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

Study Overview
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Brief Summary
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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
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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

Official Title
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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-Naïve and Experienced, Pediatric Subjects, 2 to 18 Years Old and of GW433908 BID Administered to PI-Naïve, Pediatric Subjects 2 to < 6 Years Old

Conditions
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Infection, Human Immunodeficiency Virus I

Intervention / Treatment
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* Drug: LEXIVA (GW433908)
* Drug: Ritonavir


Participation Criteria
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Eligibility Criteria
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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: non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is pre-menarchial); or, 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

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 2 - 18 yrs old (FPV/RTV BID)<br>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) | Drug: LEXIVA (GW433908)<br>* Fosamprenavir suspension or tablet bid<br>Drug: Ritonavir<br>* Ritonavir solution bid<br>* Other names: LEXIVA (GW433908);|
| Experimental: 2 - less than 6yrs old (FPV BID)<br>Cohort 1A - 2 - less than 6yrs old (FPV BID) | Drug: LEXIVA (GW433908)<br>* Fosamprenavir suspension or tablet bid<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Week 48 | 
| Plasma APV Cmax | The maximum concentration at steady state (Cmax) was measured. | Week 48 | 
| Plasma APV Cτ | The plasma concentration at the end of the dosing interval at steady-state (Cτ) was measured. | 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. | 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). | Week 48 | 
| Plasma APV Tmax | The time to reach the maximum concentration (Cmax) at steady state is defined as tmax. | Week 48 | 
| Plasma APV t1/2 | 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. | Week 48 | 
| Number of Participants Who Permanently Discontinued the Treatment Due to Any Adverse Event (AE) | 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. | Week 48 | 
| Change From Baseline in Triglycerides, Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Serum Glucose at 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. | Baseline (Day 1) and Week 48 | 
| Change From Baseline in Serum Lipase at 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. | Baseline (Day 1) and Week 48 | 
| Change From Baseline in Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) at 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. | Baseline (Day 1) and Week 48 | 
| Number of Participants With Treatment-emergent (TE) Grade 3/4 Clinical Chemistry Laboratory Abnormalities | 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. | Baseline (Day 1) until Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Week 48 | 
| Plasma RTV Cmax | The maximum concentration at steady state (Cmax) was measured. | Week 48 | 
| Plasma RTV Cτ | The plasma concentration at the end of the dosing interval at steady-state (Cτ) was measured. | 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. | 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). | Week 48 | 
| Plasma RTV Tmax | The time to reach the maximum concentration (Cmax) at steady state is defined as (tmax). | 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. | 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. | 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. | 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. | 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. | Week 48 | 
| Plasma FPV Tmax | The majority of the FPV data were below the quantification limit. Therefore, plasma FPV PK parameters were not estimated. | 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. | 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. | 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. | Baseline and Weeks 2, 12, 24, and 48 | 
| Median Plasma HIV-1 RNA (log10 Copies/mL) at Baseline and Weeks 2, 12, 24, and 48 (Observed Analysis) | Blood samples of participants were collected to assess the decrease in the number of HIV-1 RNA. | Baseline and Weeks 2, 12, 24, and 48 | 
| Median Change From Plasma HIV-1 RNA (log10 Copies/mL) at Weeks 2, 12, 24, and 48 (Observed Analysis) | 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. | Baseline and Weeks 2, 12, 24, and 48 | 
| 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) | Blood samples of participants were collected to assess the decrease in the number of HIV-1 RNA. | Baseline and Weeks 2, 12, 24, and 48 | 
| Cluster of Differentiation Antigen 4 (CD4+) Cell Count at Baseline and at 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. | Baseline and Weeks 2, 12, 24, and 48 | 
| Change From Baseline in CD4+ Cell Count at 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. | Baseline and Weeks 2, 12, 24, and 48 | 
| Percentage of Total Lymphocytes (TLs) That Are CD4+ Cells at 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. | Baseline and Weeks 2, 12, 24, and 48 | 
| Change From Baseline in the Percentage of Total Lymphocytes (TLs) That Are CD4+ Cells at 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. Change from Baseline in percentage was calculated as the value at Weeks 2, 12, 24, and 48 minus the value at Baseline. | Baseline and Week 2, 12, 24, 48 | 
| Number of Confirmed Virologic Failure Participants (Par.) With Treatment-emergent HIV Genotypic Resistance in Reverse Transcriptase and Protease | 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. | Week 48 | 
| Number of Confirmed Virologic Failure Participants (Par.) Since the Week 48 Analysis With Treatment-emergent HIV Genotypic Resistance in Reverse Transcriptase and Protease | 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. | After Week 48 through Week 240 | 
| Number of Confirmed Virologic Failure Participants (Par.) With Treatment-emergent Reductions in Drug Susceptibility (DS) | 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. | Baseline through 48 Weeks | 
| Number of Confirmed Virologic Failure Participants (Par.) Since the Week 48 Analysis With Treatment-emergent Reductions in Drug Susceptibility (DS) | 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. | Week 60 through Week 240 | 
| 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 | 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. | Weeks 2, 12, 24, and 48 | 
| Correlation Between Plasma APV Exposure and Plasma vRNA, CD4+ Cell Counts, and the Occurrence of Adverse Events | No formal analysis has been performed or is planned to correlate plasma APV PK with efficacy and safety outcomes. | Week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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antiretroviral therapy, pediatrics, AGENERASE, amprenavir, fosamprenavir, HIV Infection, ritonavir, protease inhibitor, LEXIVA