Clinical trial NCT00766597: Safety and Immune Response to Vicriviroc in Combination Regimens in HIV-Infected ART Experienced Children and Adolescents
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: HIV Infections
Keywords: Treatment Experienced
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2008-10-06
Enrollment: 9
Sex: ALL
Minimum age (years): 2
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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
* Participants harboring dual or mixed tropic virus (R5/X4) or X4 virus or non phenotypable virus
* Current or anticipated use of any disallowed medications
* Use of efavirenz, nevirapine, and delavirdine for 21 days prior to Step II entry
* Pregnant within 3 days of Step II entry

Primary outcomes:
measure: Number of Participants With Suspected Adverse Drug Reaction Leading to Treatment Termination
timeFrame: From study entry to Week 24 or the early study termination whichever occurred earlier
measure: Number of Participants With Adverse Events of Grade 3 or Higher Severity
timeFrame: From study entry to Week 24 or the early study termination whichever occurred earlier
measure: Number of Participants Who Failed to Meet PK Targets
timeFrame: At Week 24
Secondary outcomes:
measure: 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)
timeFrame: At Baseline, Week 24
measure: Number of Participants With Changes in Co-receptor Tropism From Baseline
timeFrame: At Baseline, Week 24
measure: Change in CD4 Counts
timeFrame: At Baseline, Week 24
measure: Change in CD4 Percent
timeFrame: At Baseline, Week 24
measure: Change in Polymerase Genome and Envelope Sequence
timeFrame: At Baseline, Week 24
measure: Change in Plasma HIV RNA PCR
timeFrame: At Baseline, Week 24
Other outcomes:
Locations:
city: San Diego
country: United States
facility: UCSD Mother-Child-Adolescent Program CRS
state: California
city: Washington
country: United States
facility: Children's National Med. Ctr. Washington DC NICHD CRS
state: District of Columbia
city: Washington
country: United States
facility: Howard Univ. Washington DC NICHD CRS
state: District of Columbia
city: Chicago
country: United States
facility: Chicago Children's CRS
state: Illinois
city: Bronx
country: United States
facility: Jacobi Med. Ctr. Bronx NICHD CRS
state: New York
city: Bronx
country: United States
facility: Bronx-Lebanon Hosp. IMPAACT CRS
state: New York
city: New York
country: United States
facility: Metropolitan Hosp. NICHD CRS
state: New York
city: Memphis
country: United States
facility: St. Jude/UTHSC CRS
state: Tennessee
city: San Juan
country: Puerto Rico
facility: Univ. of Puerto Rico Ped. HIV/AIDS Research Program CRS
Study officials:
affiliation: University of California
name: Rolando M Viani, M.D., M.T.P.
role: STUDY_CHAIR
affiliation: University of California, San Diego
name: Stephen A Spector, M.D.
role: STUDY_CHAIR
References:
citation: Lorenzen T, Stoehr A, Walther I, Plettenberg A. CCR5 antagonists in the treatment of treatment-experienced patients infected with CCR5 tropic HIV-1. Eur J Med Res. 2007 Oct 15;12(9):419-25.
citation: Rusconi S, Scozzafava A, Mastrolorenzo A, Supuran CT. An update in the development of HIV entry inhibitors. Curr Top Med Chem. 2007;7(13):1273-89. doi: 10.2174/156802607781212239.