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

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

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.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Optimized Background Therapy (OBT); Drug: maraviroc (UK-427,857); Drug: maraviroc (UK-427,857)

Detailed Description

(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).

• Study Type: Interventional
• Enrollment (Actual): 190
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Darlinghurst, New South Wales, Australia, 2010
      • Pfizer Investigational Site
    • Surry Hills, New South Wales, Australia, 2010
      • Pfizer Investigational Site
  • Queensland
    • Herston, Queensland, Australia, 4029
      • Pfizer Investigational Site
  • Victoria
    • Carlton, Victoria, Australia, 3053
      • Pfizer Investigational Site
    • Melbourne, Victoria, Australia, 3004
      • Pfizer Investigational Site
• Belgium
  • Brussels, Belgium, 1070
    • Pfizer Investigational Site
  • Brussels, Belgium, 1000
    • Pfizer Investigational Site
  • Brussels, Belgium, 1200
    • Pfizer Investigational Site
  • Liege, Belgium, 4000
    • Pfizer Investigational Site
• Canada
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3A 1R9
      • Pfizer Investigational Site
  • Ontario
    • Toronto, Ontario, Canada, M5B 1W8
      • Pfizer Investigational Site
    • Toronto, Ontario, Canada, M5G 2N2
      • Pfizer Investigational Site
  • Quebec
    • Montreal, Quebec, Canada, H3G 1A4
      • Pfizer Investigational Site
    • Montreal, Quebec, Canada, H2L 4P9
      • Pfizer Investigational Site
    • Montreal, Quebec, Canada, H2L 5B1
      • Pfizer Investigational Site
    • Montreal, Quebec, Canada, H2X 2P4
      • Pfizer Investigational Site
• Germany
  • Berlin, Germany, 12157
    • Pfizer Investigational Site
  • Hamburg, Germany, 20246
    • Pfizer Investigational Site
  • Hamburg, Germany, 20099
    • Pfizer Investigational Site
  • Hamburg, Germany, 20146
    • Pfizer Investigational Site
  • Koeln, Germany, 50924
    • Pfizer Investigational Site
• Netherlands
  • Utrecht, Netherlands, 3584 CX
    • Pfizer Investigational Site
• Spain
  • Barcelona, Spain, 08025
    • Pfizer Investigational Site
  • Cordoba, Spain, 14004
    • Pfizer Investigational Site
  • Madrid, Spain, 28006
    • Pfizer Investigational Site
  • Madrid, Spain, 28046
    • Pfizer Investigational Site
  • Alicante
    • Elche, Alicante, Spain, 03202
      • Pfizer Investigational Site
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • Pfizer Investigational Site
• Switzerland
  • Zürich, Switzerland, 8091
    • Pfizer Investigational Site
• United Kingdom
  • Brighton, United Kingdom, BN2 1ES
    • Pfizer Investigational Site
  • Edinburgh, United Kingdom, EH4 2XU
    • Pfizer Investigational Site
  • London, United Kingdom, SE5 9RS
    • Pfizer Investigational Site
  • London, United Kingdom, SW10 9TH
    • Pfizer Investigational Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Pfizer Investigational Site
  • Arizona
    • Phoenix, Arizona, United States, 85006
      • Pfizer Investigational Site
  • California
    • Beverly Hills, California, United States, 90211
      • Pfizer Investigational Site
    • Fountain Valley, California, United States, 92708
      • Pfizer Investigational Site
    • Hayward, California, United States, 94545
      • Pfizer Investigational Site
    • Los Angeles, California, United States, 90069
      • Pfizer Investigational Site
    • Los Angeles, California, United States, 90027
      • Pfizer Investigational Site
    • Los Angeles, California, United States, 90028
      • Pfizer Investigational Site
    • Newport Beach, California, United States, 92663
      • Pfizer Investigational Site
    • Oakland, California, United States, 94602
      • Pfizer Investigational Site
    • San Francisco, California, United States, 94118
      • Pfizer Investigational Site
    • San Francisco, California, United States, 94102
      • Pfizer Investigational Site
    • San Francisco, California, United States, 94115-1931
      • Pfizer Investigational Site
    • Union City, California, United States, 94587
      • Pfizer Investigational Site
  • District of Columbia
    • Washington, District of Columbia, United States, 20036
      • Pfizer Investigational Site
    • Washington, District of Columbia, United States, 20009
      • Pfizer Investigational Site
  • Florida
    • Miami, Florida, United States, 33133
      • Pfizer Investigational Site
    • North Miami Beach, Florida, United States, 33169
      • Pfizer Investigational Site
    • Orlando, Florida, United States, 32806
      • Pfizer Investigational Site
    • Orlando, Florida, United States, 32803
      • Pfizer Investigational Site
    • Sarasota, Florida, United States, 34243
      • Pfizer Investigational Site
    • Tampa, Florida, United States, 33614
      • Pfizer Investigational Site
    • Vero Beach, Florida, United States, 32960
      • Pfizer Investigational Site
  • Georgia
    • Atlanta, Georgia, United States, 30308
      • Pfizer Investigational Site
  • Massachusetts
    • Springfield, Massachusetts, United States, 01107
      • Pfizer Investigational Site
  • New Mexico
    • Santa Fe, New Mexico, United States, 87505
      • Pfizer Investigational Site
  • New York
    • Albany, New York, United States, 12208
      • Pfizer Investigational Site
    • Bronx, New York, United States, 10461
      • Pfizer Investigational Site
    • Bronx, New York, United States, 10467
      • Pfizer Investigational Site
    • Brooklyn, New York, United States, 11203
      • Pfizer Investigational Site
    • Manhasset, New York, United States, 11030
      • Pfizer Investigational Site
    • New York, New York, United States, 10018
      • Pfizer Investigational Site
    • Stony Brook, New York, United States, 11794
      • Pfizer Investigational Site
    • Stony Brook, New York, United States, 11794-7310
      • Pfizer Investigational Site
  • North Carolina
    • Huntersville, North Carolina, United States, 28078
      • Pfizer Investigational Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19106
      • Pfizer Investigational Site
    • Philadelphia, Pennsylvania, United States, 19130
      • Pfizer Investigational Site
  • South Carolina
    • Columbia, South Carolina, United States, 29206
      • Pfizer Investigational Site
  • Texas
    • Dallas, Texas, United States, 75204
      • Pfizer Investigational Site
    • Dallas, Texas, United States, 75246
      • Pfizer Investigational Site
  • Virginia
    • Annandale, Virginia, United States, 22003
      • Pfizer Investigational Site
  • Washington
    • Puyallup, Washington, United States, 98372
      • Pfizer Investigational Site
    • Tacoma, Washington, United States, 98405
      • Pfizer Investigational Site
    • Vancouver, Washington, United States, 98664
      • Pfizer Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: ViiV Healthcare
• Collaborators: Pfizer

Publications and helpful links

General Publications

• Saag M, Goodrich J, Fatkenheuer G, Clotet B, Clumeck N, Sullivan J, Westby M, van der Ryst E, Mayer H; A4001029 Study Group. A double-blind, placebo-controlled trial of maraviroc in treatment-experienced patients infected with non-R5 HIV-1. J Infect Dis. 2009 Jun 1;199(11):1638-47. doi: 10.1086/598965.

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start: November 1, 2004
• Primary Completion (Actual): December 1, 2005
• Study Completion (Actual): April 1, 2009

Study Registration Dates

• First Submitted: December 7, 2004
• First Submitted That Met QC Criteria: December 7, 2004
• First Posted (Estimate): December 8, 2004

Study Record Updates

• Last Update Posted (Estimate): December 7, 2010
• Last Update Submitted That Met QC Criteria: November 19, 2010
• Last Verified: November 1, 2010

More Information

Terms related to this study

• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; HIV Fusion Inhibitors; Viral Fusion Protein Inhibitors; CCR5 Receptor Antagonists; Maraviroc
• Other Study ID Numbers: A4001029