| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Bladder Pain Syndrome (BPS), formerly addressed as IC/PBS (interstitial cystitis /Painful Bladder Syndrome) |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Female diseases of the urinary and reproductive systems and pregancy complications [C13] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008927 |
| E.1.2 | Term | Chronic interstitial cystitis |
| E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
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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 |
| The aim of this study is to investigate the efficacy and safety of OXN PR in the treatment of BPS and to further support the evidence for the use of opioids in this indication. The main objective is to estimate the Subjects’ average pain over the last 24 Hours assessed at each study Visit during treatment with OXN PR compared with placebo as measured by the Pain Intensity Scale (NRS 0 – 10). |
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| E.2.2 | Secondary objectives of the trial |
- To assess the frequency of pain rescue medication intake.
- To assess BPI-SF at each clinic Visit during treatment with study medication.
- To assess the efficacy based on the O’Leary-Sant Interstitial Cystitis Symptom Index (ICSI) score/ O’Leary-Sant Interstitial Cystitis Problem Index (ICPI) score.
- To assess overall health based on the SF-36 v2.
- To assess micturition (volume and time) based on 24 hours patient diary assessing 2 days in the last week prior to Visits 6, 8, 10 and 16.
- To assess urinary urgency using the Patients' Perception of Intensity of Urgency Scale (PPIUS).
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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 |
Pharmacogenomic sub-study (compare protocol section 12.2):
All subjects enrolled in the study OXN2503 will be considered for enrollment into the pharmacogenomic sub-study sponsored by Mundipharma Research GmbH. Pharmacogenomic samples will be stored at the clinical laboratory to provide a resource for future studies which will examine why subjects may respond differently to certain drugs by analyzing specific genetic markers. Genetic variants in genes of the drug targets such as the opioid receptors or genes involved in their signaling 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 |
Inclusion criteria:
1. Females, 18 years of age or older.
2. Females less than one year post-menopausal must have a negative serum or urine pregnancy test recorded 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 vasectomised partner).
3. Subjects with a history of severe pain due to BPS for at least 6 months (mean average BPS pain over last 6 months ≥ 5, NRS 0 – 10) prior to entry into the study and based on the Investigators’ judgement and clinical experience the Subjects are likely to benefit from WHO step III opioid therapy for the duration of the study.
4. Subjects who experience the complaint of suprapubic pain related to bladder filling, accompanied by all of the following 3 criteria, in the absence of proven urinary infection or other obvious pathology:
• Must have a total score of ≥ 8 on the O'Leary-Sant Interstitial Cystitis Symptom Index (ICSI) and a score of > 0 on each of the 4 questions on the ICSI.
• Must have a total score of ≥ 8 on the O'Leary-Sant Interstitial Cystitis Problem Index (ICPI) and a score of > 0 on each of the 4 questions on the ICPI.
• Must have an average of ≥ 8 voids per day and an average of ≥ 2 voids at night (nocturia) within the last month.
5. Subject’s treatment of pain due to BPS is insufficient (insufficient efficacy or tolerability, based on a clinical judgement).
6. Subjects with a documented history of attempts to optimise the treatment of pain due to BPS.
7. Subject’s pre-study BPS treatment is expected to remain stable throughout the duration of the study (OXN PR or matching placebo are given as add-on therapy).
8. Subjects must not have received opioid containing medication in the last 6 months or ibuprofen (Ibu) during the last 2 weeks on a regular basis (i.e. prescribed medication or more than occasional self medication use for cough, cold etc).
9. Subjects taking pre-study, non-opioid analgesics, and any other concomitant medications, including medications for the treatment of depression and are considered necessary for the Subject’s welfare, and are anticipated to remain stable throughout the Double-blind Phase of the study, and are to be continued under the supervision of the investigator.
10. Subjects willing and able to participate in all aspects of the study and comply with the use of study medication.
Criteria for entry into the Double-blind Phase:
1. Subjects continue to comply with Screening Inclusion/Exclusion criteria.
2. Subjects must have an average of ≥ 8 voids per day and an average of ≥ 2 voids (nocturia) at night as assessed in a diary recording 2 periods of 24 hours during the Screening Period.
3. Subjects must not have any indication for current acute bacterial cystitis based on urinalysis (urine dipstick) assessed at Visit 2.
4. Subjects with a mean pain value of ≥ 5 (average pain value over the last 24 hours) as assessed during the last 7 days prior to Visit 2. |
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| E.4 | Principal exclusion criteria |
Exclusion criteria:
1. Females who are pregnant (positive β-hCG test) or lactating.
2. Subjects with any contraindication/history of hypersensitivity to oxycodone, naloxone, ibuprofen (Ibu), related products or other ingredients.
3. Subjects who previously received ibuprofen regularly for treatment of BPS pain without demonstrating any relevant analgesic effect.
4. Subjects with a history of, or existing peptic ulceration that would place the Subject at risk upon exposure to ibuprofen or that may confound the analysis and/or interpretation of the study results.
5. Subjects with a history of bronchospasm, rhinitis, urticaria, particularly associated with therapy with aspirin or other non-sterioidal anti-inflammatory drugs (NSAIDs).
6. Subjects with any situation in which opioids are contraindicated like severe respiratory depression with hypoxia and/or hypercapnia, severe chronic obstructive lung disease, cor pulmonale, severe bronchial asthma or paralytic ileus.
7. Subjects with myxoedema, untreated hypothyroidism, Addison`s disease or increase of intracranial pressure.
8. Subjects with uncontrolled seizures or convulsive disorder.
9. 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.
10. Abnormal aspartate aminotransferase (AST; SGOT), alanine aminotransferase (ALT; SGPT), or alkaline phosphatase levels (> 3 times the upper limit of normal), gamma glutamyl transpeptidase (GGT or GGTP) > 3 times the upper limit of normal.
11. Abnormal total bilirubin and/or creatinine level(s) (> 1.5 times the upper limit of normal).
12. Active alcohol or drug abuse and/or history of opioid abuse.
13. Subjects with a positive urine drug test at screening Visit 1, which indicates unreported illicit drug use or unreported use of a concomitant medication not required to treat the Subjects’ medical condition(s).
14. Subjects suffering from documented confusable diseases for bladder pain syndrome (see Appendix 12.5) determined by the medical history/physical examination, urine dip stick test or if needed ultrasound.
15. Chronic or intermittent pain that results from pain conditions other than Bladder Pain Syndrome (BPS) requiring opioid analgesics.
16. Subjects who received a botulinum toxin injection in the bladder wall within the last 6 months prior to the Screening Visit.
17. Subjects who received a hydrodistension within the last 4 months prior to the Screening Visit.
18. Subjects who have had cystoscopic evaluation within 4 weeks prior to the Screening Visit.
19. Subjects presently taking, or who have taken, naloxone ≤ 30 days prior to the Screening Visit.
20. Subjects presently taking or who have taken monoamine oxidase inhibitors (MAOI) ≤ 2 weeks prior to the Screening Visit.
21. 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.
22. Subjects who participated in a clinical research study involving a new chemical entity or an experimental drug within 30 days prior to the Screening Visit.
23. Surgery within 2 months prior to the Screening Visit, or planned surgery during the 8-week Double-blind Phase that may affect GI motility, bladder function or pain. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The Efficacy Variable of main interest is the Pain Intensity Scale – Average pain over the last 24 hours, as assessed at each study Visit during the Double-blind phase |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Evaluation after study end. No interim analysis planned |
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| E.5.2 | Secondary end point(s) |
- Frequency of analgesic rescue medication use.
- The ICSI and the ICPI measure urinary and pain symptoms and assesses how problematic symptoms are for patients with interstitial cystitis (IC). Psychometric performance of both instruments is good, with the ICSI demonstrating excellent ability to discriminate characteristics between patients and controls. Both indices have been useful in the evaluation and management of patients with IC and should be particularly useful in clinical trials of new therapies for this condition, where reliable, validated, and reproducible outcome measures are critically important. The ICSI contains 4 items that measure urgency and frequency of urination, night-time urination, and pain or burning. The ICSI index score is the sum of the item scores (range: 0 – 20) and it is a valid, reliable, and responsive measure of change in IC symptoms.
- Pain severity subscale score and interference of pain subscale score from the Brief Pain Inventory- Short Form (modified BPI-SF). The Pain severity subscale score is the mean of the (non-missing scores from the) 4 pain intensity items and the Interference subscale score is the mean of the (non-missing scores from the) 7 interference items. Further detail on the computation of these subscale scores will be specified in the statistical analysis plan.
- The SF-36 v2 health survey. The summary scores to be employed are the SF-36 v2 scores for the 8 subscales (physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health, the health transition question, and 2 summary measures of physical health (aggregate of physical functioning, role-physical, bodily pain and general health scales) and mental health (aggregate of the vitality, social functioning, role-emotional and mental health scales). The scoring algorithms for the subscale scores are described in the statistical analysis plan.
- Micturition diary (volume and time).PPIUS. The PPIUS is a validated, 5-point scale designed to assess patient perception of intensity of urgency. The scale ranges from 0 to 4 with grades 3 and 4 representing urgency and urgency incontinence.
- Pain Intensity Scale – Average pain over the last 24 hours, as assessed at each study Visit during the Open-label Phase. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Evaluation after study end. No interim analysis planned |
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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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 4 |
| 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 | 0 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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