| 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 | 14.1 |
| 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 | 14.1 |
| 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 |
|
| 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
To assess the efficacy of OXN for the management of opioid-induced constipation (OIC) compared with OXY in 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. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and female subjects aged 18 years or older with a clinical diagnosis of low back pain (lasting at least several hours daily) as their predominant pain condition for at least 3 months prior to screening visit (visit 1).
2. The low back pain must be related to nonmalignant and nonneuropathic conditions and may be with or without radiation (Quebec Task Force Classification 1 to 3)
3. Subjects must require opiod 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 opiod therapy for the duration of the study.
4. Subjects must be:
a. On ongoing around-the-clock 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),
b. 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.
5. For subjects on <40 mg of morphine or equivalent per day, both the
"average pain over the last 24 hours" and the "average pain over the
past 14 days" scores at the screening (visit 1) must be ≥ 5.
6. Subjects must have a self-reported history of OIC as defined by having
had while on opioids <3 complete spontaneous bowel movements
(CSBM) per week and 1 or more of the following for at least
25% of bowel movements (BMs):
a. Hard or lumpy stools
b. Straining during bowel movements
c. 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 occurring in the
absence of laxative or enema use in the previous 24 h.
7. Subjects must be willing to discontinue their current laxative regimen, including prokinetic drugs (e.g., metoclopramide).
8. Subjects must agree to the use of oral bisacodyl as their only laxative
rescue medication. Subjects taking daily fiber supplements, bulking
agents, probiotics, or macrobiotics are eligible if they are
maintained on a stable regimen for the 2 weeks before visit 1 and are
willing to maintain that regimen throughout the study, and, in the
investigator's opinion, they are willing and able to maintain adequate
hydration.
9. For subjects receiving adjunct therapy (such as transcutaneous
electrical nerve stimulation (TENS), physical therapy, biofeedback
therapy, relaxation therapy, acupuncture therapy, herbal remedies, or
nutraceuticals), 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 (4 weeks for
glucosamine and/or chondroitin sulfate) before the screening visit (visit
1) and remain unchanged during the study.
10. 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.
11. Female subjects who are premenopausal or postmenopausal less
than 1 year, or who have not had surgical sterilization (i.e., tubal
ligation, partial or complete hysterectomy) must have a negative serum
pregnancy test, be nonlactating, and willing to use adequate and reliable contraception throughout the study (e.g., barrier with additional spermicidal foam or jelly, intra-uterine device, hormonal
contraception).
12. 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. This does not include subjects
who have experienced common opioid side effects (e.g., nausea,
constipation).
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 uric-acidlowering 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. Subjects with
neuropathic conditions that have been painful or required therapy
(such as gabapentin or other neuropathic pain treatments) within the
past 3 months are also excluded.
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
3.
11. Subjects with irritable bowel syndrome (IBS) or inflammatory bowel
disease (e.g., 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 glucosegalactose 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 (excluding herbal and neutraceutical
medications as per the inclusion criteria 10). NSAIDs, aspirin, COX-2
inhibitors, and acetaminophen may be used intermittently during the
course of the study for headache, fever, or acute pain other than
low back pain; low dose aspirin for cardiovascular disease prophylaxis is
allowed. Muscle relaxants may be used intermittently during the course
of the study for treatment of acute muscle spasms. Medications
such as antiepileptics and antidepressants may be continued only if not
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, use of implanted lumbar spine
stimulator, use of implanted pump for intrathecal delivery of pain
medication, or inhalation analgesia. Subjects who have received
intrathecal pain medication through an implanted pump within 4 weeks
of the screening visit (visit 1) are excluded from entering the study.
18. The subject must not have had any of the following within the
indicated time periods before screening (visit 1):
- nerve/plexus block in the lumbar spine within 4 weeks
- neuroablation 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
19. 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.
20. Subjects with a history of malignancy within past 2 years, with
exception of basal cell carcinoma that has been successfully treated.
21. Subjects with current uncontrolled depression or other uncontrolled
psychiatric disorder |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
“Average pain over the last 24 hours” obtained at visits 6 through 9 (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) |
-Sleep Disturbance Subscale of the MOS Sleep Scale (assessed at visits 3, 4, 7, 8, and 9)
-PGIC (assessed at visit 9 or at the time of early study discontinuation or study drug discontinuation)
- 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 |
|
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| 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 |
| Denmark |
| Slovakia |
| Sweden |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 3 |
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