| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
The intended indication is:
Severe pain, which can be adequately managed only with opioid analgesics. The opioid antagonist naloxone is added to counteract opioid-induced constipation by blocking the action of oxycodone at opioid receptors locally in the gut. |
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| E.1.1.1 | Medical condition in easily understood language |
| Severe non-malignant pain or malignant pain, requiring opioids |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10058019 |
| E.1.2 | Term | Cancer pain |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10033371 |
| E.1.2 | Term | Pain |
| E.1.2 | System Organ Class | 10018065 - General disorders and administration site conditions |
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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 |
1. To demonstrate that subjects taking OXN PR have improvement in symptoms of constipation as measured by the Bowel Function Index (BFI) compared to subjects taking OxyPR.
2. To demonstrate non-inferiority of OXN PR compared to OxyPR with respect to the analgesic efficacy based on the subjects' "Average Pain over last 24 Hours" assessed at each Double-blind Phase visit as measured by the Pain Intensity Scale. |
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| E.2.2 | Secondary objectives of the trial |
1. To assess "Average Pain over last 24 Hours" based on the Pain Intensity Scale collected daily in the subject diary during the Double-blind Phase.
2. To assess analgesic rescue medication use.
3. To assess laxative rescue medication use.
4. To assess aspects of constipation (Complete Spontaneous Bowel Movement (CSBMs)).
5. To assess quality of life aspects based on the EuroQol EQ-5D.
6. To assess bowel function, pain and safety parameters during the extension phase. |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
All subjects enrolled in the study OXN3506 will be considered for enrolment into the pharmacogenomic sub-study sponsored by Mundipharma Research GmbH & Co. KG.
Informed consent for the collection, storage and future analysis of genetic pharmacogenomic samples will be obtained during the Screening Phase of the main study OXN3506 by the Investigator or their designate. There is a separate consent form for the pharmacogenomic sub-study and subjects do not have to consent to this sub-study in order to participate in the main trial.
Pharmacogenomic samples will be stored at the clinical laboratory to provide a resource for future analysis which will examine why subjects may respond differently to certain drugs by analysing specific genetic markers. Genetic variants in genes of the drug targets such as the opioid receptors or genes involved in their signalling pathways could affect the drug efficacy. Similarly, variations in genes involved in the metabolism of the compounds, e.g. Cytochrome P450 2D6, can have an influence on the bioavailability of the compounds which could lead to an increased level of side effects or an alteration of the drug efficacy. Therefore some drugs may be more effective in certain subject groups or they may cause more side effects in certain subjects depending on their genetic makeup. All pharmacogenomic samples will be used by the sponsor or designees and research will be monitored and reviewed by a committee of scientists and clinicians.
Pharmacogenomic samples will be collected in other opioid trials and may be combined with pharmacogenomic samples collected from this study in order to assess a wider group of subjects’ response to treatment.
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| E.3 | Principal inclusion criteria |
1. Male or female subjects at least 18 years (females <than 1 year post-menopausal must have a -ve serum or urine pregancy test prior to the 1st dose of study medication, be non-lactating & willing to use adequate & 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. < than 1% per year, when used consistently & correctly such as sterilisation, implants, injectables, combined oral contraceptives, some IUDs, sexual abstinence or vasectomised partner.
2. Subjects who are receiving WHO step III opioid analgesic medications for the treatment of non-malignant or malignant pain.
3. Documented history of non-malignant or malignant pain that requires around-the-clock opiod therapy (100-160mg oxycodone PR per day for a minimum of 5 weeks).
4. subjects with constipation caused or aggravated by opioids:
- Subject's medical need of regular intake of laxatives to have at least 3 bowel evacuations per week, or having <than 3 bowel evacuations when not taking a laxative.
- In the opinion of the Subject & investigator confirm that the subject's constipation is induced or worsened by the subject's pre-study opioid medication (present at screening).
5. Subjects must be willing to discontinue their current opioid analgesic routine & willing to comply with the use of opioid study medication.
6. Subjects must be willing to discontinue their current laxative regimen & willing to comply with the use of oral bisacodyl as lacative rescue medication.
7. Subjects taking daily fibre supplementation or bulking agents are eligible if they can be maintained on a stable dose & regimen throughout the study, & in the investigator's opinion are willing & able to maintain adequate hydration.
8. Subjects must be willing & able (eg. mental & 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 & compliance with protocol requirments as evidenced by providing written, informed consent.
9. 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 & will remain stable throughout the double-blind phase of the study.
10. In the investigator's opinion the non-opioid analgesic medication dose will remain stable during the double-blind phase.
11. Subjects who are dissatisfied (lack of efficacy or unacceptable tolerability) with their current WHO step III opioid analgesic medication.
12. Criteria for entry into Run-in Period:
- Subjects continue to satisfy Screening Inclusion/Eclusion criteria.
13. Criteria for entry into the Double-blind Phase:
- Subjects continue to satisfy Screening Inclusion/Exclusion criteria
- Subjects should be on a stable dose of 50, 60, 70 or 80 mg oxycodone PR twice daily on at least 4 consecutive days prior to randomisation.
- Subjects must rate their pain ("Average Pain" over last 24 Hours) as </= 4 on 0-10 scale with < / = to 2 doses of OxyIR analgesic rescue medication per day for either the last 3 consecutive days or 4 of the last 7 days.
- Subjects must have confirmed opioid related constipation, which is defined as having <3 CSBM-NSs during the last 7 days of the Run-in Period.
- Subjects demonstrate compliance with rescue medication use (OxyIR), oral bisacodyl), taking open-label OxyPR, and completing daily diaries.
14. Criteria for entry to the Extension Phase:
- Subjects who completed the 5 weeks Double-blind Phase or discontinued prematurely the Double-blind Phase due to constipation.
- Subjects who require continuation of daily opioid analgesic treatment & are likely to benefit from chronic opioid therapy for the duration of the Extension Phase.
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| E.4 | Principal exclusion criteria |
1. Any history of hypersensitivity to oxycodone, naloxone, related products, bisacodyl or other ingredients of the study medication.
2. Any contraindication to oxycodone, naloxone, bisacodyl and other ingredients of the study medication.
3. Active alcohol or drug abuse and/or history of opioid abuse.
4. Subjects with a +ve urine drug test at screeing Visit 1, which indicates unreported illicit drug use or unreported use of a concomitant medication not required to treat the subject's medical condition(s).
5. Evidence of clinically significant cardiovascular, renal, hepatic, gastrointestinal (eg. paralytic ileus) or psychiatric disease, as determined by medical history, clinical laboratory tests, ECG results & 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 resulrs.
6. Chronic or intermittant pain that results from Fibromyalgia or Rheumatoid Arthritis.
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. Surgery within 2 months prior to the start of the Screening Period, or planned surgery during the 5-week Double-blind Phase that may affect GI motility or pain.
10. Subjects presently taking, or who have taken, naloxone or methylnaltrexone </=30 days prior to the start of the Screening Period.
11. Subjects suffering from diarrhoea.
12. Subjects with any situation in which opioids are contraindicated e.g, severe respiratory depression with hypoxia and/or hypercapnia, severe chronic obstructive lung disease, parlaytic ileus.
13. Subjects with hyperthyroidism (non-compensated), addison's disease, increase of intracranial pressure.
14. Abnormal aspartate aminotransferase (AST; SGOT), alanine aminotransferase (ALT; SGPT), or alkaline phosphatase lavels (>3 times the upper limit of normal) or an abnormal total bilirubin and/or creatinine level(s) (>1.5 times the upper limit of normal), gamma glutamyl transpeptidase (GGT or GGTP) >/= 3 time the upper limit of normal. Bilirubin or creatinine values below the lower limit of normal are not necessarility a criterion for an improvement of organ function. Therefore values out of the lower normal range do not automatically lead to an exclusion of the subject from the study. The decision to discontinue a subject from the study due to bilirubin or creatinine level below the lower limit of normal should be based on the medical judgement of the investigator. Furthermore the decision should also be based on the presence or absence of pathophysiological impairment of respective organs.
15. Subjests presently taking or who have taken monoamine oxidase inhibitors (MAOI) </= 2 weeks prior to the start of the Screening Period.
Exclusion criteria for subjects suffering from non-malignant pain:
16. Subjects who participated in a clinical research study involving a new chemical entity or an experimental drug within 30 days of study entry (start of Screening Period).
Exclusion criteria for subjects suffering from cancer pain:
17. Subjects with known or suspected unstable brain metastases or spinal cord compression that may require changes in steroid treatment throughout the duration of the study.
18. Cyclic chemotherapy in the 2 weeks before the screening visit or planned during the study that has shown in the past to significantly influence bowel function. If subjects are having their first cycle of chemotherapy during the 2 weeks before the screening visit or during the study they should be excluded from the study.
19. Radiotherapy that, in the investigator's opinion, would influence bowel function or pain during the study.
20. Subjects who have received a new chemical entity or an experimental drug within 30 days of study entry (defined as start of the screening period). Concurrent participation in another clinical trial is not permitted unless long-term survival data will be assessed in an epidemiological study only.
21. Subjects with an expected life expectancy of <6 months.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Assessment of constipation symptoms through measurement of Bowel Function
Assessment of analgesic efficacy through measurement of Pain Intensity |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Core Phase Visit 7 to 10 inclusive (day 7 to 35)
Extension Phase Visit 11 to 19 inclusive (day 0 to 168) |
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| E.5.2 | Secondary end point(s) |
Assessment of Pain over last 24 hours
Need for Analgesic rescue
Need for Laxative rescue
Assessment of constipation
Assesment of QoL |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| During the double-blind phase |
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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 | Yes |
| 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) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
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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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 75 |
| 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 |
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| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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