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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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.

Conditions
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Infection, Human Immunodeficiency Virus, HIV Infections

Intervention / Treatment
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* Drug: GW433908
* Drug: ritonavir


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 4 Weeks
Maximum Age: 2 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: Arm A - 4weeks - less than 2 years old (FPV/RTV bid)<br>Cohort 2A - 4weeks - less than 6 months old. Fosamprenavir (FPV) 50 mg/mL oral suspension/ritonavir (RTV) 80 mg/mL oral solution twice daily (BID) Cohort 1A - 6 months - less than 2yrs old. Fosamprenavir (FPV) 50 mg/mL oral suspension/ritonavir (RTV) 80 mg/mL oral solution twice daily (BID) | Drug: GW433908<br>* Fosamprenavir suspension bid<br>Drug: ritonavir<br>* Ritonavir solution bid<br>* Other names: GW433908;|
| Experimental: Arm B- 4weeks - less than 2 years old (FPV bid)<br>Cohort 2B - 4weeks - less than 6 months old. Fosamprenavir (FPV) 50 mg/mL oral suspension twice daily (BID) Cohort 1B - 6 months - less than 2yrs old. Fosamprenavir (FPV) 50 mg/mL oral suspension twice daily (BID) | Drug: GW433908<br>* Fosamprenavir suspension 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. hours, hr. | 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 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. | 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). | 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. | Week 48 | 
| Plasma Unbound APV Percent Protein Binding (%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. APV %Cτ unbound is the percentage of the total APV Cτ that is unbound. | Week 48 | 
| Absolute Values of Alanine Amino Transferase (ALT) and Aspartate Amino Transferase (AST) at Baseline (Day 1), Weeks 4, 12, 24, 36, and 48 | Blood samples of the participants were collected for the evaluation of ALT and AST. Clinical chemistry analyses were carried out using the observed analysis strategy. | Baseline (Day 1) and Weeks 4, 12, 24, 36, and 48 | 
| Absolute Values of Cholesterol, Glucose, High Density Lipoprotein (HDL) Cholesterol, Low Density Lipoprotein (LDL) and Triglyceride (TG) at Baseline (Day 1), Weeks 4, 12, 24, 36, and 48 | Blood samples of all participants were generally collected under non-fasting conditions (given the age of participants) for the evaluation of cholesterol, serum glucose, HDL cholesterol, LDL cholesterol and triglyceride (TG). Clinical chemistry analyses were carried out using the observed analysis strategy. | Baseline (Day 1) and Weeks 4, 12, 24, 36, and 48 | 
| Absolute Values of Serum Lipase at Baseline (Day 1), Weeks 4, 12, 24, and 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 the indicated time point minus the value at Baseline. | Baseline (Day 1) and Weeks 4, 12, 24, and 48 | 
| Number of Participants With the Indicated Treatment-emergent (TE) Grade 3/4 Laboratory Abnormalities | TE toxicities were presented for each laboratory parameter. A toxicity was considered TE if it was greater 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. Per the Division of AIDS Table for Grading the Severity of Adult and Pediatric AEs, Grade 3=severe; Grade 4=potentially life-threatening. | Baseline (Day 1) until Week 48 | 
| Number of Participants With the Indicated Treatment-emergent (TE) Grade 3/4 Adverse Events (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. An AE is considered TE if it has an onset date on or after the date of the first dose of study drug, and on or before the date of the final dose of study drug. As per the Division of AIDS Table for Grading the Severity of Adult and Pediatric AEs, Grade 3=severe; Grade 4=potentially life-threatening. | Baseline (Day 1) until Week 48 | 
| Number of Participants Who Permanently Discontinued the Treatment Due to an 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. | Baseline (Day 1) until Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | Baseline (Day 1) and up to week 684 | 
| Plasma FPV Concentrations |  | 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. | 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. | 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. | Baseline and Weeks 4, 12, 24, 36, and 48 | 
| Median Plasma HIV-1 RNA (log10 Copies/mL) at Baseline and Weeks 4, 12, 24, 36, and 48 (Observed Analysis) | Blood samples of participants were collected to assess the decrease in the number of HIV-1 RNA copies. | Baseline and Weeks 4, 12, 24, 36, and 48 | 
| Median Change From Baseline in Plasma HIV-1 RNA (log10 Copies/mL) at Weeks 4, 12, 24, 36, and 48 (Observed Analysis) | Blood samples of participants were collected to assess the decrease in the number of HIV-1 RNA copies. Change from Baseline in plasma HIV-1 RNA was calculated as the value at the indicated time point minus the value at Baseline. | Baseline and Weeks 4, 12, 24, 36, and 48 | 
| Number of Participants With at Least a 1.0 log10 HIV-1 RNA Decrease From Baseline at Weeks 4, 12, 24, 36, and 48 (MSD=F Analysis) | Blood samples of participants were collected to assess the decrease in the number of HIV-1 RNA copies. In the 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 4, 12, 24, 36, and 48 | 
| Median Percent Cluster of Differentiation Antigen 4 (CD4+) Cell Count at Baseline and at Weeks 4, 12, 24, 36, 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. CD4+ cells are white blood cells that are important in fighting infection. HIV infects CD4+ cells, replicates in them, and destroys them. A 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 4, 12, 24, 36, and 48 | 
| Median Percent Change From Baseline in CD4+ Cell Count at Weeks 4, 12, 24, 36, 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 indicated time points minus the value at Baseline. | Baseline and Weeks 4, 12, 24, 36, and 48 | 
| Number of Participants With the Indicated Virological Outcome 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 (withdrew consent, loss to follow-up, moved, etc.). | Week 48 | 
| Plasma Ritonavir (RTV) AUC (0-τ) | Plasma samples were assayed for RTV concentrations using a validated assay. The GSK Department of Clinical Pharmacology Modeling and Simulation conducted 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 Expressed in mL/Min/kg | Apparent clearance of drug from plasma following extravascular administration (CL/F) was calculated as 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 Expressed in mL/Min | Apparent clearance of drug from plasma following extravascular administration (CL/F) was calculated as dose in mg/kg units divided by AUC(0-τ). | Week 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. | Baseline through Week 48 | 
| 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 Week 48 | 
| Number of Participants Reporting Perfect Adherence at Weeks 2, 12, 24, and 48 as Assessed by the Study Coordinator Using the Adherence Questionnaire | A separate questionnaire was administered for FPV and RTV. Items 1-4 of the Adherence Questionnaire measured a participant's adherence with FPV or RTV during the last 3 days and the weekend prior to the indicated study visits. Perfect adherence was defined as not missing any doses of FPV or RTV since the last study visit. | Weeks 2, 12, 24, and 48 | 
| Number of Participants With the Indicated Response Scores for the Parent/Guardian (P/G) Perception of FPV Oral Suspension Questionnaire: Items 1 to 4 | P/G perceptions of FPV/RTV BID were assessed using a P/G Perception of Study Medication questionnaire administered during Weeks 2, 24, and 48/premature study discontinuation. Questions 1 to 4 ask directly about the P/G's assessment of 1=color, 2=texture/consistency, 3=odor, and 4=general satisfaction. Questions 5 to 10 ask about the P/G's perception of the child's assessment of the oral suspension. Data are reported as the number of participants with the indicated response by question, response category (1-3=dislike, 4=neutral, 5-7=like), and timing of visit. | Weeks 2, 24, and 48/premature study discontinuation | 
| Number of Participants With the Indicated Response Scores for the Parent/Guardian Perception of the Child's Assessment of FPV Oral Suspension Questionnaire: Items (I) 5 to 10 | Parent/guardian perceptions of FPV/RTV BID was assessed using a Parent/Guardian Perception of Study Medication questionnaire. Questions 1 to 4 ask directly about the parent/guardian's assessment of the color, texture/consistency, odor, and general satisfaction. Questions 5 to 10 ask about the parent/guardian's perception of the child's assessment of the oral suspension (Items: 5=reaction to new medicine [med.]; 6=taste; 7=acceptance; 8=swallowing; 9=willingness compared to other med.; 10=overall liking. Data for items 6/10 are reported in response categories: 1-3=dislike; 4=neutral; 5-7=like. | Weeks (W) 2, 24, and 48/premature study discontinuation | 
| Correlation Between Steady-state Plasma APV PK Parameters to Changes in Plasma HIV-1 RNA Concentrations, CD4+ Percentages, and/or 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 | 
| 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 Expressed in mL/Min/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 Expressed in mL/Min | The majority of the FPV data were below the quantification limit. Therefore, plasma FPV PK parameters were not estimated. | Week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pediatrics, ritonavir, amprenavir, AGENERASE, HIV, Lexiva, protease inhibitors, HIV Infection, fosamprenavir