Trial of Maraviroc (UK-427,857) in Combination With Optimized Background Therapy Versus Optimized Background Therapy Alone for the Treatment of Antiretroviral-Experienced NonCCR5-Tropic HIV-1 Infected Subjects

Study Overview
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Brief Summary
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Maraviroc (UK-427,857), a selective and reversible CCR5 co-receptor 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 in the United States, maraviroc (UK-427,857) is approved for use as part of combination antiretroviral treatment in treatment-experienced and treatment-naive adult subjects. At least 50% of treatment-experienced patients are infected with R5-tropic HIV-1 exclusively. However, even in patients infected with a dual tropic (R5 + X4) phenotype, a large proportion of the virus population still uses CCR5 exclusively. Thus, the purpose of this study is to evaluate the antiretroviral activity, and safety, of maraviroc (UK-427,857) (in combination with other agents) in HIV infected, treatment experienced patients who are failing their current antiretroviral regimen and not infected with R5-tropic virus exclusively. This study will involve more than 200 centers globally to achieve a total randomized subject population of 192 subjects. Patients will be randomly (1:1:1) 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. Randomization was stratified by Enfuvirtide use in OBT (yes/no) and Screening HIV-1 RNA level (viral load) (<100,000/≥ 100, 000 copies per milliliter [copies per mL]). The study will enroll over approximately a 9 month period with 48 weeks of treatment. 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.

Detailed Description
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(i) Subjects remained on their assigned therapy for 48 weeks, unless the subject was discontinued early for protocol-defined treatment failure or other reasons such as adverse event, loss to follow-up, withdrawal of consent, or death. (ii) If a subject met the criteria for treatment failure or discontinued for another reason (eg, pregnancy, adverse event) and required an alternative regimen, the subject was followed until the Week 48 visit according to protocol guidelines. The new regimen, selected by the Investigator based on the results of resistance testing at the time of failure, had to be recorded in the CRF. (iii) Open-label maraviroc (UK-427,857) was provided by the sponsor, until it was commercially available, to subjects who completed 48 weeks of therapy and for whom it was medically appropriate to continue therapy with maraviroc (UK-427,857).

Official Title
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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, Non CCR5-Tropic HIV-1 Infected Subjects

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Optimized Background Therapy (OBT)
* Drug: maraviroc (UK-427,857)
* Drug: Optimized Background Therapy (OBT)
* Drug: maraviroc (UK-427,857)
* Drug: Optimized Background Therapy (OBT)


Participation Criteria
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Eligibility Criteria
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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 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 two of the four antiretroviral drug classes, OR, Antiretroviral-class experience greater than or equal to 3 months (sequential or cumulative) with at least three of the following: One nucleoside or nucleotide reverse transcriptase inhibitor (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 Exclusion Criteria: 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 judgment, 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, 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 Malignancy requiring parenteral chemotherapy that must be continued for the duration of the trial R5 virus phenotype only No option to use at least one non-nucleoside reverse transcriptase inhibitor or protease inhibitor, or enfuvirtide, based on resistance testing Any other clinical condition that, in the Investigator's judgment, would potentially compromise study compliance or the ability to evaluate safety/efficacy

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: Optimized Background Therapy (OBT)<br>* OBT (3-6 drugs based on treatment history and resistance testing)<br>Drug: maraviroc (UK-427,857)<br>* maraviroc (UK-427,857) 150 mg taken once daily<br>* Other names: Selzentry, Celsentri;|
| Experimental: 2<br> | Drug: Optimized Background Therapy (OBT)<br>* OBT (3-6 drugs based on treatment history and resistance testing)<br>Drug: maraviroc (UK-427,857)<br>* maraviroc (UK-427,857) 150 mg taken twice daily<br>* Other names: Selzentry, Celsentri;|
| Experimental: 3<br> | Drug: Optimized Background Therapy (OBT)<br>* OBT (3-6 drugs based on treatment history and resistance testing)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Human Immunodeficiency Virus (HIV-1) Viral Load (Ribonucleic Acid [RNA]) | Change from baseline in log 10-transformed plasma viral load (HIV-1 RNA) levels (log 10 copies per milliliter [log10 copies/mL]). Baseline value calculated as average of pre-dose measurements collected at screening, randomization, and baseline visits. | Baseline to Week 24 and Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With HIV-1 RNA Levels < 400 Copies/mL |  | Week 24, Week 48 | 
| Number of Subjects With HIV-1 RNA Levels < 400 Copies/mL or at Least 0.5 Log 10-transformed Decrease From Baseline in HIV-1 RNA Levels | Number of subjects with HIV-1 RNA levels < 400 copies/mL or at least 0.5 log 10-transformed decrease from baseline in HIV-1 RNA levels. Baseline value calculated as average of pre-dose measurements collected at screening, randomization, and baseline visits. | Baseline, Week 24, Week 48 | 
| Number of Subjects With HIV-1 RNA Levels < 400 Copies/mL or at Least 1.0 Log 10-transformed Decrease From Baseline in HIV-1 RNA Levels | Number of subjects with HIV-1 RNA levels < 400 copies/mL or at least 1.0 log 10-transformed decrease from baseline in HIV-1 RNA levels. Baseline value calculated as average of pre-dose measurements collected at screening, randomization, and baseline visits. | Baseline, Week 24, Week 48 | 
| Number of Subjects With HIV-1 RNA Levels < 50 Copies/mL |  | Baseline, Week 24, Week 48 | 
| Change From Baseline in CD4 Cell Count | Change from baseline in CD4 cell count (measured as cells per microliter [cells/µL]). Baseline value calculated as the average of pre-dose measurements collected at screening, randomization, and baseline visits. | Baseline to Week 24 and Week 48 | 
| Change From Baseline in CD8 Cell Count | Change from baseline in CD8 cell count (measured as cells/µL). Baseline value calculated as the average of pre-dose measurements collected at screening, randomization, and baseline visits. | Baseline to Week 24 and Week 48 | 
| Time (50% Quartile Point Estimate) to Virologic Failure | Time to virologic failure based on observed HIV-1 RNA levels and failure events (death; permanent discontinuation of test drug [perm DC]; lost to follow-up [LTFU]; new anti-retroviral drug added (except background drug change to drug of same class); or on open label for early non-response or rebound). Failure: at Time 0 if level not <400 copies/mL (2 consecutive visits) before event(s) or last available visit; at time of earliest event if level <400 copies/mL (on 2 consecutive visits); failure if level ≥400 copies/mL (2 consecutive visits) or 1 visit ≥400 copies/mL followed by perm DC or LTFU. | Day 1 through Week 24 and through Week 48 | 
| Change From Baseline in Time Averaged Difference (TAD) in log10 HIV-1 RNA | Change from baseline of TAD in log10 HIV-1 RNA viral load calculated as [AUC of HIV-1 RNA viral load (log10 copies/mL) / time period] - Baseline HIV-1 RNA viral load (log10 copies/mL). Baseline value calculated as the average of pre-dose measurements collected at screening, randomization, and baseline visits. | Baseline to Week 24 and Week 48 | 
| Number of Subjects Per Genotype and Phenotype at Baseline and at Time of Failure | Number of subjects per genotype and phenotype (tests for presence of non CCR5-tropic HIV-1 and for resistance to reverse transcriptase, protease, and fusion inhibitors) at baseline and at time of failure through Week 48 visit. Sensitivity to drug categorized as 0-1, 2-4, >4; scores defined as 0=resistance, 1=sensitive or susceptible with higher number indicating greater sensitivity or susceptibility. | Baseline through Week 48 | 
| Number of Subjects Per Tropism Status at Screening and at the Time of Treatment Failure (Analysis at Week 24) | Number of subjects per Tropism status (CCR5 [R5], CXCR4 [X4], Dual Mixed [DM], or Non-reportable/Non-phenotypable [NR/NP]) at Screening (Scr) and at time of treatment failure (Tx fail). Treatment failure defined as insufficient clinical response. HIV-1 RNA viral load <500 copies/ml categorized as below lower limit of quantification (BLQ). Tropism may have been assessed at either the Screening or Baseline visit. The assessment for time of treatment failure is defined as the last on-treatment assessment. | Screening through Week 24 | 
| Number of Subjects Per Tropism Status at Screening and Time of Treatment Failure (Analysis at Week 48) | Number of subjects per Tropism status (CCR5 [R5], CXCR4 [X4], Dual Mixed [DM], or Non-reportable/Non-phenotypable [NR/NP]) at Screening (Scr) and at time of treatment failure (Tx fail). Treatment failure defined as insufficient clinical response. HIV-1 RNA viral load <500 copies/ml categorized as below lower limit of quantification (BLQ). Tropism may have been assessed at either the Screening or Baseline visit. The assessment for time of treatment failure is defined as the last on-treatment assessment. | Screening through Week 48 | 
| Number of Subjects With Treatment Failure at Week 24 by Overall Susceptibility Score (OSS) at Screening | Number of subjects for association between screening resistance and virologic response as determined by treatment failure and OSS at screening. OSS categorized as 0-1, 2-4, >4 (maximum value of 6) and calculated as the sum of the net assessment of in vitro phenotypic and genotypic susceptibility using a binary scoring system (0= reduced susceptibility, 1=susceptible) for each antiretroviral agent in OBT. Higher scores indicate greater susceptibility. | Screening, Week 24 | 
| Number of Subjects With Treatment Failure at Week 48 by Overall Susceptibility Score (OSS) at Screening | Number of subjects for association between screening resistance and virologic response as determined by treatment failure and OSS at screening. OSS categorized as 0, 1, 2, or ≥3 (maximum value of 6) and calculated as the sum of the net assessment of in vitro phenotypic and genotypic susceptibility using a binary scoring system (0= reduced susceptibility, 1=susceptible) for each antiretroviral agent in OBT. Higher scores indicate greater susceptibility. | Screening, Week48 | 
| Number of Subjects With Acquired Immunodeficiency Syndrome (AIDS)-Defining Opportunistic Illnesses (Analysis at Week 24) | Number of subjects with AIDS-defining opportunistic illnesses based on investigator classification guided by a predefined list of clinical Category C Adverse Events per Center for Disease Control (CDC) HIV Classification System. Includes events occurring up to 7 days after last dose of study drug. | Baseline through Week 24 | 
| Number of Subjects With Acquired Immunodeficiency Syndrome (AIDS)-Defining Opportunistic Illnesses (Analysis at Week 48) | Number of subjects with AIDS-defining opportunistic illnesses based on investigator classification guided by a predefined list of clinical Category C Adverse Events per CDC HIV Classification System. Includes events occurring up to 7 days after last dose of study drug. | Baseline through Week 48 |