Multicenter Pilot Study To Define The Marker As An Alternate For Tropism Assay

Study Overview
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Brief Summary
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The purpose of this pilot study is to determine whether there is a correlation between viral load reduction (at Day 4, 7 or 14) following a short course (14 days) of Maraviroc added to a failing regimen, and the R5 result of the TrofileTM assay at screening.

Detailed Description
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The study A4001060 has been discontinued on April 22, 2008. A review of the poor rate of enrollment has projected difficulties in completing the study in a timely manner, despite the best efforts by the sponsor and the sites. Given the difficulties encountered in this pilot study and the need to conduct an even larger confirmatory study, the decision to discontinue the study has therefore been made. It should be noted that safety concerns have not been seen in this study and have not factored into this decision.

Official Title
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Surrogate Marker For Tropism-A Multi-Center, Open Label, Pilot Study

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: maraviroc
* Procedure: Trofile Assay and HIV RNA quantification assay


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥ 16 years of age (or minimum adult age as determined by local regulatory authorities or as dictated by local law) at the screening visit. Have an HIV RNA ≥ 1000 copies/mL, at screening. Subjects receiving another investigational antiretroviral compound through participation in a phase 3 or 4 clinical study are eligible to participate in this trial provided. That the 2 investigational agents are required to offer the subject a regimen with 2 or 3 active antiretroviral drugs (i.e. one or fewer approved treatment is available to the subject due to prior resistance or intolerance), Neither protocol prohibits the use of the other antiretroviral agent, AND the dosing of the two agents when used together is known AND a letter from the Pfizer clinical pharmacologists for maraviroc identifies the dose of maraviroc to be used with other investigational agents. Based on screening genotypic resistance testing results the subject must be able to receive at least 3 active drugs other than maraviroc in the new OBT. This is defined as: Having three drugs considered susceptible by genotype interpretation (if etravirine will be used, fewer than 3 etravirine resistance mutations will be taken as etravirine susceptibility); or, Having two drugs considered susceptible by genotype interpretation (if etravirine will be used, fewer than 3 etravirine resistance mutations will be taken as etravirine susceptibility) and be willing to include raltegravir in the OBT not having used raltegravir in the past. Exclusion Criteria: Potentially life threatening (Grade 4) laboratory abnormality or medical condition. Severe hepatic impairment (Child-Pugh classification B or C). End stage renal disease or other disease states requiring dialysis therapy.

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Screening
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Single<br> | Drug: maraviroc<br>* Treatment-experienced subjects on failed therapy, with HIV RNA ≥ 1000 copies/mL, are eligible who will receive a tropism assay at screening (Day -14 to 0). Subjects who are eligible will receive maraviroc added to a failing regimen from Day 1 to 14. On day 15, subjects will discontinue the current treatment regimen and begin a new OBT. Subjects with only R5 HIV will continue receiving maraviroc plus OBT. Subjects with non-R5 virus will discontinue receiving maraviroc but continue to receive the new OBT. Investigator selects OBT based on results of phenotype/genotype testing at baseline. The nominal dose for maraviroc is 300 mg BID. The maraviroc dose should be adjusted based on OBT patient is taking. If OBT includes CYP3A4 inhibitor (with or without inducers) maraviroc dose should be 150 mg BID and if OBT includes CYP3A4 inducer (without inhibitors) maraviroc dose should be 600mg BID. If OBT does not include any CYP3A4 inducers or inhibitors maraviroc dose should be 300 mg BID.<br>Procedure: Trofile Assay and HIV RNA quantification assay<br>* Trofile Assay and HIV RNA quantification assay<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Percentage of Participants With HIV-1 Ribonucleic Acid (RNA) With R5 & Non-R5 Tropism Results From the Trofile(tm) Assay | Spearman's correlation coefficient to assess percentage of participants achieving HIV-1 RNA with tropism | Baseline, Day 4, 7, 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subjects Achieving HIV-1 RNA <400 Copies/mL | Number of Subjects Achieving HIV-1 RNA <400 Copies/mL at each time point | Days 4, 7, 14, 28, and Weeks 8, 12, 18, and 24 | 
| Subjects Achieving HIV-1 RNA <50 Copies/mL | Number of Subjects Achieving HIV-1 RNA <50 Copies/mL at each time point | Days 4, 7, 14, 28, and Weeks 8, 12, 18, and 24 | 
| Subjects With Virologic Failure | For this protocol, virologic failure will be confirmed by a repeat viral load test within 2 weeks of first viral load meeting any of the following criteria: 1. Failing to achieve a reduction in HIV-1 RNA > 0.5 log10 copies/mL from baseline by the second viral load determination (unless the viral load is below level of quantification [LOQ]); 2. Experiencing a > 0.5 log10 increase from nadir in HIV-1 RNA after achieving an HIV-1 RNA reduction from baseline > 0.5 log10 copies/mL; or 3. Experiencing an HIV-1 RNA >1000 copies/mL after having achieved an HIV-1 RNA below LOQ. | Baseline up to Week 24 | 
| Time to Virologic Failure | For this protocol, virologic failure will be confirmed by a repeat viral load test within 2 weeks of first viral load meeting any of the following criteria: 1. Failing to achieve a reduction in HIV-1 RNA > 0.5 log10 copies/mL from baseline by the second viral load determination (unless the viral load is below level of quantification [LOQ]); 2. Experiencing a > 0.5 log10 increase from nadir in HIV-1 RNA after achieving an HIV-1 RNA reduction from baseline > 0.5 log10 copies/mL; or 3. Experiencing an HIV-1 RNA >1000 copies/mL after having achieved an HIV-1 RNA below LOQ. | Baseline up to Week 24 | 
| Change in Lymphocyte Subset CD4 From Baseline | Calculated average of CD4 at Day 7, 14, 28 and Week 24 minus CD4 at Day 1 | Day 1 (Baseline), Day 7, 14, 28 and Weeks 24 | 
| Change in Lymphocyte Subset CD8 From Day 1 | Calculated average of CD8 at Day 7, 14, 28 and Week 24 minus CD8 at Day 1 | Day 1(Baseline), Day 7, 14, 28 and Weeks 24 | 
| Change in Lymphocyte Subsets; CD4 and CD8 From Screening. | Calculated avergae of {CD4 or CD8 at Day 1 - CD4 or CD8 at Screening} | Screening (Day -14 to 0), Day 1. | 
| Change in Detectable Tropism From Screening | Number of subjects who switch their tropism status from screening to Baseline | Screening (Day -21 to 0), Baseline. | 
| Change in Detectable Tropism From Baseline | Number of subjects who switch their tropism status from Baseline to Days 7, 14, and Week 24/End of Study(EOS)/Discontinuation | Baseline, Day 15 and Week 24/End of Study/Discontinuation | 
| Change in Detectable Resistance (Genotype) and Susceptibility (Phenotype) to Drugs in the Regimen From Screening | Change in detectable resistance (genotype) and susceptibility (phenotype) to drugs in the regimen from Screening | Screening (Day -21), Baseline (Day 0), Day 14 (after addition of MVC to a failing regimen), Week 24, and time of Virologic Failure. | 
| Number of Subjects With Susceptibility to Maraviroc | Phenotypic susceptibility to maraviroc | Screening (Day -21 to 0), Day 14, Week 24 | 
| Change in Gene Sequence in Gp-160, and the V3 Loop From Screening Visit (Day -21 to 0) to Day 14, Time of Virologic Failure (See Section 6.5.1) and Week 24 | Change in gene sequence in gp-160, and the V3 loop from Screening visit (Day -21 to 0) to Day 14, time of virologic failure (See Section 6.5.1) and Week 24 | Screening (Day -21 to 0), Day 14, time of virologic failure, and Week 24 | 
| Correlation of Mutations in gp160 and the V3 Loop and Decreased Susceptibility to Maraviroc |  | Screening (Day -21 to 0), Day 14, time of virologic failure, Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Treatment Experienced