Attenuation of D-dimer Using Vorapaxar to Target Inflammatory and Coagulation Endpoints

Study Overview
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Brief Summary
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ADVICE is a randomised, international, double-blind, placebo-controlled trial. The purpose of the ADVICE study is to compare the safety and efficacy of vorapaxar in reducing d-dimer expression and markers of cellular immune activation over a period of 12 weeks among people with HIV infection who are successfully treated with combination antiretroviral therapy containing an HIV integrase inhibitor. A secondary objective of the study will be to demonstrate that following cessation of vorapaxar in patients with well controlled HIV replication there will be an increase in the levels of d-dimer over a 6 week period. 60 participants from 4 clinical sites in Australia and the USA will be recruited and followed for a minimum of 18 weeks.

Detailed Description
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Consenting participants will be screened and within 14 days randomly allocated to receive either vorapaxar (2.5mg) or matched placebo once daily for 12 weeks (phase 1). Participants will be seen one week after randomisation and then at weeks 4, 8 and 12 (phase 1). At the week 12 visit, patients will not be dispensed any study treatment. In phase 2 all study treatment will stop for 6 weeks. At week 18 patients will be seen for a final study visit.

Official Title
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A Double Blind Randomised Comparison of Vorapaxar Versus Placebo for the Treatment of HIV Associated Inflammation and Coagulopathy in Patients With Well Controlled HIV Replication

Conditions
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HIV

Intervention / Treatment
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* Drug: vorapaxar
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 positive by licensed diagnostic test aged ≥40 years plasma HIV RNA <50 copies/mL for at least 24 weeks screening CD4+ cell count > 50 cells/mm3 treated for at least 12 weeks with a suppressive regimen of combination antiretroviral therapy that does not include HIV protease inhibitors and/or NNRTIs (except rilpivirine) plasma d-dimer >200ng/mL (>0.2μg/mL or >0.2mg/L) fibrinogen equivalent units or >100ng/mL (>0.1 μg/mL or >0.1mg/L) d-dimer units in the absence of established cause (deep vein thrombosis/embolism) provision of written informed consent Exclusion Criteria: Absolute neutrophil count (ANC) <1000 cells/μL hemoglobin <10.0 g/dL platelet count <75,000 cells/μL AST and/or ALT >2.5 x ULN estimated glomerular filtration rate <30mL/min/1.73m2 ) using CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation history of myocardial infarction or unstable atherosclerotic disease history of ischemic stroke or transient ischaemic attack (TIA) active peptic/duodenal ulcer or other bleeding disorder within the previous 12 months intent to have surgery within the 6 month period after randomisation current use of aspirin or P2Y12 antiplatelet therapy use of anticoagulants, (eg. heparin or warfarin), fibrinolytic therapy, chronic use (more than 5 consecutive days) of nonsteroidal anti-inflammatory drugs (NSAIDS), strong CYP3A4 inhibitors or inducers. See Manual of Operations for full list of medications to avoid. participants unlikely to be able to remain in follow-up pregnant or nursing mothers in the clinical judgement of the investigator, participation in this trial is deemed inappropriate as this may conflict with the well-being of the participant.

Ages Eligible for Study
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Minimum Age: 40 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: vorapaxar<br>2.5mg of vorapaxar po qd | Drug: vorapaxar<br>* 2.5mg of vorapaxar taken orally once daily for 12 weeks<br>* Other names: Zontivity;|
| Placebo Comparator: Placebo<br>sugar pill po qd | Drug: Placebo<br>* Sugar pill taken orally once daily for 12 weeks<br>* Other names: sugar pill;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Percent Change From Baseline for D-dimer (ng/mL) to the Average of Weeks 8 and 12 | Mean of week 8 and week 12 minus week 0 (on log10 scale) then back transforming the log10 difference to obtain percentage change from baseline. | at week 8 and week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants in Each Treatment Group With Plasma HIV-1 RNA <50 Copies/mL | Number of participants in each treatment group with plasma HIV-1 RNA <50 copies/mL at week 18 | at week 18 | 
| Mean Change From Baseline to Week 12 in CD4+ Cell Counts | Mean of week 12 CD4+ cell count minus mean of week 0 CD4+ cell count | at week 12 | 
| Mean Change From Baseline to Week 12 in CD8+ Cell Counts | Mean of week 12 CD8+ cell count minus mean of week 0 CD4+ cell count | at week 12 | 
| Number of Patients in Each Treatment Group With D-dimer <165ng/mL at Week 12 | Number of patients in each treatment group with d-dimer <165ng/mL at week 12 | week 12 | 
| Number of Patients in Each Treatment Group With D-dimer > or Equal to 165ng/mL at Week 18 | Number of patients in each treatment group with d-dimer > or equal to 165ng/mL at week 18 | week 18 | 
| Mean Change From Baseline in log10 D-Dimer | Differences between treatment groups in mean change from week 0 log10 d-dimer to week 18 | at week 18 | 
| Mean Change From Baseline in log10 Hs-CRP at Week 18 | Differences between treatment groups in mean change from baseline log10 hs-CRP to week 18. ie Week 18 log10 hs-CRP minus week 0 log10 hs-CRP | at week 18 | 
| Percent Change From Baseline Hs-CRP (ug/mL) to the Average of Week 8 and Week 12 | Mean of week 8 and week 12 minus week 0 (on log10 scale) then back transformed the log10 difference to obtain percentage change from baseline. | week 8 and 12 | 
| Mean Percent Change From Baseline IL-6 (pg/mL) to the Average of Week 8 and Week 12 | Mean of week 8 and week 12 minus week 0 (on log10 scale) then back transformed the log10 difference to obtain percentage change from baseline. | at week 8 and week 12 | 
| Differences Between Treatment Groups in Mean Change From Baseline log10 IL-6 | Differences between treatment groups in mean change from baseline log10 IL-6 at week 18 | at week 18 | 
| Total Number of Participants With BARC Type 1, 2, 3, 4, or 5 Bleeding Episodes | Bleeding Academic Research Consortium (BARC) Definitions for Bleeding Events Type 1 -bleeding that is not actionable and does not cause the patient to seek unscheduled performance of studies, hospitalization, or treatment by a healthcare professional; may include episodes leading to self-discontinuation of medical therapy by the patient without consulting a healthcare professional Type 2 - overt, actionable sign of haemorrhage (eg, more bleeding than would be expected for a clinical circumstance, including bleeding found by imaging alone) that does not fit the criteria for type 3, 4, or 5 but does meet at least one of the following criteria: (1) requiring nonsurgical, medical intervention by a healthcare professional, (2) leading to hospitalization or increased level of care, or (3) prompting evaluation Type 3- Bleeding requiring surgical intervention for control (excluding dental/nasal/skin/hemorrhoid) Type 4 - Coronary Artery Bypass Graft procedure-related bleeding Type 5 - | at week 18 | 
| Total Number of Participants With Any SAE Between Baseline and Week 18 | Total number of participants with any SAE between baseline and week 18 | week 18 | 
| Total Number of Participants With Any AE Between Baseline to Week 18 | Total number of participants with any AE between week 0 to week 18 | week 18 | 
| Changes From Baseline in Renal Function Measured by the CKD-EPI Estimate of Creatinine Clearance at Week 12 | Changes from baseline in renal function measured by the CKD-EPI estimate of creatinine clearance at week 12 | at week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, d-dimer, hs-CRP, activated T-lymphocytes