Clinical trial NCT00098293: Trial of Maraviroc (UK-427,857) in Combination With Zidovudine/Lamivudine Versus Efavirenz in Combination With Zidovudine/Lamivudine
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV-1
Keywords: Aids
HIV
Lead sponsor: ViiV Healthcare
Sponsor class: INDUSTRY
Collaborators: name: Pfizer
First posted: 2004-12-07
Enrollment: 916
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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

Primary outcomes:
measure: 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
timeFrame: Week 48
measure: 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
timeFrame: Week 48
Secondary outcomes:
measure: 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
timeFrame: Week 48
measure: 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
timeFrame: Week 96
measure: Change From Baseline in Log 10-transformed Plasma Viral Load (HIV-1 RNA) Levels at Week 48 and 96
timeFrame: Baseline, Week 48, Week 96
measure: Time-Averaged Difference (TAD) in log10-transformed HIV-1 RNA Levels
timeFrame: Baseline up to Week 48 and Week 96
measure: Change From Baseline in Lymphocyte Cluster of Differentiation 4 (CD4) Count at Week 48 and 96
timeFrame: Baseline, Week 48, Week 96
measure: Change From Baseline in Lymphocyte Cluster of Differentiation 8 (CD8) Count at Week 48 and 96
timeFrame: Baseline, Week 48, Week 96
measure: Time to Virologic Failure
timeFrame: Week 48, Week 96
measure: Number of Participants Per Tropism Status at Baseline and at the Time of Treatment Failure Through Week 48
timeFrame: Baseline, time of failure through Week 48
measure: Number of Participants Per Tropism Status at Baseline and at the Time of Treatment Failure Through Week 96
timeFrame: Baseline, time of failure through Week 96
measure: Number of Participants With Phenotypic Resistance at Time of Treatment Failure Through Week 48 and 96
timeFrame: Screening, time of failure through Week 48, Week 96
measure: Number of Participants With NRTI Associated Mutations at Time of Treatment Failure Through Week 48 and 96
timeFrame: Screening, time of failure through Week 48, Week 96
measure: Number of Participants With Efavirenz Associated Mutations at Time of Treatment Failure Through Week 48 and 96
timeFrame: Screening, time of failure through Week 48, Week 96
measure: 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
timeFrame: Baseline, Week 48, Week 96
Other outcomes:
measure: Percentage of Participants With Viral Load of Less Than 400 Copies/mL and Less Than 50 Copies/mL of HIV-1 RNA at Week 96
timeFrame: Week 96
Locations:
city: Birmingham
country: United States
facility: Pfizer Investigational Site
state: Alabama
city: Birmingham
country: United States
facility: Pfizer Investigational Site
state: Alabama
city: Beverly Hills
country: United States
facility: Pfizer Investigational Site
state: California
city: Los Angeles
country: United States
facility: Pfizer Investigational Site
state: California
city: Los Angeles
country: United States
facility: Pfizer Investigational Site
state: California
city: Los Angeles
country: United States
facility: Pfizer Investigational Site
state: California
city: Newport Beach
country: United States
facility: Pfizer Investigational Site
state: California
city: Oakland
country: United States
facility: Pfizer Investigational Site
state: California
city: Sacramento
country: United States
facility: Pfizer Investigational Site
state: California
city: San Francisco
country: United States
facility: Pfizer Investigational Site
state: California
city: San Francisco
country: United States
facility: Pfizer Investigational Site
state: California
city: Aurora
country: United States
facility: Pfizer Investigational Site
state: Colorado
city: Jacksonville
country: United States
facility: Pfizer Investigational Site
state: Florida
city: Miami Beach
country: United States
facility: Pfizer Investigational Site
state: Florida
city: Miami
country: United States
facility: Pfizer Investigational Site
state: Florida
city: Miami
country: United States
facility: Pfizer Investigational Site
state: Florida
city: Orlando
country: United States
facility: Pfizer Investigational Site
state: Florida
city: Sarasota
country: United States
facility: Pfizer Investigational Site
state: Florida
city: Tampa
country: United States
facility: Pfizer Investigational Site
state: Florida
city: Atlanta
country: United States
facility: Pfizer Investigational Site
state: Georgia
city: Chicago
country: United States
facility: Pfizer Investigational Site
state: Illinois
city: Indianapolis
country: United States
facility: Pfizer Investigational Site
state: Indiana
city: Baltimore
country: United States
facility: Pfizer Investigational Site
state: Maryland
city: Boston
country: United States
facility: Pfizer Investigational Site
state: Massachusetts
city: Boston
country: United States
facility: Pfizer Investigational Site
state: Massachusetts
city: Boston
country: United States
facility: Pfizer Investigational Site
state: Massachusetts
city: Springfield
country: United States
facility: Pfizer Investigational Site
state: Massachusetts
city: Omaha
country: United States
facility: Pfizer Investigational Site
state: Nebraska
city: Albany
country: United States
facility: Pfizer Investigational Site
state: New York
city: Brooklyn
country: United States
facility: Pfizer Investigational Site
state: New York
city: Flushing
country: United States
facility: Pfizer Investigational Site
state: New York
city: Manhasset
country: United States
facility: Pfizer Investigational Site
state: New York
city: New York
country: United States
facility: Pfizer Investigational Site
state: New York
city: Huntersville
country: United States
facility: Pfizer Investigational Site
state: North Carolina
city: Cincinnati
country: United States
facility: Pfizer Investigational Site
state: Ohio
city: Oklahoma City
country: United States
facility: Pfizer Investigational Site
state: Oklahoma
city: Oklahoma City
country: United States
facility: Pfizer Investigational Site
state: Oklahoma
city: Philadelphia
country: United States
facility: Pfizer Investigational Site
state: Pennsylvania
city: Columbia
country: United States
facility: Pfizer Investigational Site
state: South Carolina
city: Dallas
country: United States
facility: Pfizer Investigational Site
state: Texas
city: Dallas
country: United States
facility: Pfizer Investigational Site
state: Texas
city: Houston
country: United States
facility: Pfizer Investigational Site
state: Texas
city: Houston
country: United States
facility: Pfizer Investigational Site
state: Texas
city: Annandale
country: United States
facility: Pfizer Investigational Site
state: Virginia
city: Puyallup
country: United States
facility: Pfizer Investigational Site
state: Washington
city: Tacoma
country: United States
facility: Pfizer Investigational Site
state: Washington
city: El Palomar
country: Argentina
facility: Pfizer Investigational Site
state: Provincia de Buenos Aires
city: Neuquen
country: Argentina
facility: Pfizer Investigational Site
state: Provincia de Neuquen
city: Buenos Aires
country: Argentina
facility: Pfizer Investigational Site
city: Ciudad de Buenos Aires
country: Argentina
facility: Pfizer Investigational Site
city: Ciudad de Buenos Aires
country: Argentina
facility: Pfizer Investigational Site
city: Ciudad de Buenos
country: Argentina
facility: Pfizer Investigational Site
city: Provincia de Buenos Aires
country: Argentina
facility: Pfizer Investigational Site
city: Provincia de Santa Fe
country: Argentina
facility: Pfizer Investigational Site
city: Burwood
country: Australia
facility: Pfizer Investigational Site
state: New South Wales
city: Darlinghurst
country: Australia
facility: Pfizer Investigational Site
state: New South Wales
city: Surrey Hills
country: Australia
facility: Pfizer Investigational Site
state: New South Wales
city: Wentworthville
country: Australia
facility: Pfizer Investigational Site
state: New South Wales
city: Herston
country: Australia
facility: Pfizer Investigational Site
state: Queensland
city: Miami
country: Australia
facility: Pfizer Investigational Site
state: Queensland
city: Melbourne
country: Australia
facility: Pfizer Investigational Site
state: Victoria
city: North Fitzroy
country: Australia
facility: Pfizer Investigational Site
state: Victoria
city: South Yarra
country: Australia
facility: Pfizer Investigational Site
state: Victoria
city: Brussels
country: Belgium
facility: Pfizer Investigational Site
city: Brussels
country: Belgium
facility: Pfizer Investigational Site
city: Gent
country: Belgium
facility: Pfizer Investigational Site
city: Leuven
country: Belgium
facility: Pfizer Investigational Site
city: Rio de Janeiro
country: Brazil
facility: Pfizer Investigational Site
state: RJ
city: Calgary
country: Canada
facility: Pfizer Investigational Site
state: Alberta
city: Edmonton
country: Canada
facility: Pfizer Investigational Site
state: Alberta
city: Edmonton
country: Canada
facility: Pfizer Investigational Site
state: Alberta
city: Vancouver
country: Canada
facility: Pfizer Investigational Site
state: British Columbia
city: Vancouver
country: Canada
facility: Pfizer Investigational Site
state: British Columbia
city: Vancouver
country: Canada
facility: Pfizer Investigational Site
state: British Columbia
city: Vancouver
country: Canada
facility: Pfizer Investigational Site
state: British Columbia
city: Winnipeg
country: Canada
facility: Pfizer Investigational Site
state: Manitoba
city: Halifax
country: Canada
facility: Pfizer Investigational Site
state: Nova Scotia
city: Hamilton
country: Canada
facility: Pfizer Investigational Site
state: Ontario
city: Ottawa
country: Canada
facility: Pfizer Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: Pfizer Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: Pfizer Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: Pfizer Investigational Site
state: Ontario
city: Montreal
country: Canada
facility: Pfizer Investigational Site
state: Quebec
city: Montreal
country: Canada
facility: Pfizer Investigational Site
state: Quebec
city: Montreal
country: Canada
facility: Pfizer Investigational Site
state: Quebec
city: Montreal
country: Canada
facility: Pfizer Investigational Site
state: Quebec
city: Montreal
country: Canada
facility: Pfizer Investigational Site
state: Quebec
city: Montreal
country: Canada
facility: Pfizer Investigational Site
state: Quebec
city: Sainte-Foy
country: Canada
facility: Pfizer Investigational Site
state: Quebec
city: Antella (FI)
country: Italy
facility: Pfizer Investigational Site
city: Brescia
country: Italy
facility: Pfizer Investigational Site
city: Milano
country: Italy
facility: Pfizer Investigational Site
city: Modena
country: Italy
facility: Pfizer Investigational Site
city: Roma
country: Italy
facility: Pfizer Investigational Site
city: Roma
country: Italy
facility: Pfizer Investigational Site
city: Torino
country: Italy
facility: Pfizer Investigational Site
city: Del. Tlalpan C.P.
country: Mexico
facility: Pfizer Investigational Site
state: Mexico City
city: Del. Tlalpan, C.P.
country: Mexico
facility: Pfizer Investigational Site
state: Mexico D.F.
city: Del. Tlalpan, C.P.
country: Mexico
facility: Pfizer Investigational Site
state: Mexico D.F.
city: Delegacion Tlalpan C. P
country: Mexico
facility: Pfizer Investigational Site
state: Mexico D.F.
city: Amsterdam
country: Netherlands
facility: Pfizer Investigational Site
city: Rotterdam
country: Netherlands
facility: Pfizer Investigational Site
city: Utrecht
country: Netherlands
facility: Pfizer Investigational Site
city: Bialystok
country: Poland
facility: Pfizer Investigational Site
city: Bydgoszcz
country: Poland
facility: Pfizer Investigational Site
city: Chorzow
country: Poland
facility: Pfizer Investigational Site
city: Gdansk
country: Poland
facility: Pfizer Investigational Site
city: Krakow
country: Poland
facility: Pfizer Investigational Site
city: Szczecin
country: Poland
facility: Pfizer Investigational Site
city: Warszawa
country: Poland
facility: Pfizer Investigational Site
city: Ponce
country: Puerto Rico
facility: Pfizer Investigational Site
city: Rio Piedras
country: Puerto Rico
facility: Pfizer Investigational Site
city: San Juan
country: Puerto Rico
facility: Pfizer Investigational Site
city: San Juan
country: Puerto Rico
facility: Pfizer Investigational Site
city: Port Elizabeth
country: South Africa
facility: Pfizer Investigational Site
state: Eastern Cape
city: Bloemfontein
country: South Africa
facility: Pfizer Investigational Site
state: Free State
city: Johannesburg
country: South Africa
facility: Pfizer Investigational Site
state: Gauteng
city: Pretoria
country: South Africa
facility: Pfizer Investigational Site
state: Gauteng
city: Dundee
country: South Africa
facility: Pfizer Investigational Site
state: KwaZulu Natal
city: Bloomfontein
country: South Africa
facility: Pfizer Investigational Site
city: Cape Town
country: South Africa
facility: Pfizer Investigational Site
city: Cape Town
country: South Africa
facility: Pfizer Investigational Site
city: Cape Town
country: South Africa
facility: Pfizer Investigational Site
city: Cape Town
country: South Africa
facility: Pfizer Investigational Site
city: Johannesburg
country: South Africa
facility: Pfizer Investigational Site
city: Pretoria North
country: South Africa
facility: Pfizer Investigational Site
city: Pretoria
country: South Africa
facility: Pfizer Investigational Site
city: Soweto, Johannesburg
country: South Africa
facility: Pfizer Investigational Site
city: Basel
country: Switzerland
facility: Pfizer Investigational Site
city: Bern
country: Switzerland
facility: Pfizer Investigational Site
city: Genève
country: Switzerland
facility: Pfizer Investigational Site
city: Lugano
country: Switzerland
facility: Pfizer Investigational Site
city: St. Gallen
country: Switzerland
facility: Pfizer Investigational Site
city: Zürich
country: Switzerland
facility: Pfizer Investigational Site
city: Zürich
country: Switzerland
facility: Pfizer Investigational Site
city: Edinburgh
country: United Kingdom
facility: Pfizer Investigational Site
state: Loth
city: Birmingham
country: United Kingdom
facility: Pfizer Investigational Site
city: Brighton
country: United Kingdom
facility: Pfizer Investigational Site
city: Edinburgh
country: United Kingdom
facility: Pfizer Investigational Site
city: London
country: United Kingdom
facility: Pfizer Investigational Site
city: London
country: United Kingdom
facility: Pfizer Investigational Site
city: London
country: United Kingdom
facility: Pfizer Investigational Site
city: London
country: United Kingdom
facility: Pfizer Investigational Site
city: Manchester
country: United Kingdom
facility: Pfizer Investigational Site
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: Vourvahis M, McFadyen L, Nepal S, Valluri SR, Fang A, Fate GD, Wood LS, Marshall JC, Chan PLS, Nedderman A, Haynes J, Savage ME, Clark A, Smith KY, Heera J. No Clinical Impact of CYP3A5 Gene Polymorphisms on the Pharmacokinetics and/or Efficacy of Maraviroc in Healthy Volunteers and HIV-1-Infected Subjects. J Clin Pharmacol. 2019 Jan;59(1):139-152. doi: 10.1002/jcph.1306. Epub 2018 Sep 7.
citation: MacInnes A, Lazzarin A, Di Perri G, Sierra-Madero JG, Aberg J, Heera J, Rajicic N, Goodrich J, Mayer H, Valdez H. Maraviroc can improve lipid profiles in dyslipidemic patients with HIV: results from the MERIT trial. HIV Clin Trials. 2011 Jan-Feb;12(1):24-36. doi: 10.1310/hct1201-24.
citation: Funderburg N, Kalinowska M, Eason J, Goodrich J, Heera J, Mayer H, Rajicic N, Valdez H, Lederman MM. Effects of maraviroc and efavirenz on markers of immune activation and inflammation and associations with CD4+ cell rises in HIV-infected patients. PLoS One. 2010 Oct 6;5(10):e13188. doi: 10.1371/journal.pone.0013188.
citation: Cooper DA, Heera J, Goodrich J, Tawadrous M, Saag M, Dejesus E, Clumeck N, Walmsley S, Ting N, Coakley E, Reeves JD, Reyes-Teran G, Westby M, Van Der Ryst E, Ive P, Mohapi L, Mingrone H, Horban A, Hackman F, Sullivan J, Mayer H. Maraviroc versus efavirenz, both in combination with zidovudine-lamivudine, for the treatment of antiretroviral-naive subjects with CCR5-tropic HIV-1 infection. J Infect Dis. 2010 Mar 15;201(6):803-13. doi: 10.1086/650697.