48-Week Study Of GW433908 And Ritonavir Or GW433908 Alone, Twice Daily In Pediatric Patients With HIV Infection

Phase 2

Completed

Conditions: Infection, Human Immunodeficiency Virus I

Interventions: Drug: LEXIVA (GW433908)
Drug: Ritonavir

Registration Number: NCT00089583

Lead Sponsor: ViiV Healthcare

Brief Summary: This is a 48-week study to collect information on the safety and activity of an investigational medicine in patients, ages 2 to 18 years old, with HIV infection .

Detailed Description: A 48 Week, Phase II, non-comparative, open-label, multi-cohort, multicenter study to evaluate the safety, tolerability, pharmacokinetics and antiviral activity of GW433908/Ritonavir BID when administered to HIV-1 infected PI-Naive and experienced, Pediatric Subjects 2 to 18 years old and of GW433908 BID Administered to PI-Naive Pediatric subjects 2 to \<6 years old

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 110

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
2 - 18 yrs old (FPV/RTV BID)	LEXIVA (GW433908)	Cohort 1B - 2 - less than 6yrs old (FPV/RTV BID) Cohort 2 - 6 to less than 12 yrs old (FPV/RTV BID) Cohort 3 - 12 - 18 yrs old (FPV/RTV BID) Cohort 4 - 2 - 18 yrs (FPV/RTV BID)
2 - 18 yrs old (FPV/RTV BID)	Ritonavir	Cohort 1B - 2 - less than 6yrs old (FPV/RTV BID) Cohort 2 - 6 to less than 12 yrs old (FPV/RTV BID) Cohort 3 - 12 - 18 yrs old (FPV/RTV BID) Cohort 4 - 2 - 18 yrs (FPV/RTV BID)
2 - less than 6yrs old (FPV BID)	LEXIVA (GW433908)	Cohort 1A - 2 - less than 6yrs old (FPV BID)

Primary Outcome Measures

Name	Time	Method
Plasma APV Tmax	Week 48	The time to reach the maximum concentration (Cmax) at steady state is defined as tmax.
Number of Participants Who Permanently Discontinued the Treatment Due to Any Adverse Event (AE)	Week 48	An AE is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
Plasma APV Cτ	Week 48	The plasma concentration at the end of the dosing interval at steady-state (Cτ) was measured.
Plasma APV CL/F Following Dosing Expressed in mg/kg	Week 48	Apparent clearance of drug from plasma following extravascular administration (CL/F) was calculated using the formulation: APV Dose in mg/kg units divided by AUC(0-τ). For FPV, doses were expressed in APV molar equivalents (50 mg of FPV = 43.2 mg of APV). Normalizing CL/F for bodyweight allows for comparison of CL/F across populations.
Plasma Amprenavir (APV) AUC (0-tau[τ])	Week 48	Plasma samples were assayed for APV concentrations using a validated assay. The GlaxoSmithKline (GSK) Department of Clinical Pharmacology Modeling and Simulation conducted pharmacokinetic (PK) analysis of the plasma APV concentration-time data using a model-independent approach. As a measure of total drug exposure, the area under the plasma-concentration-versus-time curve over the dosing interval at steady-state (AUC\[0-τ\]), where τ is the length of the dosing interval, was calculated by the linear up/log down trapezoidal method. hr, hour; µg, micrograms; mL, milliliter.
Plasma APV Cmax	Week 48	The maximum concentration at steady state (Cmax) was measured.
Plasma APV CL/F Following Dosing Expressed in mg	Week 48	Apparent clearance of drug from plasma following extravascular administration (CL/F) was calculated as dose/AUC(0-τ). For FPV, doses were expressed in APV molar equivalents (50 mg of FPV = 43.2 mg of APV).
Plasma APV t1/2	Week 48	The apparent terminal phase half-life (t1/2) is calculated as loge2/λz. The apparent terminal phase rate constant (λz) is the slope of the terminal portion of the logarithmically transformed concentration-time data as estimated by linear regression.
Change From Baseline in Triglycerides, Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Serum Glucose at Week 48	Baseline (Day 1) and Week 48	Blood samples of all participants were collected under fasting conditions for the evaluation of triglycerides, total cholesterol, HDL cholesterol, LDL cholesterol, and serum glucose. Clinical chemistry analyses were carried out using the observed analysis strategy. Change from Baseline in triglycerides, total cholesterol, HDL cholesterol, LDL cholesterol, and serum glucose was calculated as the value at Week 48 minus the value at Baseline.
Change From Baseline in Serum Lipase at Week 48	Baseline (Day 1) and Week 48	Blood samples of all participants were collected for the evaluation of serum lipase. Clinical chemistry analyses were carried out using the observed analysis strategy. Change from Baseline in serum lipase was calculated as the value at Week 48 minus the value at Baseline.
Number of Participants With Treatment-emergent (TE) Grade 3/4 Clinical Chemistry Laboratory Abnormalities	Baseline (Day 1) until Week 48	A toxicity was considered TE if it was \> than the Baseline grade, and if it was observed on/after the date of the first dose of study drug (SD), and on/before the date of the last dose of SD. Leucopenia is the decrease in the number of leucocytes (white blood cells \[WBCs\]); neutropenia is the decrease in the number of neutrophils (type of WBCs). Per the Division of AIDS Table for Grading the Severity of Adult and Pediatric AEs: Grade 3 is "severe"; Grade 4 is "potentially life-threatening." ULN, upper limit of normal; LDL, low-density lipoprotein; PC, platelet count.
Change From Baseline in Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) at Week 48	Baseline (Day 1) and Week 48	Blood samples of the participants were collected for the evaluation of AST and ALT. Clinical chemistry analyses were carried out using the observed analysis strategy. Change from Baseline in AST and ALT was calculated as the value at Week 48 minus the value at Baseline.

Secondary Outcome Measures

Name	Time	Method
Plasma RTV Cmax	Week 48	The maximum concentration at steady state (Cmax) was measured.
Plasma Ritonavir (RTV) AUC (0-τ)	Week 48	Plasma samples were assayed for RTV concentrations using a validated assay. The GlaxoSmithKline (GSK) Department of Clinical Pharmacology Modeling and Simulation conducted pharmacokinetic (PK) analysis of the plasma RTV concentration-time data using a model-independent approach. As a measure of total drug exposure, the area under the plasma-concentration-versus-time curve over the dosing interval at steady-state (AUC\[0-τ\]), where τ is the length of the dosing interval, was calculated by the linear up/log down trapezoidal method.
Plasma RTV CL/F Following Dosing Expressed in mg	Week 48	Apparent clearance of drug from plasma following extravascular administration (CL/F) was calculated as dose/AUC(0-τ).
Plasma RTV Tmax	Week 48	The time to reach the maximum concentration (Cmax) at steady state is defined as (tmax).
Plasma RTV t1/2	Week 48	alf-life (t1/2) is calculated as loge2/λz. The apparent terminal phase rate constant (λz) is the slope of the terminal portion of the logarithmically transformed concentration-time data as estimated by linear regression.
Plasma FPV AUC (0-τ)	Week 48	The majority of the FPV data were below the quantification limit. Therefore, plasma FPV PK parameters were not estimated.
Plasma FPV Cmax and Cτ	Week 48	The majority of the FPV data were below the quantification limit. Therefore, plasma FPV PK parameters were not estimated.
Plasma FPV CL/F Following Dosing Expressed in mg/kg	Week 48	The majority of the FPV data were below the quantification limit. Therefore, plasma FPV PK parameters were not estimated.
Plasma FPV CL/F Following Dosing Expressed in mg	Week 48	The majority of the FPV data were below the quantification limit. Therefore, plasma FPV PK parameters were not estimated.
Change From Baseline in the Percentage of Total Lymphocytes (TLs) That Are CD4+ Cells at Weeks 2, 12, 24, and 48	Baseline and Week 2, 12, 24, 48	Blood samples of participants were collected for the measurement of the percentage of total lymphocytes that are CD4+ cells. Observed analysis was used for the summary of proportion endpoints using viral load data. Change from Baseline in percentage was calculated as the value at Weeks 2, 12, 24, and 48 minus the value at Baseline.
Number of Confirmed Virologic Failure Participants (Par.) With Treatment-emergent HIV Genotypic Resistance in Reverse Transcriptase and Protease	Week 48	A blood sample was drawn for par. failing to respond to therapy, and the mutations present in the virus were identified. For each par., the mutations found at the time of failure were compared with any mutations found in the blood sample at baseline. New International AIDS Society-USA defined resistance mutations that developed at the time of failure were tabulated by drug class. VF, virologic failure; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor. Par. are grouped by study arm and prior therapy experience.
Number of Confirmed Virologic Failure Participants (Par.) Since the Week 48 Analysis With Treatment-emergent HIV Genotypic Resistance in Reverse Transcriptase and Protease	After Week 48 through Week 240	A blood sample was drawn for par. remaining in the study after Week 48 and failing to respond to therapy, and the mutations present in the virus were identified. For each par., the mutations found at the time of failure were compared with any mutations found in the blood sample at baseline. New International AIDS Society-USA defined resistance mutations that developed at the time of failure were tabulated by drug class. VF, virologic failure; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor. Par. are grouped by study arm and prior therapy experience.
Number of Confirmed Virologic Failure Participants (Par.) With Treatment-emergent Reductions in Drug Susceptibility (DS)	Baseline through 48 Weeks	A blood sample was drawn for par. failing to respond to therapy, and changes in DS for HIV isolated from the par. for each drug used in the study were assessed. The changes in DS detected by phenotypic assay in virus from the sample collected at the time of failure was compared with DS in the virus from the blood sample at baseline. Par. are grouped by study arm and prior therapy experience. DS is the state of HIV being susceptible to the antiretroviral agent (the virus can be inhibited by the drug). Reduced DS (i.e., HIV is resistant to the antiretroviral agent) can lead to treatment failure.
Plasma RTV Cτ	Week 48	The plasma concentration at the end of the dosing interval at steady-state (Cτ) was measured.
Plasma RTV CL/F Following Dosing Expressed in mg/kg	Week 48	Apparent clearance of drug from plasma following extravascular administration (CL/F) was calculated using the formulation: RTV Dose in mg/kg units divided by AUC(0-τ). Normalizing CL/F for bodyweight allows for comparison of CL/F across populations.
Plasma FPV Tmax	Week 48	The majority of the FPV data were below the quantification limit. Therefore, plasma FPV PK parameters were not estimated.
Plasma FPV t1/2	Week 48	The majority of the FPV data were below the quantification limit. Therefore, plasma FPV PK parameters were not estimated.
Number of Participants (Par.) With Virological Outcome (Plasma HIV-1 Ribonucleic Acid [RNA] <400 Copies/mL) at Week 48	Week 48	Blood samples of participants were collected to measure plasma HIV-1 RNA concentrations. PI-exp = PI-experienced.Virologic success was defined as plasma HIV-1 RNA \<400 copies/mL. Virologic failure: (1) HIV-1 RNA \>=400 copies/mL, (2) change of background antiretroviral treatment (ART), (3) discontinued study due to lack of efficacy, (4) discontinued study with last HIV-1 \>=400 copies/mL. No virologic data at Week 48 window: (a) discontinued study due to an adverse event or death, (b) discontinued study due to other reasons, (c) missing data during window but still on study.
Percentage of Total Lymphocytes (TLs) That Are CD4+ Cells at Baseline and Weeks 2, 12, 24, and 48	Baseline and Weeks 2, 12, 24, and 48	Blood samples of participants were collected for the measurement of the percentage of total lymphocytes that are CD4+ cells. Observed analysis was used for the summary of proportion endpoints using viral load data.
Number of Participants (Par.) With Plasma HIV-1 Ribonucleic Acid (RNA) <400 Copies Per Milliliter at Baseline and Weeks 2,12, 24, and 48 (MSD=F)	Baseline and Weeks 2, 12, 24, and 48	Blood samples of participants were collected to measure plasma HIV-1 RNA concentrations. PI-exp = PI-experienced. Viral load, measured in RNA copies per milliliter of plasma, is an efficacy measure for antiretroviral drugs. In the Missing, Switch, or Discontinuation = Failure (MSD=F) analysis, participants who had missing data at or had discontinued the study prior to a certain time point or had changed their background antiretroviral regimen are classified as non-responders.
Median Plasma HIV-1 RNA (log10 Copies/mL) at Baseline and Weeks 2, 12, 24, and 48 (Observed Analysis)	Baseline and Weeks 2, 12, 24, and 48	Blood samples of participants were collected to assess the decrease in the number of HIV-1 RNA.
Median Change From Plasma HIV-1 RNA (log10 Copies/mL) at Weeks 2, 12, 24, and 48 (Observed Analysis)	Baseline and Weeks 2, 12, 24, and 48	Blood samples of participants were collected to assess the decrease in the number of HIV-1 RNA. Change from Baseline at Weeks 2, 12, 24, and 48 was calculated as value at Week 2, 12, 24, and 48 minus the value at Baseline.
Number of Participants With at Least a 1.0 log10 HIV-1 RNA Decrease From Baseline at Weeks 2, 12, 24, and 48 (Observed Analysis)	Baseline and Weeks 2, 12, 24, and 48	Blood samples of participants were collected to assess the decrease in the number of HIV-1 RNA.
Cluster of Differentiation Antigen 4 (CD4+) Cell Count at Baseline and at Weeks 2, 12, 24, and 48	Baseline and Weeks 2, 12, 24, and 48	Blood samples of participants were collected for the measurement of CD4+ cell count. Observed analysis was used for the summary of proportion endpoints using viral load data. CD4+ cells are white blood cells that are important in fighting infection. HIV infects CD4+ cells, replicates in them, and destroys them. CD4+ cell count provides a measure of the status of the immune system and to what extent it is affected by HIV.
Change From Baseline in CD4+ Cell Count at Weeks 2, 12, 24, and 48	Baseline and Weeks 2, 12, 24, and 48	Blood samples of participants were collected for the measurement of CD4+ cell count. Observed analysis was used for the summary of proportion endpoints using viral load data. Change from Baseline was calculated as the value at Weeks 2, 12, 24, and 48 minus the value at Baseline.
Number of Confirmed Virologic Failure Participants (Par.) Since the Week 48 Analysis With Treatment-emergent Reductions in Drug Susceptibility (DS)	Week 60 through Week 240	A blood sample was drawn for par. remaining in the study after Week 48 and failing to respond to therapy, and changes in DS for HIV isolated from the par. for each drug used in the study were assessed. The changes in DS detected by phenotypic assay in virus from the sample collected at the time of failure was compared with DS in the virus from the blood sample at baseline. Par. are grouped by study arm and prior therapy experience. DS is the state of HIV being susceptible to the antiretroviral agent (the virus can be inhibited by the drug). Reduced DS (i.e., HIV is resistant to the antiretroviral agent) can lead to treatment failure.
Number of Participants Reporting Perfect Adherence Over the 3 Days Prior to the Study Visits at Weeks 2, 12, 24, and 48 as Assessed by Study Coordinator Using the Pediatric AIDS Clinical Trials Group (PACTG) Adherence Questionnaire	Weeks 2, 12, 24, and 48	The PACTG Adherence Questionnaire records individual study drugs, the expected number of doses/24 hour period, and the number of doses missed in the 3 days prior to the study visit. Responses were summarized by age cohort, study drug, treatment regimen, and visit for exploratory analysis only.
Correlation Between Plasma APV Exposure and Plasma vRNA, CD4+ Cell Counts, and the Occurrence of Adverse Events	Week 48	No formal analysis has been performed or is planned to correlate plasma APV PK with efficacy and safety outcomes.