Safety Study to Assess Opiate Withdrawal Signs and Symptoms in Opioid Dependent Patients

Study Overview
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Brief Summary
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This study will evaluate whether crushed EMBEDA capsules induce clinical opiate withdrawal signs and symptoms in opioid-dependent patients with chronic non-cancer pain who are stabilized on EMBEDA.

Detailed Description
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The decision to terminate the trial was due to a lack of study drug supply. Decision was not based on any safety concerns. The date of the notification of termination letter was March 11, 2011.

Official Title
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A Single-Center, Randomized, Double-Blind, Two-Way Crossover Study to Evaluate Whether a Single-Dose Administration of Crushed and Whole EMBEDA Induces Clinical Opiate Withdrawal Signs and Symptoms in Opioid-Dependent Patients With Chronic, Non-Cancer Pain Who Are Stabilized on EMBEDA¿

Conditions
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Chronic Pain

Intervention / Treatment
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* Drug: EMBEDA™ (morphine sulfate/naltrexone hydrochloride) crush
* Drug: EMBEDA™ (morphine sulfate/naltrexone hydrochloride) whole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chronic moderate to severe non-cancer pain that has been treated with opioid analgesics for at least three months (with stabilized pain control and stabilized dose for 28 days prior to enrollment). Receiving an opioid dose equivalent to 20 mg - 120 mg morphine once or twice daily. Patient displays signs and symptoms of withdrawal (i.e., COWS score ≥5) following naloxone administration during the Naloxone Challenge. If female and able to become pregnant, must use an approved method of birth control. Excluding the chronic moderate to severe non-cancer pain, the patient is judged by the Investigator to be in generally good health at screening based upon the results of a medical history, physical examination, laboratory profile, and 12 lead electrocardiogram (ECG). Exclusion Criteria: Female who is pregnant or breastfeeding. Patient has a known allergy or history of significant adverse reaction to morphine, other opioids, naltrexone, acetaminophen, or related compounds. Patient is receiving systemic chemotherapy, has an active malignancy of any type, or has been diagnosed with cancer within the 5 years prior to screening (excluding squamous or basal cell carcinoma of the skin). History of, or ongoing, alcohol or drug abuse. Patient has made a donation of blood or has had a significant blood loss within 30 days prior to screening.

Ages Eligible for Study
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Minimum Age: 21 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

Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EMBEDA™ (morphine sulfate/naltrexone hydrochloride) crush<br>EMBEDA (morphine sulfate plus naltrexone hydrochloride ER) capsules crushed and mixed in solution and administered orally at each patient's stable dose, given either once daily or twice daily. | Drug: EMBEDA™ (morphine sulfate/naltrexone hydrochloride) crush<br>* Placebo capsules plus EMBEDA capsules crushed and mixed in solution administered orally at each patient's stable dose, given either once daily or twice daily<br>|
| Experimental: EMBEDA™ (morphine sulfate/naltrexone hydrochloride) whole<br>EMBEDA (morphine sulfate plus naltrexone hydrochloride ER) capsules, administered orally and intact at each patient's stable dose, given either once daily or twice daily | Drug: EMBEDA™ (morphine sulfate/naltrexone hydrochloride) whole<br>* EMBEDA capsules, administered orally and intact at each patient's stable dose, given either once daily or twice daily with 150mL placebo solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Clinical Opiate Withdrawal Scale (COWS) Score Greater Than or Equal to (≥) 13 in the Treatment Phase | COWS is an 11 section clinical assessment of withdrawal symptoms, each section is rated from 0 (no symptom) to 4 or 5 (most severe symptom). Total score is classified into a 4 point rating scale (mild 5-12, moderate 13-24, moderately severe 25-36 and severe more than 36 points). | Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, 24 hours (hr) post-dose and unscheduled assessment (UA) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average Numeric Pain Rating Scale (NPRS) in Titration/Stabilization and Maintenance Phases | Average pain scores in the previous 24 hours using an 11 point NPRS ranging from no pain (0) to worst pain (10). | Baseline up to Day 63 | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) During the Treatment Phase | Average Tmax for Morphine, Naltrexone and 6-β-Naltrexol | Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hr post-dose | 
| Maximum Observed Plasma Concentration (Cmax) During the Treatment Phase | Average Cmax for Morphine, Naltrexone and 6-β-Naltrexol | Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hr post-dose | 
| Minimum Observed Plasma Concentration (Cmin) During the Treatment Phase | Average Cmin for Morphine, Naltrexone and 6-β-Naltrexol | Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hr post-dose | 
| Apparent Oral Clearance (CL/F) During the Treatment Phase | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hr post-dose | 
| Volume of Distribution (Vd/F)During the Treatment Phase | Average Vd/F for Morphine, Naltrexone and 6-β-Naltrexol | Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hr post-dose | 
| Plasma Decay Half-Life (t1/2) During the Treatment Phase | Average plasma decay half-life of morphine, naltrexone and 6-β-Naltrexol. Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. | Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hr post-dose | 
| Area Under the Curve From Time Zero to End of Dosing Interval (AUC0-τ) During the Treatment Phase | Average AUC0-τ for Morphine, Naltrexone and 6-β-Naltrexol reported. τ=24 hours | Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hr post-dose | 
| Area Under the Curve From Time Zero to the Time of Last Measurable Concentration (AUC0-last) During the Treatment Phase | Average AUC0-last for Morphine, Naltrexone and 6-β-Naltrexol. Area under the plasma concentration time-curve from time zero to the last measured concentration. | Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hr post-dose | 
| Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] During the Treatment Phase | AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞). Average AUC 0-∞ for Morphine, Naltrexone and 6-β-Naltrexol reported. | Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, and 24 hr post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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opioid, morphine, naltrexone, withdrawal signs, withdrawal symptoms