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.
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 59
- 试验地点
- 1
- 主要终点
- Plasma APV CL/F Following Dosing Expressed in mL/Min
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 4 Weeks 至 2 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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).
研究组 & 干预措施
Arm A - 4weeks - less than 2 years old (FPV/RTV bid)
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)
干预措施: GW433908 (Drug)
Arm A - 4weeks - less than 2 years old (FPV/RTV bid)
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)
干预措施: ritonavir (Drug)
Arm B- 4weeks - less than 2 years old (FPV bid)
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)
干预措施: GW433908 (Drug)
结局指标
主要结局
Plasma APV CL/F Following Dosing Expressed in mL/Min
时间窗: 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).
Number of Participants With the Indicated Treatment-emergent (TE) Grade 3/4 Laboratory Abnormalities
时间窗: Baseline (Day 1) until Week 48
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.
Plasma Amprenavir (APV) AUC (0-tau[τ])
时间窗: 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. hours, hr.
Plasma Unbound APV Percent Protein Binding (%Cτ)
时间窗: Week 48
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.
Absolute Values of Alanine Amino Transferase (ALT) and Aspartate Amino Transferase (AST) at Baseline (Day 1), Weeks 4, 12, 24, 36, and 48
时间窗: Baseline (Day 1) and 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.
Absolute Values of Serum Lipase at Baseline (Day 1), Weeks 4, 12, 24, and 48
时间窗: Baseline (Day 1) and 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.
Number of Participants With the Indicated Treatment-emergent (TE) Grade 3/4 Adverse Events (AE)
时间窗: Baseline (Day 1) until 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. 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.
Number of Participants Who Permanently Discontinued the Treatment Due to an AE
时间窗: Baseline (Day 1) until 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 Cmax
时间窗: Week 48
The maximum concentration at steady state (Cmax) was measured.
Plasma APV CL/F Following Dosing Expressed in mL/Min/kg
时间窗: 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 Unbound APV Cτ
时间窗: Week 48
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.
Plasma APV Cτ
时间窗: Week 48
The plasma concentration at the end of the dosing interval at steady state (Cτ) was measured.
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
时间窗: Baseline (Day 1) and 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.
次要结局
- Number of Participants With Plasma Human Immuno Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) Levels < 400 Copies/Milliliter at Each Study Visit(Baseline (Day 1) and up to Week 684)
- Change From Baseline in Plasma HIV-1 RNA Levels at Each Study Visit(Baseline (Day 1) and up to Week 684)
- Absolute Values of Cluster of Differentiation 4 (CD4+) Cell Counts by Study Visit(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(Week 48 to Week 684)
- Number of Participants With Treatment-Emergent Changes in HIV-1 Phenotypic Drug Susceptibility(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)(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)(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)(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)(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(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(Baseline and Weeks 4, 12, 24, 36, and 48)
- Number of Participants With the Indicated Virological Outcome at Week 48(Week 48)
- Plasma Ritonavir (RTV) AUC (0-τ)(Week 48)
- Plasma RTV Cmax(Week 48)
- Plasma RTV Cτ(Week 48)
- Plasma RTV CL/F Expressed in mL/Min/kg(Week 48)
- Plasma RTV CL/F Expressed in mL/Min(Week 48)
- Number of Confirmed Virologic Failure Participants (Par.) With Treatment-emergent HIV Genotypic Resistance in Reverse Transcriptase and Protease(Baseline through Week 48)
- Number of Confirmed Virologic Failure Participants (Par.) With Treatment-emergent Reductions in Drug Susceptibility (DS)(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(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(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(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(Week 48)
- Plasma FPV AUC (0-τ)(Week 48)
- Plasma FPV Cmax and Cτ(Week 48)
- Plasma FPV CL/F Expressed in mL/Min/kg(Week 48)
- Plasma FPV CL/F Expressed in mL/Min(Week 48)