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

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

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.

Study Overview

• Status: Completed
• Conditions: HIV
• Intervention / Treatment: Drug: vorapaxar; Drug: Placebo

Detailed Description

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
• Enrollment (Actual): 65
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Darlinghurst, New South Wales, Australia, 2010
      • St Vincent's Hospital
    • Darlinghurst, New South Wales, Australia, 2010
      • Taylor Square Private Clinic
  • Victoria
    • Carlton, Victoria, Australia, 3053
      • Melbourne Sexual Health Centre
    • Melbourne, Victoria, Australia, 3168
      • Monash Medical Centre
    • North Fitzroy, Victoria, Australia, 3068
      • Northside Clinic
• United States
  • Maryland
    • Georgetown, Maryland, United States, 20007
      • Georgetown University Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55415
      • Hennepin County Medical Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: vorapaxar; 2.5mg of vorapaxar po qd	Drug: vorapaxar; 2.5mg of vorapaxar taken orally once daily for 12 weeks; Other Names: Zontivity
Placebo Comparator: Placebo; sugar pill po qd	Drug: Placebo; Sugar pill taken orally once daily for 12 weeks; Other Names: sugar pill

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Kirby Institute
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID); Merck Sharp & Dohme LLC; University of Minnesota; University of Melbourne
• Investigators: Study Director: Sean Emery, University of NSW, Kirby Institute

Publications and helpful links

General Publications

• ADVICE study group. Vorapaxar for HIV-associated inflammation and coagulopathy (ADVICE): a randomised, double-blind, placebo-controlled trial. Lancet HIV. 2018 Oct;5(10):e553-e559. doi: 10.1016/S2352-3018(18)30214-5. Epub 2018 Sep 23. Erratum In: Lancet HIV. 2019 Jan 25;:

Study record dates

Study Major Dates

• Study Start: September 1, 2015
• Primary Completion (Actual): November 1, 2017
• Study Completion (Actual): January 1, 2018

Study Registration Dates

• First Submitted: March 16, 2015
• First Submitted That Met QC Criteria: March 16, 2015
• First Posted (Estimate): March 20, 2015

Study Record Updates

• Last Update Posted (Actual): March 6, 2019
• Last Update Submitted That Met QC Criteria: March 5, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: HIV, d-dimer, hs-CRP, activated T-lymphocytes
• Additional Relevant MeSH Terms: Platelet Aggregation Inhibitors; Vorapaxar
• Other Study ID Numbers: 2014-01-ADV; AI000585-26-288416 (Other Identifier: NIAID)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided