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

Kirby Institute65 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

HIV

Interventions

Eligibility

Sex: ALLMin age: 40 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. HIV-1 positive by licensed diagnostic test 2. aged ≥40 years 3. plasma HIV RNA \<50 copies/mL for at least 24 weeks 4. screening CD4+ cell count \> 50 cells/mm3 5. 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) 6. 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) 7. provision of written informed consent Exclusion Criteria: 1. Absolute neutrophil count (ANC) \<1000 cells/μL 2. hemoglobin \<10.0 g/dL 3. platelet count \<75,000 cells/μL 4. AST and/or ALT \>2.5 x ULN 5. estimated glomerular filtration rate \<30mL/min/1.73m2 ) using CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation 6. history of myocardial infarction or unstable atherosclerotic disease 7. history of ischemic stroke or transient ischaemic attack (TIA) 8. active peptic/duodenal ulcer or other bleeding disorder within the previous 12 months 9. intent to have surgery within the 6 month period after randomisation 10. current use of aspirin or P2Y12 antiplatelet therapy 11. 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. 12. participants unlikely to be able to remain in follow-up 13. pregnant or nursing mothers 14. 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.

Outcomes

Primary Outcomes

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.

Time frame: at week 8 and week 12

Secondary Outcomes

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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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.

Time frame: 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.

Time frame: 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

Time frame: 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 -

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: at week 12

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

Overview

Conditions

Interventions

Eligibility

Locations (7)

Outcomes

Primary Outcomes

Secondary Outcomes