Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

Drug Interactions Between Voriconazole and Atazanavir Coadministered as Atazanavir/Ritonavir in Healthy Participants

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00833482
First received: January 30, 2009
Last updated: September 24, 2012
Last verified: September 2012
Results First Received: July 23, 2012  
Study Type: Interventional
Study Design: Allocation: Non-Randomized;   Endpoint Classification: Pharmacokinetics Study;   Intervention Model: Single Group Assignment;   Masking: Open Label
Conditions: Human Immunodeficiency Virus Type 1 (HIV-1)
HIV Infections
Interventions: Drug: Voriconazole
Drug: Atazanavir
Drug: Ritonavir

  Participant Flow
  Hide Participant Flow

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
A total of 185 participants were enrolled in the study, and 153 were not treated, because they no longer met study criteria, withdrew consent, or were alternate participants who were no longer needed. The remaining 32 participants received treatment.

Reporting Groups
  Description
Voriconazole, 200 BID (EM) Participants with functional CYP2C19 alleles (EM) received voriconazole, 400 mg, twice daily (BID) on Day 1, then 200 mg BID on Days 2 and 3. Voriconazole dose was given at least 1 hour after a meal.
Atazanavir/Ritonavir, 300/100 QD (EM) EM participants received atazanavir/ritonavir, 300/100 mg once daily (QD), on Days 11 through 20. Atazanavir/ritonavir dose was administered in the morning within 5 minutes of completing a light meal.
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) EM participants received atazanavir/ritonavir, 300/100 mg QD, plus voriconazole, 400 mg BID on Day 21 then 200 mg BID on Days 22-30. Atazanavir/ritonavir dose was administered in the morning within 5 minutes of completing a light meal, and 1 hour before voriconazole morning dose.
Voriconazole, 50 mg BID (PM) Participants who were poor metabolizers of CYP2C19 (PM)received voriconazole, 100 mg BID, on Day 1 then 50 mg BID on Days 2 and 3. Voriconazole dose was given at least 1 hour after a meal.
Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM) PM participants received atazanavir/ritonavir, 300/100 mg QD, plus voriconazole, 100 mg BID, on Day 21, then 50 mg BID on Days 22-30.
Atazanavir/Ritonavir, 300/100 QD (PM) PM participants received atazanavir/ritonavir, 300/100 mg QD, on Days 11 through 20. Atazanavir/ritonavir dose was administered in the morning within 5 minutes of completing a light meal.

Participant Flow for 3 periods

Period 1:   Days 1-3
    Voriconazole, 200 BID (EM)     Atazanavir/Ritonavir, 300/100 QD (EM)     Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)     Voriconazole, 50 mg BID (PM)     Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM)     Atazanavir/Ritonavir, 300/100 QD (PM)  
STARTED     24 [1]   0 [1]   0     8     0     0  
COMPLETED     24     0     0     8     0     0  
NOT COMPLETED     0     0     0     0     0     0  
[1] Participants who received treatment

Period 2:   Days 11-20
    Voriconazole, 200 BID (EM)     Atazanavir/Ritonavir, 300/100 QD (EM)     Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)     Voriconazole, 50 mg BID (PM)     Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM)     Atazanavir/Ritonavir, 300/100 QD (PM)  
STARTED     0     24 [1]   0     0     0     8 [1]
COMPLETED     0     21     0     0     0     8  
NOT COMPLETED     0     3     0     0     0     0  
Adverse Event                 0                 2                 0                 0                 0                 0  
Withdrawal by Subject                 0                 1                 0                 0                 0                 0  
[1] Participants who received treatment.

Period 3:   Days 21-30
    Voriconazole, 200 BID (EM)     Atazanavir/Ritonavir, 300/100 QD (EM)     Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)     Voriconazole, 50 mg BID (PM)     Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM)     Atazanavir/Ritonavir, 300/100 QD (PM)  
STARTED     0     0     21     0     8     0  
COMPLETED     0     0     20     0     7     0  
NOT COMPLETED     0     0     1     0     1     0  
Adverse Event                 0                 0                 1                 0                 0                 0  
Withdrawal by Subject                 0                 0                 0                 0                 1                 0  



  Baseline Characteristics
  Hide Baseline Characteristics

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.
No text entered.

Reporting Groups
  Description
Extensive Metabolizers (EM) Participants with functional CYP2C19 alleles (extensive metabolizers, or EM).
Poor Metabolizers (PM) Participants without a functional CYP2C19 allele (poor metabolizers, or PM).
Total Total of all reporting groups

Baseline Measures
    Extensive Metabolizers (EM)     Poor Metabolizers (PM)     Total  
Number of Participants  
[units: participants]
  24     8     32  
Age  
[units: years]
Mean ± Standard Deviation
  31  ± 10     30  ± 7     31  ± 9  
Gender  
[units: participants]
     
Female     4     0     4  
Male     20     8     28  
Race/Ethnicity, Customized  
[units: participants]
     
Asian     2     8     10  
Black or African American     1     0     1  
White     20     0     20  
Not reported     0     0     0  
Other     1     0     1  
CYP2C19 Genotype of Participants [1]
[units: Participants]
     
1/1     11     0     11  
1/2     5     0     5  
1/17     6     0     6  
2/2     0     6     6  
2/3     0     1     1  
2/17     1     0     1  
17/17     1     0     1  
3/3     0     1     1  
[1] Genotypes with functional alleles indicative of extensive metabolizers=17/17, 1/17, 2/17, 3/17, 1/1, 1/2, and 1/3. Genotypes indicative of poor metabolizers=2/2, 2/3, and 3/3.



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Maximum Observed Plasma Concentration (Cmax) and Minimum Observed Plasma Concentration (Cmin) of Atazanavir, Administered as Atazanavir/Ritonavir With and Without Voriconazole, in Participants Who Are Extensive Metabolizers (EM)   [ Time Frame: Predose and at 1, 2, 3, 4, 5, 7, 9,13, and 24 hours postdose on Days 20 and 30 of a 30-day cycle ]

2.  Primary:   Time to Maximum Concentration (Tmax) of Atazanavir, Administered as Atazanavir/Ritonavir With and Without Voriconazole, in EM Participants   [ Time Frame: Predose and at 1, 2, 3, 4, 5, 7, 9,13, and 24 hours postdose on Days 20 and 30 of a 30-day cycle ]

3.  Primary:   Area Under the Plasma Concentration-time Curve in 1 Dosing Interval [AUC(TAU)] of Atazanavir Administered as Atazanavir/Ritonavir With and Without Voriconazole, in EM Participants   [ Time Frame: Predose and at 1, 2, 3, 4, 5, 7, 9,13, and 24 hours postdose on Days 20 and 30 of a 30-day cycle ]

4.  Primary:   Tmax of Voriconazole, Administered With and Without Atazanavir/Ritonavir, in EM Participants   [ Time Frame: Predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postdoseDays 3 and 30 of a 30-day cycle ]

5.  Primary:   Cmax and Cmin of Voriconazole, Administered With and Without Atazanavir/Ritonavir, in EM Participants   [ Time Frame: Predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postdoseDays 3 and 30 of a 30-day cycle ]

6.  Primary:   AUC(TAU)of Voriconazole, Administered With and Without Atazanavir/Ritonavir, in EM Participants   [ Time Frame: Predose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours postdoseDays 3 and 30 of a 30-day cycle ]

7.  Secondary:   Cmax and Cmin of Ritonavir, Administered As Atazanavir/Ritonavir With and Without Voriconazole, in EM Participants   [ Time Frame: Predose and at 1, 2, 3, 4, 5, 7, 9,13, and 24 hours postdose on Days 20 and 30 of a 30-day cycle ]

8.  Secondary:   Tmax of Ritonavir, Administered As Atazanavir/Ritonavir With and Without Voriconazole, in EM Participants   [ Time Frame: Predose and at 1, 2, 3, 4, 5, 7, 9,13, and 24 hours postdose on Days 20 and 30 of a 30-day cycle ]

9.  Secondary:   AUC(TAU) of Ritonavir, Administered As Atazanavir/Ritonavir With and Without Voriconazole, in EM Participants   [ Time Frame: Predose and at 1, 2, 3, 4, 5, 7, 9,13, and 24 hours postdose on Days 20 and 30 of a 30-day cycle ]

10.  Secondary:   Number of Participants With Death as Outcome, Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation, and Any AE   [ Time Frame: Days 1 to 31 (discharge), continuously ]

11.  Secondary:   Number of Participants With Marked Abnormalities in Serum Chemistry Test Results   [ Time Frame: Within 21 days of Day 1 and on Days 3, 10, 20, 26, and 31 (at discharge) ]

12.  Secondary:   Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results   [ Time Frame: Within 21 days of Day 1 and on Days 3, 10, 20, 26, and 31 (at discharge) ]
  Hide Outcome Measure 12

Measure Type Secondary
Measure Title Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results
Measure Description LLN=lower limit of normal; ULN=upper limit of normal; preRX=pretreatment. Safety criteria: Neutrophils + bands: If <.85*LLN or >1.15*ULN or ULN or if preRX<LLN, use <0.85*preRX or >ULN; if preRX>ULN, use >1.15*preRX or <LLN. Lymphocytes, relative: If <0.85*LLN or >1.15*ULN, or if preRX <LLN, use <0.85*preRX or >ULN; if preRX >ULN, use >1.15*preRX or <LLN. Blood, urine: If >= 2+, or if preRX >=1+, use >=2*preRX. White blood cells, urine: If >=2+, or if preRX >=2+, use >=4+. Red blood cells, urine: If >=2+ or if preRX >=2+, use >=4+. Not all categories were evaluated for each arm.
Time Frame Within 21 days of Day 1 and on Days 3, 10, 20, 26, and 31 (at discharge)  
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.
All participants who received study drug.

Reporting Groups
  Description
Voriconazole, 200 BID (EM) Treatment A: Participants with functional CYP2C19 alleles (EM) received voriconazole, 400 mg, twice daily (BID) on Day 1, then 200 mg BID on Days 2 and 3. Voriconazole dose was given at least 1 hour after a meal.
Atazanavir/Ritonavir, 300/100 QD (EM) Treatment B in EM participants: EM participants received atazanavir/ritonavir, 300/100 mg once daily (QD), on Days 11 through 20. Atazanavir/ritonavir dose was administered in the morning within 5 minutes of completing a light meal.
Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM) Treatment C: EM participants received atazanavir/ritonavir, 300/100 mg QD, plus voriconazole, 400 mg BID on Day 21 then 200 mg BID on Days 22-30. Atazanavir/ritonavir dose was administered in the morning within 5 minutes of completing a light meal, and 1 hour before voriconazole morning dose.
Voriconazole, 50 mg BID (PM) Treatment D: Participants who were poor metabolizers of CYP2C19 (PM)received voriconazole, 100 mg BID, on Day 1 then 50 mg BID on Days 2 and 3. Voriconazole dose was given at least 1 hour after a meal.
Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM) Treatment E: PM participants received atazanavir/ritonavir, 300/100 mg QD plus voriconazole, 100 mg BID, on Day 21, then 50 mg BID on Days 22-30.
Atazanavir/Ritonavir, 300/100 QD (PM) Treatment B in PM participants: PM participants received atazanavir/ritonavir, 300/100 mg QD, on Days 11 through 20. Atazanavir/ritonavir dose was administered in the morning within 5 minutes of completing a light meal.

Measured Values
    Voriconazole, 200 BID (EM)     Atazanavir/Ritonavir, 300/100 QD (EM)     Atazanavir/Ritonavir, 300/100mgQD + Voriconazole, 200mgBID(EM)     Voriconazole, 50 mg BID (PM)     Atanazivir/Ritonavir, 300/100 QD + Voriconazole, 50 BID (PM)     Atazanavir/Ritonavir, 300/100 QD (PM)  
Number of Participants Analyzed  
[units: participants]
  24     24     21     8     8     8  
Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results  
[units: Participants]
           
Neutrophils + bands(absolute)(*10^3 cells/uL): Low     1     0     1     0     0     0  
Lymphocytes, relative (*10*3 cells/uL): Low     1     1     1     NA [1]   NA [1]   NA [1]
Lymphocytes, relative (*10*3 cells/uL): High     5     1     1     NA [1]   NA [1]   NA [1]
Blood, urine: High     1     1     2     0     0     0  
White blood cells (WBC), urine: High     1     0     NA [1]   NA [1]   NA [1]   NA [1]
Red blood cells (RBC), urine: High     1     0     NA [1]   NA [1]   NA [1]   NA [1]
[1] Not evaluated

No statistical analysis provided for Number of Participants With Marked Abnormalities in Hematology Laboratory Test and Urinalysis Results



13.  Secondary:   Number of Participants With Investigator-identified Abnormalities in Electrocardiogram Results Not Present Prior to Administration of Study Drug and Considered Not Relevant and Not AEs by Investigator   [ Time Frame: Within 21 days of Day 1 and on Days -1, 21, and 31 (at discharge) ]

14.  Secondary:   Number of Participants With Abnormalities in Vital Signs   [ Time Frame: Within 21 days of Day 1 and on Days -1, 1, 3, 11, 21, and 31 (at discharge) ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide 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
No text entered.


  More Information
  Hide More Information

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:
unchecked 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.
unchecked 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.


Results Point of Contact:  
Name/Title: BMS Study Director
Organization: Bristol-Myers Squibb
e-mail: Clinical.Trials@bms.com


No publications provided


Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00833482     History of Changes
Other Study ID Numbers: AI424-383, 2009-009095-13
Study First Received: January 30, 2009
Results First Received: July 23, 2012
Last Updated: September 24, 2012
Health Authority: United States: Food and Drug Administration
Europe, Middle East, Africa: Committee for Medicinal Products for Human Use