| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Opioid-induced Constipation & Moderate to Severe Chronic Low back Pain |
|
| E.1.1.1 | Medical condition in easily understood language |
| Back Pain and Constipation |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Digestive System and Oral Physiological Phenomena [G10] |
| 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 | 10003988 |
| E.1.2 | Term | Back pain |
| E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| 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 |
|
| 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 assess the analgesic efficacy of OXN compared to placebo in opioid-experienced subjects with moderate to severe low back pain and opioid-induced constipation who require around-the-clock opioid therapy.
|
|
| E.2.2 | Secondary objectives of the trial |
To assess the safety and tolerability of OXN in opioid-experienced subjects with moderate to severe low back pain and opioid-induced constipation who require around-the-clock opioid therapy.
To assess the analgesic efficacy of OXN compared to placebo in opioidexperienced subjects with moderate to severe low back pain and opioidinduced constipation who require around-the-clock opioid therapy. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and female subjects ≥ 18 years of age with moderate to severe, chronic low back pain (lasting at least several hours daily) as their predominant pain condition for at least 3 months prior to screening period.
2. The low back pain must be related to nonmalignant and
nonneuropathic conditions and may be with or without radiaton (Quebec
Task Force Classification 1 to 3)
3. Subjects must be - On ongoing opioid analgesic medication for at least 4 weeks prior to the screening visit (visit 1) and on a stable dose of opioid analgesic medication equivalent to 20 to 160 mg (inclusive) of morphine per day for the last 2 weeks prior to the screening visit (visit 1)
or
Taking 0 to less than 20 mg of morphine or its equivalent per day for the last 2 weeks prior to the screening visit (visit 1) due to OIC
4. Subjects must require opioid analgesic treatment in the range of 40 to 160 mg (inclusive) of morphine or its equivalent daily and be likely to benefit from chronic around-the-clock opioid therapy for the duration of the study.
5. Subjects must have an average pain over the last 14 days score ≥ 5 at the screening visit
6. Subjects must have an average pain over the last 24 hours score ≥ 5 at the screening visit
7. Subjects must have a self-reported history of OIC, defined as having
had while on opiods <3 complete spontaneous bowel movements
(CSBM) per week and 1 or more of the following for at 25% of bowel
movements (BMs):
- hard or lump stools
- straining during bowel movements
- A sensation of incomplete evacuation after bowel movements
A CSBM is defined as a spontaneous bowel movement (SBM) that is
accompanied by the subject self-reporting a feeling of complete
evacuation. An SBM is defined as a bowel movement occuring in the
absence of laxative or enema use in the previous 24h.
8. Subjects must be willing to discontinue their current laxative regimen
9. Subjects must agree to the use of oral bisacodyl as their only laxative rescue medication.
10. For subjects receiving adjunct therapy such treatment must be stopped before treatment with OXY is initiated, or, if continued, the treatment should have been at a stable dose/intensity and frequency for 2 weeks before the
screening visit (visit 1) and remain unchanged during the study.
11. If taking oral corticosteroids, subjects must be on at a stable dose for at least 6 weeks before the screening visit (visit 1) and be willing to maintain that dose throughout the study.
12. Female subjects who are premenopausal or postmenopausal less than 1 year, or who have not had surgical sterilization must have a negative serum pregnancy test
13. Subjects who are willing and able to be compliant with the protocol, and who provide written informed consent. |
|
| E.4 | Principal exclusion criteria |
1. Subjects with any contraindication or any history of hypersensitivity
to oxycodone, naloxone, or other opioids.
2. Subjects with any contraindication to bisacodyl.
3. Subjects with neurologic signs, or presumptive or confirmed
compression of a spinal nerve root (i.e., Quebec Task Force Classification
4 to 6)
4. Subjects with acute spinal cord compression, acute compression fracture, seronegative spondyloarthropathy, acute nerve root compression, cauda equina compression, fibromyalgia, reflex sympathetic dystrophy or causalgia (complex regional pain syndrome), diabetic amyotrophy, meningitis, discitis, or back pain due to secondary infection, tumor, or postherpetic neuralgia.
5. Subjects with gout, unless controlled on stable suppressive treatment
with colchicine or uricacid-lowering therapy without any attacks for ≥ 2 years and the subject has not been using NSAIDs or COX-2 inhibitors on a regular basis.
6. Subjects with pseudogout, psoriatic arthritis, active Lyme disease,
rheumatoid arthritis or other inflammatory arthritis, or neuropathic conditions that have been painful or required therapy within the last 3 months
7. Subjects who, in the opinion of the investigator, are exhibiting significant opioid withdrawal such that they should not be in the study.
8. Subjects with evidence of significant structural abnormalities of the gastrointestinal tract (e.g., bowel obstruction, strictures) or any diseases/conditions that affect bowel transit (e.g., ileus, uncontrolled hypothyroidism).
9. Subjects with a history of prior chronic constipation (including functional constipation or pelvic floor dyssynergy) that was present for more than three months and that was not related to opioid use.
10. Subjects currently with clinically diagnosed diarrhea, defined as 3 stools/day that are loose or watery in nature within 2 weeks before visit 2.
11. Subjects with irritable bowel syndrome (IBS) or inflammatory bowel disease (eg, ulcerative colitis, Crohn‘s disease).
12. Subjects who had surgery that may affect gastrointestinal motility or gastrointestinal pain within 2 months prior to the start of the screening period, or who plan such surgery during the study.
13. Subjects with a history of fecal incontinence.
14. Subjects who require ongoing therapy with medications (other than opioids) that have contributed to the subjects‘ constipation in the judgment of the investigator.
15. Subjects with hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
16. Subjects who cannot or will not agree to completely stop all incoming opioid and nonopioid analgesic medications and other medications used for chronic pain
17. Subjects who cannot or will not agree to forego the following
treatments during the study: nerve/plexus blocks or ablation in the
lumbar spine, neurosurgical procedures for pain control in the lumbar
spine, Botulinum toxin injections for pain control in the lumbar spine,
steroid injections in the lumbar spine, or inhalation analgesia
18. Subjects who had surgical procedures directed towards the source of chronic low back pain within 6 months of the screening visit (visit 1) or planned during the study.
19. Subjects with a history of malignancy within past 2 years, with exception of basal cell carcinoma that has been successfully treated.
20. Subjects with current uncontrolled depression or other uncontrolled psychiatric disorder
21. Subjects with an average QTcF of > 470 msec at the screening visit (visit 1) will be excluded.
22. Subjects currently taking, or who have taken naloxone, naltrexone, methylnaltrexone, or alvimopan within 10 days before the screening visit (visit 1).
23. Subjects with a history of alcohol, medication, or illicit drug abuse or addiction and/or history of opioid abuse or addiction at any time.
24. Subjects with evidence of impaired liver function and impaired kidney function upon entry into the study
25. Subjects with increase of intracranial pressure and/or epilepsy
26. Subjects with clinically significant cardiovascular disease or dysrhythmias.
27. The subject must not have had any of the following within the
indicated time periods before screening;
- nerve/plexus block in the lumbar spine within 4 weeks
- neuroblation in the lumbar spine within 6 weeks
- Botulinum toxin injection for pain control in the lumbar spine within 3
months
- steroid injections of the lumbar spine within 6 weeks or any
intravenous or intramuscular steroid injections within 4 weeks
28. Patients taking moderate to strong CYP3A4 inhibitors if the dose has
not been stable for at least 1 month
29. Subjects with a positive result on urine drug testing for illicit drugs
or non-prescribed opioids or with a positive breath alcohol result at visit
1
30. Subjects who have used any investigational medication within 30
days prior to the first dose of study medication |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
“Average pain over the last 24 hours” obtained at visits 5 through 8 (weeks 2 through 12) during the double-blind period
and
Overall spontaneous bowel movements (SBM) responder rates over the 12 week double-blind period |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
-SBM Responder at least 50% of the weeks in the double-blind period
-Laxative-free Responder at least 50% of the weeks in the double-blind
-Sleep Disturbance Subscale of the MOS Sleep Scale (assessed at visits 2, 3, 6, 7, and 8)
-PGIC (assessed at visit 8 or at the time of early study discontinuation or study drug discontinuation) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | No |
| 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.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 34 |
| 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 |
| Czech Republic |
| Hungary |
| Italy |
| Poland |
| United States |
|
| 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
|
|
| 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 | 5 |
| 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 | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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