Comparison of One Morphine Sulfate Sustained-Release 200mg Capsule With Two 100 mg KADIAN Capsules Under Fed Conditions

• Sponsor: Actavis Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00759356
• Collaborator: (none)
• Enrollment: 36
• Location: 1
• Arms: 2
• Duration (Months): 1
• Patients Per Site Per Month: 35.3

Study Details

Study Description

Brief Summary

The objective of this single-dose, open-label, randomized, two-period crossover study was to compare the rate of absorption and oral bioavailability of a test formulation of morphine sulfate 200 mg sustained-release capsules manufactured by Alpharma Branded Products Division Inc. to an equivalent oral dose of the commercially available reference product, KADIAN 2 x 100 mg capsules manufactured by Alpharma Branded Products Division Inc. when administered under fed conditions.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: morphine sulfate sustained-release capsules; Drug: KADIAN	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 36 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: A Single-Dose, 2-Period, 2-Treatment, 2-Way Crossover Study Comparing the Bioavailability of a Morphine Sulfate Sustained Release Capsule 1 x 200mg to KADIAN 2 x 100mg Capsules Under Fed Conditions
• Study Start Date: Aug 1, 2004
• Actual Primary Completion Date: Sep 1, 2004
• Actual Study Completion Date: Sep 1, 2004

Arms and Interventions

Arm	Intervention/Treatment
Other: 1 Treatment A (test product) followed by Treatment B (reference product)	Drug: morphine sulfate sustained-release capsules; 1 x 200 mg, single-dose capsule; Other Names: Treatment A Test Product ; Drug: KADIAN; 2 x 100 mg, single-dose capsule; Other Names: Treatment B Reference Product
Other: 2 Treatment B (reference product) followed by Treatment A (test product)	Drug: morphine sulfate sustained-release capsules; 1 x 200 mg, single-dose capsule; Other Names: Treatment A Test Product ; Drug: KADIAN; 2 x 100 mg, single-dose capsule; Other Names: Treatment B Reference Product

Outcome Measures

Primary Outcome Measures

1. Mean Maximum Plasma Morphine Concentration [0 (predose), and 2,4,6,6.5,7,7.5,8,8.5,9,9.5,10,12,18,24,30,36,48 hrs post dose]

Secondary Outcome Measures

1. Time of Maximum Plasma Morphine Concentration [0 (predose), and 2,4,6,6.5,7,7.5,8,8.5,9,9.5,10,12,18,24,30,36,48 hrs post dose]

2. Area Under the Curve to the Last Measurable Time Point for Plasma Morphine [0 (predose), and 2,4,6,6.5,7,7.5,8,8.5,9,9.5,10,12,18,24,30,36,48 hrs post dose]

3. Area Under the Curve to Infinity for Plasma Morphine [0 (predose), and 2,4,6,6.5,7,7.5,8,8.5,9,9.5,10,12,18,24,30,36,48 hrs post dose]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Subject must be a male or non-pregnant, non-breast-feeding female.

• Subject must be between 18 and 50 years of age inclusive.

• Subject's body weight should be within +/- 15% of the ideal body weight for their height and estimated frame based on the Metropolitan Life Insurance Company Table and weigh a minimum of 50 kg (110 lbs).

• Female subjects - not surgically sterile or at least two years postmenopausal - must agree to utilize one of the following forms of contraception, if sexually active with a male partner, from screening through completion of the study. Approved forms of contraception are abstinence, hormonal (oral, implant, transdermal or injection), double barrier (condom and diaphragm with spermicide), IUD, or vasectomized partner (6 months minimum).

• Subject must voluntarily consent to participate in this study and provide their written informed consent prior to completion of any study-specific procedures.

• Subject is willing and able to remain in the study unit for the entire duration of each confinement period and return to the study site for any outpatient visits.

Exclusion Criteria:

• History or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, oncologic or psychiatric disease or any other condition which, in the opinion of the Investigator would jeopardize the safety of the subject or the validity of the study results.

• Has a clinically significant abnormal finding on the physical exam, medical history or clinical laboratory results at screening.

• History or presence of allergic or adverse response to the study drug or related drugs.

• Has been on a significantly abnormal diet during the four weeks preceding the first dose of study medication.

• Has donated blood or plasma within 30 days prior to the first dose of study medication.

• Has participated in another clinical trial within 30 days prior to first dose of study medication.

• Has used any over-the-counter (OTC) medication including vitamins, within 7 days prior to the first dose of study medication without evaluation and approval by the study investigator.

• Has used any prescription medication, except hormonal contraceptive or hormonal replacement therapy, within 7 days prior to the first dose of study medication without evaluation and approval by the study investigator.

• Has been treated with any known enzyme altering drugs such as barbiturates, phenothiazines, cimetidine, carbamazepine, etc., within 30 days prior to the first dose of study medication.

• Has smoked or used tobacco products within 60 days prior to the first dose of study medication.

• Has a history of substance abuse (including alcohol) in the past 5 years.

• Is a female with a positive pregnancy test result.

• Has a positive urine screen for drugs of abuse (amphetamines, barbiturates, benzodiazepines, cocaine, cannabinoids, opiates).

• Has had a positive test for, or has been treated for hepatitis B, hepatitis C or HIV.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	CEDRA Clinical Research, LLC	Austin	Texas	United States	78759

Sponsors and Collaborators

• Actavis Inc.

Investigators

• Principal Investigator: Daniel V. Freeland, DO, CEDRA Clinical Research, LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00759356
• Other Study ID Numbers: 20-700-1N
• First Posted: Sep 25, 2008
• Last Update Posted: Aug 17, 2010
• Last Verified: Aug 1, 2010

• Keywords provided by , ,: bioavailability; KADIAN; 200 mg; morphine sulfate sustained release capsules; 100 mg; fed conditions
• Additional relevant MeSH terms: Disease; Morphine

Study Results

Participant Flow

Pre-assignment Detail	Wash out period of at least 7 days.

Arm/Group Title	Period 1: Treatment A or B	Period 2: Treatment A or B
Arm/Group Description	Treatment A (test product) followed by Treatment B (reference product)	Treatment B (reference product) followed by Treatment A (test product)
Period Title: Overall Study
STARTED	18	18
COMPLETED	17	15
NOT COMPLETED	1	3

Baseline Characteristics

Arm/Group Title	Period 1: Treatment A or B	Period 2: Treatment A or B	Total
Arm/Group Description	Treatment A (test product) followed by Treatment B (reference product)	Treatment B (reference product) followed by Treatment A (test product)	Total of all reporting groups
Overall Participants	18	18	36
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	18 100%	18 100%	36 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	29.5 (7.5)	33.9 (6.3)	31.7 (7.2)
Sex: Female, Male (Count of Participants)
Female	12 66.7%	12 66.7%	24 66.7%
Male	6 33.3%	6 33.3%	12 33.3%
Region of Enrollment (participants) [Number]
United States	18 100%	18 100%	36 100%

Outcome Measures

1. Primary Outcome

Title	Mean Maximum Plasma Morphine Concentration
Time Frame	0 (predose), and 2,4,6,6.5,7,7.5,8,8.5,9,9.5,10,12,18,24,30,36,48 hrs post dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Morphine Sulfate SR 200 mg Capsule	KADIAN® 200 mg Capsule
Arm/Group Description
Measure Participants	28	28
Mean (Standard Deviation) [ng/mL]	37.3 (15.8)	32.8 (11.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Morphine Sulfate SR 200 mg Capsule, KADIAN® 200 mg Capsule
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The 90% confidence intervals for the ratios (test/reference) of the least squares means of the non-transformed parameters Cmax, AUClast, AUCinf, Tmax, λz, and T1/2, were calculated.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean ratio
	Estimated Value	109.8
	Confidence Interval	() 90%; 95.3 to 126.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Time of Maximum Plasma Morphine Concentration
Time Frame	0 (predose), and 2,4,6,6.5,7,7.5,8,8.5,9,9.5,10,12,18,24,30,36,48 hrs post dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Morphine Sulfate SR 200 mg Capsule	KADIAN® 200 mg Capsule
Arm/Group Description
Measure Participants	28	28
Median (Full Range) [hr]	12.00 (4.95)	12.00 (6.25)

3. Secondary Outcome

Title	Area Under the Curve to the Last Measurable Time Point for Plasma Morphine
Time Frame	0 (predose), and 2,4,6,6.5,7,7.5,8,8.5,9,9.5,10,12,18,24,30,36,48 hrs post dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Morphine Sulfate SR 200 mg Capsule	KADIAN® 200 mg Capsule
Arm/Group Description
Measure Participants	28	28
Mean (Standard Deviation) [hr*ng/mL]	691.3 (196.0)	674.1 (169.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Morphine Sulfate SR 200 mg Capsule, KADIAN® 200 mg Capsule
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The 90% confidence intervals for the ratios (test/reference) of the least squares means of the non-transformed parameters Cmax, AUClast, AUCinf, Tmax, λz, and T1/2, were calculated.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	mean ratio
	Estimated Value	101.5
	Confidence Interval	() 90%; 95.6 to 107.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Area Under the Curve to Infinity for Plasma Morphine
Time Frame	0 (predose), and 2,4,6,6.5,7,7.5,8,8.5,9,9.5,10,12,18,24,30,36,48 hrs post dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Morphine Sulfate SR 200 mg Capsule	KADIAN® 200 mg Capsule
Arm/Group Description
Measure Participants	28	28
Mean (Standard Deviation) [hr*ng/mL]	800.3 (220.9)	789.2 (237.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Morphine Sulfate SR 200 mg Capsule, KADIAN® 200 mg Capsule
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The 90% confidence intervals for the ratios (test/reference) of the least squares means of the non-transformed parameters Cmax, AUClast, AUCinf, Tmax, λz, and T1/2, were calculated.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	mean ratio
	Estimated Value	101.7
	Confidence Interval	() 90%; 95.9 to 107.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Arm/Group Title	Arm 1: Treatment A Followed by Treatment B		Arm 2: Treatment B Followed by Treatment A
Arm/Group Description
All Cause Mortality
	Arm 1: Treatment A Followed by Treatment B		Arm 2: Treatment B Followed by Treatment A
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm 1: Treatment A Followed by Treatment B		Arm 2: Treatment B Followed by Treatment A
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Arm 1: Treatment A Followed by Treatment B		Arm 2: Treatment B Followed by Treatment A
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/ (NaN)		9/ (NaN)
Gastrointestinal disorders
Abdominal Pain	4/18 (22.2%)	4	1/18 (5.6%)	2
Nausea	7/18 (38.9%)	10	8/18 (44.4%)	9
Vomiting	3/18 (16.7%)	3	3/18 (16.7%)	3
Abdominal Distention	1/18 (5.6%)	1	0/18 (0%)	0
Dyspepsia	0/18 (0%)	0	1/18 (5.6%)	1
Diarrhea	0/18 (0%)	0	2/18 (11.1%)	2
General disorders
Fatigue	1/18 (5.6%)	1	0/18 (0%)	0
Chills	0/18 (0%)	0	1/18 (5.6%)	1
Infections and infestations
Rhinitis	1/18 (5.6%)	1	0/18 (0%)	0
Musculoskeletal and connective tissue disorders
Musculoskeletal Pain	0/18 (0%)	0	1/18 (5.6%)	1
Nervous system disorders
Somnolence	3/18 (16.7%)	3	1/18 (5.6%)	1
Headache	2/18 (11.1%)	5	6/18 (33.3%)	6
Tremors	1/18 (5.6%)	1	0/18 (0%)	0
Psychiatric disorders
Anxiety	0/18 (0%)	0	1/18 (5.6%)	1
Respiratory, thoracic and mediastinal disorders
Sneezing	1/18 (5.6%)	1	0/18 (0%)	0
Vascular disorders
Flushing	1/18 (5.6%)	1	0/18 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT 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.