A Multicenter, Randomized, Double-Blind, Comparative Trial Of A Novel CCR5 Antagonist, UK-427,857, In Combination With Zidovudine/Lamivudine Versus Efavirenz In Combination With Zidovudine/Lamivudine For The Treatment Of Antiretroviral-Naive HIV-1 Infected Subjects
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 916
- 试验地点
- 1
- 主要终点
- Percentage of Participants With Viral Load of Less Than 400 Copies/Milliliter [Copies/mL] and Less Than 50 Copies/mL of Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) at Week 48 for Full Analysis Set (FAS) Population
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 goal of this study is to compare the safety and efficacy of maraviroc (UK-427,857) versus efavirenz, when each are combined with two other antiretroviral agents, in patients who are previously naive to antiretroviral therapy. This study will involve approximately 200 centers from around the world to achieve a total randomized subject population of 1071 subjects. Patients will be randomly assigned to one of three groups: maraviroc (UK-427,857) 300 mg once daily added to zidovudine/lamivudine (300 mg/150 mg twice daily), Maraviroc (UK-427,857) 300 mg twice daily added to zidovudine/lamivudine (300 mg/150 mg twice daily) or efavirenz (600 mg once daily) added to zidovudine/lamivudine (300 mg/150 mg twice daily). The study will enroll over approximately an 18 month period (5 months Phase 2b run-in, 13 months Phase 3) with 96 weeks of treatment. This may be extended for an additional 3 years depending on the results at 96 weeks. Physical examinations will be performed at study entry, weeks 4, 8, 12, 16, 20, 24, 32, 40, 48, 60, 72, 84 and 96. Blood samples will also be taken at study entry, weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, 60, 72, 84 and 96. Additionally, blood samples will be drawn twice, at least 30 minutes apart, at weeks 2 and 48 for maraviroc (UK-427,857) pharmacokinetic analysis. As part of this clinical study a blood sample will be taken for non-anonymized pharmacogenetic analysis. Patients will undergo a 12-lead electrocardiogram at study entry, weeks 24, 48 and 96. A computerized tomography (CT) scan will also be performed, at selected centers, at study entry and week 96. Patients will be asked to complete a symptom distress questionnaire at study entry, weeks 12, 24, 48 and 96.
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 2, 000 copies/mL
- •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
- •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
- •Prior treatment with efavirenz, zidovudine or lamivudine or with any other antiretroviral therapy for more than 14 days at any time
- •Active alcohol or substance abuse sufficient, in the Investigator's judgment, to prevent adherence to study medication and/or follow up
- •Lactating women, or planned pregnancy during the trial period
- •Suspected primary (acute) HIV-1 infection
- •Previous therapy with a potentially myelosuppressive, neurotoxic, hepatotoxic 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
- •Genotypic or phenotypic resistance to efavirenz, zidovudine or lamivudine
- •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 + Zidovudine/Lamivudine (Drug)
3
干预措施: Efavirenz + Zidovudine/Lamivudine (Drug)
2
Following a review of the interim analysis data, the DSMB recommended to terminate the UK-427,857 300 mg QD arm based on pre-specified protocol non-inferiority criteria not being met for the QD arm versus efavirenz
干预措施: Maraviroc (UK-427,857) + Zidovudine/Lamivudine (Drug)
结局指标
主要结局
Percentage of Participants With Viral Load of Less Than 400 Copies/Milliliter [Copies/mL] and Less Than 50 Copies/mL of Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) at Week 48 for Full Analysis Set (FAS) Population
时间窗: Week 48
Percentage of Participants With Viral Load of Less Than 400 Copies/mL and Less Than 50 Copies/mL of HIV-1 RNA at Week 48 for Per Protocol (PP) Population
时间窗: Week 48
Percentage of participants with viral load of less than 400 copies/mL and less than 50 copies/mL of HIV-1 RNA were not analyzed for participants originally randomized to maraviroc once daily arm since after termination, focus was shifted from efficacy and safety to only safety as reflected in the abbreviated set of efficacy measures noted in the amended planned analysis.
次要结局
- Change From Baseline in Lymphocyte Cluster of Differentiation 4 (CD4) Count at Week 48 and 96(Baseline, Week 48, Week 96)
- Number of Participants With Phenotypic Resistance at Time of Treatment Failure Through Week 48 and 96(Screening, time of failure through Week 48, Week 96)
- Number of Participants With NRTI Associated Mutations at Time of Treatment Failure Through Week 48 and 96(Screening, time of failure through Week 48, Week 96)
- Percentage of Participants With HIV-1 RNA Levels Less Than 50 Copies/mL at Week 48 and Week 96 by Overall Susceptibility Score (OSS) at Screening(Baseline, Week 48, Week 96)
- Percentage of Participants With HIV-1 RNA Levels of Less Than 400 Copies/mL and Less Than 50 Copies/mL at Week 48 Analyzed Using Logistic Regression(Week 48)
- Percentage of Participants With HIV-1 RNA Levels of Less Than 400 Copies/mL and Less Than 50 Copies/mL at Week 96 Analyzed Using Logistic Regression(Week 96)
- Change From Baseline in Log 10-transformed Plasma Viral Load (HIV-1 RNA) Levels at Week 48 and 96(Baseline, Week 48, Week 96)
- Time-Averaged Difference (TAD) in log10-transformed HIV-1 RNA Levels(Baseline up to Week 48 and Week 96)
- Change From Baseline in Lymphocyte Cluster of Differentiation 8 (CD8) Count at Week 48 and 96(Baseline, Week 48, Week 96)
- Time to Virologic Failure(Week 48, Week 96)
- Number of Participants Per Tropism Status at Baseline and at the Time of Treatment Failure Through Week 48(Baseline, time of failure through Week 48)
- Number of Participants Per Tropism Status at Baseline and at the Time of Treatment Failure Through Week 96(Baseline, time of failure through Week 96)
- Number of Participants With Efavirenz Associated Mutations at Time of Treatment Failure Through Week 48 and 96(Screening, time of failure through Week 48, Week 96)