| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Opioid induced constipation |
|
| 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 | 20.0 |
| 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 if Naloxone HCl Prolonged Release Tablets taken twice daily are more efficient compared to placebo in the treatment of opioid induced constipation (constipation caused by opioid treatment). To test this the number of complete spontaneous bowel movement (= a bowel movement that occur without intake of additional laxative medication within the last 24 hrs and with a sensation of a complete evacuation) will be compared between the two different strengths of test medication and placebo. |
|
| E.2.2 | Secondary objectives of the trial |
To compare the following between Naloxone HCl PR Tablets administered twice daily at a total daily dose of 24 mg and 48 mg against placebo:
1. Weekly number of complete spontaneous bowel movements (a bowel movement without a laxative being taken during the last 24 hours) and spontaneous bowel movements
2. Weekly spontaneous bowel movement and overall spontaneous bowel movement responder rate
3. Type of stool consistency using a special tool - Bristol Stool Form Scale, which is a questionnaire to measure constipation from the patient´s perspective
4. Constipation symptoms
5. Special Bowel Tool - Bowel Function Index
6. Number of times a laxative is taken as rescue medication
7. How the patient feels about their constipation
8. How the patient feels about their quality of life
9. If the patient and physician are satisfied with the Naloxone HCl PR Tablets treatment
10. Whether the patient would take the drug again
11. Whether the amount of opioid taken in relation to the amount of Naloxo |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria at Visit 1:
1 - Male or Female >18 years of age with OIC
2 - Long-term WHO step III opioid therapy for at least 3 months prior to screening for treatment of chronic non-cancer pain
3 - Receiving a stable maintenance regimen with one long-acting oral or transdermal WHO step III opioid (except tapentadol) consisting of a total daily dose of ≥40mg morphine equivalent for a minimum of 4 weeks prior with no anticipated change in opioid dose requirement over the proposed trial period
4 - Symptoms of constipation with onset after the start of opioid medication for at least the last 4 week prior to screening:
All of the following:
- <3 spontaneous bowel movements per week
- loose stools are rarely present without the use of laxatives
Two or more of the following:
- straining during at least 25% of defecations
- lumpy or hard stools in at least 25% of defecations
- sensation of incomplete evacuation in at least 25% of defecations
- sensation of anorectal obstruction for a least 25% of defecations
- manual manoeuvres for at least 25% of defecations
5 - Willingness to stop at V2 all laxatives, enemas, stool softeners, and any other medications used to treat constipation with the exception of laxative rescue medication (i.e., bisacodyl tablets) allowed per protocol.
6 - Patients willing and able (e.g. mental and physical condition) to participate in all aspects of the trial, including use of medication, correct and independent completion of subjective evaluations (e.g. electronic diary, eDiary), attending scheduled visits, completing telephone interviews, and compliant with all protocol requirements, as evidenced by providing signed written informed consent.
|
|
| E.4 | Principal exclusion criteria |
1. History of cancer in the last 2 years except basal cell carcinoma and non-metastatic squamous cell skin cancer. Patients with any malignancy in the past are eligible in case they have been continuously disease-free for at least 2 years.
2. Known or suspected reason for constipation other than OIC (e.g.idiopathic, neurological, endocrine, or metabolic).
3. Known or suspected medical conditions that might be associated with diarrhoea, intermittent loose stools or constipation, such as faecal incontinence or irritable bowel syndrome (IBS). In case of documented suspicion of IBS or justified doubts of a long ago diagnosis, the Rome IV criteria must be applied).
4. Any known or suspected gastrointestinal (GI) pathology that might increase the risk of perforation, such as chronic inflammatory bowel disease (Crohn's disease, ulcerative colitis), acute diverticulitis or history of > 1 episode of diverticulitis, intestinal obstruction or pseudoobstruction.
5. Any form of acute temporary or permanent GI ostomy, such as ileostomy or colostomy.
6. Renal impairment requiring any form of dialysis.
7. Known or suspected moderate-to-severe hepatic impairment (serum total bilirubin > 2 upper limit of normal (ULN) except in patients diagnosed with Gilbert's syndrome, International Normalised Ratio (INR) > 2 ULN (except in patients on therapeutic anti-coagulation), serum albumin < 2.8 g/dL)
8. Presence of any other significant or progressive/unstable medical condition that, in the opinion of the investigator, would compromise evaluation of the trial treatment or may jeopardise patient's safety, compliance or adherence to protocol requirements, such as significant psychiatric, cardiovascular, pulmonary, metabolic, endocrine or neurological disease.
9. Any GI pathology or surgery or intractable vomiting likely to significantly influence drug absorption.
10. Inability to swallow the trial medication whole (e.g. due to dysphagia).
11. Known or suspected acute or chronic alcoholism, delirium tremens,or toxic psychosis.
12. Signs and symptoms that may be related to opioid withdrawal.
13. Use of prohibited medication or treatments as defined in the list of not allowed medication or treatments.
14. For women: Pregnancy or breast-feeding. Women of childbearing potential unable or unwilling to undergo pregnancy tests and practice acceptable contraceptive measures. For men: Men unable or unwilling to practice acceptable contraceptive measures.
15. Previous enrolment in this trial or participation in any other drug investigational trial within the past 30 days
16. Previous treatment in a clinical trial with Naloxone HCl PR Tablets (except one re-screening in this trial). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Proportion of overall CSBM Responders.
Overall CSBM response defined as ≥ 3 CSBMs/week and an increase of ≥1 CSBM/week compared to baseline during at least 9 out of the 12 treatment weeks, including all of the last 4 weeks.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Proportion of overall SBM Responders (response defined analogously as for CSBMs).
2. Proportion of CSBM Responders by trial week, i.e. having ≥ 3 CSBMs/week and an increase of ≥ 1 CSBM/week compared to baseline
3. Proportion of SBM Responders by trial week (response defined analogously as for CSBMs)
4. Absolute and relative change of standardised number of CSBMs/week compared to baseline by trial week and overall
5. Absolute and relative change of standardised number of SBMs/week compared to baseline by trial week and overall
6. Change from baseline in proportion of type 1 and 2, type 3 and 4, and type 5-7 defecations per week according to BSFS by trial week and overall
7. CSBM "Sustained Response" defined as ≥ 3 CSBMs/week and an increase of ≥ 1 CSBM/week compared to baseline in all of the last 4 weeks
8. Absolute and relative change from baseline in each item and the total score of the SDS by trial week and overall
9. Absolute and relative change from baseline in standardised number ofdays per week with laxative rescue medication use during the double blind treatment phase by trial week and overall
10. Absolute and relative change from baseline in BFI score at the end of Week 1, 2, 4, 8 and 12
11. Absolute and relative change from baseline in Patient Assessment of Constipation – Symptoms (PAC-SYM) at the end of Week 4, 8 and 12
12. Absolute and relative change from baseline in Patient Assessment of Constipation - Quality Of Life (PAC-QOL) at the end of Week 4, 8 and 12
13. Absolute and relative change from baseline in EuroQol five
dimensions questionnaire (EQ-5D-5L) at the end of Week 4, 8 and 12
14. Patient and physician satisfaction with treatment at the end of Week
12
15. Willingness to take drug again assessed at the end of Week 12
16. Adverse events (AEs; i.e., incidence, nature, and intensity of AEs,
treatment-related AEs, serious AEs (SAEs) and AEs leading to
discontinuation) throughout the trial
17. Absolute and relative change from baseline in the mean visual
analogue scale (VAS) pain (recalled pain over the last 12 hours) score by
trial week and overall
18. Absolute and relative change from baseline in standardised number
of days per week with analgesic rescue medication use during the double
blind treatment phase by trial week and overall
19. Observed values and absolute and relative change from baseline in
clinical opioid withdrawal scale (COWS) during double blind treatment
phase
20. Observed values and absolute and relative change from baseline in
modified subjective opioid withdrawal scale (mSOWS) during double
blind treatment phase
21. Changes from baseline in vital signs (blood pressure, heart rate,
body temperature), weight, BMI, and physical examination findings
22. Changes from baseline in laboratory assessments (i.e., clinical
chemistry, haematology, blood coagulation, and urinalysis)
23. Changes from baseline in standard 12-lead ECG
Selected safety endpoints will also be reported by ratio of opioid to
naloxone, expressed as opioid TDD (in ME) divided by naloxone TDD. An
appropriate classification will be defined using blinded trial data prior to
the finalisation of the SAP. |
|
| 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 | 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 | 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) | 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) | No |
| 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 | 24 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 120 |
| 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 |
|
| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | 28 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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