| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Opioid induced constipation |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10021175 |
| E.1.2 | Term | Iatrogenic constipation |
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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 demonstrate that in a group of opioid naïve non-constipated subjects with non malignant pain treatment with OXN tablets leads to a higher responder rate compared to MOR PR. A responder is defined as a subject who meets the following criteria: A subject, whose bowel function improved, did not change or did not have an unacceptable worsening compared to pre randomisation (subjective evaluation). Subjective evaluation: To what extent did your bowel function (e.g. frequency of defecation, stool consistency, ease of defecation, painful defecation) change during the treatment with study medication: Bowel function is substantially improved; Bowel function is slightly improved; Bowel function is unchanged; Bowel function is slightly impaired, but still acceptable; Bowel function is substantially impaired, no longer acceptable
A subject who does not discontinue from the study due to an AE of constipation during the first 14 +/- 2 days of the double-blind phase.
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| E.2.2 | Secondary objectives of the trial |
The following criteria will be cross-checked for plausibility against the responder criterion
Subject’s stool frequency during the study did not decrease by more than 50% compared to baseline (last 7 days before randomisation); A subject who does not take laxatives on more than 2 occasions during the four week treatment period; A subject in which the BFI score does not increase by an average of >11 during the double-blind phase compared to baseline (randomisation); Additional objectives are - Assessment of the Bowel Function Index (BFI); Assessment of Laxative intake; Assessment of Stool frequency; Incidence and kind of related adverse reactions; To assess the BPI-SF at each study visit during treatment with study medication (OXN, MOR PR); To assess the frequency of pain rescue medication intake; To assess the stool consistency during the 4 week treatment period
To assess urinary function during the 4 week treatment period (subjective evaluation).
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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 or older (females less than one year post-menopausal must have a negative serum or urine pregnancy test recorded within 72 hours 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 IUDs (Intrauterine Device, hormonal), sexual abstinence or vasoectomised partner).
2. Documented history of non malignant pain (e.g., Low Back Pain, Osteoarthritis, Neuropathic pain) that requires opioid therapy (20-40 mg oxycodone PR per day or 40 - 80 morphine PR per day) for a minimum of 4 weeks, because non-opioid therapy used previously did not result in considerable pain relief. This non-effectiveness of non-opioid therapy is to be documented for each subject. As neuropathic pain is a kind of pain that does not react very easily to opioid treatment, the ineffectiveness of the most up-to-date non-opioid treatment is to be included in the source documentation for these subjects. (Only for HU.)
3. Subjects must not have reported constipation within the last 3 months, and subjects must not have taken laxative medication in the last 3 months before the start of the study.
4. Subjects must not have received opioid containing medication in the last 6 months on a regular basis (i.e. prescribed medication or more than occasional self medication use for cough/cold etc).
5. In the investigator’s opinion the non opioid analgesic medication dose will remain stable during the double blind phase.
6. Subjects must be willing and able 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.
7. In the investigator’s opinion the subject’s non-analgesic concomitant medications, including those medications for the treatment of depression are thought to be stable, and will remain stable throughout the double-blind period of the study.
8. The subject agrees not to significantly alter their diet in any way that may affect bowel function during the course of the study.
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| E.4 | Principal exclusion criteria |
1. Any history of hypersensitivity to oxycodone, naloxone, morphine, related products or other ingredients.
2. Any contraindication to bisacodyl and other ingredients
3. Active alcohol or drug abuse and/or history of opioid abuse.
4. Evidence of clinically significant cardiovascular, renal, hepatic, gastrointestinal (e.g. paralytic ileus), or psychiatric disease, as determined by medical history, clinical laboratory tests, ECG results, and physical examination, that would place the subject at risk upon exposure to the study medication or that may confound the analysis and/or interpretation of the study results.
5. Chronic or intermittent pain that results from Fibromyalgia, Rheumatoid Arthritis or Cancer.
6. Abnormal aspartate aminotransferase (AST; SGOT), alanine aminotransferase (ALT; SGPT), or alkaline phosphatase levels (>3 times the upper limit of normal) or an abnormal total bilirubin and/or creatinine level(s) (outside of the reference range), gamma glutamyl transpeptidase (GGT or GGTP) ≥5 times the upper limit of normal.
7. Subjects receiving hypnotics or other central nervous system (CNS) depressants that, in the investigator’s opinion, may pose a risk of additional CNS depression with opioid study medication.
8. Subjects with uncontrolled seizures or convulsive disorder.
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 the start of the Screening Period).
10. Surgery within 2 months prior to the start of the Screening Period, or planned surgery during the 4-week Double-blind Phase that may affect GI motility or pain.
11. Subjects presently taking, or who have taken, naloxone less than or equal to 30 days prior to the start of the Screening Period
12. Subjects with a history of recurrent diarrhea in the 3 months before the start of the screening period.
13. Subjects with any situation in which opioids are contraindicated, severe respiratory depression with hypoxia and/or hypercapnia, severe chronic obstructive lung disease, cor pulmonale, severe bronchial asthma, paralytic ileus
14. Subjects with myxoedema, hypothyroidism, Addison`s disease, increase of intracranial pressure.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy variable is given by a responder criterion where a responder is defined as a subject:
• whose bowel function did not approach an unacceptable worsening when compared to pre randomisation (subjective evaluation), and
• who does not discontinue from the study due to an AE of constipation during the first 14 +/- 2 days of the double-blind phase.
The responder rates of the treatment groups will then be compared by means of a one-sided Fisher’s exact test at the 5% significance level testing on superiority of the OXN results over the MOR PR results.
Efficacy Assessment(s):
Efficacy variable of main interest:
Responder rate based on:
• Subjective evaluation of bowel function
• AEs of constipation leading to discontinuation of subject
Further efficacy variables:
• Stool frequency (number of bowel movements the subject has had in the last 7 days before the study visit)
• Laxative use (frequency and amount)
• BFI score (Bowel Function Index (BFI), recorded in the Case Report Form (CRF) at each assessment visit.
• Incidence and kind of related adverse reactions
The Responder rate will be the number of positive subjective assessments. Sensitivity analysis for the responder rate will also account for the secondary measures
• Brief pain Inventory
• Patient assessment of stool consistency (mean over last 7 days assessed at each clinic visit, Bristol stool scale)
• Analgesic rescue medication use (Amount of rescue medication recorded on the rescue medication wallet.
• The subjective evaluation will also be analysed descriptively
• Urinary function
To what extent did your urinary function change during the treatment with study medication:
Urinary function is substantially improved
Urinary function is slightly improved
Urinary function is unchanged
Urinary function is slightly impaired, but still acceptable
Urinary function is substantially impaired, no longer acceptable
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | Information not present in EudraCT |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Information not present in EudraCT |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| 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 |
| Double dummy, pilot study |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 | Information not present in EudraCT |
| 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 | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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