Effects of Treatment With Aprepitant (Emend®) in HIV Infected Individuals. 375 mg Dose
The investigators' in vitro data suggest that Neurokinin-1 receptor antagonists like aprepitant will decrease the expression of CCR5, an essential co-receptor in the life cycle of HIV, in the surface of macrophages and lymphocytes to levels at least similar to those observed in patients heterozygous for the CCR5 32 mutation. Together with a direct potential antiviral effect this could alter disease progression in patients with HIV infection.
The investigators' hypothesis is that aprepitant is safe, tolerable and has antiviral activity in HIV infected individuals.
This is randomized, placebo controlled, double blind study to determine the safety and antiviral activity of aprepitant by comparing the change in HIV RNA viral load after 2 weeks of aprepitant monotherapy.
18 HIV infected males and females ≥ 18 years old who have early infection with CD4 cell counts ≥ 350 cells/mm3. Subjects will be randomized 1:1 to receive 375 mg of aprepitant (Emend®) or placebo.
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
|Official Title:||A Phase Ib, Randomized, Placebo Controlled, Double Blind Study to Determine the Safety, Viral Suppression, Pharmacokinetics and Immune Modulatory Effects of Treatment With Aprepitant (Emend®) in HIV Infected Individuals|
- Virologic: Change in log10 HIV-1 RNA from baseline to Day 14 [ Time Frame: 14 days ] [ Designated as safety issue: No ]For the purposes of assessing the primary analysis of efficacy of aprepitant in reducing viral load we will be assessing the difference between the log10 viral load at baseline and at 4 weeks, and constructing a 95% confidence interval around this mean difference within each dose group.
- Safety: Incidence of Grade 2, 3, and 4 adverse events [ Time Frame: 42 days ] [ Designated as safety issue: Yes ]The frequency of grade 2,3 and 4 adverse events for the duration of the study will be measured to assess the safety of the compund in this population. Exact binomial confidence intervals will be calculated around the event rates for any individual adverse events that occur and for the overall rate of adverse events within each body system. For each patient the highest grade occurring adverse event within each body system will be assessed. Tables for adverse events by body system and severity of adverse event will be constructed.
- Pharmacokinetic [ Time Frame: 14 days ] [ Designated as safety issue: No ]Individual patient data will be summarized using a noncompartmental analysis (NCA) approach as well as a model-based approach.
- Immunologic [ Time Frame: 14 days ] [ Designated as safety issue: No ]
A descriptive analysis of the following parameters by arm at each time point will be done:
- CCR5 mRNA copy number per cell and CCR5 density by flow cytometry.
- CD4+ cell count at baseline, Days 3, 7, 10, 14, and 42.
- Time to permanent discontinuation of study treatment for any reason.
- Baseline coreceptor phenotype (CCR5, CXCR4, or mixed).
- Time to change from CCR5-only virus to mixed CCR5/CXCR4 or CXCR4-only virus as detected by the phenotype/genotype assays that will be used in this study.
- Neurologic [ Time Frame: 14 days ] [ Designated as safety issue: No ]Evaluate individual changes from baseline to 14 days for these subjects in the HAM-D 17 Depression Rating Scale score, the HAM-A, and the PSQI
|Study Start Date:||December 2010|
|Study Completion Date:||August 2013|
|Primary Completion Date:||August 2013 (Final data collection date for primary outcome measure)|
Active Comparator: Aprepitant
Aprepitant (Emend®) 375 mg daily for 14 days
Aprepitant (Emend®) 375 mg daily for 14 days
Placebo Comparator: Placebo
Aprepitant (Emend®) placebo for 14 days
Drug: Aprepitant placebo
Aprepitant(Emend®) placebo for 14 days
Randomized, placebo controlled, double blind study to determine the safety and antiviral activity of aprepitant by comparing the change in HIV RNA viral load after 2 weeks of aprepitant monotherapy.
SAMPLE SIZE and POPULATION
18 HIV infected males and females ≥ 18 years old who have early infection with CD4 cell counts ≥ 350 cells/mm3.
Subjects will be randomized 1:1 to receive aprepitant (Emend®) or placebo.
Arm A: Aprepitant placebo Arm B: Aprepitant 375 mg QD
HYPOTHESIS AND STUDY OBJECTIVES
Hypothesis : Aprepitant is safe, tolerable, and has antiviral activity in HIV infected individuals.
To assess the safety and tolerability of 375 mg aprepitant for 2 weeks To assess the response of plasma HIV-1 RNA to 375 mg of aprepitant compared with baseline.
To investigate the course and duration of antiretroviral response 375 mg of aprepitant given over a 14-day period.
To evaluate the dose-response and pharmacokinetic and pharmacodynamic relationship between viral RNA change and aprepitant plasma levels.
To evaluate aprepitant effects on CD4+ and CD8+ T-cell counts, circulating SP levels, natural killer cell number and function and CCR5 expression in peripheral PBMCs.
To evaluate the effects of aprepitant in the viral tropism and envelope sequence of the main HIV-1 population of the participants.
To assess viral drug susceptibility in conjunction with baseline coreceptor tropism phenotype and changes in coreceptor phenotype after the exposure to aprepitant.
To evaluate aprepitant effects on fasting plasma glucose, insulin, HDL, free fatty acids, and triglyceride concentrations after 14 days of treatment.
To provide preliminary description of any change from baseline in sleep quality, anxious mood, depressed mood and neurocognitive measures after 2 weeks of aprepitant therapy.
|United States, Pennsylvania|
|Clinical Trials Unit. University of Pennsylvania|
|Philadelphia, Pennsylvania, United States, 19104--607|
|Principal Investigator:||Pablo Tebas, MD||University of Pennsylvania|