The Bioequivalence of Atripla in an Oral Liquid Formulation Compared With the Tablet Formulation in Healthy Volunteers

• Sponsor: University of Alabama at Birmingham (Other)
• Overall Status: Completed
• CT.gov ID: NCT00862823
• Collaborator: Bristol-Myers Squibb (Industry)
• Enrollment: 14
• Location: 1
• Arms: 2
• Duration (Months): 14.9
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

The primary objective of this study is to determine the average bioequivalence of tenofovir, emtricitabine and efavirenz in an extemporaneously prepared oral liquid formulation (test formulation) compared with the commercially available tablet formulation (reference formulation). The study is designed as an open-label, randomized, 2-period, 2-treatment, 2-sequence, single-dose intensive pharmacokinetic study conducted in healthy volunteers. Subjects will be randomized to receive the Atripla tablet (reference formulation) or the Atripla tablet crushed and mixed in OraSweet solution (test formulation) on Study Day 1. Subjects will undergo a 12-hour intensive pharmacokinetic evaluation after ingesting a single dose of either the test or reference formulation. On days 2 and 3, subjects will provide an additional pharmacokinetic sample 24 and 48 hours post dose, respectively. Subjects will complete a washout period from day 2 to day 14 during which no study drugs will be ingested. On day 14, subjects will ingest either the reference or test formulation (opposite of the formulation received on Study Day 1). All subjects will undergo another 12-hour intensive pharmacokinetic evaluation. On days 16 and 17 subjects will provide an additional pharmacokinetic sample 24 and 48 hours post dose, respectively. Adverse events and concomitant medications will be documented throughout the study.

The sample size is 16 and is based upon a 10% drop-out rate (i.e. due to lost to follow-up, treatment discontinuation, etc.). Since the investigators are expecting two subjects not to complete the study, the investigators expect 14 evaluable subjects. If the discontinuation rate is greater than 10%, the investigators will continue to enroll until the investigators get 14 evaluable subjects. The primary endpoint is to determine average bioequivalence for test and reference formulations of tenofovir, emtricitabine and efavirenz according to the FDA guidance on bioequivalence testing. The ratio of the test to reference formulation mean Cmax and AUC24 for each drug and the 90% confidence interval around each mean ratio will be determined. Average bioequivalence will be met if 90% confidence intervals around the Cmax, and AUC24 mean ratios for each drug falls within the FDA's predefined limits of 0.80 to 1.25.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: tenofovir, emtricitabine and efavirenz fixed dose tablet; Drug: tenofovir, emtricitabine and efavirenz tablet added to solution	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Official Title: The Stability and Bioequivalence of Tenofovir, Emtricitabine and Efavirenz (Atripla) in an Extemporaneously Prepared Oral Liquid Formulation Compared With the Commercially Available Tablet Formulation
• Study Start Date: Feb 1, 2009
• Actual Primary Completion Date: Feb 1, 2010
• Actual Study Completion Date: May 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Atripla Tablet Drug exposure after administration of Atripla Tablet	Drug: tenofovir, emtricitabine and efavirenz fixed dose tablet; Atripla contains 300mg of tenofovir, 200mg of emtricitabine and 600mg of efavirenz
Experimental: Atripla Liquid Drug exposure after administration of an extemporaneously prepared liquid formulation of Atripla	Drug: tenofovir, emtricitabine and efavirenz tablet added to solution; Atripla contains 300mg of tenofovir, 200mg of emtricitabine and 600mg of efavirenz

Outcome Measures

Primary Outcome Measures

1. Area Under the Concentration Time Curve for Tenofovir, Emtricitabine and Efavirenz [17 days]

   The area under the concentration time curve for tenofovir, emtricitabine and efavirenz

2. Maximum Concentration for Tenofovir, Emtricitabine and Efavirenz [17 days]

   The maximum concentration for tenofovir, emtricitabine and efavirenz

Eligibility Criteria

Criteria

• Ages Eligible for Study: 19 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Age ≥19 and ≤65, HIV-1 negative, Able to give consent, Non-smoking,Screening EKG within normal limits, Females of childbearing potential must have a negative pregnancy test at screening and agree to use a double-barrier method of contraception throughout the study period.

Exclusion Criteria:

• Subjects receiving any prescription or over-the-counter products will be excluded from the study. Subjects using any form of recreational drugs will be excluded. Subjects who have any of the following laboratory abnormalities within 30 days of study entry will be excluded:

• SGOT (AST)/SGPT (ALT) > 3 x upper limits of normal (ULN) (Subjects with liver disease are allowed to enroll unless their AST/ALT levels are greater than three times ULN)

• Bilirubin > 2.5 x ULN

• Amylase > 2 x ULN

• Absolute Neutrophil Count < 1000 x 103/L

• Hgb < 9.0 g/dl

• Platelets <50,000 cells/mm3

• Serum Creatinine > 2.5 mg/dl

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294

Sponsors and Collaborators

• University of Alabama at Birmingham
• Bristol-Myers Squibb

Investigators

• Principal Investigator: Jennifer R King, PharmD, University of Alabama at Birmingham

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Jennifer King, Principal Investigator, University of Alabama at Birmingham
• ClinicalTrials.gov Identifier: NCT00862823
• Other Study ID Numbers: F081030003
• First Posted: Mar 17, 2009
• Last Update Posted: Sep 14, 2012
• Last Verified: Jun 1, 2012

• Keywords provided by Jennifer King, Principal Investigator, University of Alabama at Birmingham: Healthy Volunteers
• Additional relevant MeSH terms: Tenofovir; Emtricitabine; Efavirenz

Study Results

Participant Flow

Recruitment Details	Healthy volunteers recruited in Birmingham, AL from March 2009 and August 2009

Arm/Group Title	Tablet First, Then Liquid	Liquid First, Then Tablet
Arm/Group Description	Single dose of Atripla tablet in first intervention period and Single dose of Atripla liquid in second intervnetion period	Single dose of Atripla liquid in first intervention period and single dose of Atripla tablet in second intervnetion period
Period Title: First Intervention
STARTED	6	10
COMPLETED	5	9
NOT COMPLETED	1	1
Period Title: First Intervention
STARTED	5	9
COMPLETED	5	9
NOT COMPLETED	0	0
Period Title: First Intervention
STARTED	5	9
COMPLETED	5	9
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Entire Study Population
Arm/Group Description	Includes groups randomized to receive tablet first and liquid first
Overall Participants	16
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	16 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	33.3 (10.9)
Sex: Female, Male (Count of Participants)
Female	7 43.8%
Male	9 56.3%
Region of Enrollment (participants) [Number]
United States	16 100%

Outcome Measures

1. Primary Outcome

Title	Area Under the Concentration Time Curve for Tenofovir, Emtricitabine and Efavirenz
Description	The area under the concentration time curve for tenofovir, emtricitabine and efavirenz
Time Frame	17 days

Outcome Measure Data

Analysis Population Description

US Food and Drug Administration. Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug ProductsdGeneral Considerations. Rockville, MD: United States Food and Drug Administration Center for Drug Evaluation and Research.

Arm/Group Title	Atripla Tablet	Atripla Liquid
Arm/Group Description	Includes groups randomized to receive tablet first and liquid first	Includes groups randomized to receive tablet first and liquid first
Measure Participants	14	14
Efavirenz AUC	58.7 (57.5)	56.7 (80)
Emtricitabine AUC	10.9 (24.7)	10.8 (15.9)
Tenofovir AUC	1.8 (29.2)	2.2 (36.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Atripla Tablet, Atripla Liquid
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The sample size was determined so there was an 80% chance that a 90% pairwise interval for 2 equivalent formulations would satifsy the FDA criteria for AUC and Cmax of log (0.8), log (1.2).
Statistical Test of Hypothesis	p-Value	<0.05
	Comments	Bioequivalent measurew were log-transformed
	Method	log transformation
	Comments
Method of Estimation	Estimation Parameter	Geometric Mean Ratio
	Estimated Value	0.97
	Confidence Interval	() 90%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Maximum Concentration for Tenofovir, Emtricitabine and Efavirenz
Description	The maximum concentration for tenofovir, emtricitabine and efavirenz
Time Frame	17 days

Outcome Measure Data

Analysis Population Description

US Food and Drug Administration. Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug ProductsdGeneral Considerations. Rockville, MD: United States Food and Drug Administration Center for Drug Evaluation and Research.

Arm/Group Title	Atripla Tablet	Atripla Liquid
Arm/Group Description	Includes groups randomized to receive tablet first and liquid first	Includes groups randomized to receive tablet first and liquid first
Measure Participants	14	14
Efavirenz Cmax	1.5 (39)	1.3 (28.8)
Emtricitabine Cmax	1.8 (32.3)	2.1 (21)
Tenofovir Cmax	0.3 (27.7)	0.2 (47.8)

Adverse Events

Arm/Group Title	Entire Study Population
Arm/Group Description	Includes groups randomized to receive tablet first and liquid first
All Cause Mortality
	Entire Study Population
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Entire Study Population
	Affected / at Risk (%)	# Events
Total	0/16 (0%)
Other (Not Including Serious) Adverse Events
	Entire Study Population
	Affected / at Risk (%)	# Events
Total	0/16 (0%)

Limitations/Caveats

Efavirenz exposure was highly variable and relative bioequivalence for efavirenz may have been more appropriately assessed with a larger sample size.

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.