E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Assess the effect and tolerability of standardised laxative therapy (SLT) for the reversal of opioid-induced constipation (OIC) in subjects suffering from malignant or non-malignant pain that requires around-the-clock opioid therapy |
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E.1.1.1 | Medical condition in easily understood language |
Opioid-induced constipation |
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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 | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10071128 |
E.1.2 | Term | Opioid induced constipation |
E.1.2 | System Organ Class | 100000004856 |
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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 |
Primary Objective
•To assess the effect of SLT on the frequency of soft (stool of type 3, 4 or 5 on the Bristol Stool Form Scale (BSFS)) complete bowel movements (SCBMs) per week in subjects taking World Health Organisation (WHO) step II/III opioid analgesics at Visit 8 (change from baseline to the final visit)
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E.2.2 | Secondary objectives of the trial |
The study has twelve secondary objectives. Only the first four are listed here. Please refer to Section 7.3 in the Protocol (Version 2.0, 03-Sep-2013) for the full list.
•To assess the effect of SLT on the frequency of soft (stool of type 3, 4 or 5 on the Bristol Stool Form Scale (BSFS)) complete bowel movements (SCBMs) and SCBMs non-straining (NS) per week in subjects taking World Health Organisation (WHO) step II/III opioid analgesics.
•To assess the number of subjects taking additional laxatives (including enema) or requiring procedures (e.g. manual bowel evacuation or surgical procedure) in addition to SLT.
•To assess symptoms of constipation in subjects taking SLT concomitantly with WHO step II/III opioid analgesics as measured by the Bowel Function Index (BFI).
•To assess the compliance with opioids/SLT in terms of number of subjects who did not discontinue prematurely, experience dose reduction or stop opioids/SLT due to insufficient effect and/or intolerability. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female subjects at least 18 years
2. Females less than one year post-menopausal must have a negative pregnancy test prior to the first dose of study medication, be non-lactating, and willing to use adequate and highly effective methods of contraception throughout the study. (A highly effective method of birth control is defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as sterilisation, implants, injectables, combined oral contraceptives, some intrauterine devices ((IUDs), hormonal), sexual abstinence or vasectomised partner).
3. Documented history of malignant or non-malignant pain that requires around-the-clock opioid therapy (WHO step II/III opioid analgesics).
4. Subjects treated with WHO step II/III opioid analgesics for at least 2 weeks prior to Screening Visit (Visit 1), who will continue with the opioid(s) over the proposed study period.
5. Subjects meeting the following criteria for OIC:
• Subject and Investigator confirm that the Subject’s constipation is induced, or worsened by the Subject’s opioid medication (present at Screening)
• Subjects with mean BFI score > 30 at Visit 1
• Subjects with < 3 complete bowel movements (CBMs) in the week preceding the Visit 1, based on Subject’s retrospective memory in response to Investigator’s question
6. Subjects taking at least one laxative on regular basis (i.e. on at least ≥2 intakes per week during the ≥2 weeks prior to screening) for the treatment of OIC.
7. Subjects must be willing to take SLT.
8. Subjects taking daily natural dietary fibre supplementation are eligible if they can maintain their diet throughout the study, and in the Investigator’s opinion are willing and able to maintain adequate hydration.
9. Subjects must be willing and able (e.g. mental and physical condition) to participate in all aspects of the study, including use of medication, completion of subjective evaluations, attending scheduled clinic visits, completing telephone contacts, and compliance with protocol requirements as evidenced by providing written, informed consent.
10. In the Investigator’s opinion the Subject’s concomitant medication dose will remain stable throughout the study Period (here concomitant medications mean all medications besides opioids (standard and rescue opioid treatment)).
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E.4 | Principal exclusion criteria |
Medical Conditions:
1. In the Investigator’s opinion any contraindication and precautionary condition for laxative medication(s) used in the study as per the SmPC.
2. Subjects having any potential non-opioid cause of bowel dysfunction that might be a major contributor to the constipation (Refer Appendix 18.4 for examples).
3. Surgery within 2 months prior to the start of the Screening Visit (Visit 1), or planned surgery during the Screening and Treatment periods that may affect GI motility.
4. Subjects with colostomy or ileostomy.
5. Hospitalisation expected/planned within the study Period (e.g. planned hospitalisation for the treatment of a pre-existing condition before informed consent) which can affect the outcome measure analysis.
Treatments/Medications:
6. Subjects presently taking, or who have taken opioid antagonists (e.g. naloxone, naltrexone and methylnaltrexone) or opioid antagonists containing products (e.g. oxycodone/naloxone, buprenorphine/naloxone, pentazocine/naloxone, tilidine/naloxone) ≤ 30 days prior to the start of the Screening Period.
7. Subjects already taking maximum daily dose of country specific SLT (both First and Second Line SLT) on a regular basis (i.e. ≥4 days per week) for the treatment of OIC.
8. Subjects receiving opioid substitution therapy for opioid addiction (e.g. methadone or buprenorphine).
Additional Screening Exclusion Criteria for Subjects Suffering from Non-malignant Pain:
9. Subjects who participated in a clinical research study involving a new chemical entity or an experimental drug within 30 days of study entry (defined as Visit 1).
Additional Screening Exclusion Criteria for Subjects Suffering from Malignant Pain:
10. Subjects who have received a new chemical entity or an experimental drug within 30 days of study entry (defined as Visit 1). Concurrent participation in another clinical trial is not permitted except the epidemiological study performed to assess the long-term survival data.
11. Subjects with an expected life expectancy of ≤3 months.
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E.5 End points |
E.5.1 | Primary end point(s) |
Please refer to section 14.6 of protocol for full list of outcome variables |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Please refer to section 14.6 of the protocol |
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E.5.2 | Secondary end point(s) |
Please refer to section 14.6 of protocol for full list of outcome variables |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Please refer to section 14.6 of the protocol |
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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 | 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 | 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) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
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 | |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 10 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 8 |