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

Human Immunodeficiency Virus Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00791700
• Other study ID #: A4001031
• Secondary ID: 2008-006873-33
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: April 22, 2009
• Est. completion date: June 30, 2023

Study information

• Verified date: April 2020
• Source: ViiV Healthcare
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 103
• Est. completion date: June 30, 2023
• Est. primary completion date: April 14, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 18 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• HIV Infections
• Human Immunodeficiency Virus

Intervention

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.

Locations

Country	Name	City	State
Brazil	Condomínio Edifício Parque Paulista	São Paulo
Brazil	Instituto de Infectologia Emilio Ribas	São Paulo	SP
Italy	Clinica Pediatrica Azienda Ospedaliera di Padova	Padova
Italy	Farmacia Interna	Padova
Italy	IRCCS Ospedale Pediatrico Bambino Gesu	Roma
Italy	Struttura Complessa a Direzione Universitaria Immunologia, Reumatologia e Malattie Infettive	Torino
Mexico	Hospital Infantil de Mexico Federico Gomez	Mexico	DF
Portugal	Centro Hospitalar Universitario do Algarve, EPE	Faro
Portugal	Centro Hospitalar de Lisboa Central, EPE	Lisboa
Portugal	Centro Hospitalar de Lisboa Norte, EPE	Lisboa
Portugal	Hospital S. João, E.P.E	Porto
Puerto Rico	Hospital San Juan Research Unit	San Juan
South Africa	Lakeview Hospital	Benoni	Gauteng
South Africa	Iatros International	Bloemfontein	FREE State
South Africa	Dr. Jan Fourie Medical Centre	Dundee	Kwazulu-natal
South Africa	Dr George Mukhari Hospital	Ga-Rankuwa	Gauteng
South Africa	Embassy Drive Medical Center	Pretoria
Spain	Hospital Sant Joan de Deu	Esplugues De Llobregat, Barcelona
Spain	Hospital Universitario 12 de Octubre	Madrid
Thailand	Department of Pediatrics, Faculty of Medicine, Siriraj Hospital	Bangkok
Thailand	The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT),	Bangkok
Thailand	Department of Pediatric, Faculty of Medicine, Khon Kaen University	Muang	Khon Kaen
Thailand	Department of Pediatrics, Faculty of Medicine, Chiang Mai University	Muang	Chiang MAI
United States	Children's Healthcare of Atlanta	Atlanta	Georgia
United States	Grady Health System, IDP	Atlanta	Georgia
United States	Cincinnati Center for Clinical Research	Cincinnati	Ohio
United States	Children's Medical Center of Dallas	Dallas	Texas
United States	Children's Memorial Hermann Hospital	Houston	Texas
United States	UT Physician	Houston	Texas
United States	Batson Specialty Clinic	Jackson	Mississippi
United States	Pediatric Infectious Disease Clinic	Jackson	Mississippi
United States	University of Mississippi	Jackson	Mississippi
United States	Rainbow Center at University of Florida Health	Jacksonville	Florida
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	University of Miami Miller School of Medicine	Miami	Florida
United States	Children's Hospital of Orange County	Orange	California
United States	VCU Health System Clinical Research Services	Richmond	Virginia
United States	Virginia Commonwealth University	Richmond	Virginia
United States	University of South Florida	Tampa	Florida
United States	Children's National Medical Center	Washington	District of Columbia
United States	Alfred I. DuPont Hospital for Children	Wilmington	Delaware

Sponsors (2)

Lead Sponsor	Collaborator
ViiV Healthcare	Pfizer

Countries where clinical trial is conducted

United States,  Brazil,  Italy,  Mexico,  Portugal,  Puerto Rico,  South Africa,  Spain,  Thailand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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)
Primary	Time to Reach Maximum Plasma Concentration (Tmax)		Week 2 and Week 48 (0, 1, 2, 4, 6, 8, 12 hours post-dose)
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

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