Naloxone SR Capsules in Patients With Opioid Induced Constipation

Study Overview
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Brief Summary
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For many patients taking opioids for pain relief one of the most distressing side effects is constipation. Naloxone is effective in the reversal of the effects of opioids and is used following opioid overdose. If naloxone is given by mouth it would relieve the effects of constipation but as it goes into the blood stream very quickly, it would also reverse the effects of the opioid and therefore stop the pain relief. The aim of this study is to examine a slow release formulation of naloxone to see if is can reduce constipation without reducing the pain relieving effects of the opioid.

Detailed Description
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Naloxone has been used for many years as an IV or IM injection for the reversal of opioid effects (following opioid overdose) and has been evaluated as an oral formulation to manage opioid-induced constipation. Immediate release oral naloxone preparations have however led to reversal of opioid effects and withdrawal. This has initiated the development of prolonged (slow release) naloxone preparations which prevent the systemic levels of naloxone reaching levels where the central opioid effects may be reversed. Naloxone has a high first pass metabolism (98%) and short half life ( 1hr). The objectives of this trial are to identify the optimum dosage regime of Naloxone SR capsules based on tolerability level, to improve spontaneous bowel movement frequency, and relieve GI symptoms, in patients suffering with opioid induced constipation.

Official Title
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A Multicentre, Randomised, Double-Blind, Placebo-Controlled, Multiple Ascending Dose Study Evaluating the Safety, Tolerability and Efficacy of Naloxone SR Capsules in Subjects With Constipation Due to Opioids, Taken for Persistent Non-Cancer Pain

Conditions
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Chronic Pain, Opioid Induced Constipation

Intervention / Treatment
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* Drug: Naloxone SR 5 mg capsules
* Drug: Placebo
* Drug: Naloxone SR 10 mg capsules
* Drug: Naloxone SR 20mg capsules
* Drug: Naloxone SR 2.5 mg capsules


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All subjects must give written informed consent Male or female subjects greater than 18 years of age Taking opioid full agonist therapy(oral or transdermal) for persistent non-cancer pain, for at least 4 weeks prior to baseline visit Subjects with at least a 3 week history of OIC prior to baseline; where bowel dysfunction is predominantly due to opioids and started following commencement of opioid therapy Subjects with <3 SBMs a week and experiencing one or more bowel symptoms (incomplete evacuation, straining, hard/small pellets) for 25% or more of bowel movements during the screening period Subjects must be willing to discontinue all current laxative (constipation) therapy. Bisacodyl will be provided and taken as required Exclusion Criteria: Women of childbearing potential, unless surgically sterile or using adequate contraception (either IUD, oral or depot contraceptive, or barrier plus spermicide). Women using oral contraception must have started using it at least 2 months prior to enrolment Women who are pregnant or breastfeeding Symptoms suggestive of non-opioid related bowel dysfunction (e.g. IBS - intermittent constipation or diarrhoea) or have diarrhoea or loose stools in the 4 weeks prior to baseline History of chronic constipation prior to commencing opioid therapy Gastrointestinal disorders known to affect bowel transit, or contribute to bowel dysfunction (other than OIC) Chronic faecal incontinence Subjects who have a colostomy, ileostomy, or colectomy with ileorectal anastomosis Subjects with a history of neoplastic disease within 5 years (except for basal cell carcinoma or non-metastatic squamous cell carcinoma of the skin) Subjects taking opioids for the management of drug addiction Subjects who do not meet any of the following criteria regarding baseline medications. Analgesia (including opioids and NSAIDs) should be stable throughout the trial. Any baseline analgesia must have been administered at a stable dose for a minimum of 4 weeks. If non-opioid analgesia recently discontinued, must have stopped at least 4 weeks prior to baseline Laxatives (outside that allowed by the protocol) are not permitted; these agents must have been discontinued at the screening visit. Use of drugs known to affect gut transit time (other than opioids) are not permitted (see Section 6.9 for exceptions) Use of mixed agonist/antagonist, or partial agonist opioids are not permitted (e.g. buprenorphine, pentazocine, cyclazocine, nalbuphine, nalorphine) Experimental agents must have been discontinued at least 8 weeks prior to screening, or for a period equivalent to 5 half-lives (t½) of the agent (whichever is longer) Subjects with a history of clinically significant and/or persistent disorder that, in the investigators opinion, may affect the clinical trial assessments Subjects with any laboratory tests considered clinically significant at screening. Subjects not ambulatory i.e. bedridden or require use of a commode Subjects who will be unavailable for the duration of the trial, likely to be non-compliant with the protocol, or who are felt to be unsuitable by the Investigator for any other reason

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Capsules with no active drug<br>Placebo capsules once daily for three weeks then twice daily for three weeks. | Drug: Placebo<br> <br> |
| Active Comparator: Naloxone SR 2.5 mg capsules<br>Naloxone SR 2.5 mg capsules once daily for three weeks then twice daily for three weeks. | Drug: Naloxone SR 2.5 mg capsules<br> <br> |
| Experimental: Naloxone SR 10mg capsules<br>Naloxone SR 10 mg capsules once daily for three weeks then twice daily for three weeks. | Drug: Naloxone SR 10 mg capsules<br> <br> |
| Experimental: Naloxone SR 20 mg capsules<br>Two Naloxone SR 10 mg capsules once daily for three weeks then twice daily for three weeks. | Drug: Naloxone SR 20mg capsules<br> <br> |
| Experimental: Naloxone SR 5mg capsules<br>Naloxone SR 5 mg capsules once daily for three weeks then twice daily for three weeks. | Drug: Naloxone SR 5 mg capsules<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and Severity of Treatment Emergent Adverse Events on Single Dosing. | Incidence and severity of treatment emergent adverse events on single dosing. | 3 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pain, opioid, constipation, Subjects taking opioids for chronic non-cancer pain, who, experience symptoms of opioid induced constipation