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

ViiV Healthcare110 enrolled

Overview

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 .

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

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

110

Conditions

Infection, Human Immunodeficiency Virus I

Interventions

LEXIVA (GW433908)DRUG

Fosamprenavir suspension or tablet bid

RitonavirDRUG

Ritonavir solution bid

Eligibility

Sex: ALLMin age: 2 YearsMax age: 18 Years

Medical Language ↔ Plain English

Inclusion criteria: * Males or females 2 to 18 years of age Cohorts 1A and 1B, up to one month before 6th birthday at Baseline/Day 1 Cohort 2, up to one month before 12th birthday at Baseline/Day 1 Cohort 3, up to one month before 19th birthday at Baseline/Day 1 * A female is eligible to enter and participate in this study if she is of: 1. non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is pre-menarchial); or, 2. child-bearing potential with a negative serum pregnancy test at screen, a negative urine pregnancy test on Day 1 and who agrees to use one of the following methods of contraception (any contraception method must be used consistently and correctly, i.e., in accordance with both the product label and the instructions of a physician). Premenarchial females who develop child-bearing potential while on the study will be expected to follow one of the methods of contraception listed below. Agreement for complete abstinence from intercourse from 2 weeks prior to administration of study drugs, throughout the study and for 2 weeks after discontinuation of all study medications. Should a female subject of childbearing potential decide to become sexually active during the course of the study, she must be counseled and be willing to use one of the contraception methods listed below: Double barrier contraception (male condom/spermicide, male condom/diaphragm, diaphragm/spermicide) Any intrauterine device (IUD) with published data showing that the expected failure rate is less than 1% per year (not all IUDs meet this criterion) Any other method with published data showing that the lowest expected failure rate for that method is less than 1% per year. Hormonal contraception is not recommended, due to decreased efficacy of contraception as well as increased risk of hepatic transaminase elevation (see Section 8.2). All subjects of childbearing potential or developing child-bearing potential while participating in this study should be counseled on the practice of safe/safer sex. * Parent or legal guardian (and subject whenever possible) has the ability to understand and provide written informed consent for the subject to participate in the trial. Verbal witnessed assent must be obtained from the subject whenever possible. * Screening plasma HIV-1 RNA \>=400copies/mL. * Subjects must meet one of the following criterion: Antiretroviral therapy (ART)-naïve or PI-naïve subjects (defined as having received less than one week of any PI and any length of therapy with Nucleoside Reverse Transcriptase Inhibitors (NRTIs) and/or Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)). PI-experienced subjects (defined as having received greater than one week prior PI therapy with no more than three PIs). Prior RTV boosted PI therapy will be considered as only one PI as long as the RTV dose was lower than that recommended for use of RTV as an antiretroviral age Exclusion criteria: * Prior history of having received APV or FPV for \>7 days. * NNRTI use within 14 days prior to study drug administration or anticipated need for concurrent NNRTI therapy during the treatment period of the study. * Subjects who, in the investigator's opinion, are not able to comply with the requirements of the study. * Subject is in the initial acute phase of a Centers for Disease Control and Prevention (CDC) Clinical Category C event or infection (per 1994 classification) at Baseline. Subject may be enrolled provided they are receiving treatment for the infection, such treatment not being contraindicated with FPV, and the subjects are clinically improving at the Baseline visit. * Presence of a malabsorption syndrome or other gastrointestinal dysfunction which might interfere with drug absorption or render the subject unable to take oral medication. * Pregnant or lactating females. * Presence of any serious medical condition (e.g., hemoglobinopathy, chronic anemia, a history of insulin resistance, diabetes, cardiac dysfunction, hepatitis or clinically relevant pancreatitis) which, in the opinion of the investigator, might compromise the safety of the subject. * Grade 3 or 4 transaminase levels (ALT and/or AST) within 28 days prior to study drug administration and/or clinically relevant episodes of hepatitis within the previous 6 months. * Any acute laboratory abnormality at screen which, in the opinion of the investigator, should preclude the subject's participation in the study of an investigational compound. If subjects are found to have an acute Grade 4 laboratory abnormality at screening, this test may be repeated once within the screening window. Any verified Grade 4 laboratory abnormality at screen would exclude a subject from study participation. * Treatment with radiation therapy or cytotoxic chemotherapeutic agents within 28 days of study drug administration or an anticipated need for such treatment within the study period. * Treatment with immunomodulating agents (e.g., systemic corticosteroids, interleukins, interferons) or any agent with known anti-HIV activity (e.g., hydroxyurea or foscarnet) within 28 days of study drug administration. * Treatment with any of the following medications within 28 days prior to receiving study medication or the anticipated need during the study: Drugs whose plasma concentration may be increased to unsafe levels when co-administered with FPV including: Amiodarone, astemizole, bepridil, cisapride, dihydroergotamine, ergonovine, ergotamine, flecainide, halofantrine, lidocaine, lovastatin, methylergonovine, midazolam, pimozide, propafenone, quinidine, simvastatin, terfenadine, and triazolam Drugs with the potential to significantly decrease plasma APV concentrations including: Carbamazepine, dexamethasone, phenobarbital, primidone, rifampin, St Johns Wort. * Treatment with other investigational drugs/therapies (note: treatments available through a Treatment Investigational New Drug \[IND\] or other expanded-access mechanism will be evaluated on a case-by-case basis in consultation with the sponsor) within 28 days prior to study drug administration or during the treatment period of the study. * History of drug or other allergy which, in the opinion of the investigator, contraindicates participation in the trial or known hypersensitivity to any study medications (e.g., documented hypersensitivity to a nucleoside analogue). * Substantial non-adherence based on history

Locations (39)

Outcomes

Primary Outcomes

Plasma Amprenavir (APV) AUC (0-tau[τ])

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.

Time frame: Week 48

Plasma APV Cmax

The maximum concentration at steady state (Cmax) was measured.

Time frame: Week 48

Plasma APV Cτ

The plasma concentration at the end of the dosing interval at steady-state (Cτ) was measured.

Time frame: Week 48

Plasma APV CL/F Following Dosing Expressed in mg/kg

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.

Time frame: Week 48

Plasma APV CL/F Following Dosing Expressed in mg

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).

Time frame: Week 48

Plasma APV Tmax

The time to reach the maximum concentration (Cmax) at steady state is defined as tmax.

Time frame: Week 48

Data from ClinicalTrials.gov

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Secondary Outcomes

Plasma Ritonavir (RTV) AUC (0-τ)

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.

Time frame: Week 48

Plasma RTV Cmax

The maximum concentration at steady state (Cmax) was measured.

Time frame: Week 48

Plasma RTV Cτ

The plasma concentration at the end of the dosing interval at steady-state (Cτ) was measured.

Time frame: Week 48

Plasma RTV CL/F Following Dosing Expressed in mg/kg

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.

Time frame: Week 48

Plasma RTV CL/F Following Dosing Expressed in mg

Apparent clearance of drug from plasma following extravascular administration (CL/F) was calculated as dose/AUC(0-τ).

Time frame: Week 48

Plasma RTV Tmax

The time to reach the maximum concentration (Cmax) at steady state is defined as (tmax).

Time frame: Week 48

Plasma RTV t1/2

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.

Time frame: Week 48

Plasma FPV AUC (0-τ)

The majority of the FPV data were below the quantification limit. Therefore, plasma FPV PK parameters were not estimated.

Time frame: Week 48

Plasma FPV Cmax and Cτ

The majority of the FPV data were below the quantification limit. Therefore, plasma FPV PK parameters were not estimated.

Time frame: Week 48

Plasma FPV CL/F Following Dosing Expressed in mg/kg

The majority of the FPV data were below the quantification limit. Therefore, plasma FPV PK parameters were not estimated.

Time frame: Week 48

Plasma FPV CL/F Following Dosing Expressed in mg

The majority of the FPV data were below the quantification limit. Therefore, plasma FPV PK parameters were not estimated.

Time frame: Week 48

Plasma FPV Tmax

The majority of the FPV data were below the quantification limit. Therefore, plasma FPV PK parameters were not estimated.

Time frame: Week 48

Plasma FPV t1/2

The majority of the FPV data were below the quantification limit. Therefore, plasma FPV PK parameters were not estimated.

Time frame: Week 48

Number of Participants (Par.) With Virological Outcome (Plasma HIV-1 Ribonucleic Acid [RNA] <400 Copies/mL) at 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.

Time frame: Week 48

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)

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.