A Randomized, Double-blind Study of the Safety and Efficacy of GSK1349572 50 mg Once Daily Versus Raltegravir 400 mg Twice Daily, Both Administered With an Investigator-selected Background Regimen Over 48 Weeks in HIV-1 Infected, Integrase Inhibitor-Naïve, Antiretroviral-Experienced Adults
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 724
- 试验地点
- 1
- 主要终点
- Percentage of Participants With HIV-1 Ribonucleic Acid (RNA) <50 Copies/Milliliter (c/mL) at Week 48
研究概览
简要总结
ING111762 is a 48 week, randomized, double-blind, active-controlled, multicenter, parallel group, non-inferiority study. The study will be conducted in at least 688 HIV-1 infected antiretroviral experienced, integrase-naïve subjects. Subjects will be randomized 1:1 to receive GSK1349572 50 mg once daily or raltegravir (RAL) 400 mg twice daily, each added to an investigator selected background regimen consisting of at least one fully active agent plus no more than one second single agent which may or may not be active. Antiviral activity, safety, pharmacokinetics (PK), and development of viral resistance will be evaluated.
详细描述
ING111762 is a 48 week, randomized, double-blind, active-controlled, multicenter, parallel group, non-inferiority study. The study will be conducted in at least 688 HIV-1 infected antiretroviral experienced, integrase-naïve subjects. Subjects will be randomized 1:1 to receive GSK1349572 50 mg once daily or raltegravir (RAL) 400 mg twice daily, each added to an investigator selected background regimen consisting of at least one fully active agent plus no more than one second single agent which may or may not be active. Antiviral activity, safety, pharmacokinetics (PK), and development of viral resistance will be evaluated.
Subjects must have documented genotypic or phenotypic resistance to at least one member of each of at least two antiretroviral therapy (ART) drug classes [nucleoside/nucleotide reverse transcriptase inhibitor (N[t]RTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), protease inhibitor (PI), fusion inhibitor (T20), or entry inhibitor (chemokine receptor 5 [CCR5] antagonist)].
The primary analysis will take place after the last subject completes 48 weeks on therapy. An additional data cut and analysis will be conducted after the last subject completes 24 weeks on therapy.
Subjects randomized to GSK1349572 who successfully complete Week 48 will continue to received GSK1349572 until either it is locally available, until they no longer derive clinical benefit, until they meet a protocol-defined reason for discontinuation, or until development of the compound is terminated.
ViiV Healthcare is the 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
- •Antiretroviral therapy (ART)-experienced, Human Immunodeficiency Virus (HIV) -1 infected 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 as documented by HIV-1 RNA >400 copies/mL (c/mL) at Screening and with at least one consecutive HIV-1 RNA >400 c/mL within the four months prior to Screening (unless the Screening HIV-1 RNA is > 1000 c/mL where no additional plasma HIV-1 RNA assessment is needed).
- •Have documented resistance (via Screening resistance test) to two or more different classes of antiretroviral agents. For subjects off ART for at least one month, if Screening resistance results provide a fully active agent and do not show two class resistance then historical resistance results from the subject's most recent resistance testing may be used, following consultation with the study virologist and /or medical monitor.
- •Integrase inhibitor (INI)-naïve, defined as no prior exposure to any INI (e.g. RAL, elvitegravir, or GSK1349572).
- •Able to provide written informed consent prior to Screening.
- •French subjects: In France, subjects will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.
排除标准
- •Screening resistance test result indicates no fully active antiviral agents are available for design of the background regimen.
- •Subject-virus does not yield results using genotype/phenotype/tropism at Screening (assay data is essential for eligibility determination).
- •Women who are breastfeeding.
- •Any evidence of an active AIDS-defining condition (except cutaneous Kaposi's sarcoma not requiring systemic therapy or CD4+ <200c/mm3).
- •Subjects with moderate to severe hepatic impairment as defined by Child-Pugh classification.
- •Recent history (less than or equal to 3 months) of upper or lower gastrointestinal bleed, with the exception of anal or rectal bleeding.
- •Anticipated need for hepatitis C therapy during the study.
- •History or presence of allergy or intolerance to the study drugs or their components or drugs of their class.
- •History of malignancy within the past 5 years or ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma; other localized malignancies require agreement between the investigator and study medical monitor for inclusion of the subject.
- •Treatment with an HIV-1 immunotherapeutic vaccine within 90 days prior to Screening.
- •Treatment with any of the following agents within 28 days of Screening: radiation therapy, cytotoxic chemotherapeutic agents, any immunomodulator.
- •Treatment with any agent, other than licensed ART, which has documented activity against HIV-1 in vitro within 28 days of first dose of investigational product.
- •Exposure to an experimental drug and/or experimental vaccine within either 28 days, 5 half-lives of the test agent, or twice the duration of the biological effect of the experimental test agent - whichever is longer, prior to the first dose of IP.
- •French subjects recruited at sites in France will be excluded if the subject has participated in any study using an investigational drug and/or vaccine within 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 plans to participate simultaneously in another clinical study.
- •Any acute or verified Grade 4 laboratory abnormality.
- •Alanine aminotransferase (ALT) >5 times the upper limit of normal (ULN).
- •ALT greater than or equal to 3xULN and bilirubin greater than or equal to 1.5xULN (with >35% direct bilirubin).
研究组 & 干预措施
GSK1349572 + Raltegravir Placebo
Subjects will receive GSK1349572 50mg once daily plus raltegravir placebo twice daily.
干预措施: GSK1349572 (Drug)
GSK1349572 + Raltegravir Placebo
Subjects will receive GSK1349572 50mg once daily plus raltegravir placebo twice daily.
干预措施: Raltegravir Placebo (Drug)
Raltegravir + GSK1349572 Placebo
Subjects will receive raltegravir 400mg twice daily plus GSK1349572 placebo once daily.
干预措施: Raltegravir (Drug)
Raltegravir + GSK1349572 Placebo
Subjects will receive raltegravir 400mg twice daily plus GSK1349572 placebo once daily.
干预措施: GSK1349572 Placebo (Drug)
结局指标
主要结局
Percentage of Participants With HIV-1 Ribonucleic Acid (RNA) <50 Copies/Milliliter (c/mL) at Week 48
时间窗: At Week 48
The percentage of participants with Plasma Human Immunodeficiency Virus-1 (HIV-1) Ribonucleic Acid (RNA) \<50 c/mL at Week 48 was assessed using the Missing, Switch or Discontinuation = Failure (MSDF), as codified by the Food and Drug Administration (FDA) "snapshot" algorithm. This algorithm treated all participants without HIV-1 RNA at Week 48 as nonresponders, as well as participants who switched their concomitant ART prior to Week 48 as follows: background ART substitutions non-permitted per protocol (one background ART substitution was permitted for safety or tolerability); background ART substitutions permitted per protocol unless the decision to switch was documented as being before or at the first on-treatment visit where HIV-1 RNA was assessed. Otherwise, virologic success or failure was determined by the last available HIV-1 RNA assessment while the participant was on-treatment in the randomized phase of the study.
次要结局
- Number of Participants With Post-Baseline Emergent Grade 1 to 4 Clinical Chemistry and Hematology Toxicities(From Week 48 to Week 480)
- Number of Participants (Par.) With Detectable Virus That Has Genotypic or Phenotypic Evidence of Treatment-emergent Integrase Inhibitor (INI) Resistance at Time of Protocol Defined Virology Failure (PDVF)(Baseline (Day 1) until PDVF (Up to Week 48))
- Number of Participants With Plasma HIV-1 RNA <50 c/mL at Week 24(At Week 24)
- Number of Participants With Plasma HIV-1 RNA <400 c/mL at Week 24 and Week 48(At Week 24 and Week 48)
- Absolute Values of Cluster of Differentiation 4+ (CD4+) Cell Counts at Baseline (Day 1) and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 96 and 144(Baseline (Day 1) and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 96 and 144)
- Change From Baseline in CD4+ Cell Counts at Weeks 4, 8, 12,16, 24, 32, 40, 48, 96 and 144(Baseline (Day 1) and Weeks 4, 8, 12, 16, 24, 32, 40, 48, 96 and 144)
- Number of Participants With Post-Baseline HIV-associated Conditions, Excluding Recurrences, and Disease Progressions(Up to Week 480)
- DTG PK Parameters Including Maximum Plasma Drug Concentration (Cmax), Minimal Plasma Drug Concentration (Cmin), and Average Plasma Pre-dose Concentration (C0_avg)(Pre-dose and at 1 to 3 hours or 4 to 12 hours post-dose at Week 4; Pre-dose at Week 24; Pre-dose and 1 to 3 hours or 4 to 12 hours post-dose at Week 48)
- DTG PK Parameter Including Pre-dose Concentration (C0)(Pre-dose at Weeks 4, 24 and 48)
- DTG PK Parameters Including Area Under the Plasma Concentration-time Curve From Time Zero to Time Tau Over a Dosing Interval at Steady State (AUC[0-tau])(Pre-dose and at 1 to 3 hours or 4 to 12 hours post-dose at Week 4; Pre-dose at Week 24; Pre-dose and 1 to 3 hours or 4 to 12 hours post-dose at Week 48)
- Change From Baseline in European Quality of Life-5 Dimensions-3 Levels (EQ-5D-3L) Utility Score(Baseline (Day 1) and at Weeks 24 and 48)
- Change From Baseline in European Quality of Life-5 Dimensions-3 Levels (EQ-5D-3L) Thermometer Scores(Baseline (Day 1) and at Weeks 24 and 48)