Clinical trial NCT00098306: Trial of Maraviroc (UK-427,857) in Combination With Optimized Background Therapy Versus Optimized Background Therapy Alone for the Treatment of HIV-1 Infected Subjects
Official title: 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 HIV-1 Infected Subjects.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: HIV Infections
Lead sponsor: ViiV Healthcare
Sponsor class: INDUSTRY
Collaborators: name: Pfizer
First posted: 2004-12-07
Enrollment: 601
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 purpose of this study is to evaluate the antiretroviral activity of maraviroc (UK-427,857) in HIV infected, treatment experienced patients who are failing their current antiretroviral regimen and are infected with R5-tropic virus exclusively. This study will involve more than 100 centers from the US and Canada to achieve a total randomized subject population of 500 subjects. Patients will be randomly (2:2:1) 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. The study will enroll over approximately a 9 month period with 48 weeks of treatment. This may be extended for an additional year depending on the results at 48 weeks. 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.


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 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 three of the four antiretroviral drug classes, OR, Antiretroviral-class experience greater than or equal to 6 months (sequential or cumulative) with at least three of the following: One nucleoside or nucleotide reverse transcriptase inhibitor, one non-nucleoside reverse transcriptase inhibitor, two protease inhibitors (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 judgement, 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, hepatoxic 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
* 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: Log 10-transformed Human Immunodeficiency Virus Ribonucleic Acid (HIV-1 RNA) Levels at Baseline
timeFrame: Baseline
measure: Change From Baseline in Log 10-transformed HIV-1 RNA Levels at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in Log 10-transformed HIV-1 RNA Levels at Week 48
timeFrame: Baseline and Week 48
Secondary outcomes:
measure: Percentage of Participants With HIV-1 RNA Levels Less Than 400 Copies/mL
timeFrame: Week 24 and 48
measure: Percentage of Participants With HIV-1 RNA Levels Less Than 400 Copies/mL or With at Least 0.5 log10 Decrease From Baseline
timeFrame: Week 24 and 48
measure: Percentage of Participants With HIV-1 RNA Levels Less Than 400 Copies/mL or With at Least 1.0 log10 Decrease From Baseline
timeFrame: Week 24 and 48
measure: Percentage of Participants With HIV-1 RNA Levels Less Than 50 Copies/mL
timeFrame: Week 24 and 48
measure: Cluster of Differentiation 4 (CD4) and Cluster of Differentiation 8 (CD8) Cell Count at Baseline
timeFrame: Baseline
measure: Change From Baseline in CD4 Cell Count at Week 24 and 48
timeFrame: Baseline, Week 24 and 48
measure: Change From Baseline in CD8 Cell Count at Week 24 and 48
timeFrame: Baseline, Week 24 and 48
measure: Time to Virological Failure
timeFrame: Week 48
measure: Time-Averaged Difference (TAD) From Baseline in log10 Transformed HIV-1 RNA Levels
timeFrame: Baseline to Week 24 and Week 48
measure: Number of Participants With Genotypic Susceptibility Scores (GSS) and Phenotypic Susceptibility Score (PSS) at Screening
timeFrame: Screening
measure: Number of Participants With Change in GSS and PSS From Screening at the Time of Treatment Failure Through Week 24
timeFrame: Screening and time of failure through week 24
measure: Number of Participants With Change in GSS and PSS From Screening at the Time of Treatment Failure at Week 48
timeFrame: Screening and time of failure through week 48
measure: Number of Participants Per Tropism Status at Baseline and at the Time of Treatment Failure Through Week 24
timeFrame: Baseline and time of failure through week 24
measure: Number of Participants Per Tropism Status at Baseline and at the Time of Treatment Failure Through Week 48
timeFrame: Baseline and time of failure through week 48
measure: Change From Baseline in Viral Load at Week 24 and Week 48 by Overall Susceptibility Score (OSS) at Screening
timeFrame: Baseline, Week 24 and Week 48
Other outcomes:
Locations:
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: San Francisco
country: United States
facility: Pfizer Investigational Site
state: California
city: Auroa
country: United States
facility: Pfizer Investigational Site
state: Colorado
city: Aurora
country: United States
facility: Pfizer Investigational Site
state: Colorado
city: Washington
country: United States
facility: Pfizer Investigational Site
state: District of Columbia
city: Tampa
country: United States
facility: Pfizer Investigational Site
state: Florida
city: Tampa
country: United States
facility: Pfizer Investigational Site
state: Florida
city: Vero Beach
country: United States
facility: Pfizer Investigational Site
state: Florida
city: Atlanta
country: United States
facility: Pfizer Investigational Site
state: Georgia
city: New Orleans
country: United States
facility: Pfizer Investigational Site
state: Louisiana
city: Santa Fe
country: United States
facility: Pfizer Investigational Site
state: New Mexico
city: Bronx
country: United States
facility: Pfizer Investigational Site
state: New York
city: New York
country: United States
facility: Pfizer Investigational Site
state: New York
city: Rochester
country: United States
facility: Pfizer Investigational Site
state: New York
city: Cincinnati
country: United States
facility: Pfizer Investigational Site
state: Ohio
city: Portland
country: United States
facility: Pfizer Investigational Site
state: Oregon
city: Austin
country: United States
facility: Pfizer Investigational Site
state: Texas
city: Annandale
country: United States
facility: Pfizer Investigational Site
state: Virginia
city: Vancouver
country: Canada
facility: Pfizer Investigational Site
state: British Columbia
city: Montreal
country: Canada
facility: Pfizer Investigational Site
state: Quebec
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: Lewis ME, Simpson P, Mori J, Jubb B, Sullivan J, McFadyen L, van der Ryst E, Craig C, Robertson DL, Westby M. V3-Loop genotypes do not predict maraviroc susceptibility of CCR5-tropic virus or clinical response through week 48 in HIV-1-infected, treatment-experienced persons receiving optimized background regimens. Antivir Chem Chemother. 2021 Jan-Dec;29:20402066211030380. doi: 10.1177/20402066211030380.
citation: Gulick RM, Fatkenheuer G, Burnside R, Hardy WD, Nelson MR, Goodrich J, Mukwaya G, Portsmouth S, Heera JR. Five-year safety evaluation of maraviroc in HIV-1-infected treatment-experienced patients. J Acquir Immune Defic Syndr. 2014 Jan 1;65(1):78-81. doi: 10.1097/QAI.0b013e3182a7a97a.
citation: Hardy WD, Gulick RM, Mayer H, Fatkenheuer G, Nelson M, Heera J, Rajicic N, Goodrich J. Two-year safety and virologic efficacy of maraviroc in treatment-experienced patients with CCR5-tropic HIV-1 infection: 96-week combined analysis of MOTIVATE 1 and 2. J Acquir Immune Defic Syndr. 2010 Dec 15;55(5):558-64. doi: 10.1097/QAI.0b013e3181ee3d82.
citation: Fatkenheuer G, Nelson M, Lazzarin A, Konourina I, Hoepelman AI, Lampiris H, Hirschel B, Tebas P, Raffi F, Trottier B, Bellos N, Saag M, Cooper DA, Westby M, Tawadrous M, Sullivan JF, Ridgway C, Dunne MW, Felstead S, Mayer H, van der Ryst E; MOTIVATE 1 and MOTIVATE 2 Study Teams. Subgroup analyses of maraviroc in previously treated R5 HIV-1 infection. N Engl J Med. 2008 Oct 2;359(14):1442-55. doi: 10.1056/NEJMoa0803154.
citation: Gulick RM, Lalezari J, Goodrich J, Clumeck N, DeJesus E, Horban A, Nadler J, Clotet B, Karlsson A, Wohlfeiler M, Montana JB, McHale M, Sullivan J, Ridgway C, Felstead S, Dunne MW, van der Ryst E, Mayer H; MOTIVATE Study Teams. Maraviroc for previously treated patients with R5 HIV-1 infection. N Engl J Med. 2008 Oct 2;359(14):1429-41. doi: 10.1056/NEJMoa0803152.