A Phase IIb, Dose Ranging Study of Oral GSK1265744 in Combination With Nucleoside Reverse Transcriptase Inhibitors for Induction of Human Immunodeficiency Virus -1 (HIV-1) Virologic Suppression Followed by an Evaluation of Maintenance of Virologic Suppression When Oral GSK1265744 is Combined With Oral Rilpivirine in HIV-1 Infected, Antiretroviral Therapy Naive Adult Subjects
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 244
- 试验地点
- 1
- 主要终点
- Percentage of Participants With HIV-1 Ribonucleic Acid (RNA) <50 Copies/Milliliter (mL) at Week 48 Using the Missing, Switch, Discontinuation Equals Failure (MSDF) Algorithm
研究概览
简要总结
The study is designed to select a dose of GSK1265744 primarily on the basis of antiviral activity and tolerability in HIV-1 infected, antiretroviral naive subjects.
This study consists of two parts:
Induction Phase: Approximately 200 subjects will be randomized (50 subjects in each of the 4 treatment arms). The Induction Phase consists of a 24 week dose-ranging evaluation of GSK1265744 at blinded doses of 10 mg, 30 mg and 60 mg once-daily and a control arm of open-label efavirenz (EFV) 600 mg once daily. The background dual nucleoside reverse transcriptase inhibitor (NRTI) antiretroviral therapy (ART) for all arms will be either abacavir/lamivudine (ABC/3TC) or tenofovir/emtricitabine (TDF/FTC) as selected by the Investigator. Subjects randomized to a GSK1265744 containing arm, who successfully complete 24 weeks on study and demonstrate virologic suppression (defined as having a plasma HIV-1 ribonucleic acid [RNA] <50 copies per milliliter [c/mL] before Week 24, with no signs of virologic rebound) will become eligible for the Maintenance Phase of this study.
Maintenance Phase: The background NRTIs will be discontinued and the subjects will continue their randomized dose of GSK1265744 in combination with rilpivirine (RPV) 25 mg once-daily for an additional 72 weeks. The Maintenance phase will evaluate the ability of this two drug ART regimen to maintain virologic suppression through Week 48, Week 72 and Week 96. Subjects randomized to the EFV arm will continue on their randomized regimen through Week 96.
After completion of the maintenance phase, subjects could enroll in the Open-Label Phase to continue GSK1265744 + RPV treatment as long as they continue to derive clinical benefit and until it is locally approved and commercially available.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •HIV-1 infected male or female subjects >= 18 years of age
- •Screening plasma HIV-1 RNA >=1000 c/mL
- •CD4+ cell count >=200 cells/millimeter (mm)^3
- •ART-naive defined as having =<10 days of prior therapy with any antiretroviral agent following a diagnosis of HIV-1 infection
- •Female subjects of child bearing potential are eligible to enter if they are not pregnant and willing to use protocol-specified methods of contraception to prevent pregnancy during the study
排除标准
- •Any evidence at screening of an active Centers for Disease and Prevention Control (CDC) Category C disease
- •Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening
- •History of ongoing or clinically relevant hepatitis within the previous 6 months, and subjects with moderate to severe hepatic impairment will be excluded
- •Women who are breastfeeding
- •Subject, who in the investigator's judgment, poses a significant suicide risk
- •Any clinically significant finding on screening or baseline electrocardiograph (ECG)
- •The presence of any specific laboratory abnormalities at Screening
- •History of cardiac disease
- •Clinically relevant pancreatitis
- •Subjects who are unlikely to complete the dosing schedule due to a pre-existing physical or mental condition
- •Any condition which impairs the absorption, distribution, metabolism or excretion of the investigational product
- •Any evidence of primary resistance based upon the presence of a major resistance associated mutation in the Screening HIV genotype, or any historical genotype
- •Treatment with any protocol-specified excluded medication
研究组 & 干预措施
Arm 1 GSK1265744 10 mg
In the Induction Phase subjects will receive oral tablets of GSK1265744 10 mg + matching placebo + investigator-selected background NRTIs (either abacavir/lamivudine or tenofovir/emtricitabine) once daily from Day 1 to Week 24. Subjects continuing in the Maintenance Phase will receive oral tablets of GSK1265744 10 mg + matching placebo + Rilpivirine 25 mg once daily from Week 24 to Week 96.
干预措施: GSK1265744 10 mg (Drug)
Arm 1 GSK1265744 10 mg
In the Induction Phase subjects will receive oral tablets of GSK1265744 10 mg + matching placebo + investigator-selected background NRTIs (either abacavir/lamivudine or tenofovir/emtricitabine) once daily from Day 1 to Week 24. Subjects continuing in the Maintenance Phase will receive oral tablets of GSK1265744 10 mg + matching placebo + Rilpivirine 25 mg once daily from Week 24 to Week 96.
干预措施: Rilpivirine 25 mg (Drug)
Arm 1 GSK1265744 10 mg
In the Induction Phase subjects will receive oral tablets of GSK1265744 10 mg + matching placebo + investigator-selected background NRTIs (either abacavir/lamivudine or tenofovir/emtricitabine) once daily from Day 1 to Week 24. Subjects continuing in the Maintenance Phase will receive oral tablets of GSK1265744 10 mg + matching placebo + Rilpivirine 25 mg once daily from Week 24 to Week 96.
干预措施: Placebo (Drug)
Arm 1 GSK1265744 10 mg
In the Induction Phase subjects will receive oral tablets of GSK1265744 10 mg + matching placebo + investigator-selected background NRTIs (either abacavir/lamivudine or tenofovir/emtricitabine) once daily from Day 1 to Week 24. Subjects continuing in the Maintenance Phase will receive oral tablets of GSK1265744 10 mg + matching placebo + Rilpivirine 25 mg once daily from Week 24 to Week 96.
干预措施: Abacavir/Lamivudine (ABC/3TC) or Tenofovir/Emtricitabine (TDF/FTC) (Drug)
Arm 2 GSK1265744 30 mg
In the Induction Phase subjects will receive oral tablets of GSK1265744 30 mg + matching placebo + investigator-selected background NRTIs (either abacavir/lamivudine or tenofovir/emtricitabine) once daily from Day 1 to Week 24. Subjects continuing in the Maintenance Phase will receive oral tablets of GSK1265744 30 mg + matching placebo + Rilpivirine 25 mg once daily from Week 24 to Week 96.
干预措施: GSK1265744 30 mg (Drug)
Arm 2 GSK1265744 30 mg
In the Induction Phase subjects will receive oral tablets of GSK1265744 30 mg + matching placebo + investigator-selected background NRTIs (either abacavir/lamivudine or tenofovir/emtricitabine) once daily from Day 1 to Week 24. Subjects continuing in the Maintenance Phase will receive oral tablets of GSK1265744 30 mg + matching placebo + Rilpivirine 25 mg once daily from Week 24 to Week 96.
干预措施: Rilpivirine 25 mg (Drug)
Arm 2 GSK1265744 30 mg
In the Induction Phase subjects will receive oral tablets of GSK1265744 30 mg + matching placebo + investigator-selected background NRTIs (either abacavir/lamivudine or tenofovir/emtricitabine) once daily from Day 1 to Week 24. Subjects continuing in the Maintenance Phase will receive oral tablets of GSK1265744 30 mg + matching placebo + Rilpivirine 25 mg once daily from Week 24 to Week 96.
干预措施: Placebo (Drug)
Arm 2 GSK1265744 30 mg
In the Induction Phase subjects will receive oral tablets of GSK1265744 30 mg + matching placebo + investigator-selected background NRTIs (either abacavir/lamivudine or tenofovir/emtricitabine) once daily from Day 1 to Week 24. Subjects continuing in the Maintenance Phase will receive oral tablets of GSK1265744 30 mg + matching placebo + Rilpivirine 25 mg once daily from Week 24 to Week 96.
干预措施: Abacavir/Lamivudine (ABC/3TC) or Tenofovir/Emtricitabine (TDF/FTC) (Drug)
Arm 3 GSK1265744 60 mg
In the Induction Phase subjects will receive oral tablets of GSK1265744 60 mg + investigator-selected background NRTIs (either abacavir/lamivudine or tenofovir/emtricitabine) once daily from Day 1 to Week 24. Subjects continuing in the Maintenance Phase will receive oral tablets of GSK1265744 60 mg + Rilpivirine 25 mg once daily from Week 24 to Week 96.
干预措施: GSK1265744 60 mg (Drug)
Arm 3 GSK1265744 60 mg
In the Induction Phase subjects will receive oral tablets of GSK1265744 60 mg + investigator-selected background NRTIs (either abacavir/lamivudine or tenofovir/emtricitabine) once daily from Day 1 to Week 24. Subjects continuing in the Maintenance Phase will receive oral tablets of GSK1265744 60 mg + Rilpivirine 25 mg once daily from Week 24 to Week 96.
干预措施: Rilpivirine 25 mg (Drug)
Arm 3 GSK1265744 60 mg
In the Induction Phase subjects will receive oral tablets of GSK1265744 60 mg + investigator-selected background NRTIs (either abacavir/lamivudine or tenofovir/emtricitabine) once daily from Day 1 to Week 24. Subjects continuing in the Maintenance Phase will receive oral tablets of GSK1265744 60 mg + Rilpivirine 25 mg once daily from Week 24 to Week 96.
干预措施: Abacavir/Lamivudine (ABC/3TC) or Tenofovir/Emtricitabine (TDF/FTC) (Drug)
Arm 4 Efavirenz 600 mg
In the Induction Phase and Maintenance Phase subjects will receive oral tablets of Efavirenz 600 mg + investigator-selected background NRTIs (either abacavir/lamivudine or tenofovir/emtricitabine).
干预措施: Efavirenz 600 mg (Drug)
Arm 4 Efavirenz 600 mg
In the Induction Phase and Maintenance Phase subjects will receive oral tablets of Efavirenz 600 mg + investigator-selected background NRTIs (either abacavir/lamivudine or tenofovir/emtricitabine).
干预措施: Abacavir/Lamivudine (ABC/3TC) or Tenofovir/Emtricitabine (TDF/FTC) (Drug)
结局指标
主要结局
Percentage of Participants With HIV-1 Ribonucleic Acid (RNA) <50 Copies/Milliliter (mL) at Week 48 Using the Missing, Switch, Discontinuation Equals Failure (MSDF) Algorithm
时间窗: Week 48
Plasma samples were collected for quantitative analysis of HIV-1 RNA. Percentage of participants with HIV-1 RNA \<50 copies/mL at Week 48 was determined using the MSDF algorithm based on the current US Food and Drug Administration (FDA) definition of Snapshot algorithm. This algorithm treats all participants without HIV-1 RNA data at the visit of interest (due to missing data or discontinuation of investigational product prior to visit window) as well as participants who switch their concomitant antiretroviral therapy prior to the visit of interest as non-responders. Virological response within an analysis window was determined by the last available HIV-1 RNA measurement in that window while the participant was on-treatment. MSDF response rate was calculated as number of responders in the analysis window divided by the number of participants in the analysis population. ITT-E Population comprised of all randomized participants who received at least one dose of investigational product.
次要结局
- Percentage of Participants With Plasma HIV-1 RNA <400 Copies/mL Until Week 96 Using the Observed Case Analysis(Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84 and 96)
- Change From Baseline in CD4+ Cell Count Over Time by Visit(Baseline (Day 1) and Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, 312 and 324)
- Percentage of Participants With Plasma HIV-1 RNA <400 Copies/mL Until Week 96 Using the MSDF Algorithm(Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84 and 96)
- Absolute Values for Plasma Logarithm to the Base 10 (log10) HIV-1 RNA Over Time by Visit(Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, 312 and 324)
- Absolute Values for Cluster of Differentiation 4+ (CD4+) Cell Count During Double-blind Randomized Treatment Until Week 96(Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84 and 96)
- Number of Participants With Treatment Emergent Phenotypic Resistance(Up to Week 324)
- Number of Participants With Adherence to Study Treatment(Baseline (Day 1), Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300 and 312)
- Percentage of Participants With Plasma HIV-1 RNA <50 Copies/mL Over Time by Visit Using the MSDF Algorithm(Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300 and 312)
- Percentage of Participants With Plasma HIV-1 RNA <50 Copies/mL Over Time by Visit Using Observed Case Analysis(Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, 312 and 324)
- Change From Baseline in Plasma log10 HIV-1 RNA Over Time by Visit(Baseline (Day 1) and Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, 312 and 324)
- Absolute Values for ALT, AST, CK During Double-blind Randomized Treatment Until Week 96(Baseline (Day 1) and Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84 and 96)
- Absolute Values for Hemoglobin During Double-blind Randomized Treatment Until Week 96(Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84 and 96)
- Change From Baseline in ALT, AST and CK Over Time by Visit(Baseline (Day 1) and Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, 312 and 324)
- Change From Baseline in Total Neutrophils, Platelet Count and WBC Count Over Time by Visit(Baseline (Day 1) and Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, 312 and 324)
- Number of Participants With Post-Baseline HIV-1 Associated Conditions Progression of Disease(Up to Week 324)
- Number of Participants With Maximum Treatment-emergent Hematology Toxicities-Maintenance Phase(Week 24 to Week 96)
- Change From Baseline in Estimated Creatinine Clearance Over Time by Visit(Baseline (Day 1) and Weeks 2, 4, 8, 16, 20, 24, 26, 40, 48, 60, 96, 180, 204, 252 and 264)
- Number of Participants With AEs and SAEs-Induction Phase(Up to Week 24)
- Number of Participants With Maximum Treatment-emergent Clinical Chemistry Toxicity-Induction Phase(Up to Week 24)
- Number of Participants With Treatment Emergent Genotypic Mutations Associated With Development of Resistance(Up to Week 324)
- Percentage of Participants With HIV-1 RNA <50 Copies/mL From Week 24 Through Week 96 by Visit Using MSDF Algorithm-Maintenance Phase(Weeks 24, 26, 28, 32, 36, 40, 48, 60, 72, 84 and 96)
- Number of Participants With Maximum Treatment-emergent Clinical Chemistry Toxicities-Maintenance Phase(Week 24 to Week 96)
- Absolute Values for Platelet Count, Total Neutrophils and WBC Count During Double-blind Randomized Treatment Until Week 96(Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84 and 96)
- Percentage of Participants Who Discontinued Investigational Product Due to Adverse Events(Up to Week 324)
- Percentage of Participants Who Discontinued Treatment Due to Adverse Events-Induction Phase(Up to Week 24)
- Percentage of Participants Who Discontinued Treatment Due to Adverse Events-Maintenance Phase(Week 24 to Week 96)
- Area Under the Concentration Time Curve Over the Dosing Interval (AUC[0-tau]) for GSK1265744 at Week 2(pre-dose, 1, 2, 3, 4, 8 and 24 hours post-dose at Week 2)
- Maximum Observed Concentration (Cmax) for GSK1265744 at Week 2(pre-dose, 1, 2, 3, 4, 8 and 24 hours post-dose at Week 2)
- Percentage of Participants With HIV-1 RNA <50 Copies/mL at Week 16 and Week 24 Using MSDF Algorithm-Induction Phase(Week 16 and Week 24)
- Number of Participants With AEs and SAEs Over Time(Up to Week 324)
- Absolute Values for Creatinine and Total Bilirubin During Double-blind Randomized Treatment Until Week 96(Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84 and 96)
- Absolute Values for Estimated Creatinine Clearance During Double-blind Randomized Treatment Until Week 96(Baseline (Day 1), Weeks 2, 4, 8, 16, 20, 24, 26, 40, 48, 60 and 96)
- Change From Baseline in Creatinine and Total Bilirubin Over Time by Visit(Baseline (Day 1) and Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, 312 and 324)
- Number of Participants With Clinically Significant Electrocardiogram (ECG) Findings(Up to Week 324)
- Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)-Maintenance Phase(Week 24 to Week 96)
- Number of Participants With Maximum Treatment-emergent Clinical Chemistry Toxicities Over Time(Up to Week 324)
- Number of Participants With Maximum Treatment-emergent Hematology Toxicities Over Time(Up to Week 324)
- Change From Baseline in Hemoglobin Level Over Time by Visit(Baseline (Day 1) and Weeks 2, 4, 8, 12, 16, 20, 24, 26, 28, 32, 36, 40, 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168, 180, 192, 204, 216, 228, 240, 252, 264, 276, 288, 300, 312 and 324)
- Number of Participants With Maximum Treatment-emergent Hematology Toxicities-Induction Phase(Up to Week 24)
- Concentration at the End of a Dosing Interval (Ctau) for GSK1265744 at Week 2(pre-dose, 1, 2, 3, 4, 8 and 24 hours post dose at Week 2)
- Cmax for Rilpivirine(pre-dose and 2 to 4 hours post-dose at Weeks 26 and 36)
- AUC(0 to Tau) for Rilpivirine(pre-dose and 2 to 4 hours post-dose at Weeks 26 and 36)
- Ctau for Rilpivirine(pre-dose and 2 to 4 hours post-dose at Weeks 26 and 36)