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Safety, Tolerability and Pharmacokinetics of Efavirenz in HIV-Infected Children

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb
ClinicalTrials.gov Identifier:
NCT00364793
First received: August 15, 2006
Last updated: April 11, 2014
Last verified: April 2014
Results First Received: March 6, 2014  
Study Type: Interventional
Study Design: Allocation: Non-Randomized;   Endpoint Classification: Pharmacokinetics Study;   Intervention Model: Single Group Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: HIV Infections
Intervention: Drug: Efavirenz (EFV) + Didanosine (ddI) + Emtricitabine (FTC)

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
This study initiated February 2007 and completed July 2013. All participants enrolled in countries where efavirenz (EFV) oral solution was not commercially available could remain on study until their 7th birthday or until they were able to swallow EFV capsules (whichever occurred first).

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
56 participants were enrolled but 19 were never treated. Reasons for not treating: 2 deaths, 1 lost to follow up, 6 other (not specified), 9 no longer met study criteria, 1 withdrew consent.

Reporting Groups
  Description
EFV+ddI+FTC in Infants >=3 Months to < 6 Months EFV (efavirenz) was administered in accordance with weight-based dosing nomograms and included one of the following preparations in a once a day (QD) dose: EFV capsules (50 and 200 mg) contents mixed with formula or a small amount of food vehicle (eg, yogurt, applesauce, or grape jelly), or oral solution (30 mg/mL); participants unable to meet the desired exposures using the oral solution, or those not able to tolerate the oral solution, used the capsule contents sprinkled on food. In addition, the following 2 drugs were administered: ddI (didanosine) (Pediatric Powder for Oral Solution or capsules of enteric-coated beads): 240 mg/m^2 QD; maximum daily dose of 400 mg and emtricitabine (FTC) (solution or tablets) 6 mg/kg QD; maximum daily dose of 240 mg.
EFV+ddI+FTC in Infants >=6 Months to < 2 Years EFV (efavirenz) was administered in accordance with weight-based dosing nomograms and included one of the following preparations in a once a day (QD) dose: EFV capsules (50 and 200 mg) contents mixed with formula or a small amount of food vehicle (eg, yogurt, applesauce, or grape jelly), or oral solution (30 mg/mL); participants unable to meet the desired exposures using the oral solution, or those not able to tolerate the oral solution, used the capsule contents sprinkled on food. In addition, the following 2 drugs were administered: ddI (didanosine) (Pediatric Powder for Oral Solution or capsules of enteric-coated beads): 240 mg/m^2 QD; maximum daily dose of 400 mg and FTC (emtricitabine) (solution or tablets) 6 mg/kg QD; maximum daily dose of 240 mg.
EFV+ddI+FTC in Children >= 2 Years to < 3 Years EFV (efavirenz) was administered in accordance with weight-based dosing nomograms and included one of the following preparations in a once a day (QD) dose: EFV capsules (50 and 200 mg) contents mixed with formula or a small amount of food vehicle (eg, yogurt, applesauce, or grape jelly), or oral solution (30 mg/mL); participants unable to meet the desired exposures using the oral solution, or those not able to tolerate the oral solution, used the capsule contents sprinkled on food. In addition, the following 2 drugs were administered: ddI (didanosine) (Pediatric Powder for Oral Solution or capsules of enteric-coated beads): 240 mg/m^2 QD; maximum daily dose of 400 mg and FTC (emtricitabine) (solution or tablets) 6 mg/kg QD; maximum daily dose of 240 mg.
EFV+ddI+FTC in Children >= 3 Years to <= 6 Years EFV (efavirenz) was administered in accordance with weight-based dosing nomograms and included one of the following preparations in a once a day (QD) dose: EFV capsules (50 and 200 mg) contents mixed with formula or a small amount of food vehicle (eg, yogurt, applesauce, or grape jelly), or oral solution (30 mg/mL); participants unable to meet the desired exposures using the oral solution, or those not able to tolerate the oral solution, used the capsule contents sprinkled on food. In addition, the following 2 drugs were administered: ddI (didanosine) (Pediatric Powder for Oral Solution or capsules of enteric-coated beads): 240 mg/m^2 QD; maximum daily dose of 400 mg and FTC (emtricitabine) (solution or tablets) 6 mg/kg QD; maximum daily dose of 240 mg.

Participant Flow:   Overall Study
    EFV+ddI+FTC in Infants >=3 Months to < 6 Months     EFV+ddI+FTC in Infants >=6 Months to < 2 Years     EFV+ddI+FTC in Children >= 2 Years to < 3 Years     EFV+ddI+FTC in Children >= 3 Years to <= 6 Years  
STARTED     15     10     4     8  
COMPLETED     7     5     0     5  
NOT COMPLETED     8     5     4     3  
Adverse Event                 2                 0                 0                 0  
Death                 1                 0                 1                 0  
Lack of Efficacy                 3                 3                 1                 1  
Lost to Follow-up                 1                 0                 2                 0  
Poor or non-compliance                 1                 1                 0                 1  
No longer meets criteria                 0                 0                 0                 1  
Withdrawal by Subject                 0                 1                 0                 0  



  Baseline Characteristics
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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.
Treated participants who received at least one dose of study drug (EFV) were analyzed.

Reporting Groups
  Description
EFV+ddI+FTC in Infants >=3 Months to < 6 Months EFV (efavirenz) was administered in accordance with weight-based dosing nomograms and included one of the following preparations in a once a day (QD) dose: EFV capsules (50 and 200 mg) contents mixed with formula or a small amount of food vehicle (eg, yogurt, applesauce, or grape jelly), or oral solution (30 mg/mL). In addition, the following 2 drugs were administered: ddI (didanosine) (Pediatric Powder for Oral Solution or capsules of enteric-coated beads): 240 mg/m^2 QD; maximum daily dose of 400 mg and FTC (emtricitabine) (solution or tablets) 6 mg/kg QD; maximum daily dose of 240 mg.
EFV+ddI+FTC in Infants >=6 Months to < 2 Years EFV (efavirenz) was administered in accordance with weight-based dosing nomograms and included one of the following preparations in a once a day (QD) dose: EFV capsules (50 and 200 mg) contents mixed with formula or a small amount of food vehicle (eg, yogurt, applesauce, or grape jelly), or oral solution (30 mg/mL). In addition, the following 2 drugs were administered: ddI (didanosine) (Pediatric Powder for Oral Solution or capsules of enteric-coated beads): 240 mg/m^2 QD; maximum daily dose of 400 mg and FTC (emtricitabine) (solution or tablets) 6 mg/kg QD; maximum daily dose of 240 mg.
EFV+ddI+FTC in Children >= 2 Years to < 3 Years EFV (efavirenz) was administered in accordance with weight-based dosing nomograms and included one of the following preparations in a once a day (QD) dose: EFV capsules (50 and 200 mg) contents mixed with formula or a small amount of food vehicle (eg, yogurt, applesauce, or grape jelly), or oral solution (30 mg/mL). In addition, the following 2 drugs were administered: ddI (didanosine) (Pediatric Powder for Oral Solution or capsules of enteric-coated beads): 240 mg/m^2 QD; maximum daily dose of 400 mg and FTC (emtricitabine) (solution or tablets) 6 mg/kg QD; maximum daily dose of 240 mg.
EFV+ddI+FTC in Children >= 3 Years to <= 6 Years EFV (efavirenz) was administered in accordance with weight-based dosing nomograms and included one of the following preparations in a once a day (QD) dose: EFV capsules (50 and 200 mg) contents mixed with formula or a small amount of food vehicle (eg, yogurt, applesauce, or grape jelly), or oral solution (30 mg/mL). In addition, the following 2 drugs were administered: ddI (didanosine) (Pediatric Powder for Oral Solution or capsules of enteric-coated beads): 240 mg/m^2 QD; maximum daily dose of 400 mg and FTC (emtricitabine) (solution or tablets) 6 mg/kg QD; maximum daily dose of 240 mg.
Total Total of all reporting groups

Baseline Measures
    EFV+ddI+FTC in Infants >=3 Months to < 6 Months     EFV+ddI+FTC in Infants >=6 Months to < 2 Years     EFV+ddI+FTC in Children >= 2 Years to < 3 Years     EFV+ddI+FTC in Children >= 3 Years to <= 6 Years     Total  
Number of Participants  
[units: participants]
  15     10     4     8     37  
Age  
[units: years]
Median ( Full Range )
  0.392  
  ( 0.296 to 0.501 )  
  0.825  
  ( 0.586 to 1.906 )  
  2.313  
  ( 2.094 to 2.995 )  
  3.922  
  ( 2.998 to 6.976 )  
  0.663  
  ( 0.296 to 6.976 )  
Gender  
[units: participants]
         
Female     6     0     1     6     13  
Male     9     10     3     2     24  
Race/Ethnicity, Customized [1]
[units: participants]
         
White     3     9     4     8     24  
Black or African American     7     0     0     0     7  
Asian     2     0     0     0     2  
Other     3     1     0     0     4  
Region of Enrollment  
[units: participants]
         
Panama     3     0     0     1     4  
Mexico     2     7     3     7     19  
Argentina     0     3     1     0     4  
Thailand     2     0     0     0     2  
South Africa     7     0     0     0     7  
Colombia     1     0     0     0     1  
Human Immunodeficiency Virus (HIV) Ribonucleic acid (RNA) Viral Load (log10 c/mL) [2]
[units: log10┬ác/mL]
Median ( Full Range )
  5.88  
  ( 3.34 to 6.74 )  
  5.88  
  ( 2.12 to 5.88 )  
  5.88  
  ( 4.88 to 5.88 )  
  5.26  
  ( 3.38 to 5.88 )  
  5.88  
  ( 2.12 to 6.74 )  
HIV RNA Viral Load Category [3]
[units: participants]
         
< 30,000 copies/mL     3     1     0     1     5  
30,000 to <100,000 copies/mL     0     1     1     2     4  
100,000 to <500,000 copies/mL     2     1     0     2     5  
500,000 to <=750,000 copies/mL     1     1     0     1     3  
>750,000 copies/mL     9     6     3     2     20  
CD4 Cell Count (n=13, 9, 3, 7, 32) [4]
[units: cells/mm^3]
Median ( Full Range )
  1785  
  ( 200 to 3584 )  
  1569  
  ( 516 to 2879 )  
  517  
  ( 129 to 558 )  
  540  
  ( 11 to 1363 )  
  1144  
  ( 11 to 3584 )  
[1] Ethnicity was not collected because the study was conducted outside of the United States.
[2] Human immunodeficiency virus (HIV) ribonucleic acid (RNA) values ≥ 1,000 copies per milliliter (c/mL) were considered evidence of infection. HIV RNA measures the viral load and was first measured using the ultrasensitive and standard Roche Amplicor Polymerase Chain Reaction (PCR), version 1.5, and then the method of measurement was switched to the COBAS AmpliPrep/COBAS TaqMan HIV IVD method.
[3] Human immunodeficiency virus (HIV) ribonucleic acid (RNA) values greater than, equal to (≥) 1,000 copies per milliliter (c/mL) were considered evidence of infection. Categories listed indicate the plasma viral load prior to study treatment (Baseline). HIV RNA was first measured using the ultrasensitive and standard Roche Amplicor PCR, version 1.5, and then the method of measurement was switched to the COBAS AmpliPrep/COBAS TaqMan HIV IVD method.
[4] A CD4 cell is an antigenic marker of helper/inducer T cells. These cells were counted during the hematology cell counts performed during a Complete Blood Cell count (CBC) performed by the Central Laboratory. CD4 are measured as number of cells per millimeter to the third power (cells/mm^3). Not all treated participants provided a measurement for this baseline parameter (n=number of participants with this baseline measurement).



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Maximum Observed Plasma Concentration (Cmax) and Plasma Concentration 24 Hours Post-dose (Cmin) of EFV at Week 2 - Pharmacokinetic Evaluable Population   [ Time Frame: Week 2 ]

2.  Primary:   Area Under the Plasma Concentration Time Curve (AUC) Over One Dosing Interval From Time Zero to 24 Hours Post-dose(TAU) at Week 2 - Pharmacokinetic Evaluable Population   [ Time Frame: Week 2 ]

3.  Primary:   Apparent Oral Clearance (CLT/F) of EFV at Week 2 - Pharmacokinetic Evaluable Population   [ Time Frame: Week 2 ]

4.  Primary:   Apparent Oral Clearance Adjusted for Body Weight (CLT/F/kg) of EFV at Week 2 - Pharmacokinetic Evaluable Population   [ Time Frame: Week 2 ]

5.  Secondary:   The Number of Participants With Plasma HIV RNA < 400 Copies Per Milliliter (c/mL) at Week 48 as Analyzed by Different Algorithms - All Treated Participants   [ Time Frame: Week 48 ]

6.  Secondary:   The Number of Participants With Plasma HIV RNA Levels < 50 c/mL at Week 48 as Analyzed by Different Algorithms - All Treated Participants   [ Time Frame: Week 48 ]

7.  Secondary:   The Number of Participants With Plasma HIV RNA Levels < 400 c/mL at Week 24 as Analyzed by Different Algorithms - All Treated Participants   [ Time Frame: Week 24 ]

8.  Secondary:   The Number of Participants With Plasma HIV RNA Levels < 50 c/mL at Week 24 as Analyzed by Different Algorithms - All Treated Participants   [ Time Frame: Week 24 ]

9.  Secondary:   Log10 c/mL HIV RNA Changes From Baseline Through Week 48 - Treated Participants   [ Time Frame: Baseline through Week 48 ]

10.  Secondary:   CD4 Cell Count Change From Baseline at Weeks 24 and 48 - Treated Participants   [ Time Frame: Baseline to Weeks 24 and 48 ]

11.  Secondary:   Percent of CD4 Cells Change From Baseline at Weeks 24 and 48 - Treated Participants   [ Time Frame: Baseline to Weeks 24 and 48 ]

12.  Secondary:   Number of Participants With On-Treatment Adverse Events (AEs), Related Adverse Events, Serious Adverse Events (SAEs), Death, Discontinuation Due to Adverse Events, and CDC Class C AIDS Events   [ Time Frame: Baseline to Week 96 ]

13.  Secondary:   Number of Participants With Liver Function Test Laboratory Abnormalities - Treated Population   [ Time Frame: Baseline to Week 96 ]

14.  Secondary:   Number of Participants With Lipid and Glucose Laboratory Abnormalities - Treated Participants   [ Time Frame: Baseline to Week 96 ]

15.  Secondary:   Number of Participants With Serum Chemistry Abnormalities - Treated Participants   [ Time Frame: Baseline to Week 96 ]

16.  Secondary:   Number of Participants With Hematologic Abnormalities - Treated Participants   [ Time Frame: Baseline to Week 96 ]

17.  Secondary:   Number of Treated Participants With Resistance Associated Genotypic and Phenotypic Changes in Viruses - Participants With Virologic Failure, Lack of Suppression or Viral Load Rebound   [ Time Frame: Baseline to Week 48 ]

18.  Secondary:   Number of Participants With Acquisition of Resistance to EFV Categorized by AUC Relationship - Evaluable Pharmacokinetic Population   [ Time Frame: Baseline to Week 48 ]

19.  Secondary:   Cmax and Cmin of Didanosine (ddI) at Week 2 - Pharmacokinetic Evaluable Population   [ Time Frame: Week 2 ]

20.  Secondary:   AUC (TAU) of Didanosine (ddI) at Week 2 - Pharmacokinetic Evaluable Population   [ Time Frame: Week 2 ]
  Hide Outcome Measure 20

Measure Type Secondary
Measure Title AUC (TAU) of Didanosine (ddI) at Week 2 - Pharmacokinetic Evaluable Population
Measure Description Plasma concentrations were obtained using a validated LC-MS/MS at Week 2. The lower limit of quantification (LLOQ) for ddI was 2.50 nanograms per milliliter (ng/mL). AUC(TAU) was calculated by log- and linear trapezoidal summations. If a concentration was < LLOQ at time TAU, the value of the concentration at time TAU was estimated using the quotient of the last quantifiable concentration and λ. Blood samples were collected before study drug administration and at 0.5, 1, 3, 5, 8, and 24 hours after study drug administration from an indwelling catheter or by direct venipuncture and the pharmacokinetic parameters summarized using geometric means. AUC(TAU) was measured in nanograms*time per milliliter (ng•h/mL).
Time Frame Week 2  
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 at least one dose of study drug (EFV) and had adequate pharmacokinetic (PK) profiles were analyzed.

Reporting Groups
  Description
EFV+ddI+FTC in Infants >=3 Months to < 6 Months EFV (efavirenz) was administered in accordance with weight-based dosing nomograms and included one of the following preparations in a once a day (QD) dose: EFV capsules (50 and 200 mg) contents mixed with formula or a small amount of food vehicle (eg, yogurt, applesauce, or grape jelly), or oral solution (30 mg/mL); participants unable to meet the desired exposures using the oral solution, or those not able to tolerate the oral solution, used the capsule contents sprinkled on food. In addition, the following 2 drugs were administered: ddI (didanosine) (Pediatric Powder for Oral Solution or capsules of enteric-coated beads): 240 mg/m^2 QD; maximum daily dose of 400 mg and FTC (emtricitabine) (solution or tablets) 6 mg/kg QD; maximum daily dose of 240 mg.
EFV+ddI+FTC in Infants >=6 Months to < 2 Years EFV (efavirenz) was administered in accordance with weight-based dosing nomograms and included one of the following preparations in a once a day (QD) dose: EFV capsules (50 and 200 mg) contents mixed with formula or a small amount of food vehicle (eg, yogurt, applesauce, or grape jelly), or oral solution (30 mg/mL); participants unable to meet the desired exposures using the oral solution, or those not able to tolerate the oral solution, used the capsule contents sprinkled on food. In addition, the following 2 drugs were administered: ddI (didanosine) (Pediatric Powder for Oral Solution or capsules of enteric-coated beads): 240 mg/m^2 QD; maximum daily dose of 400 mg and FTC (emtricitabine) (solution or tablets) 6 mg/kg QD; maximum daily dose of 240 mg.
EFV+ddI+FTC in Children >= 2 Years to < 3 Years EFV (efavirenz) was administered in accordance with weight-based dosing nomograms and included one of the following preparations in a once a day (QD) dose: EFV capsules (50 and 200 mg) contents mixed with formula or a small amount of food vehicle (eg, yogurt, applesauce, or grape jelly), or oral solution (30 mg/mL); participants unable to meet the desired exposures using the oral solution, or those not able to tolerate the oral solution, used the capsule contents sprinkled on food. In addition, the following 2 drugs were administered: ddI (didanosine) (Pediatric Powder for Oral Solution or capsules of enteric-coated beads): 240 mg/m^2 QD; maximum daily dose of 400 mg and FTC (emtricitabine) (solution or tablets) 6 mg/kg QD; maximum daily dose of 240 mg.
EFV+ddI+FTC in Children >= 3 Years to <= 6 Years EFV (efavirenz) was administered in accordance with weight-based dosing nomograms and included one of the following preparations in a once a day (QD) dose: EFV capsules (50 and 200 mg) contents mixed with formula or a small amount of food vehicle (eg, yogurt, applesauce, or grape jelly), or oral solution (30 mg/mL); participants unable to meet the desired exposures using the oral solution, or those not able to tolerate the oral solution, used the capsule contents sprinkled on food. In addition, the following 2 drugs were administered: ddI (didanosine) (Pediatric Powder for Oral Solution or capsules of enteric-coated beads): 240 mg/m^2 QD; maximum daily dose of 400 mg and FTC (emtricitabine) (solution or tablets) 6 mg/kg QD; maximum daily dose of 240 mg.

Measured Values
    EFV+ddI+FTC in Infants >=3 Months to < 6 Months     EFV+ddI+FTC in Infants >=6 Months to < 2 Years     EFV+ddI+FTC in Children >= 2 Years to < 3 Years     EFV+ddI+FTC in Children >= 3 Years to <= 6 Years  
Number of Participants Analyzed  
[units: participants]
  4     10     4     4  
AUC (TAU) of Didanosine (ddI) at Week 2 - Pharmacokinetic Evaluable Population  
[units: ng•h/mL]
Geometric Mean ( Geometric Coefficient of Variation )
  1445  
  ( 76% )  
  2848  
  ( 53% )  
  1038  
  ( 54% )  
  1000  
  ( 41% )  

No statistical analysis provided for AUC (TAU) of Didanosine (ddI) at Week 2 - Pharmacokinetic Evaluable Population



21.  Secondary:   CLT/F of Didanosine (ddI) at Week 2 - Pharmacokinetic Evaluable Population   [ Time Frame: Week 2 ]

22.  Secondary:   CLT/F/kg of Didanosine (ddI) at Week 2 - Pharmacokinetic Evaluable Population   [ Time Frame: Week 2 ]

23.  Secondary:   Terminal Phase Elimination Half-life (T-HALF) in Didanosine (ddI) at Week 2 - Pharmacokinetic Evaluable Population   [ Time Frame: Week 2 ]

24.  Secondary:   The Number of Participants With Plasma HIV RNA Levels < 400 c/mL at Weeks 60, 72, 84 and 96 (Observed Cases) – All Treated Participants   [ Time Frame: Weeks 60, 72, 84, and 96 ]

25.  Secondary:   The Number of Participants With Plasma HIV RNA Levels < 50 c/mL at Weeks 60, 72, 84 and 96 (Observed Cases) – All Treated Participants   [ Time Frame: Weeks 60, 72, 84, and 96 ]

26.  Secondary:   Log10 c/mL HIV RNA Changes From Baseline at Weeks 60, 72, 84 and 96 - Treated Participants   [ Time Frame: Baseline through Weeks 60, 72, 84, and 96 ]

27.  Secondary:   CD4 Cell Count Change From Baseline at Weeks 60, 72, 84, and 96 - Treated Participants   [ Time Frame: Baseline to Weeks 60, 72, 84, and 96 ]

28.  Secondary:   Percent of CD4 Cells Change From Baseline at Weeks 60, 72, 84, and 96 - Treated Participants   [ Time Frame: Baseline to Weeks 60, 72, 84, and 96 ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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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
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  More Information
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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: Bristol-Myers Squibb Study Director
Organization: Bristol-Myers Squibb
e-mail: Clinical.Trials@bms.com


No publications provided


Responsible Party: Bristol-Myers Squibb
ClinicalTrials.gov Identifier: NCT00364793     History of Changes
Other Study ID Numbers: AI266-922
Study First Received: August 15, 2006
Results First Received: March 6, 2014
Last Updated: April 11, 2014
Health Authority: United States: Food and Drug Administration