Clinical trial NCT02154360: Pharmacokinetic Characteristics and Anti-Inflammatory Effects of Aprepitant In HIV-Infected Subjects
Official title: A Phase IB, Open Label Study to Examine the Safety, Pharmacokinetic Characteristics and Anti-Inflammatory Effects of the NK-1R Antagonist, Aprepitant, In HIV-Infected Subjects Receiving Atazanavir/Ritonavir Or Darunavir/Ritonavir
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: HIV Infection
Keywords: HIV infection
NK-1R antagonists
aprepitant
ritonavir boosting
Lead sponsor: University of Pennsylvania
Sponsor class: OTHER
First posted: 2014-06-03
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Detailed description: 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. The study will recruit 12 participants receiving either darunavir/ritonavir or atazanavir/ritonavir

Eligibility criteria: Inclusion Criteria:

1. 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.
2. 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.
3. CD4+ cell count ≥ 350/mm3 for at least 6 months prior to enrollment and performed at any CLIA-certified laboratory.
4. 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.
5. 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
6. 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.
7. 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 female's reproductive potential.
8. Karnofsky performance score greater or equal than 80 within 30 days prior to study entry (Appendix I).
9. Men and women greater or equal than 18 years of age.
10. Ability and willingness of subject or legal guardian/representative to give written informed consent.
11. Willing to return for a follow-up visit on day 58.
12. 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:

1. Diabetes requiring treatment with oral hypoglycemics or insulin therapy.
2. Pregnancy within 90 days prior to study entry.
3. 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)
4. 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.
5. Breast-feeding.
6. Use of systemic corticosteroids or hormonal agents within 90 days prior to study entry.
7. 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.
8. Any vaccination within 30 days prior to study entry.
9. Use of systemic cytotoxic chemotherapy within 90 days prior to study entry.
10. History of allergy to aprepitant or its formulations.
11. Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements.
12. History of chronic active hepatitis B or C infection or severe hepatic dysfunction (Child-Pugh score \> 9) regardless of etiology
13. 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.
14. Weight \< 40 kg or 88 lbs. within 90 days prior to study entry.
15. History of severe psychiatric comorbidities, such as depression, schizophrenia, mania, psychosis

Primary outcomes:
measure: Inflammatory
timeFrame: 14 days
measure: Safety
timeFrame: 28 days
measure: Pharmacokinetic Cmin:
timeFrame: day 1, 14 and 28
measure: Pharmacokinetic Cmax
timeFrame: day 1, 14 and 28
measure: Pharmacokinetic Tmax
timeFrame: day 1, 14 and 28
measure: Pharmacokinetic AUCss
timeFrame: day 1, 14 and 28
Secondary outcomes:
measure: Inflammatory markers
timeFrame: 28 days
measure: Lipids
timeFrame: 28 days
measure: Neurological
timeFrame: 28 days
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania Clinical Research Site
state: Pennsylvania
Study officials:
affiliation: University of Pennsylvania
name: Pablo Tebas, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.