Study Of An Investigational Regimen Including FDA Approved HIV Drugs In HIV-Infected Pediatric Subjects

ViiV Healthcare59 enrolled

Overview

This is a 48-week study to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of an investigational regimen including FDA approved HIV drugs in HIV-infected pediatric subjects, ages 4 weeks to \< 2 years old.

A 48 week, Phase II, open-label, 2-cohort, multicenter study to evaluate the pharmacokinetics, safety, tolerability and antiviral activity of GW433908 and GW433908/RTV when administered to HIV-1 infected protease inhibitor (PI) naive and PI-experienced pediatric subjects aged 4 weeks to \<2 years.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Infection, Human Immunodeficiency Virus HIV Infections

Interventions

GW433908DRUG

Fosamprenavir suspension bid

ritonavirDRUG

Ritonavir solution bid

Eligibility

Sex: ALLMin age: 4 WeeksMax age: 2 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Male or female 4 weeks to \<2 years of age. Cohort 1 (6 months - \<2 years): Subjects must be \<2 years of age at the Week 2 visit therefore the maximum age at screening is 22 months. Cohort 2 (4 weeks - \<6 months): Subjects must be \<6 months of age at the Week 2 visit, therefore the maximum age at screening is 4 months for entry into this cohort. * Parent or legal guardian is willing and able to provide written informed consent for the subject to participate in the trial. * Screening plasma HIV-1 RNA level \>=400copies/mL. * Subjects who, in the investigator's opinion, and following viral resistance testing if conducted, are able to construct an active Nucleoside Reverse Transcriptase Inhibitor (NRTI) backbone regimen consisting of 2 NRTIs. * Subjects must meet one of the following criteria: Therapy-naïve or PI-naïve subjects (defined as having received less than one week of any PI). PI-experienced subjects defined as having prior experience 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 agent. Exclusion Criteria: * Prior history of having received APV. * Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) therapy within 14 days prior to study drug administration (single or multiple dose) or anticipated need for concurrent NNRTI therapy during the study period. * PI therapy within 5 days prior to study drug administration (applicable only for subjects undergoing single dose visits) * Subjects and/or parents/legal guardians 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 infections, such treatment not being contraindicated with FPV, and 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. * Presence of any serious medical condition (e.g., hemoglobinopathy, chronic anemia, diabetes, cardiac dysfunction, hepatitis, or clinically relevant pancreatitis) which, in the opinion of the investigator, might compromise the safety of the subject. * 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 would exclude a subject from study participation. * Grade 3 or higher (\>10x ULN) serum aminotransferase levels (alanine aminotransferase, ALT and/or aspartate aminotransferase, AST) within 28 days prior to study drug administration and / or clinically relevant hepatitis within the previous 6 months. * 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: Amiodarone, astemizole, bepridil, bupropion, cisapride, clorazepate, clozapine, diazepam, dihydroergotamine, encainide, ergonovine, ergotamine, estazolam, flecainide, flurazepam, lovastatin, meperidine, methylergonovine, midazolam, pimozide, piroxicam, propafenone, propoxyphene, quinidine, simvastatin, terfenadine, and triazolam (these drugs have been excluded for safety reasons). Carbamazepine, dexamethasone, phenobarbital, primidone, rifampin, St Johns Wort, (these drugs have been excluded because they have the potential to decrease plasma protease inhibitor concentrations). * Treatment with other investigational drugs/therapies within 28 days prior to receiving study medication (note: treatments available through a Treatment IND or other expanded-access mechanism will be evaluated on a case-by-case basis in consultation with the sponsor). * 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).

Locations (15)

GSK Investigational Site

Jacksonville, Florida, United States

GSK Investigational Site

Durham, North Carolina, United States

GSK Investigational Site

Buenos Aires, Argentina

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. hours, hr.

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 mL/Min/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 mL/Min

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 Unbound APV Cτ

Participants who are \<2 years old may have reduced protein binding; therefore, plasma unbound APV concentrations were measured to determine dosing recommendations at acceptable dosing volumes. Unbound or "free" APV is the fraction of drug that is not bound to protein. Cτ is the plasma concentration at the end of the dosing interval at steady state.

Data from ClinicalTrials.gov

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Secondary Outcomes

Number of Participants With Plasma Human Immuno Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) Levels < 400 Copies/Milliliter at Each Study Visit

Blood samples of participants were collected to measure plasma HIV-1 RNA concentrations.

Time frame: Baseline (Day 1) and up to Week 684

Change From Baseline in Plasma HIV-1 RNA Levels at Each Study Visit

Blood samples of participants were collected to measure plasma HIV-1 RNA copies. Baseline value was defined as the value observed at the day 1 visit or if this value is missing the last value observed before the start of investigational product. Change from baseline value was defined as post-dose value minus baseline value.

Time frame: Baseline (Day 1) and up to Week 684

Absolute Values of Cluster of Differentiation 4 (CD4+) Cell Counts by Study Visit

Blood samples of participants were collected for the measurement of the CD4+ cells.

Time frame: Baseline (Day 1) and up to week 684

Plasma FPV Concentrations

Time frame: Post -Week 48 through Week 684

Number of Participants With Treatment-Emergent Mutations at Virologic Failure Timepoint

A blood sample was drawn from participants failing to respond to therapy, and genotyping was performed to identify the mutations present in the baseline (pre-therapy) and the sample obtained at virologic failure (VF). For each participant, the HIV-1 mutations found at the time of failure were compared with any HIV-1 mutations detected 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- NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor. Participants are grouped by study arm (prior therapy experience), results displayed in this table are from participants who met virologic failure criteria from Week 48 through Week 684.

Time frame: Week 48 to Week 684

Number of Participants With Treatment-Emergent Changes in HIV-1 Phenotypic Drug Susceptibility

A blood sample was drawn from participant failing to respond to therapy, and the mutations present in the virus were identified. Phenotypic resistance was assessed for virologic failure population and evaluated for Protease Inhibitors (PIs), Nucleotide reverse transcriptase inhibitors (NRTIs), and non-NRTIs (NNTRIs) using Monogram PhenoSense Assay. Virologic failure was defined as having failed to achieve a plasma HIV-RNA of \<400 copies/mL by Week 24 or having had a confirmed HIV-RNA rebound to ≥400 c/mL at any time after achieving a plasma HIV-RNA of \<400 c/mL.

Time frame: Post-Week 48 to Week 684

Number of Participants With Plasma HIV-1 Ribonucleic Acid (RNA) <400 Copies Per Milliliter at Baseline and Weeks 4, 12, 24, 36, and 48 (MSD=F)

Blood samples of participants were collected to measure plasma HIV-1 RNA concentrations. 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.