Opioid-induced bowel dysfunction (OBD) involves not only constipation, but also a constellation of symptoms including incomplete evacuation, bloating, abdominal distension, and increased gastric reflux. Constipation is an almost inevitable consequence of opioid use in malignant and non-malignant disease states, and one of the side effects of opioids to which few patients develop tolerance. MedDRA version: 16.0 Level: LLT Classification code 10071128 Term: Opioid induced constipation System Orga
Conditions
Sponsors
Develco Pharma Schweiz AG
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male and female subjects =18 years of age. 2. Subjects with a documented history of constipation induced or worsened by their oral or sublingual WHO step-II or step-III opioid medication for at least the last 4 weeks before Visit 1. 3. Requirement of laxatives to have bowel movements (BMs), or having less than 3 BMs per week when not taking laxatives, respectively, for at least the last 4 weeks before Visit 1. 4. Subjects with documented history of chronic severe non-malignant pain that requires around-the-clock opioid therapy and likely to benefit from WHO step-III opioid therapy for the duration of the trial. 5. Subjects with predominantly non-neuropathic pain, as determined by a DN4 Neuropathic Pain Diagnostic Questionnaire score =65 years) yes F.1.3.1 Number of subjects for this age range 106
Exclusion criteria
Exclusion criteria: 1. Subjects with any situation in which opioids are contra-indicated, severe respiratory depression with hypoxia and/or hypercapnia, severe chronic obstructive pulmonary disease, cor pulmonale, severe bronchial asthma, paralytic ileus. 2. Hypersensitivity or intolerance to any active substance, i.e. oxycodone, hydromorphone, morphine, naloxone, bisacodyl, or any of the excipients of the trial medication, e.g. subjects with hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption. 3. Intake of naloxone or naltrexone or injection of methylnaltrexone within the past 30 days prior to Visit 1. 4. Subjects unwilling to discontinue pre-trial laxative medication (except fibre supplementation or bulking agents at a stable dose) and take trial specific laxative medication. 5. Any gastrointestinal pathology or surgery or intractable vomiting likely to significantly influence drug absorption. 6. Inability to swallow the trial drugs whole (e.g. due to dysphagia). 7. Surgery within 1 month, radiotherapy or neural blockade 2 weeks prior to Visit 1 and/or anticipated and/or scheduled during the course of the trial. 8. Evidence of impaired hepatic function (total bilirubin, aspartate aminotransferase [AST], alanine transaminase [ALT],gamma-glutamyltransferase [GGT], or alkaline phosphatase [AP] >3 times the upper limit of normal). 9. Evidence of moderate or severe renal function impairment (creatinine clearance [CRCL] <60 mL/min). 10. Known or suspected significant hypotension, shock or severe cardiovascular disease 11. Known or suspected clinically relevant endocrine disorder, such as myxoedema, not adequately treated hypothyroidism or adrenocortical insufficiency (e.g. Addison's disease) 12. Known or suspected clinically significant bowel disease (e.g. paralytic ileus, significant impairment of bowel motility severe enough to potentially result in ileus, obstructive or inflammatory bowel disease, anal fissures or ulcerative proctitis). 13. Subjects with a confirmed diagnosis of ongoing irritable bowel syndrome. 14. Known or suspected acute or chronic pancreatitis or clinically relevant biliary tract disease. 15. Known or suspected significant prostatic hypertrophy or urethral stricture severe enough to potentially result in urinary retention. 16. Known or suspected CNS depression (signs/symptoms: decreased vital signs, impaired thinking and perception, slurred speech, slowed reflexes, fatigue, decreased consciousness), coma, or convulsive disorder. 17. Known or suspected cranio-cerebral trauma or elevation of intracranial pressure. 18. Known or suspected acute alcoholism, delirium tremens, or toxic psychosis. 19. History of drug addiction or drug seeking behaviour, positive test of illicit drugs at screening. 20. Concomitant treatment with other naloxone preparations (apart from IMP), naltrexone or methylnaltrexone preparations, other laxatives (except stable therapy with fibre supplementation or bulking agents), other medicines that can cause constipation or influence bowel motility, other opioid analgesics (including codeine-containing compounds), non-opioid analgesics taken on an as-needed basis, monoamine oxidase (MAO) inhibitors or any form of neural blockade or radiotherapy. Substantial changes in concomitant therapies with other compounds that can influence pain response such as nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 (COX-2) inhibitors, paracetamol, corticosteroids,
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of the trial is to demonstrate that administration of Naloxone HCl PR (prolonged-release) tablets twice daily is superior to Naloxone HCl PR Placebo in the improvement / reversal of opioid-induced constipation as determined by the bowel function index (BFI).;Secondary Objective: Secondary objectives are to assess the efficacy of Naloxone HCl PR tablets administered twice daily in the comparison to Naloxone HCl PR placebo in terms of decreased BFI and increased frequency in bowel movements, improvement of stool consistency and symptoms of defecation, global improvement of OIC and on changes of constipation-related quality of life as well as in terms of reduction of the number of days with laxative rescue medication. The safety of starting dose is to be reaffirmed and dose regimen is to be determined. In addition, safety and tolerabiliy, the effect of abrupt versus tapered cessation, the non-inferiority regarding induced pain relief, the lack of systemic effects in terms of opioid withdrawal symptoms, the rate of treatment failures and effects on non-responders to standard laxatives of Naloxone HCl PR tablets administered twice daily are to be assessed.;Primary end point(s): Primary end point is defined as the absolute change in BFI score at the end of Week 12 (Visit 11) compared to baseline (Visit 4);Timepoint(s) of evaluation of this end point: Primary end point is evaluated at the end of the trial. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Relative change in BFI score at the end of Week 12 (Visit 11) compared to baseline (Visit 4) 2. Absolute and relative changes from weekly BFI score at baseline (Visit 4) to the mean BFI score of Week 9 - 12 of the double-blind dose-escalation / treatment phase 3. Absolute and relative changes from baseline (Visit 4) in BFI score at the end of each week (at each visit) during the double-blind dose-escalation / treatment phase and the extension phase 4. Proportion of subjects (“responders”) with a decrease in BFI score of =12 as compared with baseline (Visit 4) at the end of Week 12 (Visit 11) of the double-blind dose-escalation / treatment phase 5. Number of weeks with a decrease in BFI score of =12 as compared with baseline (Visit 4) during the double-blind dose-escalation / treatment phase 6. Proportion of subjects (“additional responders”) with a decrease in BFI score of =12 in =9 weeks out of the 12-week double-blind dose-escalation / treatment phase as compared with baseline (Visit 4) 7. Absolute and relative changes from baseline (Visit 4) in mean numbers of BMs, SBMs, and CSBMs per week during the last 4 weeks (Week 9 to 12) of the double-blind dose-escalation / treatment phase 8. Absolute and relative changes from baseline (Visit 4) in mean daily number of BMs, SBMs, and CSBMs at each week during the double-blind dose-escalation / treatment phase and the extension phase 9. Proportion of subjects with =3 CSBMs per week during the last 4 weeks (Week 9 to 12) of the double-blind dose-escalation / treatment phase 10. Number of weeks with =3 CSBMs during the double-blind dose-escalation / treatment phase and the extension phase 11. Number of weeks with an increase of at least 1 CSBM over baseline (Visit 4) during the double-blind dose-escalation / treatment phase and the extension phase 12. Absolute and relative change from baseline in proportion of type 1 and 2 defecations per week according to BSFS at the end of Week 12 (Visit 11) 13 | — |
Countries
Germany, Hungary, Slovakia, Spain
Contacts
Public ContactSponsor Clinical Team
Develco Pharma Schweiz AG
Outcome results
None listed