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

This study has been terminated.

(See termination reason in detailed description.)

Sponsor:

Information provided by (Responsible Party):

Pfizer

ClinicalTrials.gov Identifier:

NCT01100437

First received: April 7, 2010

Last updated: July 5, 2012

Last verified: November 2011

History of Changes

Results First Received: February 27, 2012

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Pharmacodynamics Study; Intervention Model: Crossover Assignment; Masking: Double Blind (Subject, Investigator, Outcomes Assessor)
Condition:	Chronic Pain
Interventions:	Drug: EMBEDA™ (morphine sulfate/naltrexone hydrochloride) crush Drug: EMBEDA™ (morphine sulfate/naltrexone hydrochloride) whole

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups

	Description
EMBEDA Capsule Then EMBEDA Solution	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 Solution Then EMBEDA Capsule	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 Capsule	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.

Participant Flow for 6 periods

Period 1: Screening

	EMBEDA Capsule Then EMBEDA Solution	EMBEDA Solution Then EMBEDA Capsule	EMBEDA Capsule
STARTED	4	2	8
COMPLETED	4	2	8
NOT COMPLETED	0	0	0

Period 2: Titration/Stabilization

	EMBEDA Capsule Then EMBEDA Solution	EMBEDA Solution Then EMBEDA Capsule	EMBEDA Capsule
STARTED	4	2	8
COMPLETED	4	2	2
NOT COMPLETED	0	0	6
Adverse Event	0	0	4
Non-compliance	0	0	1
Sponsor canceled study	0	0	1

Period 3: Maintenance

	EMBEDA Capsule Then EMBEDA Solution	EMBEDA Solution Then EMBEDA Capsule	EMBEDA Capsule
STARTED	4	2	2
COMPLETED	4	2	0
NOT COMPLETED	0	0	2
Withdrawal by Subject	0	0	1
Sponsor termination of study	0	0	1

Period 4: Treatment 1

	EMBEDA Capsule Then EMBEDA Solution	EMBEDA Solution Then EMBEDA Capsule
STARTED	4	2
COMPLETED	4	2
NOT COMPLETED	0	0

Period 5: Washout (4 Days)

	EMBEDA Capsule Then EMBEDA Solution	EMBEDA Solution Then EMBEDA Capsule
STARTED	4	2
COMPLETED	4	2
NOT COMPLETED	0	0

Period 6: Treatment 2

	EMBEDA Capsule Then EMBEDA Solution	EMBEDA Solution Then EMBEDA Capsule
STARTED	4	2
COMPLETED	4	2
NOT COMPLETED	0	0

Baseline Characteristics

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Reporting Groups

	Description
Entire Study Population	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.

Description

Entire Study Population

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.

Baseline Measures

	Entire Study Population
Number of Participants [units: participants]	14
Age [units: years] Median ( Full Range )	45.2 ( 32.6 to 67.1 )
Gender [units: participants]
Female	8
Male	6

Outcome Measures

Show All Outcome Measures

1. Primary:

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) ]

Show Outcome Measure 1

2. Secondary:

Average Numeric Pain Rating Scale (NPRS) in Titration/Stabilization and Maintenance Phases [ Time Frame: Baseline up to Day 63 ]

Show Outcome Measure 2

3. Secondary:

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 ]

Show Outcome Measure 3

4. Secondary:

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 ]

Show Outcome Measure 4

5. Secondary:

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 ]

Show Outcome Measure 5

6. Secondary:

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 ]

Show Outcome Measure 6

7. Secondary:

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 ]

Show Outcome Measure 7

8. Secondary:

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 ]

Show Outcome Measure 8

9. Secondary:

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 ]

Show Outcome Measure 9

10. Secondary:

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 ]

Show Outcome Measure 10

11. Secondary:

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 ]

Hide Outcome Measure 11

Measure Type	Secondary
Measure Title	Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] During the Treatment Phase
Measure 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
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
PK population; N=number of participants with evaluable data; n=number of participants with evaluable data for the specific category

Reporting Groups

	Description
EMBEDA Whole Capsules	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 Crushed in Solution	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.

Measured Values

	EMBEDA Whole Capsules	EMBEDA Crushed in Solution
Number of Participants Analyzed [units: participants]	3	6
Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] During the Treatment Phase [units: ng*h/mL] Mean ± Standard Deviation
Morphine (n=2,6)	2023.5 ± 1935.01	887.7 ± 583.83
Naltrexone (n=0,6)	NA ± NA ^[1]	1330.7 ± 1141.75
6-β-Naltrexol (n=3,6)	1469.5 ± 955.52	35297.8 ± 18407.20

[1]	No participants with evaluable data

No statistical analysis provided for Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] During the Treatment Phase

12. Other Pre-specified:

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 ]

Show Outcome Measure 12

13. Other Pre-specified:

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 ]

Show Outcome Measure 13

14. Other Pre-specified:

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 ]

Show Outcome Measure 14

15. Other Pre-specified:

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 ]

Show Outcome Measure 15

16. Other Pre-specified:

Maximum Post-dose COWS in the Treatment Phase [ Time Frame: Between 0.5 and 24 hours post-dose ]

Show Outcome Measure 16

Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: 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.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
Sponsor terminated study early on 10-Mar-2011.

Results Point of Contact:

Name/Title: Pfizer ClinicalTrials.gov Call Center
Organization: Pfizer, Inc.
phone: 1-800-718-1021
e-mail: ClinicalTrials.gov_Inquiries@pfizer.com

No publications provided

Responsible Party:	Pfizer
ClinicalTrials.gov Identifier:	NCT01100437 History of Changes
Other Study ID Numbers:	ALO-01-09-111, B4541002
Study First Received:	April 7, 2010
Results First Received:	February 27, 2012
Last Updated:	July 5, 2012
Health Authority:	United States: Food and Drug Administration

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