Trial of Maraviroc (UK-427,857) in Combination With Zidovudine/Lamivudine Versus Efavirenz in Combination With Zidovudine/Lamivudine
Condition: HIV-1
Intervention: Maraviroc + Zidovudine/Lamivudine; Efavirenz + Zidovudine/Lamivudine; Maraviroc (UK-427,857) + Zidovudine/Lamivudine
Intervention description: maraviroc (UK-427,857) 300 mg once daily added to zidovudine/lamivudine (300 mg/150 mg twice daily); efavirenz (600 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)
Intervention MeSH terms: Lamivudine; Zidovudine; Efavirenz; Maraviroc
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 916.0
Sex: All
Minimum age: 16 Years
Healthy volunteers: No
Keywords: Aids; HIV

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  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

        Exclusion Criteria:

          -  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