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

Primary Purpose

HIV Infections

Status

Completed

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

Efavirenz (EFV) + Didanosine (ddI) + Emtricitabine (FTC)

About this trial

This is an interventional treatment trial for HIV Infections focused on measuring HIV, Pediatric

Eligibility Criteria

3 Months - 6 Years (Child)All SexesDoes not accept healthy volunteers

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

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

EFV+ddI+FTC in patients >= 3 months to < 6 months

EFV+ddI+FTC in patients >=6 months to < 2 years

EFV+ddI+FTC in patients >= 2 years to < 3 years

EFV+ddI+FTC in patients >= 3 years to <= 6 years

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

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).

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).

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).

Secondary Outcome Measures

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.

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.

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.

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.

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).

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).

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).

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).

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).

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.

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.

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).

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.

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).

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.

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).

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).

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).

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).

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.

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.

Log10 c/mL HIV RNA Changes From Baseline at Weeks 60, 72, 84 and 96 - Treated Participants

CD4 Cell Count Change From Baseline at Weeks 60, 72, 84, and 96 - Treated Participants

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).

Full Information

NCT ID

NCT00364793

First Posted

August 15, 2006

Last Updated

April 11, 2014

Sponsor

Bristol-Myers Squibb

1. Study Identification

Unique Protocol Identification Number

NCT00364793

Brief Title

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

Official Title

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.

Study Type

Interventional

2. Study Status

Record Verification Date

April 2014

Overall Recruitment Status

Completed

Study Start Date

February 2007 (undefined)

Primary Completion Date

December 2011 (Actual)

Study Completion Date

July 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Bristol-Myers Squibb

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

HIV Infections

Keywords

HIV, Pediatric

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

56 (Actual)

8. Arms, Groups, and Interventions

Arm Title

EFV+ddI+FTC in patients >= 3 months to < 6 months

Arm Type

Experimental

Arm Description

Arm Title

EFV+ddI+FTC in patients >=6 months to < 2 years

Arm Type

Experimental

Arm Description

Arm Title

EFV+ddI+FTC in patients >= 2 years to < 3 years

Arm Type

Experimental

Arm Description

Arm Title

EFV+ddI+FTC in patients >= 3 years to <= 6 years

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Efavirenz (EFV) + Didanosine (ddI) + Emtricitabine (FTC)

Other Intervention Name(s)

Sustiva, BMS-561525

Intervention Description

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)

Primary Outcome Measure Information:

Title

Maximum Observed Plasma Concentration (Cmax) and Plasma Concentration 24 Hours Post-dose (Cmin) of EFV at Week 2 - Pharmacokinetic Evaluable Population

Description

Time Frame

Week 2

Title

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

Description

Time Frame

Week 2

Title

Apparent Oral Clearance (CLT/F) of EFV at Week 2 - Pharmacokinetic Evaluable Population

Description

Time Frame

Week 2

Title

Apparent Oral Clearance Adjusted for Body Weight (CLT/F/kg) of EFV at Week 2 - Pharmacokinetic Evaluable Population

Description

Time Frame

Week 2

Secondary Outcome Measure Information:

Title

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

Description

Time Frame

Week 48

Title

The Number of Participants With Plasma HIV RNA Levels < 50 c/mL at Week 48 as Analyzed by Different Algorithms - All Treated Participants

Description

Time Frame

Week 48

Title

The Number of Participants With Plasma HIV RNA Levels < 400 c/mL at Week 24 as Analyzed by Different Algorithms - All Treated Participants

Description

Time Frame

Week 24

Title

The Number of Participants With Plasma HIV RNA Levels < 50 c/mL at Week 24 as Analyzed by Different Algorithms - All Treated Participants

Description

Time Frame

Week 24

Title

Log10 c/mL HIV RNA Changes From Baseline Through Week 48 - Treated Participants

Description

Time Frame

Baseline through Week 48

Title

CD4 Cell Count Change From Baseline at Weeks 24 and 48 - Treated Participants

Description

Time Frame

Baseline to Weeks 24 and 48

Title

Percent of CD4 Cells Change From Baseline at Weeks 24 and 48 - Treated Participants

Description

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).

Time Frame

Baseline to Weeks 24 and 48

Title

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

Description

Time Frame

Baseline to Week 96

Title

Number of Participants With Liver Function Test Laboratory Abnormalities - Treated Population

Description

Time Frame

Baseline to Week 96

Title

Number of Participants With Lipid and Glucose Laboratory Abnormalities - Treated Participants

Description

Time Frame

Baseline to Week 96

Title

Number of Participants With Serum Chemistry Abnormalities - Treated Participants

Description

Time Frame

Baseline to Week 96

Title

Number of Participants With Hematologic Abnormalities - Treated Participants

Description

Time Frame

Baseline to Week 96

Title

Number of Treated Participants With Resistance Associated Genotypic and Phenotypic Changes in Viruses - Participants With Virologic Failure, Lack of Suppression or Viral Load Rebound

Description

Time Frame

Baseline to Week 48

Title

Number of Participants With Acquisition of Resistance to EFV Categorized by AUC Relationship - Evaluable Pharmacokinetic Population

Description

Time Frame

Baseline to Week 48

Title

Cmax and Cmin of Didanosine (ddI) at Week 2 - Pharmacokinetic Evaluable Population

Description

Time Frame

Week 2

Title

AUC (TAU) of Didanosine (ddI) at Week 2 - Pharmacokinetic Evaluable Population

Description

Time Frame

Week 2

Title

CLT/F of Didanosine (ddI) at Week 2 - Pharmacokinetic Evaluable Population

Description

Time Frame

Week 2

Title

CLT/F/kg of Didanosine (ddI) at Week 2 - Pharmacokinetic Evaluable Population

Description

Time Frame

Week 2

Title

Terminal Phase Elimination Half-life (T-HALF) in Didanosine (ddI) at Week 2 - Pharmacokinetic Evaluable Population

Description

Time Frame

Week 2

Title

The Number of Participants With Plasma HIV RNA Levels < 400 c/mL at Weeks 60, 72, 84 and 96 (Observed Cases) - All Treated Participants

Description

Time Frame

Weeks 60, 72, 84, and 96

Title

The Number of Participants With Plasma HIV RNA Levels < 50 c/mL at Weeks 60, 72, 84 and 96 (Observed Cases) - All Treated Participants

Description

Time Frame

Weeks 60, 72, 84, and 96

Title

Log10 c/mL HIV RNA Changes From Baseline at Weeks 60, 72, 84 and 96 - Treated Participants

Description

Time Frame

Baseline through Weeks 60, 72, 84, and 96

Title

CD4 Cell Count Change From Baseline at Weeks 60, 72, 84, and 96 - Treated Participants

Description

Time Frame

Baseline to Weeks 60, 72, 84, and 96

Title

Percent of CD4 Cells Change From Baseline at Weeks 60, 72, 84, and 96 - Treated Participants

Description

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).

Time Frame

Baseline to Weeks 60, 72, 84, and 96

10. Eligibility

Sex

All

Minimum Age & Unit of Time

3 Months

Maximum Age & Unit of Time

6 Years

Accepts Healthy Volunteers

Eligibility Criteria

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Bristol-Myers Squibb

Organizational Affiliation

Bristol-Myers Squibb

Official's Role

Study Director

Facility Information:

Facility Name

Local Institution

City

Buenos Aires

ZIP/Postal Code

1425

Country

Argentina

Facility Name

Local Institution

City

Capital Federal

ZIP/Postal Code

1425

Country

Argentina

Facility Name

Local Institution

City

Cali

Country

Colombia

Facility Name

Local Institution

City

State/Province

Distrito Federal

ZIP/Postal Code

06720

Country

Mexico

Facility Name

Local Institution

City

Guadalajara

State/Province

Jalisco

ZIP/Postal Code

44280

Country

Mexico

Facility Name

Local Institution

City

Guadalajara

State/Province

Jalisco

ZIP/Postal Code

44520

Country

Mexico

Facility Name

Local Institution

City

Morelia

State/Province

Michioacan

ZIP/Postal Code

58000

Country

Mexico

Facility Name

Local Institution

City

Monterrey

State/Province

Nuevo Leon

ZIP/Postal Code

64460

Country

Mexico

Facility Name

Local Institution

City

Colima

ZIP/Postal Code

28019

Country

Mexico

Facility Name

Local Institution

City

Puebla

ZIP/Postal Code

72000

Country

Mexico

Facility Name

Local Institution

City

San Luis Potosi

ZIP/Postal Code

78240

Country

Mexico

Facility Name

Local Institution

City

Ciudad De Panama

ZIP/Postal Code

0816-00383

Country

Panama

Facility Name

Local Institution

City

Bloemfontein

State/Province

Free State

ZIP/Postal Code

9301

Country

South Africa

Facility Name

Local Institution

City

Westdene

State/Province

Gauteng

ZIP/Postal Code

2092

Country

South Africa

Facility Name

Local Institution

City

Cape Town

State/Province

Western Cape

ZIP/Postal Code

7505

Country

South Africa

Facility Name

Local Institution

City

Bangkok

ZIP/Postal Code

10330

Country

Thailand

Facility Name

Local Institution

City

Bangkok

ZIP/Postal Code

10700

Country

Thailand

12. IPD Sharing Statement

Citations:

PubMed Identifier

26379163

Citation

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.

Results Reference

derived

Links:

URL

http://www.bms.com/studyconnect/Pages/home.aspx

Description

BMS clinical trial educational resource

Learn more about this trial

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

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

HIV Infections

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial