Fecal ostomy
8. Use of vinca alkaloids within previous 4 months
9. Body weight <38 kg
10. Renal failure defined as EGFR <30 ml/min per 1.73m2 or requires dialysis.
11. Known or suspected allergy to methylnaltrexone or similar compounds (e.g. naltrexone or naloxone)
12. Participation in a study with investigational products within 30 days before first dose of methylnaltrexone.
13. Pregnant or nursing
14. Clinically important abnormalities that may interfere with participation or compliance to the study, determined by investigator
Additional exclusion criteria for the immunologic and angiogenic analysis part of the study:
15. Chemotherapy or treatment with tyrosine kinase inhibitor during 4 weeks before inclusion or treatment scheduled during participation in this study.
16. Treatment with high dose corticosteroids during 2 weeks before inclusion in this study. This is defined as the equivalent of 30 mg of prednisone per day for ≥ 2 consecutive days.
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E.5 End points |
E.5.1 | Primary end point(s) |
The proportion of subjects that has a rescue-free laxation response within 4 hours after at least 2 of the first 4 doses (the first week of treatment).
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
- Time to first laxation
- Laxation within 4 hours after the first dose of study drug
- Laxation within 4 or 24 hours after each dose
- Laxation within 4 hours after at least 4 of the maximum 7 doses
- Number of laxations per week
- Change in BFI score between day 0 and 14
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
E.6.4 | Safety | No |
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 | No |
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 | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |