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
Overview
- Phase
- Phase 1
- Intervention
- Vicriviroc
- Conditions
- HIV Infections
- Sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)
- Enrollment
- 9
- Locations
- 9
- Primary Endpoint
- Number of Participants With Suspected Adverse Drug Reaction Leading to Treatment Termination
- Status
- Completed
- Last Updated
- 4 years ago
Overview
Brief Summary
Complications with current HIV antiretroviral therapy have left many children and adolescents with limited therapeutic options due to drug resistance. The purpose of this study is to test the effectiveness and safety of Vicriviroc (VCV), an HIV entry inhibitor and CCR5 co-receptor antagonist.
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Confirmed HIV infection
- •Treatment experienced subjects: Children or adolescents on an unchanged therapeutic regimen for at least 12 weeks and experiencing virologic failure OR participants on no treatment for 4 weeks or more but with history of virologic failure on a prior therapeutic regimen.
- •Likely to have virus that is sensitive to at least one ritonavir boosted protease inhibitor
- •HIV viral load greater than or equal to 1,000 copies/ml within 90 days prior to Step I entry
- •Able to swallow study medication, in tablets or liquid form specific to age-assigned cohort
- •Parent, legal guardian or participant able and willing to provide signed informed consent and to have the participant followed at the clinic site
- •Willing to use effective methods of contraception
- •Inclusion Criteria for Step II (In addition to the inclusion criteria for Step I):
- •Participant's plasma HIV tested at Step I must be R5 tropic
- •Genotypic sensitivity enabling the participant to take optimized background therapy (OBT) consisting of at least a ritonavir-based protease inhibitor. More information on this criterion can be found in the study protocol.
Exclusion Criteria
- •Presence of any currently active AIDS defining illness or history of malignancy
- •History of a seizure disorder that requires current anti-seizure medication for control or at risk for seizures. Those with a history of febrile seizures alone are not excluded.
- •Certain abnormal laboratory values. More information on this criterion can be found in the protocol.
- •Any vaccinations 14 days prior to Step I, or scheduled to occur within 14 days prior to entry into Step II, and the week 24 and 48 visits in Step II
- •Allergy or sensitivity to study drug or its ingredients
- •Taking any Step II disallowed medications (see protocol) and unable or unwilling to discontinue them at least one week prior to entering Step II
- •Use of NNRTIs other than etravirine 21 days prior to Step II entry
- •Pregnancy or breastfeeding. Infants who are receiving breastmilk are allowed to enroll.
- •Exclusion Criteria for Step II
- •All exclusion criteria for Step I
Arms & Interventions
Vicriviroc in tablet form (20/30 mg) or liquid form (1 mg/ml)
HIV-1 Infected Antiretroviral Therapy Experienced Participants with CCR5-tropic Virus
Intervention: Vicriviroc
Outcomes
Primary Outcomes
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
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
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
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.
Secondary Outcomes
- Change in CD4 Percent(At Baseline, Week 24)
- 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)(At Baseline, Week 24)
- Change in Polymerase Genome and Envelope Sequence(At Baseline, Week 24)
- Number of Participants With Changes in Co-receptor Tropism From Baseline(At Baseline, Week 24)
- Change in CD4 Counts(At Baseline, Week 24)
- Change in Plasma HIV RNA PCR(At Baseline, Week 24)