| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Constipation, defined as "the evacuation of hard stools less frequently than is normal for the individual", is an almost inevitable side effect of opioid use. |
|
| 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 | 16.1 |
| 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 |
| The primary objective of the trial is to demonstrate that administration of Naloxone HCl PR (prolonged-release) tablets once daily is superior to Naloxone HCl PR Placebo in the improvement / reversal of opioid-induced constipation (OIC) as determined by the Bowel Function Index (BFI). |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives are to assess the efficacy of Naloxone HCl PR
tablets administered once daily in the treatment of OIC 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 once daily are to be assessed. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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.
3. Requirement of laxatives to have bowel movements (BMs), or having less than 3 BMs per week when not taking laxatives, respectively.
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 < 4 .
6. Subjects willing and able (e.g. mental and physical condition) to participate in all aspects of the trial, including use of medication, completion of subjective evaluations, attending scheduled visits, completing telephone interviews, and compliant with protocol requirements as evidenced by providing signed written informed consent. |
|
| E.4 | Principal 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) & 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 &/or anticipated &/or scheduled during the course of the trial.
8. Evidence of impaired hepatic function (total bilirubin, aspartate aminotransferase [AST], alanine aminotransferase [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 acute urinary retention.
16. Known or suspected CNS depression (signs/symptoms: decreased vital signs, impaired thinking & 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. Known or suspected severe psychiatric disorders.
20. History of drug addiction or drug seeking behaviour, positive test of illicit drugs at screening.
21. 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, anti-depressants, anxiolytics, neuroleptics or non-drug treatments such as physical measures or acupuncture.
22. For women: Pregnancy or breast-feeding. Women of childbearing potential unable or unwilling to undergo pregnancy tests & practice adequate contraceptive measures. Reliable methods for women are hormonal contraceptives, surgical intervention (e.g. tubal ligation), intrauterine device (IUD), double-barrier methods and true sexual abstinence. For men: Men unable or unwilling to practice adequate contraceptive measures. Reliable methods for men are surgical intervention (e.g. vasectomy), double-barrier methods, sexual abstinence and reliable contraception (as described above) of the female partner.
23. Any other condition of the subject that in the opinion of the investigator may compromise evaluation of the trial treatment or may jeopardise subject's safety, compliance or adherence to protocol requirements.
24. Previous enrolment in this trial or participation in any other drug investigational trial within the past 30 days (or five half-lives of IMP whichever is longer) prior to Visit 1.
25. Persons committed to an institution by virtue of an order issued either by the judicial or other authorities.
26. Employees of the investigator or trial centre as well as family members of the employees or the investigator
27. Subjects currently on transdermal drug delivery system (TDDS) opioids. |
|
| E.5 End points |
| E.5.1 | 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). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Primary end point is evaluated at the end of the trial |
|
| E.5.2 | 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 doseescalation/ 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 doseescalation/ 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 doseescalation / 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 doseescalation / 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 (Visit 4) in proportion of type 1 and 2 defecations per week according to BSFS at the end of Week 12 (Visit 11)
13. Absolute and relative change from baseline (Visit 4) in each item of the Symptoms of Defecation Score to Week 12 (Visit 11)
14. Absolute and relative change from baseline (Visit 4) in PAC-SYM at the end of each 2-week escalation step as well as at the end of the double-blind dose-escalation / treatment phase and the extension phase
15. Absolute and relative change from baseline (Visit 4) in PAC-QOL at the end of each 2-week escalation step as well as at the end of the double-blind dose-escalation / treatment phase and the extension phase
16. Mean number of days with laxative rescue medication use per week during the single-blind Naloxone HCl PR Placebo run-in phase, the double-blind dose-escalation / treatment phase and the extension phase
17. Percentage of days with laxative use during the single-blind
Naloxone HCl PR Placebo run-in phase, the double-blind dose-escalation / treatment phase, and the extension phase
18. Differences in recurrence of OIC-related symptoms using BFI;
number of BMs, SBMs, and CSBMs; BSFS, Symptoms of Defecation Score and laxative use between abrupt and tapered cessation of Naloxone HCl PR /Naloxone HCl PR Placebo during the extension phase
19. Correlation between opioid total daily dose (TDD) (morphine
equivalents) and individually determined final IMP dose at Week 12
of double-blind dose-escalation / treatment phase |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary end points are evaluated at the end of the trial. |
|
| 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 | 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 | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
Dose-escalation to determine a dosing regimen in order to reveal an
optimal dose of Naloxone HCL PR tablets administered once daily for the treatment of opioid-induced constipation. |
|
| 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 |
| Dose-escalation to determine a dosing regimen of Naloxone HCL PR |
|
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 65 |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 15 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 15 |
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