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

Study Overview
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Brief Summary
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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
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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

Official Title
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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

Conditions
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HIV Infection

Intervention / Treatment
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* Drug: Aprepitant


Participation Criteria
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Eligibility Criteria
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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. 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. 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. Karnofsky performance score greater or equal than 80 within 30 days prior to study entry (Appendix I). Men and women greater or equal 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 58. 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: 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aprepitant<br>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<br>* Subjects will add 375 mg daily dosing of aprepitant (Emend®) to their current antiretroviral therapy for 28 days<br>* Other names: Emend;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Inflammatory markers | Change in levels of Soluble CD163 from baseline to Day 28 and 58 Plasma SP levels CD4/PD-1 expression | 28 days | 
| Lipids | Triglycerides Total cholesterol HDL LDL Insulin | 28 days | 
| Neurological | Hamilton-17 Depression Rating Scale (HAM-D-17) score Hamilton- Anxiety Symptoms (HAM-A) score Pittsburgh Sleep Quality Index (PSQI) score | 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV infection, NK-1R antagonists, aprepitant, ritonavir boosting