A Study to Compare the Bioavailability of 300 mg Trazodone Hydrochloride Extended-release Caplets and 100 mg Trazodone Hydrochloride Immediate-release Tablets at Steady State

• Sponsor: Labopharm Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01121926
• Collaborator: (none)
• Enrollment: 30
• Arms: 2
• Duration (Months): 2

Study Details

Study Description

Brief Summary

The purpose of this study was to compare the pharmacokinetic profiles at steady state of the test product, 300 mg trazodone hydrochloride (HCl) extended-release caplets (containing Contramid®), when administered once daily, and the reference product, 100 mg trazodone HCl immediate-release tablets (Apotex Corp.), when administered three times daily, for one week. For this purpose, the rate and extent of absorption of trazodone and formation of m-chlorophenylpiperazine (mCPP) after administration of multiple doses of up to 300 mg of each of the two formulations was compared.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Two-way Crossover Study to Compare the Bioavailability of 300 mg Trazodone Hydrochloride Extended-release Caplets (Containing Contramid®) (Administered Once Daily) and 100 mg Trazodone Hydrochloride Immediate-release Tablets (Administered Three Times Daily) at Steady State
• Study Start Date: Jan 1, 2008
• Actual Primary Completion Date: Mar 1, 2008
• Actual Study Completion Date: Mar 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Trazodone HCl OAD OAD: Once A Day	Drug: Trazodone HCl; Dosage form: Extended-release caplets containing 300 mg trazodone HCl and extended-release caplets containing 150 mg trazodone HCl (the 150 mg dosage form was only used for the up and down titration, and was not evaluated in the study). Dose regimen: 75 mg trazodone HCl (½ x 150 mg extended-release caplet) on Days 1 and 11, 150 mg trazodone HCl (one extended-release caplet) on Days 2 and 10, 300 mg trazodone HCl (one extended-release caplet) on Days 3 to 9, each at 23:30 after a fast of at least 4 hours.; Other Names: Oleptro
Active Comparator: Trazodone HCl (Apotex Corp.)	Drug: Trazodone HCl; Dosage form: Immediate-release tablet containing 100 mg trazodone HCl Dose regimen: 100 mg trazodone HCl (one immediate-release tablet) once (at 23:30) on Days 1 and 11, 100 mg trazodone HCl (one immediate-release tablet) twice (at 23:30 and 11:30) on Days 2 and 10, 100 mg trazodone HCl (one immediate-release tablet) three times daily (at 23:30, 07:30 and 15:30) on Days 3 to 9. Evening doses were administered after a fast of at least 4 hours.

Outcome Measures

Primary Outcome Measures

1. Bioequivalence Based on Cmax,ss [9 days]

   Cmax,ss = Maximum plasma concentration (Cmax) at steady state (ss): (Cmax,ss). Measured in nanograms per milliliter (ng/mL).

2. Bioequivalence Based on AUCss [9 days]

   AUCss = Area under the plasma concentration curve (AUC) vs. time data pairs at steady state (ss): AUCss. Measured in nanograms x hours per milliliter (ng*h/mL).

Secondary Outcome Measures

1. Minimum Plasma Concentration (Cmin,ss) [9 days]

   Minimum plasma concentration at steady state (Cmin,ss). Measured in nanograms per milliliter (ng/mL)

2. Plasma Concentration at 24 Hours Post-evening Dose (C24h) [9 days]

   Plasma concentration at 24 hours post-evening dose (C24h) in nanograms per milliliter (ng/mL)

3. Time to Peak Exposure (Tmax) [9 days]

   Time to peak exposure (Tmax) at steady state.

4. Percentage Swing [9 days]

   Percentage swing is a pharmacokinetic parameter calculated as follows: ((Cmax,ss - Cmin,ss)/Cmin,ss)*100. Where: Cmax,ss = Maximum concentration at steady state; Cmin,ss = Minimum concentration at steady state. It was calculated over 24 hours on day 9.

5. Percentage Peak-Trough Fluctuation (%PTF) [9 days]

   Percentage Peak-Trough Fluctuation (%PTF) of trazodone calculated as [100*(Cmax-Cmin)/Cav]. Cmax: Maximum plasma concentration Cmin: Minimum plasma concentration Cav: Average plasma concentration

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Healthy male and female subjects 18 to <56 years of age.

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

• Body mass not less than 60 kg.

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

• Normal electrocardiogram (ECG) and vital signs, or abnormalities which the investigator did not consider a disqualification for participation in the study.

• Willingness to undergo pre- and post-study physical examinations and 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 the use of any form of tobacco, including snuff or similar products, at least 3 months before entering the study.

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

1. had been surgically sterilized or undergone a hysterectomy, or

2. was of childbearing potential, and all of the following conditions were met:

3. Had a negative pregnancy test at screening. If this test was positive, the subject was to be excluded from the study before receiving study medication. In the circumstance that a pregnancy was discovered after the subjects received the study medication, every attempt had to be made to follow such subjects to term.

4. Had to agree to use an accepted method of contraception (i.e., spermicide and barrier methods or spermicide and non-hormonal intrauterine contraceptive device). The subject had to agree to continue with the same method throughout the study. Hormonal contraceptives were not allowed.

5. females not of childbearing potential could also have been included if they had no menstrual period for one year and were considered as post-menopausal.

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 would not affect the outcome of the study in the opinion of the investigator.

• Participation in another study with an experimental drug, where the last administration (of previous study medication) was 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 medication or any related medication.

• History of bronchial asthma.

• History of epilepsy.

• History of porphyria.

• 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 of > 100 beats per minute or < 40 beats per minute during the screening period, either supine or standing.

• Positive testing for HIV and/or Hepatitis B and/or Hepatitis C.

• Positive urine screen for drugs of abuse.

• Positive urine screen for tobacco use.

• A serum pregnancy test (beta human chorionic gonadotropin [β-HCG]) either positive or not performed or lactation.

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: NCT01121926
• Other Study ID Numbers: 04ACL108
• First Posted: May 12, 2010
• Last Update Posted: Apr 30, 2012
• Last Verified: Apr 1, 2012

• Keywords provided by Labopharm Inc.: Healthy subjects; Bioavailability; Pharmacokinetics; Trazodone; Steady-state
• Additional relevant MeSH terms: Trazodone

Study Results

Participant Flow

Arm/Group Title	Test (Trazodone Contramid® OAD) First	Reference (Trazodone IR [Apotex Corp.]) First
Arm/Group Description	Trazodone Contramid® OAD (Once-A-Day) test product (300 mg tablet administered once daily) dosed in first treatment phase followed by Trazodone IR (Apotex Corp.) reference product (100 mg tablet administered thrice daily) dosed in the second treatment phase. A drug-free period of 7 calendar days separated the last administration of study medication in Phase 1 and the first administration of study medication in Phase 2. IR = Immediate Release.	Trazodone IR (Apotex Corp.) reference product (100 mg tablet administered thrice daily) dosed in first treatment phase followed by Trazodone Contramid® OAD (Once-A-Day) test product (300 mg tablet administered once daily) dosed in the second treatment phase. A drug-free period of 7 calendar days separated the last administration of study medication in Phase 1 and the first administration of study medication in Phase 2. IR = Immediate Release.
Period Title: First Intervention Period
STARTED	15	15
COMPLETED	14	15
NOT COMPLETED	1	0
Period Title: First Intervention Period
STARTED	14	15
COMPLETED	14	13
NOT COMPLETED	0	2
Period Title: First Intervention Period
STARTED	14	13
COMPLETED	14	13
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Entire Study Population
Arm/Group Description	Includes groups randomized to receive Trazodone Contramid® OAD (Once-A-Day) test product first and Trazodone IR (Apotex Corp.) reference product first. IR = Immediate Release
Overall Participants	30
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	30 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	25.7 (8.4)
Sex: Female, Male (Count of Participants)
Female	9 30%
Male	21 70%
Region of Enrollment (participants) [Number]
South Africa	30 100%

Outcome Measures

1. Primary Outcome

Title	Bioequivalence Based on Cmax,ss
Description	Cmax,ss = Maximum plasma concentration (Cmax) at steady state (ss): (Cmax,ss). Measured in nanograms per milliliter (ng/mL).
Time Frame	9 days

Outcome Measure Data

Analysis Population Description

The dataset for pharmacokinetic analysis comprised the 27 subjects who completed the study as per protocol.

Arm/Group Title	Trazodone Contramid® OAD	Trazodone HCl (Apotex Corp.)
Arm/Group Description	Trazodone Contramid® OAD test product (300 mg tablet administered once daily) dosed in either period. A drug-free period of 7 calendar days separated the last administration of study medication in Phase 1 and the first administration of study medication in Phase 2.	Trazodone HCl (Apotex Corp.) reference product (100 mg tablet administered thrice daily) dosed in either period. A drug-free period of 7 calendar days separated the last administration of study medication in Phase 1 and the first administration of study medication in Phase 2.
Measure Participants	27	27
Mean (Standard Deviation) [ng/mL]	1812.026 (620.625)	3117.778 (757.508)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trazodone Contramid® OAD, Trazodone HCl (Apotex Corp.)
	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,ss is between 80% and 125%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean ratio
	Estimated Value	56.53
	Confidence Interval	(2-Sided) 90%; 49.99 to 63.94
	Parameter Dispersion	Type: Value:
	Estimation Comments	Test/reference (%)

2. Primary Outcome

Title	Bioequivalence Based on AUCss
Description	AUCss = Area under the plasma concentration curve (AUC) vs. time data pairs at steady state (ss): AUCss. Measured in nanograms x hours per milliliter (ng*h/mL).
Time Frame	9 days

Outcome Measure Data

Analysis Population Description

The dataset for pharmacokinetic analysis comprised the 27 subjects who completed the study as per protocol.

Arm/Group Title	Trazodone Contramid® OAD	Trazodone HCl (Apotex Corp.)
Arm/Group Description	Trazodone Contramid® OAD test product (300 mg tablet administered once daily) dosed in either period. A drug-free period of 7 calendar days separated the last administration of study medication in Phase 1 and the first administration of study medication in Phase 2.	Trazodone HCl (Apotex Corp.) reference product (100 mg tablet administered thrice daily) dosed in either period. A drug-free period of 7 calendar days separated the last administration of study medication in Phase 1 and the first administration of study medication in Phase 2.
Measure Participants	27	27
Mean (Standard Deviation) [ng*h/mL]	29131.374 (9930.767)	33058.024 (8006.118)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trazodone Contramid® OAD, Trazodone HCl (Apotex Corp.)
	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 AUCss is between 80% and 125%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean ratio
	Estimated Value	85.72
	Confidence Interval	(2-Sided) 90%; 81.05 to 90.67
	Parameter Dispersion	Type: Value:
	Estimation Comments	Test/reference (%)

3. Secondary Outcome

Title	Minimum Plasma Concentration (Cmin,ss)
Description	Minimum plasma concentration at steady state (Cmin,ss). Measured in nanograms per milliliter (ng/mL)
Time Frame	9 days

Outcome Measure Data

Analysis Population Description

The dataset for pharmacokinetic analysis comprised the 27 subjects who completed the study as per protocol.

Arm/Group Title	Trazodone Contramid® OAD	Trazodone HCl (Apotex Corp.)
Arm/Group Description	Trazodone Contramid® OAD test product (300 mg tablet administered once daily) dosed in either period. A drug-free period of 7 calendar days separated the last administration of study medication in Phase 1 and the first administration of study medication in Phase 2.	Trazodone HCl (Apotex Corp.) reference product (100 mg tablet administered thrice daily) dosed in either period. A drug-free period of 7 calendar days separated the last administration of study medication in Phase 1 and the first administration of study medication in Phase 2.
Measure Participants	27	27
Mean (Standard Deviation) [ng/mL]	673.889 (354.647)	842.763 (273.592)

4. Secondary Outcome

Title	Plasma Concentration at 24 Hours Post-evening Dose (C24h)
Description	Plasma concentration at 24 hours post-evening dose (C24h) in nanograms per milliliter (ng/mL)
Time Frame	9 days

Outcome Measure Data

Analysis Population Description

The dataset for pharmacokinetic analysis comprised the 27 subjects who completed the study as per protocol.

Arm/Group Title	Trazodone Contramid® OAD	Trazodone HCl (Apotex Corp.)
Arm/Group Description	Trazodone Contramid® OAD test product (300 mg tablet administered once daily) dosed in either period. A drug-free period of 7 calendar days separated the last administration of study medication in Phase 1 and the first administration of study medication in Phase 2.	Trazodone HCl (Apotex Corp.) reference product (100 mg tablet administered thrice daily) dosed in either period. A drug-free period of 7 calendar days separated the last administration of study medication in Phase 1 and the first administration of study medication in Phase 2.
Measure Participants	27	27
Mean (Standard Deviation) [ng/mL]	747.270 (329.025)	919.111 (289.382)

5. Secondary Outcome

Title	Time to Peak Exposure (Tmax)
Description	Time to peak exposure (Tmax) at steady state.
Time Frame	9 days

Outcome Measure Data

Analysis Population Description

The dataset for pharmacokinetic analysis comprised the 27 subjects who completed the study as per protocol.

Arm/Group Title	Trazodone Contramid® OAD	Trazodone HCl (Apotex Corp.)
Arm/Group Description	Trazodone Contramid® OAD test product (300 mg tablet administered once daily) dosed in either period. A drug-free period of 7 calendar days separated the last administration of study medication in Phase 1 and the first administration of study medication in Phase 2.	Trazodone HCl (Apotex Corp.) reference product (100 mg tablet administered thrice daily) dosed in either period. A drug-free period of 7 calendar days separated the last administration of study medication in Phase 1 and the first administration of study medication in Phase 2.
Measure Participants	27	27
Median (Full Range) [hours]	8.00	8.33

6. Secondary Outcome

Title	Percentage Swing
Description	Percentage swing is a pharmacokinetic parameter calculated as follows: ((Cmax,ss - Cmin,ss)/Cmin,ss)*100. Where: Cmax,ss = Maximum concentration at steady state; Cmin,ss = Minimum concentration at steady state. It was calculated over 24 hours on day 9.
Time Frame	9 days

Outcome Measure Data

Analysis Population Description

The dataset for pharmacokinetic analysis comprised the 27 subjects who completed the study as per protocol.

Arm/Group Title	Trazodone Contramid® OAD	Trazodone HCl (Apotex Corp.)
Arm/Group Description	Trazodone Contramid® OAD test product (300 mg tablet administered once daily) dosed in either period. A drug-free period of 7 calendar days separated the last administration of study medication in Phase 1 and the first administration of study medication in Phase 2.	Trazodone HCl (Apotex Corp.) reference product (100 mg tablet administered thrice daily) dosed in either period. A drug-free period of 7 calendar days separated the last administration of study medication in Phase 1 and the first administration of study medication in Phase 2.
Measure Participants	27	27
Mean (Standard Deviation) [Percentage swing]	210.769 (127.806)	302.805 (144.467)

7. Secondary Outcome

Title	Percentage Peak-Trough Fluctuation (%PTF)
Description	Percentage Peak-Trough Fluctuation (%PTF) of trazodone calculated as [100*(Cmax-Cmin)/Cav]. Cmax: Maximum plasma concentration Cmin: Minimum plasma concentration Cav: Average plasma concentration
Time Frame	9 days

Outcome Measure Data

Analysis Population Description

The dataset for pharmacokinetic analysis comprised the 27 subjects who completed the study as per protocol.

Arm/Group Title	Trazodone Contramid® OAD	Trazodone HCl (Apotex Corp.)
Arm/Group Description	Trazodone Contramid® OAD test product (300 mg tablet administered once daily) dosed in either period. A drug-free period of 7 calendar days separated the last administration of study medication in Phase 1 and the first administration of study medication in Phase 2.	Trazodone HCl (Apotex Corp.) reference product (100 mg tablet administered thrice daily) dosed in either period. A drug-free period of 7 calendar days separated the last administration of study medication in Phase 1 and the first administration of study medication in Phase 2.
Measure Participants	27	27
Mean (Standard Deviation) [Percentage Peak-Trough Fluctuation]	97.090 (28.357)	174.768 (69.648)

Adverse Events

Arm/Group Title	Trazodone Contramid® OAD		Trazodone HCl (Apotex Corp.)
Arm/Group Description	Trazodone Contramid® OAD test product (300 mg tablet administered once daily) dosed in either period. A drug-free period of 7 calendar days separated the last administration of study medication in Phase 1 and the first administration of study medication in Phase 2.		Trazodone HCl (Apotex Corp.) reference product (100 mg tablet administered thrice daily) dosed in either period. A drug-free period of 7 calendar days separated the last administration of study medication in Phase 1 and the first administration of study medication in Phase 2.
All Cause Mortality
	Trazodone Contramid® OAD		Trazodone HCl (Apotex Corp.)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Trazodone Contramid® OAD		Trazodone HCl (Apotex Corp.)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/28 (0%)		0/29 (0%)
Other (Not Including Serious) Adverse Events
	Trazodone Contramid® OAD		Trazodone HCl (Apotex Corp.)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/28 (39.3%)		13/29 (44.8%)
Gastrointestinal disorders
Nausea	2/28 (7.1%)	2	2/29 (6.9%)	2
Constipation	2/28 (7.1%)	2	1/29 (3.4%)	1
Dry mouth	3/28 (10.7%)	3	1/29 (3.4%)	1
Nervous system disorders
Headache	5/28 (17.9%)	5	3/29 (10.3%)	3
Dizziness	2/28 (7.1%)	3	4/29 (13.8%)	4
Psychiatric disorders
Insomnia	0/28 (0%)	0	2/29 (6.9%)	2
Respiratory, thoracic and mediastinal disorders
Nasal congestion	4/28 (14.3%)	4	1/29 (3.4%)	1
Dyspnoea	0/28 (0%)	0	2/29 (6.9%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

If a publication based on the results of this study is envisaged, approval from the Sponsor will be obtained and a draft manuscript will be submitted to the sponsor for scrutiny and comment. The choice of scientific journal will be mutually agreed on by the principal investigator and the sponsor.