Naloxone HCl PR Tablets in Patients With Opioid Induced Constipation

Inclusion Criteria:

1. Male or female patients ≥18 years of age with opioid induced constipation.

2. Long-term WHO step III opioid therapy for at least 3 months prior to screening fortreatment of chronic non-cancer related pain.

3. Receiving a stable maintenance regimen with one long-acting oral or transdermal WHOstep III opioid (except tapentadol) consisting of a total daily dose of ≥40 mg ME fora minimum of 4 weeks prior to screening, with no anticipated change in opioid doserequirement over the proposed trial period.

4. Symptoms of constipation with onset after the start of opioid medication for at leastthe last 4 weeks prior to screening,

Exclusion Criteria:

• 1. Hypersensitivity or intolerance to any active substance (i.e., naloxone, bisacodyl)or any of the excipients of the trial medication (e.g. patients with hereditaryproblems of galactose intolerance, lactase deficiency or glucose-galactosemalabsorption). Hypersensitivity or intolerance to methylnaltrexone or naloxegol.

2. History of cancer in the last 2 years except basal cell carcinoma andnon-metastatic squamous cell skin cancer. Patients with any malignancy in the past areeligible in case they have been continuously disease-free for at least 2 years.

3. Known or suspected reason for constipation other than OIC (e.g. idiopathic,neurological, endocrine, or metabolic).

4. Known or suspected medical conditions that might be associated with diarrhoea,intermittent loose stools or constipation, such as faecal incontinence or irritablebowel syndrome (IBS). In case of documented suspicion of IBS or justified doubts of along ago diagnosis, the Rome IV criteria must be applied).

5. Any known or suspected gastrointestinal (GI) pathology that might increase the riskof perforation, such as chronic inflammatory bowel disease (Crohn's disease,ulcerative colitis), acute diverticulitis or history of > 1 episode of diverticulitis,intestinal obstruction or pseudo-obstruction.

6. Any form of acute temporary or permanent GI ostomy, such as ileostomy or colostomy.

7. Renal impairment requiring any form of dialysis. 8. Known or suspectedmoderate-to-severe hepatic impairment (serum total bilirubin > 2 upper limit of normal (ULN) except in patients diagnosed with Gilbert's syndrome, International NormalisedRatio (INR) > 2 ULN (except in patients on therapeutic anti-coagulation), serumalbumin < 2.8 g/dL) 9. Presence of any other significant or progressive/unstablemedical condition that, in the opinion of the investigator, would compromiseevaluation of the trial treatment or may jeopardise patient's safety, compliance oradherence to protocol requirements, such as significant psychiatric, cardiovascular,pulmonary, metabolic, endocrine or neurological disease.

8. Any GI pathology or surgery or intractable vomiting likely to significantlyinfluence drug absorption.

9. Inability to swallow the trial medication whole (e.g. due to dysphagia). 12. Knownor suspected acute or chronic alcoholism, delirium tremens, or toxic psychosis.

10. Signs and symptoms that may be related to opioid withdrawal. 14. Use of prohibitedmedication or treatments as defined in the list of not allowed medication ortreatments.

11. For women: Pregnancy or breast-feeding. Women of childbearing potential unable orunwilling to undergo pregnancy tests and practice acceptable contraceptive measures.Acceptable methods for women are hormonal contraceptives, surgical intervention (e.g.bilateral tubal occlusion), intrauterine device, intrauterine hormone-releasingsystem, double-barrier methods and true sexual abstinence (i.e. when this is in linewith the preferred and usual lifestyle of the subject). Periodic abstinence (e.g.,calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are notacceptable methods of contraception. For men: Men unable or unwilling to practiceacceptable contraceptive measures. Acceptable methods for men are surgicalintervention (e.g. vasectomy), true sexual abstinence and acceptable contraception (asdescribed above) of the female partner.

12. Previous enrolment in this trial or participation in any other druginvestigational trial within the past 30 days (or five half-lives of IMP whichever islonger) prior to Visit 1 (except one re-screening in this trial).

13. Previous treatment in a clinical trial with Naloxone HCl PR Tablets (except onere-screening in this trial).

14. Persons committed to an institution by virtue of an order issued either by thejudicial or other authorities.

15. Employees of the investigator or trial centre, with direct involvement in theproposed trial or other studies under the direction of that investigator or trialcentre, as well as family members of the employees or the investigator.