A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of a Novel CCR5 Antagonist, UK-427,857, in Combination With Optimized Background Therapy Versus Optimized Background Therapy Alone for the Treatment of Antiretroviral-Experienced HIV-1 Infected Subjects.
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 601
- 试验地点
- 1
- 主要终点
- Log 10-transformed Human Immunodeficiency Virus Ribonucleic Acid (HIV-1 RNA) Levels at Baseline
研究概览
简要总结
Maraviroc (UK-427,857), a selective and reversible CCR5 coreceptor antagonist, has been shown to be active in vitro against a wide range of clinical isolates (including those resistant to existing classes). In HIV-1 infected patients, maraviroc (UK-427,857) given as monotherapy for 10 days reduced HIV-1 viral load by up to 1.6 log, consistent with currently available agents. Safety and toleration have been studied in over 400 subjects for up to 28 days at 300 mg twice daily. No significant effects were seen on the QTc interval. The purpose of this study is to evaluate the antiretroviral activity of maraviroc (UK-427,857) in HIV infected, treatment experienced patients who are failing their current antiretroviral regimen and are infected with R5-tropic virus exclusively. This study will involve more than 100 centers from the US and Canada to achieve a total randomized subject population of 500 subjects. Patients will be randomly (2:2:1) assigned to one of three groups: Optimized Background Therapy [OBT (3-6 drugs based on treatment history and resistance testing)] + maraviroc (UK-427,857) 150 mg taken once daily, OBT + maraviroc (UK-427,857) 150 mg taken twice daily, or OBT alone. The study will enroll over approximately a 9 month period with 48 weeks of treatment. This may be extended for an additional year depending on the results at 48 weeks. Physical examinations will be performed at study entry, weeks 4, 8, 12, 16, 20, 24, 32, 40, and 48. Blood samples will also be taken at study entry, weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, and 48. Additionally, blood samples will be drawn twice, at least 30 minutes apart, at weeks 2 and 24 for maraviroc (UK-427,857) pharmacokinetic analysis. As part of this clinical study a blood sample will also be taken for non-anonymized pharmacogenetic analysis. Patients will undergo a 12-lead electrocardiogram at study entry, weeks 24 and 48.
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
- 16 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Men or women at least 16 years of age (or minimum age as determined by local regulatory authorities)
- •HIV-1 RNA viral load of greater than or equal to 5,000 copies/mL
- •Stable pre-study antiretroviral regimen, or on no antiretroviral agents, for at least 4 weeks
- •Documented genotypic or phenotypic resistance to three of the four antiretroviral drug classes, OR, Antiretroviral-class experience greater than or equal to 6 months (sequential or cumulative) with at least three of the following: One nucleoside or nucleotide reverse transcriptase inhibitor, one non-nucleoside reverse transcriptase inhibitor, two protease inhibitors (excluding low-dose ritonavir) and/or enfuvirtide
- •Be willing to remain on randomized treatment without any changes or additions to the OBT regimen, except for toxicity management or upon meeting criteria for treatment failure
- •A negative urine pregnancy test at the baseline visit for Women of Child Bearing Potential (WOCBP)
- •Effective barrier contraception for WOCBP and males
排除标准
- •Patients requiring treatment with more than 6 antiretroviral agents (excluding low-dose ritonavir)
- •Prior treatment with maraviroc (UK-427,857) or another experimental HIV entry inhibitor for more than 14 days
- •Suspected or documented active, untreated HIV-1 related opportunistic infection (OI) or other condition requiring acute therapy
- •Treatment for an active opportunistic infection, or unexplained temperature >38.5 degrees Celsius for 7 consecutive days
- •Active alcohol or substance abuse sufficient, in the Investigator's judgement, to prevent adherence to study medication and/or follow up
- •Lactating women, or planned pregnancy during the trial period
- •Significant renal insufficiency
- •Previous therapy with a potentially myelosuppressive, neurotoxic, hepatoxic and/or cytotoxic agent within 30 days prior to randomization or the expected need for such therapy during the study period
- •Documented or suspected acute hepatitis or pancreatitis within 30 days prior to randomization
- •Significantly elevated liver enzymes or cirrhosis
- •Significant neutropenia, anemia or thrombocytopenia
- •Malabsorption or an inability to tolerate oral medications
- •Symptomatic postural hypotension or severe cardiovascular or cerebrovascular disease
- •Certain medications
- •Malignancy requiring parenteral chemotherapy that must be continued for the duration of the trial
- •X4- or dual/mixed-tropic virus or repeated assay failure
- •Any other clinical condition that, in the Investigator's judgement, would potentially compromise study compliance or the ability to evaluate safety/efficacy
研究组 & 干预措施
1
干预措施: Maraviroc (UK-427,857) (Drug)
1
干预措施: Optimized Background Therapy (Drug)
2
干预措施: Optimized Background Therapy (Drug)
2
干预措施: Placebo (Drug)
3
干预措施: Optimized Background Therapy (Drug)
结局指标
主要结局
Log 10-transformed Human Immunodeficiency Virus Ribonucleic Acid (HIV-1 RNA) Levels at Baseline
时间窗: Baseline
Baseline value calculated as average of pre-dose measurements collected at screening, randomization, and immediately pre-dose.
Change From Baseline in Log 10-transformed HIV-1 RNA Levels at Week 24
时间窗: Baseline and Week 24
Change from baseline in log 10-transformed plasma viral load (HIV-1 RNA) levels (log10 copies/mL). Baseline value calculated as average of pre-dose measurements collected at screening, randomization, and immediately pre-dose.
Change From Baseline in Log 10-transformed HIV-1 RNA Levels at Week 48
时间窗: Baseline and Week 48
Change from baseline in log 10-transformed plasma viral load (HIV-1 RNA) levels (log10 copies/mL). Baseline value calculated as average of pre-dose measurements collected at screening, randomization and immediately pre-dose.
次要结局
- Percentage of Participants With HIV-1 RNA Levels Less Than 400 Copies/mL(Week 24 and 48)
- Percentage of Participants With HIV-1 RNA Levels Less Than 400 Copies/mL or With at Least 0.5 log10 Decrease From Baseline(Week 24 and 48)
- Percentage of Participants With HIV-1 RNA Levels Less Than 400 Copies/mL or With at Least 1.0 log10 Decrease From Baseline(Week 24 and 48)
- Percentage of Participants With HIV-1 RNA Levels Less Than 50 Copies/mL(Week 24 and 48)
- Cluster of Differentiation 4 (CD4) and Cluster of Differentiation 8 (CD8) Cell Count at Baseline(Baseline)
- Change From Baseline in CD4 Cell Count at Week 24 and 48(Baseline, Week 24 and 48)
- Change From Baseline in CD8 Cell Count at Week 24 and 48(Baseline, Week 24 and 48)
- Time to Virological Failure(Week 48)
- Time-Averaged Difference (TAD) From Baseline in log10 Transformed HIV-1 RNA Levels(Baseline to Week 24 and Week 48)
- Number of Participants With Genotypic Susceptibility Scores (GSS) and Phenotypic Susceptibility Score (PSS) at Screening(Screening)
- Number of Participants With Change in GSS and PSS From Screening at the Time of Treatment Failure Through Week 24(Screening and time of failure through week 24)
- Number of Participants With Change in GSS and PSS From Screening at the Time of Treatment Failure at Week 48(Screening and time of failure through week 48)
- Number of Participants Per Tropism Status at Baseline and at the Time of Treatment Failure Through Week 24(Baseline and time of failure through week 24)
- Number of Participants Per Tropism Status at Baseline and at the Time of Treatment Failure Through Week 48(Baseline and time of failure through week 48)
- Change From Baseline in Viral Load at Week 24 and Week 48 by Overall Susceptibility Score (OSS) at Screening(Baseline, Week 24 and Week 48)