A Phase IIb Study to Select a Once Daily Dose of GSK1349572 Administered With Either Abacavir/Lamivudine or Tenofovir/Emtricitabine 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
- 208
- 试验地点
- 1
- 主要终点
- Number of Participants With Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) <50 Copies/Milliliter (c/mL) at Week 16
研究概览
简要总结
This Phase IIb study in HIV-infected antiretroviral naive subjects will select an optimal once daily dose of GSK1349572 from a range of doses for future evaluation.
详细描述
This Phase IIb study in HIV-infected antiretroviral naive adult subjects will include a dose-ranging evaluation of GSK1349572 10mg, 25mg and 50mg once daily blinded doses and a control arm of open label efavirenz 600mg once daily. Background ART for all study subjects will be chosen by the investigators and will be either Truvada or Epzicom/Kivexa. Data from the three doses of GSK1349572 will be compared on the basis of antiviral activity, safety/tolerability and pharmacokinetics over 16-24 weeks.
Several planned interim analyses will evaluate data in real time; any doses considered inferior will be dropped and subjects on those doses of GSK1349572 will have the option to switch to either the highest dose still under investigation or the selected dose. Subjects will be able to remain in the study, unless they reach a stopping criterion, for at least 96 weeks.
ViiV Healthcare is the new sponsor of this study, and GlaxoSmithKline is in the process of updating systems to reflect the change in sponsorship.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
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 adults at least 18 years of age. Women capable of becoming pregnant must use appropriate contraception during the study (as defined by the protocol);
- •HIV-1 infection with a screening plasma HIV-1 RNA greater than or equal to 1000copies/mL;
- •CD4+ cell count greater than or equal to 200cells/mm3 (or higher as local guidelines dictate);
- •ART-naive (less than or equal to 10 days of prior therapy with any antiretroviral agent). Any previous exposure to an HIV integrase inhibitor other than GSK1349572 will be exclusionary.
- •No evidence of viral resistance to any antiretroviral drug indicative of primary transmitted resistance at screening;
- •Able to understand and comply with protocol requirements;
- •Able to provide written informed consent prior to screening;
- •French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.
- •Note: Subjects starting abacavir as part of the NRTI backbone must have been screened and be negative for the HLA-B*5701 allele.
排除标准
- •Any pre-existing or serious mental or physical disorder which could compromise ability to comply with the protocol or compromise subject safety;
- •Women who are pregnant or breastfeeding;
- •An active AIDS-defining condition at the screening visit;
- •Previous participation in an experimental drug and/or vaccine trial(s) within 30 days or 5 half-lives;
- •History of clinically relevant pancreatitis or hepatitis within the previous 6 months, including HBsAg positive result. Asymptomatic HCV infection will not be exclusionary, however subject who will require HCV therapy during the trial should be excluded. Any subject with a history of liver cirrhosis with or without hepatitis viral co-infection will be excluded.
- •Any condition which could interfere with the absorption, distribution, metabolism or excretion of the drug;
- •Any acute or Grade 4 laboratory abnormality at screening;
- •History of upper gastrointestinal bleed and/or subjects with active peptic ulcer disease;
- •Estimated creatinine clearance <50 mL/min;
- •Alanine aminotransferase (ALT) greater than or equal to 5 times ULN;
- •Alanine aminotransferase (ALT) greater than or equal to 3xULN and bilirubin greater than or equal to 1.5xULN (with >35% direct bilirubin);
- •Lipase greater than or equal to 3xULN;
- •Hemoglobin < 100 g/L(10 g/dL);
- •History of allergy to the study drugs or their components or drugs of their class;
- •Treatment with radiation therapy, cytotoxic chemotherapeutic agents, any agents with activity against HIV-1 or immunomodulators within 28 days prior to screening;
- •Treatment with an HIV-1 immunotherapeutic vaccine within 90 days prior to screening;
- •History of protocol-defined cardiac diseases;
- •Personal or family history of prolonged QT syndrome;
- •Any clinically significant finding, as specified in the protocol, on electrocardiograph (ECG);
- •Significant blood loss in excess of 500 mL within a 56 day period prior to screening visit;
- •Immunization within 30 days prior to first dose of investigational product;
- •French subjects: The subject has participated in any study using an investigational drug during the previous 60 days or 5 half-lives, or twice the duration of the biological effect of the experimental drug or vaccine - whichever is longer, prior to screening for the study or the subject will participate simultaneously in another clinical study.
研究组 & 干预措施
10 mg GSK1349572
subjects will receive GSK1349572 10mg once daily blinded to dose
干预措施: GSK1349572 (Drug)
25mg GSK1349572
subjects will receive GSK1349572 25mg once daily blinded to dose
干预措施: GSK1349572 (Drug)
50mg GSK1349572
subjects will receive GSK1349572 50mg once daily blinded to dose
干预措施: GSK1349572 (Drug)
efavirenz control
efavirenz will serve as the internal control arm
干预措施: efavirenz (Drug)
结局指标
主要结局
Number of Participants With Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) <50 Copies/Milliliter (c/mL) at Week 16
时间窗: Week 16
Plasma samples were collected for quantitative HIV-1 RNA analysis at Week 16. The analysis was performed using the time to loss of virological response (TLOVR) dataset. In the TLOVR dataset, participant responses at a specified threshold of HIV-1 RNA (\<50 copies/mL) are determined by using the Food and Drug Administration's TLOVR algorithm. Using the TLOVR algorithm, participants are considered to have failed on therapy if they never achieved confirmed RNA levels below the threshold, if they had confirmed rebound of RNA above the threshold, if they made a non-permitted change in background regimen, or if they permanently discontinued investigational product for any reason. Data are reported per the Week 16 report. In later cuts of the data, the Week 16 values may have changed (because of the nature of the TLOVR algorithm).ITT-E Population included all randomized participants who received at least one dose of study medication
次要结局
- Viral Change Over the Initial 2 Weeks of Treatment(Baseline and Week 2)
- Change From Baseline in HIV-1 RNA at the Indicated Time Points(Baseline (Day 1), Week 1, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 32, Week 40, Week 48, Week 60, Week 72, Week 84, and Week 96)
- Number of Participants With the Indicated Type of HIV-1 Disease Progression (AIDS or Death)(From Baseline up to Week 96)
- Number of Participants With the Indicated Grade 1 to Grade 4 Treatment-emergent Clinical Chemistry and Hematology Toxicities(From Baseline up to Week 96/Early Withdrawal)
- Number of Participants With the Indicated Treatment-emergent Integrase (IN) Mutations Detected at the Time of Protocol-defined Virologic Failure (PDVF), as a Measure of Genotypic Resistance(From Baseline up to Week 96/Early Withdrawal)
- Change From Baseline in Cluster of Differentiation 4+ (CD4+) Cell Counts at the Indicated Time Points(Baseline (Day 1), Week 1, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 32, Week 40, Week 48, Week 60, Week 72, Week 84, and Week 96)
- Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Events (SAE)(From Baseline up to Week 96/Early Withdrawal)
- Relationship Between the Change From Baseline in Plasma HIV-1 RNA at Week 2 and the Indicated Plasma DTG PK Parameters(Week 2)
- Relationship Between the Change From Baseline in CD4+ Cell Counts at Week 96 and the Indicated Plasma DTG PK Parameters(Week 96)
- Number of Participants With New HIV-associated Conditions of the Indicated Class(From Baseline up to Week 96)
- Plasma DTG Concentration(Week 2, Week 12, and Week 24)
- AUC(0-tau) of DTG(Pre-dose and 2, 3, 4, 8, and 24 hours post-dose at Week 2)
- Number of Participants With the Indicated Fold Increase in DTG FC (Fold Change in IC50 Relative to Wild-type Virus) at the Time of PDVF, as a Measure of Post-Baseline Phenotypic Resistance(From Baseline up to Week 96/Early Withdrawal)
- Maximal Concentration (Cmax), Minimal Concentration (Cmin), and Concentration at the End of Dosing Interval (Ctau) of DTG(Pre-dose and 2, 3, 4, 8, and 24 hours post-dose at Week 2)
- Pre-dose Concentration (C0) and C0 Avg of DTG(Week 2, Week 12, and Week 24)
- Time to Maximal Drug Concentration (Tmax) of DTG(Pre-dose and 2, 3, 4, 8, and 24 hours post-dose at Week 2)
- Number of Participants With Plasma HIV-1 RNA <50 c/mL(Baseline (Day 1), Week 1, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 32, Week 40, Week 48, Week 60, Week 72, Week 84, and Week 96)
- Number of Participants With Plasma HIV-1 RNA <400 c/mL(Baseline (Day 1), Week 1, Week 2, Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 32, Week 40, Week 48, Week 60, Week 72, Week 84, and Week 96)
- Number of Participants With the Indicated Treatment-emergent Major Mutations of Other Classes Detected at the Time of Protocol-defined Virologic Failure (PDVF), as a Measure of Genotypic Resistance(From Baseline up to Week 96/Early Withdrawal)
- Relationship Between the Indicated Safety Parameters at Week 96 and the Indicated Plasma DTG PK Parameters(Week 96)
- Relationship Between Gastrointestinal System Organ Class AEs of Special Interest at Week 96 and the Indicated Plasma DTG PK Parameters(Week 96)