Effects of Treatment With Aprepitant (Emend®) in HIV Infected Individuals

DESIGN

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.

DURATION

42 days.

SAMPLE SIZE and POPULATION

27 HIV infected males and females ≥ 18 years old who have early infection with CD4 cell counts ≥ 350 cells/mm3.

REGIMEN

Subjects will be randomized 1:1:1 to receive two different doses of aprepitant (Emend®) or placebo.

• Arm A: Aprepitant placebo
• Arm B: Aprepitant 125 mg QD
• Arm C: Aprepitant 250 mg QD

HYPOTHESIS AND STUDY OBJECTIVES

• Hypothesis : Aprepitant is safe, tolerable, and has antiviral activity in HIV infected individuals.
• Primary Objectives:

• To assess the safety and tolerability of aprepitant for 2 weeks at two different doses.
• To assess the response of plasma HIV-1 RNA to two different doses of aprepitant compared with baseline.
• Secondary Objectives:

• To investigate the course and duration of antiretroviral response to 2 different doses 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.

Inclusion criteria

• HIV-1 infection, as documented by any licensed ELISA test kit and confirmed by Western blot at any time prior to study entry. HIV-1 culture, HIV-1 antigen, plasma HIV-1 RNA, or a second antibody test by a method other than ELISA is acceptable as an alternative confirmatory test.
• CD4+ cell count ≥ 350/mm3 obtained within 90 days prior to study entry and performed at any CLIA-certified laboratory.
• Plasma HIV-1 RNA of ≥ 2000 copies/mL as measured by any standard assay (the Roche UltraSensitive HIV-1 Monitor assay (Roche Molecular Systems), or Version 3 bDNA assay or other) and performed within 90 days prior to study entry by any laboratory that is CLIA-certified (or its equivalent) for the assay.
• CCR5 tropic virus exclusively as determined by the Monogram tropism assay (PhenoSense Entry™).
• Laboratory values obtained within 30 days prior to study entry, as follows:

• Absolute neutrophil count (ANC) greater than 750/mm3
• Hemoglobin greater than 10.0 g/dL
• Platelet count greater than 100,000/mm3
• Creatinine less than 2 x ULN (fasting)
• AST (SGOT), ALT (SGPT), and alkaline phosphatase less than 2 x ULN
• Total bilirubin less than 2.5 x ULN
• Albumin greater than 3 g/dL
• Serum lipase less than 1.5 x ULN
• Female subjects of reproductive potential must have a negative spot urine pregnancy test result (with a sensitivity of at least 50 mIU/mL) performed at entry, prior to starting initial study treatment.
• All subjects must agree not to participate in a conception process while on study drug and for 30 days after stopping the medication.

If participating in sexual activity that could lead to pregnancy, the female study subject must use at least one of the forms of contraception listed below while receiving the protocol-specified medication and for 30 days after stopping the medication:

• Condoms (male or female) with or without a spermicidal agent
• Diaphragm or cervical cap with spermicide
• IUD

Female subjects, who are not of reproductive potential defined as women who have been post-menopausal for at least 24 consecutive months, or women who have undergone surgical sterilization, (e.g. hysterectomy, bilateral oophorectomy, or salpingotomy) are eligible without requiring the use of contraception. Subject reported history is acceptable for documentation of sterilization, other contraceptive methods, menopause and a child's reproductive potential.

• Karnofsky performance score greater than 80 within 30 days prior to study entry.
• Men and women greater than 18 years of age.
• Ability and willingness of subject or legal guardian/representative to give written informed consent.
• Willing to return for a follow-up visit on day 42.
• Subjects taking any precautionary concomitant medications must be on stable doses for > 8 weeks prior to study entry and have no plans to change medications or doses for the duration of the study.

Exclusion criteria

• Receipt of antiretroviral treatment within the 16 weeks prior to study entry or intent to initiate antiretroviral therapy within 60 days after entry.
• Diabetes requiring treatment with oral hypoglycemics or insulin therapy.
• Pregnancy within 90 days prior to study entry.
• Breast-feeding.
• Use of drugs that are inhibitors or inducers of metabolism by the cytochrome P450 CYP3A4 or CYP2C9 (such as warfarin and phenytoin) within 7 days of study entry.
• Use of systemic corticosteroids or hormonal agents within 90 days prior to study entry.
• Use of any immunomodulator, HIV vaccines, or investigational therapy within 90 days prior to study entry.
• Any vaccination within 30 days prior to study entry.
• Use of systemic cytotoxic chemotherapy within 90 days prior to study entry.
• History of allergy to aprepitant or its formulations.
• Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements.
• History of chronic active hepatitis B or C infection or severe hepatic dysfunction (Child-Plug score > 9) regardless of etiology.
• Serious illness requiring systemic treatment and/or hospitalization until subject either completes therapy or is clinically stable on therapy, in the opinion of the investigator, for at least 14 days prior to study entry.
• Weight < 40 kg or 88 lbs within 90 days prior to study entry.
• History of severe psychiatric comorbidities, such as depression, schizophrenia, mania, psychosis.