| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Opioid induced bowel dysfunction |
|
| MedDRA Classification |
| 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 |
The primary objectives are:
1) To establish the dose-response relationship of MOA-728 by observing spontaneous bowel movements, and to establish appropriate doses to take into confirmatory phase 3 studies.
2) To evaluate the safety, and tolerability of oral MOA-728 given daily in a population of subjects with chronic, non-malignant pain who have opioid-induced bowel dysfunction. |
|
| E.2.2 | Secondary objectives of the trial |
1) evaluating the dose-response relationship of oral MOA-728 on secondary endpoints to support the dose selection for subsequent confirmatory studies.
2) evaluating exposure-response relationships.
3) exploring subject reported outcomes for perceived benefits of treatment with MOA-728. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Outpatient men and women who are at least 18 years of age and able to sign an informed consent form.
2. A history of chronic non-malignant pain with a documented history of the non-malignant condition (ie, osteoarthritis, back pain, or neuropathic pain) underlying the chronic pain of at least 2 months duration before the screening visit.
3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2 at the screening visit.
4. Stable pain and medical status for at least 1 month before the screening visit.
5. Taking oral, transdermal, intravenous, or subcutaneous opioids for at least 1 month and receiving a daily dose ≥ 20 mg of morphine equivalents per day for at least 2 weeks before the screening visit and during the single-blind, placebo run-in period with no changes anticipated during the study.
6. A history of constipation due to opioid use for at least 1 month before the screening visit. Constipation is defined as < 3 spontaneous bowel movements per week on average and one or more of the following:
· Hard or lumpy stools for at least 25% of bowel movements.
· A sensation of incomplete evacuation following at least 25% of bowel movements.
· Straining during at least 25% of bowel movements.
7. Constipation due to opioid use during the single-blind, placebo run-in. Constipation is defined as ≤ 2 spontaneous (no laxative/enema use during prior 24 hrs) bowel movements per week that were associated with 1 or more of the following:
· A Bristol Stool Form Scale score of 1 or 2 for at least 1 of the bowel movements.
· A sensation of incomplete evacuation following at least 1 of the bowel movements.
· Straining during at least 1 of the bowel movements.
8. At least one bowel movement (spontaneous or non-spontaneous) during the single-blind, placebo run-in period.
9. A daily score ≤ 6 on the Pain Intensity Scale for at least 12 days during the single-blind, placebo run-in period.
10. For women, a negative serum pregnancy test result at screening and a negative urine pregnancy test at baseline.
11. All men and women who are not surgically sterile or postmenopausal must agree and commit to the use of a medically acceptable method of birth control or sexual abstinence for the duration of the study and for 15 days after the last dose of test article.
12. Willingness to discontinue all prestudy laxative therapy and utilize only study-permitted rescue laxatives/enemas during the screening and treatment phases.
13. Willingness and ability to participate in all aspects of the study, including use of oral medication, completion of subjective evaluations, attending scheduled clinic visits, access to a telephone, and compliance with all protocol requirements, as evidenced by written informed consent. |
|
| E.4 | Principal exclusion criteria |
1. Prior treatment with methylnaltrexone.
2. Women who are pregnant, are breastfeeding, or plan to become pregnant during the study.
3. A diagnosis of inflammatory bowel disease, irritable bowel syndrome, impaction, bowel obstruction, adhesions, megacolon, rectal prolapse, fecal incontinence, or other significant gastrointestinal disorder or history of gastrointestinal surgery likely to affect absorption or disposition of an orally administered drug.
4. History of rectal bleeding unexplained by hemorrhoids or fissures.
5. Need for manual disimpaction or pelvic floor support techniques, including manual maneuvers, within 14 days before the screening visit.
6. Clinical evidence of outlet obstruction or impaction on physical examination.
7. History of malignancy other than basal- or squamous- cell skin carcinoma within 5 years before the screening visit.
8. A history of chronic constipation before the initiation of opioid therapy.
9. A history of alcohol or drug abuse within 1 year before the screening visit.
10. Any unstable hepatic, renal, pulmonary, cardiovascular (including uncontrolled hypertension), ophthalmologic, neurologic, or psychiatric disease, or any other medical condition that might compromise the study or put the subject at greater risk during study participation.
11. A history or presence of orthostatic hypotension.
12. A creatinine value > 2 times the upper limit of normal on screening laboratory tests.
13. An alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value > 2 times the upper limit of normal on screening laboratory tests.
14. Other clinically important abnormalities on screening physical examination, electrocardiogram (ECG), or laboratory tests.
15. Planned surgery during the study.
16. Known allergy, hypersensitivity, or other contraindication to opioids, opioid derivatives, or opioid antagonists (ie, codeine, naltrexone, or naloxone).
17. Current treatment with partial opioid agonists (eg, buprenorphine) or combination agonists/antagonists.
18. Use of investigational treatments within 14 days of the screening visit.
19. Non-compliance with test article (> 3 consecutive days) or IVRS subject diary completion (> 3 days) during the placebo run-in period.
20. Involvement in litigation related to the subject’s underlying medical condition. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The change from baseline in the number of spontaneous bowel movements (SBMs) per week to the end of the double-blind treatment period (study day 28). |
|
| 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 | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Information not present in EudraCT |
| E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Adaptive design bayesian algorithm for treatment allocation. |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 | Information not present in EudraCT |
| 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 |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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