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

• Sponsor: Pfizer (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01100437
• Collaborator: (none)
• Enrollment: 14
• Location: 1
• Arms: 2
• Duration (Months): 11
• Patients Per Site Per Month: 1.3

Study Details

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
• 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: Apr 1, 2010
• Actual Primary Completion Date: Mar 1, 2011
• Actual Study Completion Date: Mar 1, 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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [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

Criteria

• Ages Eligible for Study: 21 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

	Site	City	State	Country	Postal Code
1	Lifetree Clinical Research	Salt Lake City	Utah	United States	84106

Sponsors and Collaborators

• Pfizer

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

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

Publications

None provided.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT01100437
• Other Study ID Numbers: ALO-01-09-111; B4541002
• First Posted: Apr 9, 2010
• Last Update Posted: Jul 13, 2012
• Last Verified: Nov 1, 2011

• Keywords provided by Pfizer: opioid; morphine; naltrexone; withdrawal signs; withdrawal symptoms
• Additional relevant MeSH terms: Chronic Pain; Naltrexone; Morphine

Study Results

Participant Flow

Arm/Group Title	EMBEDA Capsule Then EMBEDA Solution	EMBEDA Solution Then EMBEDA Capsule	EMBEDA Capsule
Arm/Group Description	EMBEDA (morphine sulfate plus naltrexone hydrochloride) Extended Release (ER) capsule(s) were administered orally once or twice a day (20 milligrams [mg] to 120 mg). During the open label titration and stabilization phase EMBEDA was administered and titrated to a dose that adequately managed the participants pain up to 35 days. In the open label Maintenance Phase the participant was administered the established stable dose for a minimum of 7 days up to 28 days. The participant was then randomized to one of two double-blind treatment sequences for the Treatment Phase. During the Treatment Phase the participant was administered whole EMBEDA capsules orally at participant's stable dose along with a matched placebo solution in the first intervention period. In the second intervention period the participant received crushed EMBEDA capsules that were mixed in solution and administered orally at participant's stable dose along with matched placebo capsules.	EMBEDA (morphine sulfate plus naltrexone hydrochloride) ER capsule(s) were administered orally once or twice a day (20 mg to 120 mg). During the open label titration and stabilization phase EMBEDA was administered and titrated to a dose that adequately managed the participants pain up to 35 days. In the open label Maintenance Phase the participants were administered the established stable dose for a minimum of 7 days up to 28 days. The participant was then randomized to one of two double-blind treatment sequences for the Treatment Phase. During the Treatment Phase the participant was administered crushed EMBEDA capsules orally at participants stable dose mixed in solution along with matched placebo capsules in the first intervention period. In the second intervention period the participant received whole EMBEDA capsules administered orally at participant's stable dose along with matched placebo solution.	EMBEDA (morphine sulfate plus naltrexone hydrochloride) ER capsule(s) were administered orally once or twice a day (20 mg to 120 mg). During the titration and stabilization phase EMBEDA was administrated and titrated to a dose that adequately managed the participants pain for up to 35 days. In the Maintenance Phase the participant's were administered the established stable dose for a minimum of 7 days up to 28 days. Participants were not randomized to treatment phase.
Period Title: Screening
STARTED	4	2	8
COMPLETED	4	2	8
NOT COMPLETED	0	0	0
Period Title: Screening
STARTED	4	2	8
COMPLETED	4	2	2
NOT COMPLETED	0	0	6
Period Title: Screening
STARTED	4	2	2
COMPLETED	4	2	0
NOT COMPLETED	0	0	2
Period Title: Screening
STARTED	4	2	0
COMPLETED	4	2	0
NOT COMPLETED	0	0	0
Period Title: Screening
STARTED	4	2	0
COMPLETED	4	2	0
NOT COMPLETED	0	0	0
Period Title: Screening
STARTED	4	2	0
COMPLETED	4	2	0
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Entire Study Population
Arm/Group Description	EMBEDA (morphine sulfate plus naltrexone hydrochloride) ER capsule(s) were administered orally once or twice a day (20 mg to 120 mg). During the titration and stabilization phase EMBEDA was administered and titrated to a dose that adequately managed the participant's pain up to 35 days. The participants then started the Maintenance Phase and were administered the established stable dose of EMBEDA for a minimum of 7 days up to 28 days. Eligible participants were randomized into the 2 treatment groups.
Overall Participants	14
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	45.2
Sex: Female, Male (Count of Participants)
Female	8 57.1%
Male	6 42.9%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Clinical Opiate Withdrawal Scale (COWS) Score Greater Than or Equal to (≥) 13 in the Treatment Phase
Description	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).
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)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population (ITT): all randomized participants who received at least one dose of double-blind treatment in the Treatment Phase and had at least one post-dose pharmacodynamic assessment completed in the Treatment Phase.

Arm/Group Title	EMBEDA Whole Capsules	EMBEDA Crushed in Solution
Arm/Group Description	EMBEDA whole capsules, administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo solution in any treatment period.	EMBEDA capsules crushed mixed in solution and administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily with matched placebo whole capsules in any treatment period.
Measure Participants	6	6
Number [participants]	1 7.1%	3 NaN

2. Secondary Outcome

Title	Average Numeric Pain Rating Scale (NPRS) in Titration/Stabilization and Maintenance Phases
Description	Average pain scores in the previous 24 hours using an 11 point NPRS ranging from no pain (0) to worst pain (10).
Time Frame	Baseline up to Day 63

Outcome Measure Data

Analysis Population Description

ITT; N=number of participants with evaluable data; n=number of participants evaluated at the specific time point

Arm/Group Title	EMBEDA Capsules
Arm/Group Description	EMBEDA whole capsules, administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo solution in any treatment period.
Measure Participants	6
Titration/Stabilization-Baseline (n=6)	5.5 (1.05)
Titration/Stabilization-Visit 2b (n=6)	5.2 (2.23)
Titration/Stabilization-Visit 2c (n=2)	5.5 (3.54)
Titration/Stabilization-Visit 2d (n=1)	3.0 (NA)
Maintenance (n=6)	4.2 (1.94)

3. Secondary Outcome

Title	Time to Reach Maximum Observed Plasma Concentration (Tmax) During the Treatment Phase
Description	Average Tmax for Morphine, Naltrexone and 6-β-Naltrexol
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

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) population: all randomized participants who received at least one dose of EMBEDA (whole or crushed) in the Treatment Phase and had at least one PK assessment completed in the Treatment Phase; n=number of participants with evaluable data for the specific category

Arm/Group Title	EMBEDA Whole Capsules	EMBEDA Crushed in Solution
Arm/Group Description	EMBEDA whole capsules, administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo solution in any treatment period.	EMBEDA capsules crushed mixed in solution and administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily with matched placebo whole capsules in any treatment period.
Measure Participants	6	6
Morphine (n=6,6)	5.67 (2.658)	1.29 (0.813)
Naltrexone (n=0,6)	NA (NA)	1.46 (0.697)
6-β-Naltrexol (n=4,6)	6.13 (11.919)	1.63 (0.787)

4. Secondary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) During the Treatment Phase
Description	Average Cmax for Morphine, Naltrexone and 6-β-Naltrexol
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

Outcome Measure Data

Analysis Population Description

PK population; n=number of participants with evaluable data for specific category

Arm/Group Title	EMBEDA Whole Capsules	EMBEDA Crushed in Solution
Arm/Group Description	EMBEDA whole capsules, administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo solution in any treatment period.	EMBEDA capsules crushed mixed in solution and administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily with matched placebo whole capsules in any treatment period.
Measure Participants	6	6
Morphine (n=6,6)	27.5 (14.14)	70.4 (47.88)
Naltrexone (n=0,6)	NA (NA)	321.1 (225.05)
6-β-Naltrexol (n=4,6)	24.4 (15.40)	3398.3 (1327.97)

5. Secondary Outcome

Title	Minimum Observed Plasma Concentration (Cmin) During the Treatment Phase
Description	Average Cmin for Morphine, Naltrexone and 6-β-Naltrexol
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

Outcome Measure Data

Analysis Population Description

PK population; n=number of participants with evaluable data for specific category

Arm/Group Title	EMBEDA Whole Capsules	EMBEDA Crushed in Solution
Arm/Group Description	EMBEDA whole capsules, administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo solution in any treatment period.	EMBEDA capsules crushed mixed in solution and administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily with matched placebo whole capsules in any treatment period.
Measure Participants	6	6
Morphine (n=6,6)	13.8 (6.89)	11.2 (8.86)
Naltrexone (n=0,6)	NA (NA)	6.9 (1.17)
6-β-Naltrexol (n=4,6)	15.9 (9.29)	42.7 (66.93)

6. Secondary Outcome

Title	Apparent Oral Clearance (CL/F) During the Treatment Phase
Description	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.
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

Outcome Measure Data

Analysis Population Description

PK population; N=number of participants with evaluable data; n=number of participants with evaluable data for the specific category

Arm/Group Title	EMBEDA Whole Capsules	EMBEDA Crushed in Solution
Arm/Group Description	EMBEDA whole capsules, administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo solution in any treatment period.	EMBEDA capsules crushed mixed in solution and administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily with matched placebo whole capsules in any treatment period.
Measure Participants	3	6
Morphine (n=2,6)	37.6 (11.53)	77.2 (25.36)
Naltrexone (n=0,6)	NA (NA)	75151.0 (51706.48)
6-β-Naltrexol (n=3,6)	45143.6 (14157.49)	1758.0 (381.67)

7. Secondary Outcome

Title	Volume of Distribution (Vd/F)During the Treatment Phase
Description	Average Vd/F for Morphine, Naltrexone and 6-β-Naltrexol
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

Outcome Measure Data

Analysis Population Description

PK population; N=number of participants with evaluable data; n=number of participants with evaluable date for the specific category

Arm/Group Title	EMBEDA Whole Capsules	EMBEDA Crushed in Solution
Arm/Group Description	EMBEDA whole capsules, administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo solution in any treatment period.	EMBEDA capsules crushed mixed in solution and administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily with matched placebo whole capsules in any treatment period.
Measure Participants	3	6
Morphine (n=2,6)	3173.1 (1724.61)	1668.2 (830.08)
Naltrexone (n=0,6)	NA (NA)	304171.8 (206998.86)
6-β-Naltrexol (n=3,6)	3447244.4 (1868128.43)	26304.5 (10730.59)

8. Secondary Outcome

Title	Plasma Decay Half-Life (t1/2) During the Treatment Phase
Description	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.
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

Outcome Measure Data

Analysis Population Description

PK population; N=number of participants with evaluable data; n=number of participants with evaluable data for the specific category

Arm/Group Title	EMBEDA Whole Capsules	EMBEDA Crushed in Solution
Arm/Group Description	EMBEDA whole capsules, administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo solution in any treatment period.	EMBEDA capsules crushed mixed in solution and administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily with matched placebo whole capsules in any treatment period.
Measure Participants	3	6
Morphine (n=2,6)	56.2 (14.55)	17.0 (10.99)
Naltrexone (n=0,6)	NA (NA)	3.0 (1.10)
6-β-Naltrexol (n=3,6)	50.9 (11.77)	10.1 (2.43)

9. Secondary Outcome

Title	Area Under the Curve From Time Zero to End of Dosing Interval (AUC0-τ) During the Treatment Phase
Description	Average AUC0-τ for Morphine, Naltrexone and 6-β-Naltrexol reported. τ=24 hours
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

Outcome Measure Data

Analysis Population Description

PK population; n=number of participants with evaluable data for the specific category

Arm/Group Title	EMBEDA Whole Capsules	EMBEDA Crushed in Solution
Arm/Group Description	EMBEDA whole capsules, administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo solution in any treatment period.	EMBEDA capsules crushed mixed in solution and administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily with matched placebo whole capsules in any treatment period.
Measure Participants	6	6
Morphine (n=6,6)	513.4 (310.87)	542.6 (366.62)
Naltrexone (n=0,6)	NA (NA)	1314.7 (1119.25)
6-β-Naltrexol (n=4,6)	463.5 (290.94)	28891.2 (14871.70)

10. Secondary Outcome

Title	Area Under the Curve From Time Zero to the Time of Last Measurable Concentration (AUC0-last) During the Treatment Phase
Description	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.
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

Outcome Measure Data

Analysis Population Description

PK population; n=number of participants with evaluable data for the specific category

Arm/Group Title	EMBEDA Whole Capsules	EMBEDA Crushed in Solution
Arm/Group Description	EMBEDA whole capsules, administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo solution in any treatment period.	EMBEDA capsules crushed mixed in solution and administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily with matched placebo whole capsules in any treatment period.
Measure Participants	6	6
Morphine (n=6,6)	513.4 (310.87)	542.6 (366.62)
Naltrexone (n=0,6)	NA (NA)	1300.0 (1131.24)
6-β-Naltrexol (n=4,6)	450.3 (312.56)	28891.2 (14871.69)

11. Secondary Outcome

Title	Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] During the Treatment Phase
Description	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.
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

Outcome Measure Data

Analysis Population Description

PK population; N=number of participants with evaluable data; n=number of participants with evaluable data for the specific category

Arm/Group Title	EMBEDA Whole Capsules	EMBEDA Crushed in Solution
Arm/Group Description	EMBEDA whole capsules, administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo solution in any treatment period.	EMBEDA capsules crushed mixed in solution and administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily with matched placebo whole capsules in any treatment period.
Measure Participants	3	6
Morphine (n=2,6)	2023.5 (1935.01)	887.7 (583.83)
Naltrexone (n=0,6)	NA (NA)	1330.7 (1141.75)
6-β-Naltrexol (n=3,6)	1469.5 (955.52)	35297.8 (18407.20)

12. Other Pre-specified Outcome

Title	Time to First Occurrence of a COWS Score ≥ 13 for Each Treatment During the Treatment Phase
Description	Average time to first occurrence of a COWS score ≥ 13
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

Outcome Measure Data

Analysis Population Description

ITT; Subset of participants with COWS >= 13

Arm/Group Title	EMBEDA Whole Capsules	EMBEDA Crushed in Solution
Arm/Group Description	EMBEDA whole capsules, administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo solution in any treatment period.	EMBEDA capsules crushed mixed in solution and administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily with matched placebo whole capsules in any treatment period.
Measure Participants	1	3
Mean (Standard Error) [h]	2.5 (NA)	0.7 (0.02)

13. Other Pre-specified Outcome

Title	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

Outcome Measure Data

Analysis Population Description

ITT; Subset of participants with COWS ≥ 13

Arm/Group Title	EMBEDA Whole Capsules	EMBEDA Crushed in Solution
Arm/Group Description	EMBEDA whole capsules, administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo solution in any treatment period.	EMBEDA capsules crushed mixed in solution and administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily with matched placebo whole capsules in any treatment period.
Measure Participants	1	3
Mean (Standard Deviation) [ng/mL]	16.00 (NA)	86.30 (53.316)

14. Other Pre-specified Outcome

Title	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

Outcome Measure Data

Analysis Population Description

ITT; Subset of participants with COWS ≥ 13

Arm/Group Title	EMBEDA Whole Capsules	EMBEDA Crushed in Solution
Arm/Group Description	EMBEDA whole capsules, administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo solution in any treatment period.	EMBEDA capsules crushed mixed in solution and administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily with matched placebo whole capsules in any treatment period.
Measure Participants	1	3
Mean (Standard Deviation) [picogram/milliliter (pg/mL)]	NA (NA)	350.50 (195.869)

15. Other Pre-specified Outcome

Title	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

Outcome Measure Data

Analysis Population Description

ITT; Subset of all participants with COWS ≥ 13

Arm/Group Title	EMBEDA Whole Capsules	EMBEDA Crushed in Solution
Arm/Group Description	EMBEDA whole capsules, administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo solution in any treatment period.	EMBEDA capsules crushed mixed in solution and administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily with matched placebo whole capsules in any treatment period.
Measure Participants	1	3
Mean (Standard Deviation) [pg/mL]	NA (NA)	3375.00 (827.315)

16. Other Pre-specified Outcome

Title	Maximum Post-dose COWS in the Treatment Phase
Description	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).
Time Frame	Between 0.5 and 24 hours post-dose

Outcome Measure Data

Analysis Population Description

ITT

Arm/Group Title	EMBEDA Whole Capsules	EMBEDA Crushed in Solution
Arm/Group Description	EMBEDA whole capsules, administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo solution in any treatment period.	EMBEDA capsules crushed mixed in solution and administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily with matched placebo whole capsules in any treatment period.
Measure Participants	6	6
Mean (Standard Deviation) [units on a scale]	3.7 (4.63)	10.7 (6.83)

Adverse Events

Time Frame	Study procedure related adverse events (AEs) were collected from the time of written Informed Consent and all other AEs from the time of the first dose of EMBEDA at Visit 2.
Adverse Event Reporting Description	The same event may appear as both an AE and a serious adverse events (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Arm/Group Title	EMBEDA Whole Capsule Treatment Period		EMBEDA Crushed in Solution Treatment Period		EMBEDA Capsule Titration/Stabilization Period		EMBEDA Capsules Maintenance Period
Arm/Group Description	EMBEDA whole capsules, administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo solution in any treatment period.		EMBEDA capsules crushed mixed in solution and administered orally at participant's stable dose (20 mg to 120 mg), given once or twice daily along with matched placebo whole capsules in any treatment period .		EMBEDA capsule(s) administered orally once or twice a day (20 mg go 120 mg) to adequately manage the participants pain.		EMBEDA capsule(s) administered orally once or twice a day dose (20 mg go 120 mg) at the participants stable dose for 7 days minimum.
All Cause Mortality
	EMBEDA Whole Capsule Treatment Period		EMBEDA Crushed in Solution Treatment Period		EMBEDA Capsule Titration/Stabilization Period		EMBEDA Capsules Maintenance Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	EMBEDA Whole Capsule Treatment Period		EMBEDA Crushed in Solution Treatment Period		EMBEDA Capsule Titration/Stabilization Period		EMBEDA Capsules Maintenance Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/6 (0%)		0/14 (0%)		0/8 (0%)
Other (Not Including Serious) Adverse Events
	EMBEDA Whole Capsule Treatment Period		EMBEDA Crushed in Solution Treatment Period		EMBEDA Capsule Titration/Stabilization Period		EMBEDA Capsules Maintenance Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/6 (66.7%)		6/6 (100%)		12/14 (85.7%)		1/8 (12.5%)
Cardiac disorders
Tachycardia	0/6 (0%)		1/6 (16.7%)		0/14 (0%)		0/8 (0%)
Eye disorders
Lacrimation increased	1/6 (16.7%)		2/6 (33.3%)		1/14 (7.1%)		0/8 (0%)
Mydriasis	0/6 (0%)		2/6 (33.3%)		0/14 (0%)		0/8 (0%)
Gastrointestinal disorders
Nausea	3/6 (50%)		4/6 (66.7%)		4/14 (28.6%)		0/8 (0%)
Abdominal pain	1/6 (16.7%)		3/6 (50%)		2/14 (14.3%)		0/8 (0%)
Abdominal pain upper	1/6 (16.7%)		2/6 (33.3%)		0/14 (0%)		0/8 (0%)
Diarrhoea	0/6 (0%)		3/6 (50%)		1/14 (7.1%)		0/8 (0%)
Flatulence	0/6 (0%)		2/6 (33.3%)		0/14 (0%)		0/8 (0%)
Dry mouth	1/6 (16.7%)		0/6 (0%)		0/14 (0%)		0/8 (0%)
Haematochezia	0/6 (0%)		1/6 (16.7%)		0/14 (0%)		0/8 (0%)
Retching	0/6 (0%)		1/6 (16.7%)		0/14 (0%)		0/8 (0%)
Gastrooesophageal reflux disease	0/6 (0%)		0/6 (0%)		0/14 (0%)		1/8 (12.5%)
Constipation	0/6 (0%)		0/6 (0%)		3/14 (21.4%)		0/8 (0%)
Vomiting	0/6 (0%)		0/6 (0%)		2/14 (14.3%)		0/8 (0%)
Abdominal discomfort	0/6 (0%)		0/6 (0%)		1/14 (7.1%)		0/8 (0%)
Abdominal distension	0/6 (0%)		0/6 (0%)		1/14 (7.1%)		0/8 (0%)
General disorders
Irritability	1/6 (16.7%)		1/6 (16.7%)		0/14 (0%)		0/8 (0%)
Chest discomfort	0/6 (0%)		1/6 (16.7%)		0/14 (0%)		0/8 (0%)
Chills	1/6 (16.7%)		1/6 (16.7%)		1/14 (7.1%)		0/8 (0%)
Fatigue	1/6 (16.7%)		0/6 (0%)		0/14 (0%)		0/8 (0%)
Pain	1/6 (16.7%)		1/6 (16.7%)		3/14 (21.4%)		0/8 (0%)
Pyrexia	0/6 (0%)		0/6 (0%)		1/14 (7.1%)		0/8 (0%)
Infections and infestations
Sinusitis	0/6 (0%)		1/6 (16.7%)		0/14 (0%)		0/8 (0%)
Upper respiratory tract infection	0/6 (0%)		0/6 (0%)		1/14 (7.1%)		0/8 (0%)
Investigations
Oxygen saturation decreased	0/6 (0%)		1/6 (16.7%)		0/14 (0%)		0/8 (0%)
Metabolism and nutrition disorders
Decreased appetite	0/6 (0%)		0/6 (0%)		2/14 (14.3%)		0/8 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/6 (0%)		2/6 (33.3%)		1/14 (7.1%)		0/8 (0%)
Back pain	0/6 (0%)		1/6 (16.7%)		3/14 (21.4%)		0/8 (0%)
Bone pain	0/6 (0%)		1/6 (16.7%)		0/14 (0%)		0/8 (0%)
Muscle twitching	0/6 (0%)		1/6 (16.7%)		0/14 (0%)		0/8 (0%)
Musculoskeletal stiffness	0/6 (0%)		1/6 (16.7%)		0/14 (0%)		0/8 (0%)
Myalgia	1/6 (16.7%)		0/6 (0%)		0/14 (0%)		0/8 (0%)
Flank pain	0/6 (0%)		0/6 (0%)		1/14 (7.1%)		0/8 (0%)
Osteoarthritis	0/6 (0%)		0/6 (0%)		1/14 (7.1%)		0/8 (0%)
Nervous system disorders
Headache	3/6 (50%)		3/6 (50%)		0/14 (0%)		0/8 (0%)
Tremor	1/6 (16.7%)		4/6 (66.7%)		2/14 (14.3%)		0/8 (0%)
Dizziness	1/6 (16.7%)		1/6 (16.7%)		1/14 (7.1%)		0/8 (0%)
Restless legs syndrome	0/6 (0%)		1/6 (16.7%)		0/14 (0%)		0/8 (0%)
Somnolence	0/6 (0%)		0/6 (0%)		2/14 (14.3%)		0/8 (0%)
Balance disorder	0/6 (0%)		0/6 (0%)		1/14 (7.1%)		0/8 (0%)
Dysgeusia	0/6 (0%)		0/6 (0%)		1/14 (7.1%)		0/8 (0%)
Neuralgia	0/6 (0%)		0/6 (0%)		1/14 (7.1%)		0/8 (0%)
Sciatica	0/6 (0%)		0/6 (0%)		1/14 (7.1%)		0/8 (0%)
Psychiatric disorders
Anxiety	1/6 (16.7%)		6/6 (100%)		6/14 (42.9%)		0/8 (0%)
Restlessness	1/6 (16.7%)		3/6 (50%)		2/14 (14.3%)		0/8 (0%)
Insomnia	0/6 (0%)		0/6 (0%)		5/14 (35.7%)		0/8 (0%)
Agitation	0/6 (0%)		0/6 (0%)		2/14 (14.3%)		0/8 (0%)
Euphoric mood	0/6 (0%)		0/6 (0%)		1/14 (7.1%)		0/8 (0%)
Respiratory, thoracic and mediastinal disorders
Yawning	2/6 (33.3%)		4/6 (66.7%)		0/14 (0%)		0/8 (0%)
Rhinorrhoea	1/6 (16.7%)		2/6 (33.3%)		1/14 (7.1%)		0/8 (0%)
Dysphonia	1/6 (16.7%)		0/6 (0%)		0/14 (0%)		0/8 (0%)
Dyspnoea	0/6 (0%)		1/6 (16.7%)		0/14 (0%)		0/8 (0%)
Epistaxis	0/6 (0%)		1/6 (16.7%)		0/14 (0%)		0/8 (0%)
Nasal congestion	0/6 (0%)		1/6 (16.7%)		1/14 (7.1%)		0/8 (0%)
Oropharyngeal pain	0/6 (0%)		0/6 (0%)		1/14 (7.1%)		0/8 (0%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	1/6 (16.7%)		2/6 (33.3%)		1/14 (7.1%)		0/8 (0%)
Cold sweat	0/6 (0%)		0/6 (0%)		1/14 (7.1%)		0/8 (0%)
Vascular disorders
Flushing	2/6 (33.3%)		3/6 (50%)		1/14 (7.1%)		0/8 (0%)

Limitations/Caveats

Sponsor terminated study early on 10-Mar-2011.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.