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

An Open-label Study of Liquid and Sprinkled Formulations of Efavirenz Administered in Combination With Didanosine and Emtricitabine in HIV-infected Infants and Children 3 Months to 6 Years of Age.

The primary purpose of this study is to find the dose of Efavirenz for young children. The safety and how the medication is tolerated will also be studied.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Efavirenz (EFV) + Didanosine (ddI) + Emtricitabine (FTC)

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, 1425
    • Local Institution
  • Capital Federal, Argentina, 1425
    • Local Institution
• Colombia
  • Cali, Colombia
    • Local Institution
• Mexico
  • Colima, Mexico, 28019
    • Local Institution
  • Puebla, Mexico, 72000
    • Local Institution
  • San Luis Potosi, Mexico, 78240
    • Local Institution
  • Distrito Federal
    • Df, Distrito Federal, Mexico, 06720
      • Local Institution
  • Jalisco
    • Guadalajara, Jalisco, Mexico, 44280
      • Local Institution
    • Guadalajara, Jalisco, Mexico, 44520
      • Local Institution
  • Michioacan
    • Morelia, Michioacan, Mexico, 58000
      • Local Institution
  • Nuevo Leon
    • Monterrey, Nuevo Leon, Mexico, 64460
      • Local Institution
• Panama
  • Ciudad De Panama, Panama, 0816-00383
    • Local Institution
• South Africa
  • Free State
    • Bloemfontein, Free State, South Africa, 9301
      • Local Institution
  • Gauteng
    • Westdene, Gauteng, South Africa, 2092
      • Local Institution
  • Western Cape
    • Cape Town, Western Cape, South Africa, 7505
      • Local Institution
• Thailand
  • Bangkok, Thailand, 10700
    • Local Institution
  • Bangkok, Thailand, 10330
    • Local Institution

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 months to 6 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• HIV-1 infected; >=3 months of age to <=6 years of age (at time of treatment); screening plasma viral load >=1000 copies/mL

Exclusion Criteria:

• Genotypic or phenotypic resistance to EFV, ddl, or FTC/lamivudine (3TC) at screening

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: EFV+ddI+FTC in patients >= 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, 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.	Drug: Efavirenz (EFV) + Didanosine (ddI) + Emtricitabine (FTC); Oral Solution, Capsules or Tablets, Oral, once daily Efavirenz (EFV) per weight-based dosing nomogram (max 720 mg) Didanosine (ddI) 240 mg/m2 (max 400 mg) Emtricitabine (FTC) 6 mg/kg (max 200 mg) Where EFV oral solution is commercially available: 48 weeks or until 3rd birthday (whichever is longer); Where EFV oral solution NOT commercially available: until 7th birthday or until able to swallow EFV capsules (whichever occurs first); Other Names: Sustiva; BMS-561525
Experimental: EFV+ddI+FTC in patients >=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, 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.	Drug: Efavirenz (EFV) + Didanosine (ddI) + Emtricitabine (FTC); Oral Solution, Capsules or Tablets, Oral, once daily Efavirenz (EFV) per weight-based dosing nomogram (max 720 mg) Didanosine (ddI) 240 mg/m2 (max 400 mg) Emtricitabine (FTC) 6 mg/kg (max 200 mg) Where EFV oral solution is commercially available: 48 weeks or until 3rd birthday (whichever is longer); Where EFV oral solution NOT commercially available: until 7th birthday or until able to swallow EFV capsules (whichever occurs first); Other Names: Sustiva; BMS-561525
Experimental: EFV+ddI+FTC in patients >= 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, 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.	Drug: Efavirenz (EFV) + Didanosine (ddI) + Emtricitabine (FTC); Oral Solution, Capsules or Tablets, Oral, once daily Efavirenz (EFV) per weight-based dosing nomogram (max 720 mg) Didanosine (ddI) 240 mg/m2 (max 400 mg) Emtricitabine (FTC) 6 mg/kg (max 200 mg) Where EFV oral solution is commercially available: 48 weeks or until 3rd birthday (whichever is longer); Where EFV oral solution NOT commercially available: until 7th birthday or until able to swallow EFV capsules (whichever occurs first); Other Names: Sustiva; BMS-561525
Experimental: EFV+ddI+FTC in patients >= 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, 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.	Drug: Efavirenz (EFV) + Didanosine (ddI) + Emtricitabine (FTC); Oral Solution, Capsules or Tablets, Oral, once daily Efavirenz (EFV) per weight-based dosing nomogram (max 720 mg) Didanosine (ddI) 240 mg/m2 (max 400 mg) Emtricitabine (FTC) 6 mg/kg (max 200 mg) Where EFV oral solution is commercially available: 48 weeks or until 3rd birthday (whichever is longer); Where EFV oral solution NOT commercially available: until 7th birthday or until able to swallow EFV capsules (whichever occurs first); Other Names: Sustiva; BMS-561525

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Observed Plasma Concentration (Cmax) and Plasma Concentration 24 Hours Post-dose (Cmin) of EFV at Week 2 - Pharmacokinetic Evaluable Population	Cmax and Cmin were derived from plasma concentrations versus time using a validated liquid chromatography tandem mass spectrometry method (LC-MS/MS). The lower limit of quantification (LLOQ) for EFV was 10.0 nanograms per milliliter (ng/mL) and the upper limit of quantification (ULOQ) was 8,000 ng/mL. Cmax and Cmin were recorded directly from experimental observations. 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 were summarized using geometric means. Cmax and Cmin were measured in ng/mL.	Week 2
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	Plasma concentrations were obtained using a validated liquid chromatography tandem mass spectrometry method (LC-MS/MS). The lower limit of quantification (LLOQ) for EFV was 10.0 nanograms per milliliter (ng/mL) and the upper limit of quantification (ULOQ) was 8,000 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 micromolars*time (µM•h).	Week 2
Apparent Oral Clearance (CLT/F) of EFV at Week 2 - Pharmacokinetic Evaluable Population	Plasma concentrations of EFV were obtained using a validated liquid chromatography tandem mass spectrometry method (LC-MS/MS). The lower limit of quantification (LLOQ) for EFV was 10.0 nanograms per milliliter (ng/mL) and the upper limit of quantification (ULOQ) was 8,000 ng/mL. CLT/F was calculated by dividing the dose of EFV by AUC(TAU) of EFV. 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 were summarized using geometric means. CLT/F was measured in liters per hour (L/h).	Week 2
Apparent Oral Clearance Adjusted for Body Weight (CLT/F/kg) of EFV at Week 2 - Pharmacokinetic Evaluable Population	Plasma concentrations of EFV were determined using a validated liquid chromatography tandem mass spectrometry method (LC-MS/MS). The lower limit of quantification (LLOQ) for EFV was 10.0 nanograms per milliliter (ng/mL) and the upper limit of quantification (ULOQ) was 8,000 ng/mL. CLT/F/kg was calculated by dividing CLT/F by body weight in kilograms (kg). 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 were summarized using geometric means. CLT/F/kg was measured in liters per hour per kilogram (L/h/kg).	Week 2

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Algorithms: Confirmed Virologic Response (CVR) non-completer = failure (NC = F): participants were responders if they achieved confirmed HIV RNA < 400 c/mL at Week 48; participants were failures if virologic rebound occurred at or before Week 48; therapy discontinued before Week 48; no response by Week 48, or missing HIV RNA at Week 48 and beyond. Virologic Response - Observed Cases (VR-OC): participants were responders according to a single on-treatment HIV RNA < 400 c/mL closest to the planned Week 48 visit and within the predefined Week 48 visit window; those on treatment and missing their Week 48 measurement were responders only if previous and subsequent measurements to the Week 48 visit window were < 400 c/mL; denominator was all who remained on treatment through Week 48. Snapshot: participants were responders according to the last on-treatment HIV RNA < 400 c/mL in the predefined Week 48 visit window; denominator was all treated participants.	Week 48
The Number of Participants With Plasma HIV RNA Levels < 50 c/mL at Week 48 as Analyzed by Different Algorithms - All Treated Participants	Algorithms: Confirmed Virologic Response (CVR) non-completer = failure (NC = F): participants were responders if they achieved confirmed HIV RNA < 50 c/mL at Week 48; participants were failures if virologic rebound occurred at or before Week 48; therapy discontinued before Week 48; no response by Week 48, or missing HIV RNA at Week 48 and beyond. Virologic Response - Observed Cases (VR-OC): participants were responders according to a single on-treatment HIV RNA < 50 c/mL closest to the planned Week 48 visit and within the predefined Week 48 visit window; those on treatment and missing their Week 48 measurement were responders only if previous and subsequent measurements to the Week 48 visit window were < 50 c/mL; denominator was all who remained on treatment through Week 48. Snapshot: participants were responders according to the last on-treatment HIV RNA < 50 c/mL in the predefined Week 48 visit window; denominator was all treated participants.	Week 48
The Number of Participants With Plasma HIV RNA Levels < 400 c/mL at Week 24 as Analyzed by Different Algorithms - All Treated Participants	Algorithms: Confirmed Virologic Response (CVR) non-completer = failure (NC = F): participants were responders if they achieved confirmed HIV RNA < 400 c/mL at Week 24; participants were failures if virologic rebound occurred at or before Week 24; therapy discontinued before Week 24; no response by Week 24, or missing HIV RNA at Week 24 and beyond. Virologic Response - Observed Cases (VR-OC): participants were responders according to a single on-treatment HIV RNA < 400 c/mL closest to the planned Week 24 visit and within the predefined Week 24 visit window; those on treatment and missing their Week 24 measurement were responders only if previous and subsequent measurements to the Week 24 visit window were < 400 c/mL; denominator was all who remained on treatment through Week 24.	Week 24
The Number of Participants With Plasma HIV RNA Levels < 50 c/mL at Week 24 as Analyzed by Different Algorithms - All Treated Participants	Algorithms: Confirmed Virologic Response (CVR) non-completer = failure (NC = F): participants were responders if they achieved confirmed HIV RNA < 50 c/mL at Week 24; participants were failures if virologic rebound occurred at or before Week 24; therapy discontinued before Week 24; no response by Week 24, or missing HIV RNA at Week 24 and beyond. Virologic Response - Observed Cases (VR-OC): participants were responders according to a single on-treatment HIV RNA < 50 c/mL closest to the planned Week 24 visit and within the predefined Week 24 visit window; those on treatment and missing their Week 24 measurement were responders only if previous and subsequent measurements to the Week 24 visit window were < 50 c/mL; denominator was all who remained on treatment through Week 24.	Week 24
Log10 c/mL HIV RNA Changes From Baseline Through Week 48 - Treated Participants	HIV RNA measured as log10 copies per milliliter (c/mL) plasma. HIV RNA values ≥ 1,000 c/mL were considered evidence of infection. A decrease in number of c/mL is an improvement for the participant. 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. The Baseline visit was within 50 days after the screening visit and was prior to start of study medication (Week 1).	Baseline through Week 48
CD4 Cell Count Change From Baseline at Weeks 24 and 48 - Treated Participants	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 millimeters to the third power (cells/mm^3). An increase from baseline in the number of CD4 cells is an improvement. The Baseline visit was within 50 days after the screening visit and was prior to start of study medication (Week 1).	Baseline to Weeks 24 and 48
Percent of CD4 Cells Change From Baseline at Weeks 24 and 48 - Treated Participants	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). Percent of CD4 cells is the number of CD4 cells per total number of cells measured*100. An increase in the percent of CD4 cells is an improvement. The Baseline visit was within 50 days after the screening visit and was prior to start of study medication (Week 1).	Baseline to Weeks 24 and 48
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	Center for Disease Control and Prevention (CDC) classification of Class C events used to define acquired immunodeficiency syndrome (AIDS): include pneumocystis pneumonia, pneumonia, pulmonary tuberculosis. AE=new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or missing relationship to study drug. AE Severity: Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling (Division of AIDs Table, published December 2004). Baseline=within 50 days post screening, prior to start of study drug. 2 categories for death presented (on-treatment and enrolled/not treated).	Baseline to Week 96
Number of Participants With Liver Function Test Laboratory Abnormalities - Treated Population	Abnormalities were determined from laboratory measurements analyzed at the central or local laboratory. Division of AIDS Table (DAIDS) for Grading Severity of Adult and Pediatric AEs version (v) Dec 2004. Upper limit of normal (ULN): lower limit of normal (LLN), alanine transaminase (ALT); aspartate aminotransferase (AST); alkaline phosphatase (ALP). ALT Grade (Gr) 1: 1.25 to 2.5*ULN; Gr 2: 2.6 to 5.0*ULN; Gr 3: 5.1 to 10.0*ULN; Gr 4: >10.0*ULN. AST Gr 1: 1.25 to 2.5*ULN; Gr 2: 2.6 to 5.0*ULN; Gr 3: 5.1 to 10.0*ULN; Gr 4: >10.0*ULN. Total bilirubin Gr 1: 1.25 to 1.5*ULN; Gr 2: 1.6 to 2.5*ULN; Gr 3: 2.6 to 5.0*ULN; Gr 4: >5.0*ULN. ALP (U/L) Gr 1: 1.25 to 2.5*ULN, Gr 2: 2.6 to 5.0*ULN, Gr 3: 5.1 to 10.0*ULN, Gr 4: >10.0*ULN. Albumin (low) Gr 1: 3 grams per deciliter (g/dL) to <LLN ; Gr 2: 2.0-2.9 g/dL; Gr 3: < 2 g/dL. Gr 4: Not applicable. Baseline visit was within 50 days after the screening visit and was prior to start of study medication (Week 1).	Baseline to Week 96
Number of Participants With Lipid and Glucose Laboratory Abnormalities - Treated Participants	Abnormalities were determined from measurements analyzed at central or local laboratory. DAIDS Grading Severity of Adult and Pediatric AEs v Dec 2004. Total Cholesterol (fasting) Gr 1: 170 - 199 mg/dL; Gr 2: 200 - 300 mg/dL; Gr 3 >300 mg/dL; Gr 4 Not Applicable(NA). LDL cholesterol, fasting: Gr 1: 110-129 mg/dL; Gr 2: 130-189 mg/dL; Gr 3 >=190 mg/dL; Gr 4 NA. Triglycerides, fasting: Gr 1: NA; Gr 2 500-750 mg/dL; Gr 3: 751-1,200 mg/dL; Gr 4: >1,200 mg/dL. Glucose, serum, high, fasting and (non-fasting): Gr 1: 110 - 125 (116-160) mg/dL; Gr 2: 126-250 (161- 250) mg/dL; Gr 3: 251-500 (251-500) mg/dL; Gr 4: >500 (> 500) mg/dL. Glucose, serum, low, >=1 month of age (<1 month): Gr 1: 55-64 (50-54) mg/dL; Gr 2: 40-54 (40-49) mg/dL; Gr 3: 30-39 (30-39) mg/dL; Gr 4: <30 (<30) mg/dL. Baseline: within 50 days after the screening visit and was prior to start of study medication (Week 1). Only those in 4th arm were old enough to fast prior to testing; other arms did not have fasting samples taken.	Baseline to Week 96
Number of Participants With Serum Chemistry Abnormalities - Treated Participants	Central/local laboratory. DAIDS v 2004. Bicarbonate, low: Gr 1: 16 milliequivalents per liter (mEq/L) - < LLN; Gr 2: 11.0-15.9 mEq/L; Gr 3: 8.0-10.9 mEq/L; Gr 4: <8.0 mEq/L; calcium, high Gr 1: 10.6-11.5 mg/dL; Gr 2: 11.6-12.5 mg/dL; Gr 3 12.6-13.5 mg/dL; Gr 4: >13.5 mg/dL; calcium, low Gr1: 7.8-8.4 mg/dL; Gr2: 7.0-7.7 mg/dL; Gr3: 6.1-6.9 mg/dL; Gr 4: <6.1 mg/dL; creatinine Gr1: 1.1-1.3*ULN; Gr 2: 1.4-1.8*ULN; Gr 3: 1.9-3.4*ULN; Gr 4: >=3.5*ULN; lipase Gr 1: 1.1-1.5*ULN; Gr 2: 1.6-3.0*ULN; Gr 3: 3.1-5.0*ULN; Gr 4: >5.0*ULN; potassium high (low) Gr 1: 5.6-6.0 (3.0-3.4) mEq/L; Gr 2: 6.1-6.5 (2.5-2.9) mEq/L; Gr 3: 6.6-7.0 (2.0-2.4) mEq/L; Gr 4: >7.0 (<2.0) mEq/L; sodium, high (low) Gr 1: 146-150 (130-135) mEq/L; Gr 2: 151-154 (125-129) mEq/L; Gr 3: 155-159 (121-124) mEq/L; Gr 4: >=160 (<=120) mEq/L; uric acid Gr 1: 7.5-10.0 mg/dL; Gr 2: 10.1-12.0 mg/dL; Gr 3: 12.1-15.0 mg/dL; Gr 4: >15.0 mg/dL. Baseline within 50 days post screening, prior to start of study medication.	Baseline to Week 96
Number of Participants With Hematologic Abnormalities - Treated Participants	Abnormalities were determined from laboratory measurements analyzed at the central or local laboratory. DAIDS DAIDS Grading Severity of Adult and Pediatric AEs v Dec 2004. Hemoglobin Gr 1: 8.5-10.0 g/dL; Gr 2: 7.5-8.4 g/dL; Gr 3: 6.50-7.4 g/dL; Gr 4: <6.5 g/dL; Platelets, decreased: Gr 1: 100.000-124.999*10^9/L; Gr 2: 50.000-99.999*10^9/L; Gr 3: 25.000-49.999*10^9/L; Gr 4: <25.000*10^9/L; White blood cell count (WBC) decreased Gr 1: 2.000-2.500*10^9/L; Gr 2: 1.500-1.999*10^9/L; Gr 3: 1.000-1.499*10^9/L; Gr 4: <1.000*10^9/L. Baseline visit was within 50 days post screening and was prior to start of study drug (Week 1).	Baseline to Week 96
Number of Treated Participants With Resistance Associated Genotypic and Phenotypic Changes in Viruses - Participants With Virologic Failure, Lack of Suppression or Viral Load Rebound	At baseline, treatment-naïve screened by genotype; treatment-experienced screened by genotype and phenotype. Genotypic resistance: presence of substitutions in reverse transcriptase (RT) gene and/or presence of mutations that confer resistance to nucleoside reverse transcriptase inhibitor class. Phenotype resistance: FTC: > 3.1* the 50% inhibitory concentration (IC50) of the control strain; EFV: > 3.3* IC50 ; ddI: > 2.6*IC50. Virologic failure: <1 log10 decrease in HIV RNA from Week 16 on; confirmatory HIV RNA within 14-35 days; HIV RNA > 10,000 c/mL with prior value < 400 c/mL; confirmatory HIV RNA 14-35 days. Monogram Biosciences Phenosense™ assay ( EFV and FTC: biologic cutoffs=3 and 3.5, respectively; ddI: clinical cutoff: lower limit=1.39; upper limit = 2.2.); VircoTYPE™ HIV-1 v 4.3.01( EFV, FTC: biologic cutoffs=3.3 and 3.1, respectively;ddI: clinical cutoff: lower limit = 0.9; upper limit = 2.6. No genotypic/phenotypic changes in presence of virologic failure=no resistance.	Baseline to Week 48
Number of Participants With Acquisition of Resistance to EFV Categorized by AUC Relationship - Evaluable Pharmacokinetic Population	PK parameters were evaluated 2 weeks post start of dosing. Based on observed AUC, measured in micromoles (μM)*h, dosing was increased, remained the same, or decreased at next visit to achieve the desired AUC (110-380 μM*h). Number of participants who became resistant was categorized by those who required additional dosing after Week 2 (AUC<110 μM*h) and those who did not. AUC: derived from plasma concentration of EFV versus time. Plasma concentrations for determination of AUC were obtained using a validated LC-MS/MS method. LLOQ for EFV = 10.0 ng/mL and ULOQ = 8,000 ng/mL. AUC calculated by log- and linear trapezoidal summations. Genotypic resistance=presence of substitutions in the RT gene and/or presence of mutations that confer resistance to entire nucleoside reverse transcriptase inhibitor class. Phenotypic resistance=EFV: > 3.3* IC50 of control strain. Assays: Monogram Biosciences Phenosense™ GT (EFV biologic cutoff=3) and VircoTYPE™ HIV-1 v 4.3.01( EFV biologic cutoff=3.3).	Baseline to Week 48
Cmax and Cmin of Didanosine (ddI) at Week 2 - Pharmacokinetic Evaluable Population	Cmax and Cmin were derived from plasma concentration versus time. Plasma concentrations for ddI were determined using a validated LC/MS/MS assay. All reportable Cmin values were <LLOQ in all age groups except >=6 months to < 2 years (Group 2); LLOQ/2 was imputed for those summary statistics;in Group 2, 9 of 10 Cmin values were <LLOQ; LLOQ/2 was imputed for those samples for summary statistics. The lower limit of quantification (LLOQ) for ddI was 2.50 nanograms per milliliter (ng/mL). Cmax and Cmin were recorded directly from experimental observations. 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 were summarized using geometric means. Cmax and Cmin were measured in ng/mL.	Week 2
AUC (TAU) of Didanosine (ddI) at Week 2 - Pharmacokinetic Evaluable Population	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).	Week 2
CLT/F of Didanosine (ddI) at Week 2 - Pharmacokinetic Evaluable Population	Plasma concentrations for ddI were determined using a validated LC/MS/MS assay. The LLOQ for ddI was 2.50 nanograms per milliliter (ng/mL). CLT/F was calculated by dividing the dose of ddI by AUC(TAU) of ddI. 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 were summarized using geometric means. CLT/F was measured in liters per hour (L/h).	Week 2
CLT/F/kg of Didanosine (ddI) at Week 2 - Pharmacokinetic Evaluable Population	Plasma concentrations for ddI were determined using a validated LC/MS/MS assay. The LLOQ for ddI was 2.50 nanograms per milliliter (ng/mL). CLT/F/kg was calculated by dividing CLT/F by body weight in kilograms (kg). 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 were summarized using geometric means. CLT/F/kg was measured in liters per hour per kilogram (L/h/kg).	Week 2
Terminal Phase Elimination Half-life (T-HALF) in Didanosine (ddI) at Week 2 - Pharmacokinetic Evaluable Population	Plasma concentrations for ddI were determined using a validated LC/MS/MS assay. The LLOQ for ddI was 2.50 nanograms per milliliter (ng/mL). 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 T-HALF was summarized using a mean. Terminal elimination plasma half-life=ln2 divided by K where K is the absolute value of the slope of the terminal phase of the plasma profile as determined by log-linear regression of at least three data points. T-HALF was measured in hours (h).	Week 2
The Number of Participants With Plasma HIV RNA Levels < 400 c/mL at Weeks 60, 72, 84 and 96 (Observed Cases) - All Treated Participants	Virologic Response - Observed Cases (VR-OC): participants were responders at a specific week according to a single on-treatment HIV RNA < 400 c/mL closest to the planned visit and within the predefined visit window; those on treatment and missing their specific week measurement were responders only if previous and subsequent measurements to that week visit window were < 400 c/mL; denominator was all who remained on treatment through the specific week.	Weeks 60, 72, 84, and 96
The Number of Participants With Plasma HIV RNA Levels < 50 c/mL at Weeks 60, 72, 84 and 96 (Observed Cases) - All Treated Participants	Virologic Response - Observed Cases (VR-OC): participants were responders at a specific week according to a single on-treatment HIV RNA < 50 c/mL closest to the planned visit and within the predefined visit window; those on treatment and missing their specific week measurement were responders only if previous and subsequent measurements to that week visit window were < 50 c/mL; denominator was all who remained on treatment through the specific week.	Weeks 60, 72, 84, and 96
Log10 c/mL HIV RNA Changes From Baseline at Weeks 60, 72, 84 and 96 - Treated Participants	HIV RNA measured as log10 copies per milliliter (c/mL) plasma. HIV RNA values ≥ 1,000 c/mL were considered evidence of infection. A decrease in number of c/mL is an improvement for the participant. 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. The Baseline visit was within 50 days after the screening visit and was prior to start of study medication (Week 1).	Baseline through Weeks 60, 72, 84, and 96
CD4 Cell Count Change From Baseline at Weeks 60, 72, 84, and 96 - Treated Participants	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 millimeters to the third power (cells/mm^3). An increase from baseline in the number of CD4 cells is an improvement. The Baseline visit was within 50 days after the screening visit and was prior to start of study medication (Week 1).	Baseline to Weeks 60, 72, 84, and 96
Percent of CD4 Cells Change From Baseline at Weeks 60, 72, 84, and 96 - Treated Participants	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). Percent of CD4 cells is the number of CD4 cells per total number of cells measured*100. An increase in the percent of CD4 cells is an improvement. The Baseline visit was within 50 days after the screening visit and was prior to start of study medication (Week 1).	Baseline to Weeks 60, 72, 84, and 96

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb

Publications and helpful links

General Publications

• Pavia-Ruz N, Rossouw M, Saez-Llorens X, Bunupuradah T, Taylor M, Yang R, Sevinsky H, Krystal M, Lataillade M, Seekins D, Biguenet S. Efavirenz Capsule Sprinkle and Liquid Formulations With Didanosine and Emtricitabine in HIV-1-infected Infants and Children 3 Months to 6 Years of Age: Study AI266-922. Pediatr Infect Dis J. 2015 Dec;34(12):1355-60. doi: 10.1097/INF.0000000000000913.

Helpful Links

• BMS clinical trial educational resource

Study record dates

Study Major Dates

• Study Start: February 1, 2007
• Primary Completion (Actual): December 1, 2011
• Study Completion (Actual): July 1, 2013

Study Registration Dates

• First Submitted: August 15, 2006
• First Submitted That Met QC Criteria: August 15, 2006
• First Posted (Estimate): August 16, 2006

Study Record Updates

• Last Update Posted (Estimate): April 29, 2014
• Last Update Submitted That Met QC Criteria: April 11, 2014
• Last Verified: April 1, 2014

More Information

Terms related to this study

• Keywords: HIV, Pediatric
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antimetabolites; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Emtricitabine; Didanosine; Efavirenz
• Other Study ID Numbers: AI266-922