Comparative Bioavailability Study of Two Prototypes of Trazodone Controlled-release Products and Two Marketed Reference Products in Healthy Volunteers

• Sponsor: Labopharm Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01121913
• Collaborator: (none)
• Enrollment: 24
• Arms: 4

Study Details

Study Description

Brief Summary

The objectives of this study were:

• to compare the pharmacokinetic profiles of two prototype controlled-release (CR) trazodone hydrochloride (HCl) 300 mg tablets versus two reference products: Trittico® AC (2 x 150 mg CR tablets) and Desyrel® (3 x 100 mg IR (immediate-release) tablets) under fasting condition;

• to assess the controlled release properties of the two prototype formulations;

• to select a prototype formulation for further development;

• to validate the blood sampling schedule for future pivotal pharmacokinetic studies;

• to determine the appropriate sample size for pivotal studies based in the intra-subject variability.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Trazodone HCl; Drug: Trazodone HCl; Drug: Trazodone HCl; Drug: Trazodone HCl	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Four-way Crossover Pilot Study to Compare the Relative Bioavailability of Two Prototype Once-a-day Trazodone Hydrochloride Products and Two Marketed Reference Products Following an Equivalent Daily Dose Administration Under Fasting Conditions in Healthy Volunteers
• Study Start Date: Mar 1, 2005
• Actual Primary Completion Date: Apr 1, 2005

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Trazodone Contramid® OAD (test product 1) Test product 1 and Test product 2 are two different prototype formulations of Trazodone Contramid® OAD (once a day)	Drug: Trazodone HCl; The dosage of trazodone.HCl during this treatment phase was a single oral dose of 300 mg (one CR tablet) at 07:30 (after an overnight fast of at least 10 hours) on clinic days.
Experimental: Trazodone Contramid® OAD(test product 2) Test product 1 and Test product 2 are two different prototype formulations of Trazodone Contramid® OAD (once a day)	Drug: Trazodone HCl; The dosage of trazodone.HCl during this treatment phase was a single oral dose of 300 mg (one CR tablet) at 07:30 (after an overnight fast of at least 10 hours) on clinic days.; Other Names: Oleptro
Active Comparator: Triticco®	Drug: Trazodone HCl; The dosage of trazodone.HCl during this treatment phase was 2 oral doses of 150 mg each: one controlled-release (CR) tablet at 07:30 (after an overnight fast of at least 10 hours) and 19:30 (after a fast of at least 2 hours) on clinic days.
Active Comparator: Desyrel®	Drug: Trazodone HCl; The dosage of trazodone.HCl during this treatment phase was three oral doses of 100 mg each: one immediate-release (IR) tablet at 07:30 (after an overnight fast of at least 10 hours), 15:30 and 23:30 (both dosages after a fast of at least 2 hours) on clinic days.

Outcome Measures

Primary Outcome Measures

1. Bioequivalence Based on AUC(0-t) [72 hours]

   AUC(0-t) = Area under the plasma concentration curve vs (versus) time data pairs, where t is the time of the last quantifiable concentration. Measured in nanogram x hours per milliliter (ng*h/mL).

2. Bioequivalence Based on AUC(0-∞) [72 hours]

   AUC(0-∞) = Area under the plasma concentration curve vs time data pairs, with extrapolation to infinity (∞). Measured in nanogram x hours per milliliter (ng*h/mL).

3. Bioequivalence Based on Cmax [72 hours]

   Cmax = Maximum plasma concentration. Measured in nanogram per milliliter (ng/mL).

Secondary Outcome Measures

1. Apparent Terminal Half-life (t½.z) [72 hours]

   Apparent terminal half-life (t½.z) of trazodone in hours

2. Time to the Maximum Concentration (Tmax) [72 hours]

3. Apparent First Order Terminal Rate Constant [λz] [72 hours]

   Apparent First order terminal rate constant [λz] of trazodone in plasma expressed in 1/hours.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Healthy male and female subjects 18 to 45 years of age (inclusive).

• Body mass within 10% of the ideal mass in relation to height and age, according to the BMI.

• Body mass not less than 70 kg. The normal total circulating blood volume in males and in females is about 71 mL/kg and 65 mL/kg of the body mass, respectively (Meyer, 1988). No subject will have more than 13% of estimated blood volume taken during the study (Standards for the Practice of Blood Transfusion in South Africa, 1999).

• Findings within the range of clinical acceptability in medical history and physical examination, and laboratory results within the "normal ranges" for the relevant laboratory tests (unless the clinical investigator considers the deviation to be irrelevant for the purpose of the study).

• Normal ECG and vital signs, or abnormalities which the clinical investigator does not consider a disqualification for participation in the study.

• Willingness to undergo pre- and post-study physical examinations, and pre- and post study laboratory investigations.

• Ability to comprehend and willingness to sign both statements of informed consent (for screening and phase-related procedures).

• Non-smoker or past smoker who stopped smoking at least 3 months before entering the study.

• For females, the following conditions are to be met:

1. has been surgically sterilized, or

2. is of childbearing potential, and all of the following conditions are met:

3. had a normal menstrual flow within 1 month before study entry, and

4. has a negative urine pregnancy test at screening. If this test is positive, the subject will be excluded from the study before receiving study medication. In the rare circumstance that a pregnancy is discovered after the subjects received the study drug, every attempt must be made to follow such subjects to term, and

5. must agree to use an accepted method of contraception (i.e., spermicide and barrier methods or spermicide and intrauterine contraceptive device). The subject must agree to continue with the same method throughout the study. Hormonal contraceptives will be allowed, with a stable dose for at least one month prior to the first intake of study medication.

Exclusion Criteria:

• Evidence of psychiatric disorder, antagonistic personality, poor motivation, emotional or intellectual problems likely to limit the validity of consent to participate in the study or limit the ability to comply with protocol requirements.

• History of, or current compulsive alcohol abuse (> 10 drinks weekly), or regular exposure to other substances of abuse.

• Use of any medication, prescribed or over-the-counter, within 2 weeks prior to the first administration of study medication except if this will not affect the outcome of the study in the opinion of the clinical investigator. Use of hormonal contraceptive agents by females is allowed.

• Participation in another study with an experimental drug within 8 weeks before the first administration of study medication.

• Treatment within the previous 3 months with any drug with a well-defined potential for adversely affecting a major organ or system with evidence to this effect.

• A major illness during the 3 months before commencement of the screening period.

• History of hypersensitivity to the study drug or any related drugs.

• History of bronchial asthma.

• History of epilepsy.

• Relevant history or laboratory or clinical findings indicative of acute or chronic disease, likely to influence study outcome.

• Donation or loss of blood equal to or exceeding 500 mL during the 8 weeks before the first administration of study medication.

• Diagnosis of hypotension made during the screening period.

• Diagnosis of hypertension made during the screening period or current diagnosis of hypertension.

• Resting pulse rate of > 100 beats per minute or < 45 beats per minute during the screening period, either supine or standing.

• Positive testing for HIV, hepatitis B surface antigen and/or Hepatitis C antibodies.

• Positive urine screen for drugs of abuse.

• A urine pregnancy test (ß-HCG) either positive or not performed or lactation.

• Positive urine screen for tobacco use (SureStepTM Smoke Check Tests and One-Step Cotinine (COT) Tests).

• History of marijuana, barbiturate, amphetamine or narcotic abuse within 12 months prior to study start.

• Significant liver disease, defined as active hepatitis or elevated liver enzymes (e.g. aspartate aminotransferase, alanine aminotransferase) >2 times the upper boundary of the normal range.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Labopharm Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Approved labelling

Publications

None provided.

• Responsible Party: Labopharm Inc.
• ClinicalTrials.gov Identifier: NCT01121913
• Other Study ID Numbers: 04ACL101
• First Posted: May 12, 2010
• Last Update Posted: Apr 27, 2012
• Last Verified: Apr 1, 2012

• Keywords provided by Labopharm Inc.: Healthy subjects
• Additional relevant MeSH terms: Trazodone

Study Results

Participant Flow

Arm/Group Title	Trazodone Contramid® OAD (Prototype 1) First	Trazodone Contramid® OAD (Prototype 2) First	Triticco® First	Desyrel® First
Arm/Group Description	1 * 300 mg Trazodone Contramid® OAD (prototype 1) tablet test product dosed in treatment phase I; followed by 2 * 150 mg Triticco® tablets (at 07:30 and 19:30) reference product dosed in treatment phase II; 1 * 300 mg Trazodone Contramid® OAD (prototype 2) tablet test product dosed in treatment phase III; and 3 * 100 mg Desyrel® tablets (at 07:30, 15:30 and 23:30) reference product dosed in treatment phase IV. There was a washout period of 7 days between treatment phases.	1 * 300 mg Trazodone Contramid® OAD (prototype 2) tablet test product dosed in treatment phase I, followed by 1 * 300 mg Trazodone Contramid® OAD (prototype 1) tablet test product dosed in treatment phase II; 3 * 100 mg Desyrel® tablets (at 07:30, 15:30 and 23:30) reference product dosed in treatment phase III; and 2 * 150 mg Triticco® tablets (at 07:30 and 19:30) reference product dosed in treatment phase IV. There was a washout period of 7 days between treatment phases.	2 * 150 mg Triticco® tablets (at 07:30 and 19:30) reference product dosed in treatment phase I; followed by 3 * 100 mg Desyrel® tablets (at 07:30, 15:30 and 23:30) reference product dosed in treatment phase II; 1 * 300 mg Trazodone Contramid® OAD (prototype 1) tablet test product dosed in treatment phase III; and 1 * 300 mg Trazodone Contramid® OAD (prototype 2) tablet test product dosed in treatment phase IV. There was a washout period of 7 days between treatment phases.	3 * 100 mg Desyrel® tablets (at 07:30, 15:30 and 23:30) reference product dosed in treatment phase I; followed by 1 * 300 mg Trazodone Contramid® OAD (prototype 2) tablet test product dosed in treatment phase II; 2 * 150 mg Triticco® tablets (at 07:30 and 19:30) reference product dosed in treatment phase III; and 1 * 300 mg Trazodone Contramid® OAD (prototype 1) tablet test product dosed in treatment phase IV. There was a washout period of 7 days between treatment phases.
Period Title: First Intervention Period
STARTED	6	6	6	6
COMPLETED	6	6	5	6
NOT COMPLETED	0	0	1	0
Period Title: First Intervention Period
STARTED	6	6	5	6
COMPLETED	5	6	5	6
NOT COMPLETED	1	0	0	0
Period Title: First Intervention Period
STARTED	5	6	5	6
COMPLETED	5	6	4	6
NOT COMPLETED	0	0	1	0
Period Title: First Intervention Period
STARTED	5	6	4	6
COMPLETED	5	6	3	6
NOT COMPLETED	0	0	1	0
Period Title: First Intervention Period
STARTED	5	6	3	6
COMPLETED	5	6	3	6
NOT COMPLETED	0	0	0	0
Period Title: First Intervention Period
STARTED	5	6	3	6
COMPLETED	4	6	3	6
NOT COMPLETED	1	0	0	0
Period Title: First Intervention Period
STARTED	4	6	3	6
COMPLETED	4	6	3	6
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Entire Study Population
Arm/Group Description	Includes groups randomized to receive Trazodone Contramid® OAD (prototype 1) First, Trazodone Contramid® OAD (prototype 2) First, Triticco® First, and Desyrel® First.
Overall Participants	24
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	24 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	24.9 (7.3)
Sex: Female, Male (Count of Participants)
Female	6 25%
Male	18 75%
Region of Enrollment (participants) [Number]
South Africa	24 100%

Outcome Measures

1. Primary Outcome

Title	Bioequivalence Based on AUC(0-t)
Description	AUC(0-t) = Area under the plasma concentration curve vs (versus) time data pairs, where t is the time of the last quantifiable concentration. Measured in nanogram x hours per milliliter (ng*h/mL).
Time Frame	72 hours

Outcome Measure Data

Analysis Population Description

The dataset for pharmacokinetic analysis comprised the 19 subjects who completed the study as per protocol.

Arm/Group Title	Trazodone Contramid® OAD (Prototype 1)	Trazodone Contramid® OAD (Prototype 2)	Triticco®	Desyrel®
Arm/Group Description	1 * 300 mg Trazodone Contramid® OAD (prototype 1) tablet test product dosed in either treatment phase.	1 * 300 mg Trazodone Contramid® OAD (prototype 2) tablet test product dosed in either treatment phase.	2 * 150 mg Triticco® tablets (at 07:30 and 19:30) reference product dosed in either treatment phase.	3 * 100 mg Desyrel® tablets (at 07:30, 15:30 and 23:30) reference product dosed in either treatment phase.
Measure Participants	19	19	19	19
Mean (Standard Deviation) [ng*h/mL]	33883 (8069)	32445 (8868)	32928 (8313)	31841 (7398)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trazodone Contramid® OAD (Prototype 1), Triticco®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Bioequivalence is established when the ratio of geometric Least Squares means (LS means) and confidence interval calculated from the exponential of the difference between the Test and Reference product for the ln-transformed parameter AUC(0-t) is between 80% and 125%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean ratio
	Estimated Value	102
	Confidence Interval	(2-Sided) 90%; 91.8 to 114
	Parameter Dispersion	Type: Value:
	Estimation Comments	Trazodone Contramid® OAD (prototype 1)/Triticco®

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Trazodone Contramid® OAD (Prototype 1), Desyrel®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Bioequivalence is established when the ratio of geometric Least Squares means (LS means) and confidence interval calculated from the exponential of the difference between the Test and Reference product for the ln-transformed parameter AUC(0-t) is between 80% and 125%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean ratio
	Estimated Value	105
	Confidence Interval	(2-Sided) 90%; 93.9 to 117
	Parameter Dispersion	Type: Value:
	Estimation Comments	Trazodone Contramid® OAD (prototype 1)/Desyrel®

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Trazodone Contramid® OAD (Prototype 2), Triticco®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Bioequivalence is established when the ratio of geometric Least Squares means (LS means) and confidence interval calculated from the exponential of the difference between the Test and Reference product for the ln-transformed parameter AUC(0-t) is between 80% and 125%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean ratio
	Estimated Value	95.3
	Confidence Interval	(2-Sided) 90%; 85.5 to 106
	Parameter Dispersion	Type: Value:
	Estimation Comments	Trazodone Contramid® OAD (prototype 2)/Triticco®

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Trazodone Contramid® OAD (Prototype 2), Desyrel®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Bioequivalence is established when the ratio of geometric Least Squares means (LS means) and confidence interval calculated from the exponential of the difference between the Test and Reference product for the ln-transformed parameter AUC(0-t) is between 80% and 125%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean ratio
	Estimated Value	97.7
	Confidence Interval	(2-Sided) 90%; 87.7 to 109
	Parameter Dispersion	Type: Value:
	Estimation Comments	Trazodone Contramid® OAD (prototype 2)/Desyrel®

2. Primary Outcome

Title	Bioequivalence Based on AUC(0-∞)
Description	AUC(0-∞) = Area under the plasma concentration curve vs time data pairs, with extrapolation to infinity (∞). Measured in nanogram x hours per milliliter (ng*h/mL).
Time Frame	72 hours

Outcome Measure Data

Analysis Population Description

The dataset for pharmacokinetic analysis comprised the 19 subjects who completed the study as per protocol.

Arm/Group Title	Trazodone Contramid® OAD (Prototype 1)	Trazodone Contramid® OAD (Prototype 2)	Triticco®	Desyrel®
Arm/Group Description	1 * 300 mg Trazodone Contramid® OAD (prototype 1) tablet test product dosed in either treatment phase.	1 * 300 mg Trazodone Contramid® OAD (prototype 2) tablet test product dosed in either treatment phase.	2 * 150 mg Triticco® tablets (at 07:30 and 19:30) reference product dosed in either treatment phase.	3 * 100 mg Desyrel® tablets (at 07:30, 15:30 and 23:30) reference product dosed in either treatment phase.
Measure Participants	19	19	19	19
Mean (Standard Deviation) [ng*h/mL]	35122 (8655)	33373 (9299)	34165 (9105)	32485 (7621)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trazodone Contramid® OAD (Prototype 1), Triticco®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Bioequivalence is established when the ratio of geometric Least Squares means (LSmeans) and confidence interval calculated from the exponential of the difference between the Test and Reference product for the ln-transformed parameter AUC(0-∞) is between 80% and 125%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean ratio
	Estimated Value	102
	Confidence Interval	(2-Sided) 90%; 91.8 to 114
	Parameter Dispersion	Type: Value:
	Estimation Comments	Trazodone Contramid® OAD (prototype 1)/Triticco®

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Trazodone Contramid® OAD (Prototype 1), Desyrel®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Bioequivalence is established when the ratio of geometric Least Squares means (LSmeans) and confidence interval calculated from the exponential of the difference between the Test and Reference product for the ln-transformed parameter AUC(0-∞) is between 80% and 125%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean ratio
	Estimated Value	106
	Confidence Interval	(2-Sided) 90%; 95.1 to 118
	Parameter Dispersion	Type: Value:
	Estimation Comments	Trazodone Contramid® OAD (prototype 1)/Desyrel®

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Trazodone Contramid® OAD (Prototype 2), Triticco®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Bioequivalence is established when the ratio of geometric Least Squares means (LSmeans) and confidence interval calculated from the exponential of the difference between the Test and Reference product for the ln-transformed parameter AUC(0-∞) is between 80% and 125%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean ratio
	Estimated Value	94.9
	Confidence Interval	(2-Sided) 90%; 85.1 to 106
	Parameter Dispersion	Type: Value:
	Estimation Comments	Trazodone Contramid® OAD (prototype 2)/Triticco®

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Trazodone Contramid® OAD (Prototype 2), Desyrel®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Bioequivalence is established when the ratio of geometric Least Squares means (LSmeans) and confidence interval calculated from the exponential of the difference between the Test and Reference product for the ln-transformed parameter AUC(0-∞) is between 80% and 125%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean ratio
	Estimated Value	98.4
	Confidence Interval	(2-Sided) 90%; 88.3 to 110
	Parameter Dispersion	Type: Value:
	Estimation Comments	Trazodone Contramid® OAD (prototype 2)/Desyrel®

3. Primary Outcome

Title	Bioequivalence Based on Cmax
Description	Cmax = Maximum plasma concentration. Measured in nanogram per milliliter (ng/mL).
Time Frame	72 hours

Outcome Measure Data

Analysis Population Description

The dataset for pharmacokinetic analysis comprised the 19 subjects who completed the study as per protocol.

Arm/Group Title	Trazodone Contramid® OAD (Prototype 1)	Trazodone Contramid® OAD (Prototype 2)	Triticco®	Desyrel®
Arm/Group Description	1 * 300 mg Trazodone Contramid® OAD (prototype 1) tablet test product dosed in either treatment phase.	1 * 300 mg Trazodone Contramid® OAD (prototype 2) tablet test product dosed in either treatment phase.	2 * 150 mg Triticco® tablets (at 07:30 and 19:30) reference product dosed in either treatment phase.	3 * 100 mg Desyrel® tablets (at 07:30, 15:30 and 23:30) reference product dosed in either treatment phase.
Measure Participants	19	19	19	19
Mean (Standard Deviation) [ng/mL]	1260 (402)	1475 (489)	1688 (442)	2081 (492)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trazodone Contramid® OAD (Prototype 1), Triticco®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Bioequivalence is established when the ratio of geometric Least Squares means (LSmeans) and confidence interval calculated from the exponential of the difference between the Test and Reference product for the ln-transformed parameter Cmax is between 75% and 133%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean ratio
	Estimated Value	73.3
	Confidence Interval	(2-Sided) 90%; 63.2 to 85
	Parameter Dispersion	Type: Value:
	Estimation Comments	Trazodone Contramid® OAD (prototype 1)/Triticco®

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Trazodone Contramid® OAD (Prototype 1), Desyrel®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Bioequivalence is established when the ratio of geometric Least Squares means (LSmeans) and confidence interval calculated from the exponential of the difference between the Test and Reference product for the ln-transformed parameter Cmax is between 75% and 133%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean ratio
	Estimated Value	59.8
	Confidence Interval	(2-Sided) 90%; 51.5 to 69.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Trazodone Contramid® OAD (prototype 1)/Desyrel®

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Trazodone Contramid® OAD (Prototype 2), Triticco®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Bioequivalence is established when the ratio of geometric Least Squares means (LSmeans) and confidence interval calculated from the exponential of the difference between the Test and Reference product for the ln-transformed parameter Cmax is between 75% and 133%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean ratio
	Estimated Value	83
	Confidence Interval	(2-Sided) 90%; 71.5 to 96.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Trazodone Contramid® OAD (prototype 2)/Triticco®

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Trazodone Contramid® OAD (Prototype 2), Desyrel®
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Bioequivalence is established when the ratio of geometric Least Squares means (LSmeans) and confidence interval calculated from the exponential of the difference between the Test and Reference product for the ln-transformed parameter Cmax is between 75% and 133%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean ratio
	Estimated Value	67.7
	Confidence Interval	(2-Sided) 90%; 58.4 to 78.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Trazodone Contramid® OAD (prototype 2)/Desyrel®

4. Secondary Outcome

Title	Apparent Terminal Half-life (t½.z)
Description	Apparent terminal half-life (t½.z) of trazodone in hours
Time Frame	72 hours

Outcome Measure Data

Analysis Population Description

The dataset for pharmacokinetic analysis comprised the 19 subjects who completed the study as per protocol.

Arm/Group Title	Trazodone Contramid® OAD (Prototype 1)	Trazodone Contramid® OAD (Prototype 2)	Triticco®	Desyrel®
Arm/Group Description	1 * 300 mg Trazodone Contramid® OAD (prototype 1) tablet test product dosed in either treatment phase.	1 * 300 mg Trazodone Contramid® OAD (prototype 2) tablet test product dosed in either treatment phase.	2 * 150 mg Triticco® tablets (at 07:30 and 19:30) reference product dosed in either treatment phase.	3 * 100 mg Desyrel® tablets (at 07:30, 15:30 and 23:30) reference product dosed in either treatment phase.
Measure Participants	19	19	19	19
Mean (Standard Deviation) [Hours]	11.2 (3.92)	10.9 (3.55)	10.6 (3.25)	9.77 (2.49)

5. Secondary Outcome

Title	Time to the Maximum Concentration (Tmax)
Time Frame	72 hours

Outcome Measure Data

Analysis Population Description

The dataset for pharmacokinetic analysis comprised the 19 subjects who completed the study as per protocol.

Arm/Group Title	Trazodone Contramid® OAD (Prototype 1)	Trazodone Contramid® OAD (Prototype 2)	Triticco®	Desyrel®
Arm/Group Description	1 * 300 mg Trazodone Contramid® OAD (prototype 1) tablet test product dosed in either treatment phase.	1 * 300 mg Trazodone Contramid® OAD (prototype 2) tablet test product dosed in either treatment phase.	2 * 150 mg Triticco® tablets (at 07:30 and 19:30) reference product dosed in either treatment phase.	3 * 100 mg Desyrel® tablets (at 07:30, 15:30 and 23:30) reference product dosed in either treatment phase.
Measure Participants	19	19	19	19
Median (Full Range) [Hours]	12.0	6.00	13.0	8.50

6. Secondary Outcome

Title	Apparent First Order Terminal Rate Constant [λz]
Description	Apparent First order terminal rate constant [λz] of trazodone in plasma expressed in 1/hours.
Time Frame	72 hours

Outcome Measure Data

Analysis Population Description

The dataset for pharmacokinetic analysis comprised the 19 subjects who completed the study as per protocol.

Arm/Group Title	Trazodone Contramid® OAD (Prototype 1)	Trazodone Contramid® OAD (Prototype 2)	Triticco®	Desyrel®
Arm/Group Description	1 * 300 mg Trazodone Contramid® OAD (prototype 1) tablet test product dosed in either treatment phase.	1 * 300 mg Trazodone Contramid® OAD (prototype 2) tablet test product dosed in either treatment phase.	2 * 150 mg Triticco® tablets (at 07:30 and 19:30) reference product dosed in either treatment phase.	3 * 100 mg Desyrel® tablets (at 07:30, 15:30 and 23:30) reference product dosed in either treatment phase.
Measure Participants	19	19	19	19
Mean (Standard Deviation) [1/hours]	0.07 (0.02)	0.07 (0.02)	0.07 (0.02)	0.08 (0.02)

Adverse Events

Arm/Group Title	Trazodone Contramid® OAD (Prototype 1)		Trazodone Contramid® OAD (Prototype 2)		Triticco®		Desyrel®
Arm/Group Description	1 * 300 mg Trazodone Contramid® OAD (prototype 1) tablet test product dosed in either treatment phase.		1 * 300 mg Trazodone Contramid® OAD (prototype 2) tablet test product dosed in either treatment phase.		2 * 150 mg Triticco® tablets (at 07:30 and 19:30) reference product dosed in either treatment phase.		3 * 100 mg Desyrel® tablets (at 07:30, 15:30 and 23:30) reference product dosed in either treatment phase.
All Cause Mortality
	Trazodone Contramid® OAD (Prototype 1)		Trazodone Contramid® OAD (Prototype 2)		Triticco®		Desyrel®
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Trazodone Contramid® OAD (Prototype 1)		Trazodone Contramid® OAD (Prototype 2)		Triticco®		Desyrel®
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		0/20 (0%)		0/23 (0%)		0/21 (0%)
Other (Not Including Serious) Adverse Events
	Trazodone Contramid® OAD (Prototype 1)		Trazodone Contramid® OAD (Prototype 2)		Triticco®		Desyrel®
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/21 (33.3%)		9/20 (45%)		14/23 (60.9%)		14/21 (66.7%)
Cardiac disorders
Palpitations	1/21 (4.8%)	1	0/20 (0%)	0	0/23 (0%)	0	0/21 (0%)	0
Eye disorders
Eye pruritus	0/21 (0%)	0	0/20 (0%)	0	0/23 (0%)	0	1/21 (4.8%)	1
Ocular hyperaemia	0/21 (0%)	0	0/20 (0%)	0	0/23 (0%)	0	1/21 (4.8%)	1
Gastrointestinal disorders
Abdominal discomfort	0/21 (0%)	0	1/20 (5%)	1	0/23 (0%)	0	1/21 (4.8%)	2
Dry mouth	0/21 (0%)	0	0/20 (0%)	0	1/23 (4.3%)	1	2/21 (9.5%)	2
Nausea	1/21 (4.8%)	2	0/20 (0%)	0	1/23 (4.3%)	1	5/21 (23.8%)	5
Vomiting	1/21 (4.8%)	1	0/20 (0%)	0	0/23 (0%)	0	1/21 (4.8%)	1
General disorders
Fatigue	1/21 (4.8%)	1	1/20 (5%)	1	4/23 (17.4%)	4	2/21 (9.5%)	2
Infections and infestations
Gastroenteritis	0/21 (0%)	0	0/20 (0%)	0	0/23 (0%)	0	1/21 (4.8%)	1
Nasopharyngitis	2/21 (9.5%)	2	1/20 (5%)	1	0/23 (0%)	0	0/21 (0%)	0
Musculoskeletal and connective tissue disorders
Myalgia intercostal	0/21 (0%)	0	0/20 (0%)	0	0/23 (0%)	0	1/21 (4.8%)	1
Nervous system disorders
Dizziness	4/21 (19%)	4	6/20 (30%)	6	6/23 (26.1%)	7	8/21 (38.1%)	9
Headache	2/21 (9.5%)	3	1/20 (5%)	1	4/23 (17.4%)	5	6/21 (28.6%)	6
Syncope	0/21 (0%)	0	1/20 (5%)	1	1/23 (4.3%)	1	0/21 (0%)	0
Tremor	1/21 (4.8%)	1	0/20 (0%)	0	0/23 (0%)	0	0/21 (0%)	0
Hypotensive shock	0/21 (0%)	0	0/20 (0%)	0	1/23 (4.3%)	1	0/21 (0%)	0
Respiratory, thoracic and mediastinal disorders
Nasal congestion	0/21 (0%)	0	1/20 (5%)	1	3/23 (13%)	3	1/21 (4.8%)	1
Oropharyngeal pain	0/21 (0%)	0	0/20 (0%)	0	0/23 (0%)	0	1/21 (4.8%)	1
Skin and subcutaneous tissue disorders
Hyperhidrosis	1/21 (4.8%)	1	0/20 (0%)	0	0/23 (0%)	0	0/21 (0%)	0
Vascular disorders
Hypotension	0/21 (0%)	0	0/20 (0%)	0	0/23 (0%)	0	1/21 (4.8%)	1
Hypotension with convulsions	0/21 (0%)	0	0/20 (0%)	0	0/23 (0%)	0	1/21 (4.8%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The scientific results from this study are the property of the Sponsors, ie, Labopharm Inc., Canada and A.C.R.A.F. S.p.A., Italy. No data reported in the final integrated clinical trial report of this study will be used for publication in scientific journals and/or for presentation at scientific meetings without a previous agreed written consent between the Sponsors.