Pharmacokinetic Characteristics and Anti-Inflammatory Effects of Aprepitant In HIV-Infected Subjects

NCT02154360 | Completed Phase 1 DMC

• 1 other identifier: UPenn 819693
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

This is an open-label, single arm, phase I study to determine the safety, PK characteristics and anti-inflammatory effects of the NK-R1 coadministered with ritonavir-containing antiretroviral therapy in individuals with well-controlled viral replication. Our hypothesis is that Aprepitant will be safe, well tolerated, and will have anti-inflammatory properties when administered concomitantly with the protease inhibitor ritonavir.

Conditions

HIV Infection

Keywords

HIV infection; NK-1R antagonists; aprepitant; ritonavir boosting

Outcome Measures

Primary Outcomes (6)

• Inflammatory

  Change in levels of Soluble CD163 from baseline to Day 14.

  14 days

• Safety

  Incidence of Grade 2, 3, and 4 adverse events (using the DAIDS grading scale) by body system and by type. Lack of virologic control is considered a safety event for the purpose of this trial.

  28 days

• Pharmacokinetic Cmin:

  Trough plasma aprepitant concentration.

  day 1, 14 and 28

• Pharmacokinetic Cmax

  Maximum plasma concentration.

  day 1, 14 and 28

• Pharmacokinetic Tmax

  Time to maximum plasma concentration

  day 1, 14 and 28

• Pharmacokinetic AUCss

  Area under the plasma concentration-time curve at steady-state (based on steady-state assessment of trough concentrations or via modeling).

  day 1, 14 and 28

Secondary Outcomes (3)

• Inflammatory markers

  28 days

• Lipids

  28 days

• Neurological

  28 days

Study Arms (1)

Aprepitant

EXPERIMENTAL

Subjects will add 375 mg daily dosing of aprepitant (Emend®) to their current antiretroviral therapy for 28 days. * 6 participants will be receiving an antiretroviral regimen containing atazanavir/ritonavir (300/100 mg) daily plus two other antiretrovirals. * 6 participants will be receiving an antiretroviral regimen containing darunavir/ritonavir (800/100 mg) daily plus two other antiretrovirals.

Drug: Aprepitant

Interventions

Aprepitant DRUG

Subjects will add 375 mg daily dosing of aprepitant (Emend®) to their current antiretroviral therapy for 28 days

Also known as: Emend

Aprepitant

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Antiretroviral treatment with a regimen that includes either atazanavir 300 mg daily with ritonavir 100 mg daily or darunavir/ritonavir on a combination of 800/100 mg daily for at least 6 months prior to enrollment.
• CD4+ cell count ≥ 350/mm3 for at least 6 months prior to enrollment and performed at any CLIA-certified laboratory.
• Plasma HIV-1 RNA below the limit of quantification of an ultrasensitive assay as measured by any standard assay (the Roche Amplicor, the UltraSensitive HIV-1 Monitor assay (Roche Molecular Systems), or Version 3 bDNA assay or other) for at least 6 months prior to enrollment by any laboratory that is CLIA-certified (or its equivalent) for the assay.
• Laboratory values obtained within 30 days prior to study entry, as follows:
• Absolute neutrophil count (ANC) greater or equal than 750/mm3
• Hemoglobin greater or equal than 10.0 g/dL
• Platelet count greater or equal than 100,000/mm3
• Creatinine less or equal than 2 x ULN (fasting)
• AST (SGOT), ALT (SGPT), and alkaline phosphatase less or equal than 2 x ULN
• Total bilirubin less or equal than 2.5 x ULN
• Albumin greater or equal than 3 g/dL
• 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.

You may not qualify if:

• Diabetes requiring treatment with oral hypoglycemics or insulin therapy.
• Pregnancy within 90 days prior to study entry.
• Use of inhibitors of metabolism by the cytochrome P450 3A4 with the exception of ritonavir, atazanavir and darunavir (i.e. Diltiazem, Ketoconazole, Clarithromycin, Nelfinavir, Itraconazole, Nefazodone, Troleandomycin)
• Use of inducers of metabolism by the cytochrome P450 3A4 (i.e.: Rifampin, Carbamazepine, Phenytoin) with the exception of the protease inhibitors considered in this trial.
• Breast-feeding.
• 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. However, if the experimental agent has a short half life, as determined by the Principal Investigator, the required wash out period can be reduced to 30 days.
• 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-Pugh 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

Sponsors & Collaborators

• University of Pennsylvania: lead

Study Sites (1)

Hospital of the University of Pennsylvania Clinical Research Site

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (4)

• Tebas P, Tuluc F, Barrett JS, Wagner W, Kim D, Zhao H, Gonin R, Korelitz J, Douglas SD. A randomized, placebo controlled, double masked phase IB study evaluating the safety and antiviral activity of aprepitant, a neurokinin-1 receptor antagonist in HIV-1 infected adults. PLoS One. 2011;6(9):e24180. doi: 10.1371/journal.pone.0024180. Epub 2011 Sep 8.

  PMID: 21931661 BACKGROUND

• Manak MM, Moshkoff DA, Nguyen LT, Meshki J, Tebas P, Tuluc F, Douglas SD. Anti-HIV-1 activity of the neurokinin-1 receptor antagonist aprepitant and synergistic interactions with other antiretrovirals. AIDS. 2010 Nov 27;24(18):2789-96. doi: 10.1097/QAD.0b013e3283405c33.

  PMID: 20975512 BACKGROUND

• Wang X, Douglas SD, Lai JP, Tuluc F, Tebas P, Ho WZ. Neurokinin-1 receptor antagonist (aprepitant) inhibits drug-resistant HIV-1 infection of macrophages in vitro. J Neuroimmune Pharmacol. 2007 Mar;2(1):42-8. doi: 10.1007/s11481-006-9059-6. Epub 2007 Jan 12.

  PMID: 18040825 BACKGROUND

• Spitsin S, Tebas P, Barrett JS, Pappa V, Kim D, Taylor D, Evans DL, Douglas SD. Antiinflammatory effects of aprepitant coadministration with cART regimen containing ritonavir in HIV-infected adults. JCI Insight. 2017 Oct 5;2(19):e95893. doi: 10.1172/jci.insight.95893.

  PMID: 28978797 DERIVED

MeSH Terms

Conditions

HIV Infections

Interventions

Aprepitant

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Morpholines; Oxazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Pablo Tebas, MD

  University of Pennsylvania

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 22, 2014
• First Posted: June 3, 2014
• Study Start: May 1, 2014
• Primary Completion: December 1, 2015
• Study Completion: June 1, 2016
• Last Updated: August 17, 2017

Record last verified: 2017-08

Locations

US (1)