An Open Label Pharmacokinetic, Safety And Efficacy Study Of Maraviroc In Combination With Background Therapy For The Treatment Of HIV-1 Infected, CCR5 -Tropic Children

AN OPEN-LABEL, MULTICENTER, MULTIPLE-DOSE PHARMACOKINETIC, SAFETY AND EFFICACY TRIAL OF MARAVIROC IN COMBINATION WITH OPTIMIZED BACKGROUND THERAPY FOR THE TREATMENT OF ANTIRETROVIRAL-EXPERIENCED CCR5-TROPIC HIV-1 INFECTED CHILDREN 2 - <18 YEARS OF AGE

The primary purpose of this study is to determine the pharmacokinetic properties (what the body does to maraviroc) and to determine a suitable dosing schedule of maraviroc in HIV-1 infected children and adolescents. This study will also determine whether maraviroc is safe to use in children and adolescents.

Study Overview

• Status: Active, not recruiting
• Conditions: Human Immunodeficiency Virus
• Intervention / Treatment: Drug: Maraviroc

• Study Type: Interventional
• Enrollment (Actual): 103
• Phase: Phase 2

Contacts and Locations

Study Locations

• Brazil
  • São Paulo, Brazil, 01416-000
    • Condomínio Edifício Parque Paulista
  • SP
    • São Paulo, SP, Brazil, 01246-900
      • Instituto de Infectologia Emilio Ribas
• Italy
  • Padova, Italy, 35128
    • Clinica Pediatrica Azienda Ospedaliera di Padova
  • Padova, Italy, 35128
    • Farmacia Interna
  • Roma, Italy, 00165
    • Irccs Ospedale Pediatrico Bambino Gesu
  • Torino, Italy, 10126
    • Struttura Complessa a Direzione Universitaria Immunologia, Reumatologia e Malattie Infettive
• Mexico
  • DF
    • Mexico, DF, Mexico, 06720
      • Hospital Infantil de México Federico Gómez
• Portugal
  • Faro, Portugal, 8000-386
    • Centro Hospitalar Universitario do Algarve, EPE
  • Lisboa, Portugal, 1169-045
    • Centro Hospitalar de Lisboa Central, EPE
  • Lisboa, Portugal, 1649-035
    • Centro Hospitalar de Lisboa Norte, EPE
  • Porto, Portugal, 4202-451
    • Hospital S. João, E.P.E
• Puerto Rico
  • San Juan, Puerto Rico, 00935
    • Hospital San Juan Research Unit
• South Africa
  • Pretoria, South Africa, 0083
    • Embassy Drive Medical Center
  • FREE State
    • Bloemfontein, FREE State, South Africa, 9301
      • Iatros International
  • Gauteng
    • Benoni, Gauteng, South Africa, 1501
      • Lakeview Hospital
    • Ga-Rankuwa, Gauteng, South Africa, 0208
      • Dr George Mukhari Hospital
  • Kwazulu-natal
    • Dundee, Kwazulu-natal, South Africa, 3000
      • Dr. Jan Fourie Medical Centre
• Spain
  • Esplugues De Llobregat, Barcelona, Spain, 08950
    • Hospital Sant Joan de Déu
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
• Thailand
  • Bangkok, Thailand, 10330
    • The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT),
  • Bangkok, Thailand, 10700
    • Department of Pediatrics, Faculty of Medicine, Siriraj Hospital
  • Chiang MAI
    • Muang, Chiang MAI, Thailand, 50200
      • Department of Pediatrics, Faculty of Medicine, Chiang Mai University
  • Khon Kaen
    • Muang, Khon Kaen, Thailand, 40002
      • Department of Pediatric, Faculty of Medicine, Khon Kaen University
• United States
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital Los Angeles
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • Alfred I. DuPont Hospital for Children
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Florida
    • Jacksonville, Florida, United States, 32209
      • Rainbow Center at University of Florida Health
    • Miami, Florida, United States, 33136
      • University of Miami Miller School of Medicine
    • Tampa, Florida, United States, 33612
      • University of South Florida
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta
    • Atlanta, Georgia, United States, 30308
      • Grady Health System, IDP
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi
    • Jackson, Mississippi, United States, 39213
      • Pediatric Infectious Disease Clinic
    • Jackson, Mississippi, United States, 39216
      • Batson Specialty Clinic
  • Ohio
    • Cincinnati, Ohio, United States, 45206
      • Cincinnati Center for Clinical Research
  • Texas
    • Dallas, Texas, United States, 75235
      • Children's Medical Center of Dallas
    • Houston, Texas, United States, 77030
      • Children's Memorial Hermann Hospital
    • Houston, Texas, United States, 77030
      • UT Physician
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University
    • Richmond, Virginia, United States, 23298
      • VCU Health System Clinical Research Services

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subjects who are 2-18 years of age, treatment experienced for 6 months or longer with at least 2 ARV drug classes, with HIV-1 RNA ≥1,000 copies/mL

Exclusion Criteria:

• X4- or dual/mixed-tropic virus detected by the Trofile™ viral tropism assay
• Concomitant therapy with other investigational agents (other than experimental ARV agents available through pre-approval access programs)
• Known ≥Grade 3 of any of the following laboratory tests at Screening or within 30 days prior to Baseline Visit: Neutrophil count, hemoglobin, platelets, AST, ALT, and creatinine, lipase;
• Total bilirubin ≥Grade 3, unless ALL of the following are true: Current regimen includes atazanavir; ALT/AST < 2.5 X ULN; No symptoms other than jaundice or icterus.
• Other laboratory values ≥Grade 3, must be reviewed by Pfizer.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Maraviroc; Subjects will be stratified by age and formulation into one of the following cohorts: Cohort 1: ≥2-<6 years of age, maraviroc liquid formulation; Cohort 2: ≥6-<12 years of age, maraviroc tablet formulation; Cohort 3: ≥6-<12 years of age, maraviroc liquid formulation and Cohort 4: ≥12-<18 years of age, maraviroc tablet formulation.	Drug: Maraviroc; Maraviroc will be administered twice daily either as a liquid or tablet formulation, depending on the age of the subject. The dosage administered will be dependent upon the subject's body surface area as well as the background therapy.; Other Names: Selzentry

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic(PK): Maraviroc PK Parameter, Average Plasma Concentration (Cavg), Trough Concentration(Cmin), Maximum Plasma Concentration (Cmax)	Cavg: calculated as area under the curve divided by a dosing interval of 12 hours. Cmin: directly observed plasma concentration prior to the next dose. Geometric Coefficient of Variation is defined as the geometric standard deviation to the power of the reciprocal of the geometric mean.	Week 2 and Week 48 (0, 1, 2, 4, 6, 8, 12 hours post-dose)
Area Under the Curve at Steady State (AUCtau)	AUCtau is the area under the plasma concentration time curve (AUC) at steady state from time zero (pre-dose) to end of dosing interval (tau), here dosing interval is 12 hours.	Week 2 and Week 48 (0, 1, 2, 4, 6, 8, 12 hours post-dose)
Time to Reach Maximum Plasma Concentration (Tmax)		Week 2 and Week 48 (0, 1, 2, 4, 6, 8, 12 hours post-dose)
Incidence and Severity of Grade 3 and Grade 4 Treatment-Emergent Adverse Events(AEs) (All Causality)	Incidence is reported in terms of number of events of AEs. The investigator used the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric AEs as follows: Grade 1= Symptoms causing no or minimal interference with usual social and functional activities; Grade 2= Symptoms causing greater than minimal interference with usual social and functional activities; Grade 3= Symptoms causing inability to perform usual social and functional activities; Grade 4= Symptoms causing inability to perform basic self-care functions or medical or operative intervention indicated to prevent permanent impairment, persistent disability, or death. Data have been reported in the measure for Grade 3 and 4 as per system organ class and preferred term.	Baseline up to 5 years
Treatment Discontinuation: Secondary Reasons- Serious Adverse Event (SAE) Related to Study Drug	The primary reason for a participant discontinuing from study drug or the clinical study was recorded in the source documents as well as the case report form. A discontinuation had to be reported immediately to the study medical monitor or his/her designated representative if it was due to an SAE and was considered as a secondary reason.	Baseline up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With HIV-1 RNA <400 Copies/mL Through Week 48 Using Missing, Discontinuation = Failure (MD=F) Approach	The proportion of participants who achieved HIV-1 RNA <400 copies/mL at week 24 or 48 was assessed according to Food and Drug Administration's (FDA's) Missing, Switch, Discontinuation'=Failure (MSDF) Snapshot algorithm. The algorithm uses the plasma HIV-1 RNA in the Week 24 or 48 visit window, follows the "virology-first principle" and considers a participant who has a missing plasma HIV-1 RNA, or switches to prohibited ARV regimen or discontinues from the study or study drug for any reason, or dies, as a failure.	Week 24 and Week 48 post-treatment
Percentage of Participants With HIV-1 RNA <48 Copies/mL Through Week 48 Using Missing, Discontinuation = Failure (MD=F)Approach	The proportion of participants who achieved HIV-1 RNA <48 copies/mL at week 24 or 48 was assessed according to Food and Drug Administration's (FDA's) Missing, Switch, Discontinuation'=Failure (MSDF) Snapshot algorithm. The algorithm uses the plasma HIV-1 RNA in the Week 24 or 48 visit window, follows the "virology-first principle" and considers a participant who has a missing plasma HIV-1 RNA, or switches to prohibited ARV regimen or discontinues from the study or study drug for any reason, or dies, as a failure.	Week 24 and Week 48 post-treatment
Percentage of Participants With HIV-1 RNA Levels <400 Copies/mL at Weeks 24 and 48 Using Missing, Discontinuation = Failure (MD=F)Approach	Participants who have been discontinued from the study, have been lost to follow-up, or have missing HIV-1 RNA data prior to the time point of interest were considered to have HIV-1 RNA levels > lower limit of quantification (LLOQ) . This referred to as [non-completer = failure; NC=F] or [missing, discontinuation = failure; MD=F].	Week 24 and Week 48 post-treatment
Percentage of Participants With HIV-1 RNA Levels < 48 Copies/mL at Weeks 24 and 48 Using MD=F Approach	Participants who have been discontinued from the study, have been lost to follow-up, or have missing HIV-1 RNA data prior to the time point of interest were considered to have HIV-1 RNA levels > lower limit of quantification (LLOQ) . This referred as [non-completer = failure; NC=F] or [missing, discontinuation = failure; MD=F].	Week 24 and Week 48 post-treatment
Percentage of Participants With HIV-1 RNA <400 Copies/mL and <48 Copies/mL Using the Time to Loss of Virologic Response Algorithm (TLOVR) at Week 48	TLOVR is defined as the time from first dose of study medication (Day 1) until the time of virologic failure using the a TLOVR algorithm.	Week 48
Percentage of Participants With >= 1.0 log10 Reduction in HIV-1RNA Concentration From Baseline to Week 24 and Week 48	Percentage of participants with at least a 1.0 log10 reduction in HIV-1 RNA from baseline to Week 24 and Week 48 were tabulated.	Baseline to Week 24, Week 48 post-treatment
Change From Baseline in HIV-1 RNA (Original)	Plasma HIV-1 RNA was determined using the Roche COBAS AmpliPrep/COBAS TaqMan HIV-1 Test (lower limit of quantification [LLOQ] <48 copies/mL). Blood samples were taken at the time points indicated in the participant evaluation schedule. Screening HIV-1 RNA >1000 copies/ml was used to determine eligibility for the study.	Baseline, Week 24, Week 48 post-treatment
Change From Baseline in HIV-1 RNA (Log10 Copies/mL)	Plasma HIV-1 RNA was determined using the Roche COBAS AmpliPrep/COBAS TaqMan HIV-1 Test (lower limit of quantification [LLOQ] <48 copies/mL). Blood samples were taken at the time points indicated in the participant evaluation schedule. Screening HIV-1 RNA >1000 copies/ml was used to determine eligibility for the study.	Baseline, Week 24, Week 48 post-treatment
Change From Baseline in Cluster of Differentiation 4 (CD4+) Cell Count at Weeks 24 and 48	Change from baseline in CD4 cell count to Week 24 and Week 48 were tabulated in aggregated and broken down by age cohort using summary statistics.	Baseline, Week 24, Week 48 post-treatment
Change From Baseline in Percentage (%) of CD4+ Cells at Weeks 24 and 48	Change from baseline in CD4 % to Week 24 and Week 48 were tabulated in aggregated and broken down by age cohort using summary statistics.	Baseline, Week 24 and Week 48 post-treatment
Number of Participants With Protocol Defined Virologic Failure	The occurrence of any one of the following criteria would constitute Virologic failure: Criteria A=Decrease from Baseline plasma HIV-1 RNA <1 log10 and plasma HIV-1 RNA >400 copies/mL starting at Week 12 and confirmed at consecutive Week 16; Criteria B=Decrease from Baseline plasma HIV-1 RNA <2.0 log10 and plasma HIV-1 RNA >400 copies/mL at Week 24 OR plasma HIV-1 RNA >10,000 copies/mL on and after Week 24, and confirmed within 14 to 21 days; Criteria C=Increase from nadir plasma HIV-1 RNA of >=1 log10 (>=1,000 copies/mL if nadir plasma HIV-1 RNA <48 copies/mL) at any time, and confirmed within 14 to 21 days.	Week 48
Number of Participants With Viral Tropism Between Screening and Confirmed Protocol Defined Virologic Failure (PDVF) Prior to Week 48	Virus tropism was determined using the Monogram Biosciences Trofile™ viral tropism assay. Change in detected tropism from screening to the time of failure prior to Week 48 was reported. X4=CXCR4 tropic virus; R5=CCR5-tropic virus; X4=CXCR4-tropic virus. Number of participants as per tropism to respective virus has been reported.	Screening to Week 48
Number of Participants With Emergence of Reverse Transcriptase Inhibitor (RTI) and Protease Inhibitor (PI) Resistance Associated Mutations (RAMs) Between Screening and On-Treatment Confirmed PDVF	Phenotypic and genotypic susceptibility to reverse transcriptase and protease inhibitors was evaluated at screening using the Monogram Biosciences PhenoSense™ GT (PSGT) assay. Samples from a confirmatory PDVF visit or early termination of MVC were planned to be analyzed if the plasma HIV-1 RNA was ≥400 copies/mL. Data for participants with respective gene mutation category has been reported. Participants with more than one mutation are counted more than once.	48 weeks
Percentage of Participants With Optimized Background Treatment Susceptibility Scores	Data was summarized by the total ARV activity of the background regimen using simple and weighted total optimized background treatment susceptibility scores as well as by screening genotype. Simple total optimized background treatment (OBT) susceptibility scores were categorized as 0, 1, >=2 and weighted total OBT susceptibility scores were categorized as 0 to 0.5, 1 to 1.5 and >=2. However, net susceptibility scores were imputed for simple analysis based on genotype. Susceptibility scores indicate the level resistance to the study medication. Scores ranged from 0 to 1 as 1 = susceptible and potential low-level resistance; 0.5 = low and intermediate-level resistance; 0 = high-level resistance, where higher scores indicated lower resistance.	48 weeks

Collaborators and Investigators

• Sponsor: ViiV Healthcare
• Collaborators: Pfizer

Publications and helpful links

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): April 22, 2009
• Primary Completion (Actual): April 14, 2015
• Study Completion (Anticipated): June 30, 2023

Study Registration Dates

• First Submitted: November 12, 2008
• First Submitted That Met QC Criteria: November 12, 2008
• First Posted (Estimate): November 14, 2008

Study Record Updates

• Last Update Posted (Actual): April 28, 2020
• Last Update Submitted That Met QC Criteria: April 17, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: Open label pharmacokinetic safety and efficacy in HIV-1 infected pediatrics
• 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; Slow Virus Diseases; HIV Infections; Acquired Immunodeficiency Syndrome; 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: A4001031; 2008-006873-33 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No