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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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
ViiV Healthcare
ClinicalTrials.gov Identifier:
NCT00791700
First received: November 12, 2008
Last updated: March 10, 2016
Last verified: March 2016
  Purpose
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.

Condition Intervention Phase
Human Immunodeficiency Virus (HIV)
Drug: Maraviroc
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by ViiV Healthcare:

Primary Outcome Measures:
  • Pharmacokinetic (PK) Parameters for Participants With Data in Stage 1 Enrolled in Stage 2 - Week 48 [ Time Frame: Week 2 and Week 48 (0, 1, 2, 4, 6, 8, 12 hours post-dose) ] [ Designated as safety issue: Yes ]
    A PK analysis was performed using PK data from participants that participated in Stage 1 (PK Populations 2 and 3) where intensive maraviroc (MVC) PK data were available at Week 2. The primary aim of this analysis was to describe and summarize MVC PK parameters at Week 2 and Week 48 by cohort and Optimized Background Treatment (OBT) group. Geometric Coefficient of Variation is defined as the geometric standard deviation to the power of the reciprocal of the geometric mean.

  • PK Parameters for Stage 1 Participants Enrolled in Stage 2 - Week 2 Results for Stage 2 Doses - AUCtau (Area Under the Curve at Steady State) [ Time Frame: Week 2 and Week 48 (0, 1, 2, 4, 6, 8, 12 hours post-dose) ] [ Designated as safety issue: No ]
    A PK analysis was performed using PK data from participants that participated in Stage 1 (PK Populations 2 and 3) where intensive maraviroc (MVC) PK data were available at Week 2. The primary aim of this analysis was to describe and summarize MVC PK parameters (AUCtau) at Week 2 and Week 48 by cohort and Optimized Background Treatment (OBT) group. Correlations between MVC PK and efficacy as well as compliance were also assessed.

  • PK Parameters for Stage 1 Participants Enrolled in Stage 2 - Week 2 Results for Stage 2 Doses - Tmax (Time at Maximum Concentration) [ Time Frame: Week 2 and Week 48 (0, 1, 2, 4, 6, 8, 12 hours post-dose) ] [ Designated as safety issue: No ]
    A PK analysis was performed using PK data from participants that participated in Stage 1 (PK Populations 2 and 3) where intensive maraviroc (MVC) PK data were available at Week 2. The primary aim of this analysis was to describe and summarize MVC PK parameters (Tmax) at Week 2 and Week 48 by cohort and Optimized Background Treatment (OBT) group. Correlations between MVC PK and efficacy as well as compliance were also assessed.

  • Incidence and Severity of Grade 3 and Grade 4 Treatment-Emergent Adverse Events (All Causality) [ Time Frame: 48 weeks ] [ Designated as safety issue: Yes ]
    Safety was assessed by spontaneous reports, physical examination and laboratory test results in all participants who received at least 1 dose of study drug. The investigator used the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric AEs.

  • Treatment Discontinuation Secondary to Serious Adverse Event (SAE) Related to Study Drug [ Time Frame: Week 48 ] [ Designated as safety issue: Yes ]
    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.


Secondary Outcome Measures:
  • Percentage of Participants With HIV‑1 RNA <400 Copies/mL Through Week 48 (MSDF) [ Time Frame: Week 24 and Week 48 post-treatment. ] [ Designated as safety issue: No ]
    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. The percentage of participants is reported below.

  • Percentage of Participants With HIV‑1 RNA <48 Copies/mL Through Week 48 (MSDF) [ Time Frame: Week 24 and Week 48 post-treatment ] [ Designated as safety issue: No ]
    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. The percentage of participants is reported below.

  • Percentage of Participants With HIV-1 RNA Levels <400 Copies/mL at Weeks 24 and 48 Using Missing, Discontinuation = Failure (MD=F)Approach [ Time Frame: Week 24 and Week 48 post-treatment ] [ Designated as safety issue: No ]
    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 will be referred to as [non-completer = failure; NC=F] or [missing, discontinuation = failure; MD=F]. The proportion of participants (100*n/N) is reported below.

  • Percentage of Participants With HIV-1 RNA Levels < 48 Copies/mL at Weeks 24 and 48 Using MD=F Approach [ Time Frame: Week 24 and Week 48 post-treatment ] [ Designated as safety issue: No ]
    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 will be referred to as [non-completer = failure; NC=F] or [missing, discontinuation = failure; MD=F]. The proportion of participants (100*n/N) is reported below. The proportion of participants (100*n/N) is reported below.

  • 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 [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants With >= 1.0 log10 Reduction in HIV-1RNA Concentration From Baseline to Week 24 and Week 48 [ Time Frame: Week 24 and Week 48 post-treatment ] [ Designated as safety issue: No ]
    Percentage of subjects with at least a 1.0 log10 reduction in HIV-1 RNA from baseline to Week 24 and Week 48 were tabulated.

  • Summary of Change From Baseline in HIV-1 RNA (Original) by Visit [ Time Frame: Week 24 and Week 48 post-treatment ] [ Designated as safety issue: No ]
    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.

  • Summary of Change From Baseline in HIV-1 RNA (Log10 Copies/mL) by Visit [ Time Frame: Week 24 and Week 48 post-treatment ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Cluster of Differentiation 4 (CD4+) Cell Count at Weeks 24 and 48 [ Time Frame: Week 24 and Week 48 post-treatment ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in CD4+ Percent (%) at Weeks 24 and 48 [ Time Frame: Week 24 and Week 48 post-treatment ] [ Designated as safety issue: No ]
    Change from baseline in CD4 % to Week 24 and Week 48 were tabulated in aggregated and broken down by age cohort using summary statistics.

  • Protocol Defined Virologic Failure [ Time Frame: Week 48 ] [ Designated as safety issue: No ]

    The occurrence of any one of the following criteria would constitute Virologic failure:

    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; 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; 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.


  • Shift Table of Viral Tropism Between Screening and Confirmed PDVF Prior to Week 48 [ Time Frame: Screening and Week 48 ] [ Designated as safety issue: No ]
    Virus tropism was determined using the Monogram Biosciences Trofile™ viral tropism assay. A shift table of the change in detected tropism from screening to the time of failure was produced in the aggregate and also broken down by age cohort.

  • Summary of the Emergence of Reverse Transcriptase Inhibitor (RTI) and Protease Inhibitor (PI) Resistance Associated Mutations (RAMs) Between Screening and On-Treatment Confirmed PDVF: Total and by Cohort Prior to Week 48 [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
    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. Participants with more than one mutation are counted more than once.

  • Optimized Background Treatment (OBT) Susceptibility Scores (Net/Overall) by Outcome [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
    Outcome (Response, PDVF or other/remainder) was summarized by the total ARV activity of the background regimen using simple and weighted totals (TOBT and p-wTOBTss, respectively) in the aggregate, categorized as 0, 1, ≥2 (TOBT) and 0 0.5, 1 1.5 and ≥2 (p-wOBTss) respectively, as well as by screening genotype. Six participants (Response: n=5; Other failure: n=1) failed to have successful PhenoSense GT analysis at screening, and so a net susceptibility score was not generated. One more participant was not included in the wOBTss analysis due to failed phenotype analysis. However, net susceptibility scores were imputed for simple analysis based on genotype. Susceptibility scores indicate the level resistance to the study medication. Scores include: 1 = susceptible and potential low-level resistance; 0.5 = low and intermediate-level resistance; 0 = high-level resistance.


Enrollment: 103
Study Start Date: April 2009
Estimated Study Completion Date: July 2019
Primary Completion Date: April 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: Selzentry

  Eligibility

Ages Eligible for Study:   2 Years to 18 Years   (Child, Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00791700

  Show 43 Study Locations
Sponsors and Collaborators
ViiV Healthcare
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
Responsible Party: ViiV Healthcare
ClinicalTrials.gov Identifier: NCT00791700     History of Changes
Other Study ID Numbers: A4001031  2008-006873-33 
Study First Received: November 12, 2008
Results First Received: October 6, 2015
Last Updated: March 10, 2016
Health Authority: United States: Food and Drug Administration

Keywords provided by ViiV Healthcare:
Open label pharmacokinetic safety and efficacy in HIV-1 infected pediatrics

Additional relevant MeSH terms:
Immunologic Deficiency Syndromes
Acquired Immunodeficiency Syndrome
HIV Infections
Immune System Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases
Maraviroc
CCR5 Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on September 23, 2016