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

• ClinicalTrials.gov Identifier: NCT01100437
• Recruitment Status: Terminated
• First Posted: April 9, 2010
• Results First Posted: March 28, 2012
• Last Update Posted: July 13, 2012
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Chronic Pain	Drug: EMBEDA™ (morphine sulfate/naltrexone hydrochloride) crush; Drug: EMBEDA™ (morphine sulfate/naltrexone hydrochloride) whole	Phase 4

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 14 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Official Title: 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¿
• Study Start Date: April 2010
• Actual Primary Completion Date: March 2011
• Actual Study Completion Date: March 2011

Arms and Interventions

Arm	Intervention/treatment
Experimental: EMBEDA™ (morphine sulfate/naltrexone hydrochloride) crush; 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; 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
Experimental: EMBEDA™ (morphine sulfate/naltrexone hydrochloride) whole; 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; EMBEDA capsules, administered orally and intact at each patient's stable dose, given either once daily or twice daily with 150mL placebo solution

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Clinical Opiate Withdrawal Scale (COWS) Score Greater Than or Equal to (≥) 13 in the Treatment Phase [ Time Frame: 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) ]
   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).

Secondary Outcome Measures :

1. Average Numeric Pain Rating Scale (NPRS) in Titration/Stabilization and Maintenance Phases [ Time Frame: Baseline up to Day 63 ]
   Average pain scores in the previous 24 hours using an 11 point NPRS ranging from no pain (0) to worst pain (10).
2. Time to Reach Maximum Observed Plasma Concentration (Tmax) During the Treatment Phase [ Time Frame: 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 ]
   Average Tmax for Morphine, Naltrexone and 6-β-Naltrexol
3. Maximum Observed Plasma Concentration (Cmax) During the Treatment Phase [ Time Frame: 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 ]
   Average Cmax for Morphine, Naltrexone and 6-β-Naltrexol
4. Minimum Observed Plasma Concentration (Cmin) During the Treatment Phase [ Time Frame: 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 ]
   Average Cmin for Morphine, Naltrexone and 6-β-Naltrexol
5. Apparent Oral Clearance (CL/F) During the Treatment Phase [ Time Frame: 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 ]
   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.
6. Volume of Distribution (Vd/F)During the Treatment Phase [ Time Frame: 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 ]
   Average Vd/F for Morphine, Naltrexone and 6-β-Naltrexol
7. Plasma Decay Half-Life (t1/2) During the Treatment Phase [ Time Frame: 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 ]
   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.
8. Area Under the Curve From Time Zero to End of Dosing Interval (AUC0-τ) During the Treatment Phase [ Time Frame: 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 ]
   Average AUC0-τ for Morphine, Naltrexone and 6-β-Naltrexol reported. τ=24 hours
9. Area Under the Curve From Time Zero to the Time of Last Measurable Concentration (AUC0-last) During the Treatment Phase [ Time Frame: 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 ]
   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.
10. Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] During the Treatment Phase [ Time Frame: 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 ]
    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.

Other Outcome Measures:

1. Time to First Occurrence of a COWS Score ≥ 13 for Each Treatment During the Treatment Phase [ Time Frame: Prior to dose, 0, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 12, 24 hr post-dose and UA ]
   Average time to first occurrence of a COWS score ≥ 13
2. Morphine Plasma Concentration at First COWS ≥ 13 in the Treatment Phase [ Time Frame: 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 ]
3. Naltrexone Plasma Concentration at First COWS ≥ 13 in the Treatment Phase [ Time Frame: 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 ]
4. 6-β-Naltrexone Plasma Concentration at First COWS ≥ 13 in Treatment Phase [ Time Frame: 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 ]
5. Maximum Post-dose COWS in the Treatment Phase [ Time Frame: Between 0.5 and 24 hours post-dose ]
   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).

Eligibility Criteria

• Ages Eligible for Study: 21 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, Utah

Lifetree Clinical Research

Salt Lake City, Utah, United States, 84106

Sponsors and Collaborators

Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

More Information

Additional Information:

To obtain contact information for a study center near you, click here. 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Setnik B, Roland CL, Goli V, Sommerville K, Webster L. A clinical trial to determine if corelease of morphine and naltrexone from crushed extended-release capsules induces withdrawal in opioid-dependent patients: a descriptive analysis of six patients. J Opioid Manag. 2013 Mar-Apr;9(2):139-50. doi: 10.5055/jom.2013.0155.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT01100437
• Other Study ID Numbers: ALO-01-09-111; B4541002
• First Posted: April 9, 2010
• Results First Posted: March 28, 2012
• Last Update Posted: July 13, 2012
• Last Verified: November 2011

Keywords provided by Pfizer:

opioid; morphine; naltrexone; withdrawal signs; withdrawal symptoms

Additional relevant MeSH terms:

Chronic Pain; Pain; Neurologic Manifestations; Naltrexone; Morphine; Analgesics, Opioid; Narcotics; Central Nervous System Depressants; Physiological Effects of Drugs; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Alcohol Deterrents; Narcotic Antagonists