Safety and Immune Response to Vicriviroc in Combination Regimens in HIV-Infected ART Experienced Children and Adolescents
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I/II Open-Label Study to Evaluate the PK, Safety, Tolerability and Antiviral Activity of Vicriviroc, a Novel CCR5 Antagonist in Combination Regimens in HIV-Infected ART Experienced Children and Adolescents|
- Number of Participants With Suspected Adverse Drug Reaction Leading to Treatment Termination [ Time Frame: From study entry to Week 24 or the early study termination whichever occurred earlier ] [ Designated as safety issue: Yes ]The protocol required reporting of signs and symptoms and laboratory abnormalities of >=Grade 2 and all grades of fever. The DAIDS Adverse Event (AE) Grading Table, Version 1.0, December 2004 (Clarification, August 2009) was used for grading of AEs. Expedited adverse event reporting followed Version 2.0 of the DAIDS Expedited Adverse Event Manual.The attribution of relationship of serious adverse events to study drug for the purposes of employing the start, stop and pause rules is to be determined by the Study Team. Gradation of relationship will use the following terminology: Not related, Probably not related, Possibly related, Probably related or Definitely related.
- Number of Participants With Adverse Events of Grade 3 or Higher Severity [ Time Frame: From study entry to Week 24 or the early study termination whichever occurred earlier ] [ Designated as safety issue: Yes ]Adverse events were graded using the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 1.0, December 2004, Clarification August 2009, which is available on the RCC website at (http://rcc.tech-res.com/). All grade 3 and higher signs, symptoms, and laboratory toxicities were included.
- Number of Participants Who Failed to Meet PK Targets [ Time Frame: At Week 24 ] [ Designated as safety issue: No ]For Stage I subjects who are enrolled in Step II, the average of the pre-dose and 24 hour post dose sample from the intensive PK evaluations of said subjects will be used as the estimate of Cmin. The whole cohort will fail the PK targets if the population target (median vicriviroc Cmin should be =>200 ng/mL) is not met, and that nearly all of subjects' Cmin failed to be > 100 ng/mL.
- Number of Participants Who Failed to Achieve =>1-log Drop From Baseline in HIV-1 Viral Load and HIV-1 Viral Load of =>400 Copies/mL (Virologic Failures) [ Time Frame: At Baseline, Week 24 ] [ Designated as safety issue: No ]Plasma HIV RNA (RNA) concentrations were determined at entry and at regular intervals using the HIV-1 MONITOR Test, version 1.5 (Roche Molecular Diagnostics) or RealTime HIV-1 (Abbott Molecular). The primary definition of virologic success will require subjects to have achieved and maintained 1-log drops from baseline of HIV-1 RNA or HIV-1 RNA <400 copies/mL.
- Number of Participants With Changes in Co-receptor Tropism From Baseline [ Time Frame: At Baseline, Week 24 ] [ Designated as safety issue: No ]Among all patients enrolled in Step I, the prevalence of detectable coreceptor phenotype, R5 tropic, R5/X4 mixed and X4 tropic viruses will be evaluated. The extent to which coreceptor phenotype in Step I is associated with Step I CD4 cell count, HIV RNA, and age will be evaluated. The association of Step I coreceptor phenotype and nadir CD4, HIV subtype, number of ART regimens, and years of ART will be evaluated. At the time of virologic failure, the extent of change from Step I and/or baseline R5 tropic virus to R5/X4 mixed or to X4 tropic virus as detected by the TrofileTM assay will be evaluated.
- Change in CD4 Counts [ Time Frame: At Baseline, Week 24 ] [ Designated as safety issue: No ]Change in CD4 count from baseline to weeks 24 will be presented both in the aggregate and broken down by age cohort.
- Change in CD4 Percent [ Time Frame: At Baseline, Week 24 ] [ Designated as safety issue: No ]Change in CD4 percent from baseline to weeks 24 will be presented both in the aggregate and broken down by age cohort.
- Change in Polymerase Genome and Envelope Sequence [ Time Frame: At Baseline, Week 24 ] [ Designated as safety issue: No ]Number of subjects with changes in genotypic and phenotypic drug resistance to the OBT and to vicriviroc (envelope sequence) from baseline to Week 24 and/or virologic failure will be presented both in the aggregate and broken down by age cohort.
- Change in Plasma HIV RNA PCR [ Time Frame: At Baseline, Week 24 ] [ Designated as safety issue: No ]Changes in HIV RNA (copies/mL) from baseline to Week 24 will be presented both in the aggregate and broken down by age cohort.
|Study Start Date:||August 2009|
|Study Completion Date:||August 2010|
|Primary Completion Date:||July 2010 (Final data collection date for primary outcome measure)|
Experimental: Vicriviroc in tablet form (20/30 mg) or liquid form (1 mg/ml)
HIV-1 Infected Antiretroviral Therapy Experienced Participants with CCR5-tropic Virus
Administered orally in either tablet or liquid form at a dosage of approximately 0.8/mg/kg every 24 hours, with a ritonavir boosted protease inhibitor containing background regimen
Highly active antiretroviral therapy (HAART) that includes a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI) has become the standard treatment of HIV-infected adults and children. When effective, HAART decreases the viral population, increases the body's immune responses, and leads to decreased disease progression and increased survival. However, several factors including poor adherence, drug toxicities, and drug resistance complicate HIV management and allow for children and adolescents to develop resistance to multiple drug classes, leaving them with very limited therapeutic options. Fortunately, drugs with new mechanisms of action, such as HIV entry inhibitors, demonstrate activity even in people with resistance to the currently available reverse transcriptase and protease inhibitors.
The purpose of this study is to test the effectiveness and safety of Vicriviroc (VCV), an HIV entry inhibitor. Vicriviroc targets the CCR5 chemokine receptor, which HIV uses to bind and enter CD4+ cells.
This study is a two-stage, age-stratified, non-comparative study to explore the safety, tolerability, pharmacokinetic profile and antiviral activity of the investigational CCR5 inhibitor Vicriviroc in HIV-infected treatment experienced children and adolescents.
In Step I participants will be screened for the co-receptor CCR5 to assess whether they can enter Step II. Only participants with CCR5-tropic virus are eligible for Step II - the main portion of the study to evaluate the study outcome measures. Those participants who continue to Step II will be assigned to one of four age-stratifies cohorts which will receive varying forms, either liquid or tablet, of Vicriviroc:
Cohort I: 12 years to less than 19 years of age, to receive tablet formulation of VCV
Cohort II: 6 years to less than 12 years of age, to receive tablet formulation of VCV
Cohort III: 6 years to less than 12 years of age, to receive liquid formulation of VCV
Cohort IV: 2 years to less than 6 years of age, to receive liquid formulation of VCV
Dose strengths of 20 mg and 30 mg will be used, or in liquid formulation at a concentration of 1mg/mL.
Step II is composed of Stage I and Stage II. Stage I is a dose ranging study designed to explore how the body responds to different doses of vicriviroc, including safety factors associated with dosage. After optimal dosage information and safety measures have been assessed for the different cohorts in Stage I, Stage II will open. Stage II will evaluate the long term safety, tolerability and effectiveness of vicriviroc.
The study, including Steps I and II will last for approximately 48 weeks. Follow-up for all subjects exposed to vicriviroc will last for 5 years after initial exposure. Visits will be every 3 months for subjects on study provided vicriviroc and every 6 months for subjects who discontinue vicriviroc.
The study was terminated shortly after the initiation, when the drug company decided to discontinue development of the study drug. As of study termination, nine participants had enrolled under Cohort I in Step I, but only 4 participants had CCR5 tropism and received the study medication under Step II. All 4 participants had limited post-baseline data.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00766597
|United States, California|
|UCSD Mother-Child-Adolescent Program CRS|
|San Diego, California, United States|
|United States, District of Columbia|
|Children's National Med. Ctr. Washington DC NICHD CRS|
|Washington, District of Columbia, United States, 20010|
|Howard Univ. Washington DC NICHD CRS|
|Washington, District of Columbia, United States, 20060|
|United States, Illinois|
|Chicago Children's CRS|
|Chicago, Illinois, United States, 60614|
|United States, New York|
|Jacobi Med. Ctr. Bronx NICHD CRS|
|Bronx, New York, United States, 10461|
|Bronx-Lebanon Hosp. IMPAACT CRS|
|Bronx, New York, United States|
|Metropolitan Hosp. NICHD CRS|
|New York, New York, United States, 10029|
|United States, Tennessee|
|St. Jude/UTHSC CRS|
|Memphis, Tennessee, United States, 38105|
|Univ. of Puerto Rico Ped. HIV/AIDS Research Program CRS|
|San Juan, Puerto Rico, 00935|
|Study Chair:||Rolando M Viani, M.D., M.T.P.||University of California|
|Study Chair:||Stephen A Spector, M.D.||University of California, San Diego|