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

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ClinicalTrials.gov Identifier: NCT02394730
Recruitment Status : Completed
First Posted : March 20, 2015
Results First Posted : February 28, 2019
Last Update Posted : March 6, 2019
Sponsor:
Collaborators:
National Institute of Allergy and Infectious Diseases (NIAID)
University of Minnesota - Clinical and Translational Science Institute
University of Melbourne
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Kirby Institute

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
HIV Drug: vorapaxar Drug: Placebo Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 65 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : September 2015
Actual Primary Completion Date : November 2017
Actual Study Completion Date : January 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

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 Name: Zontivity

Placebo Comparator: Placebo
sugar pill po qd
Drug: Placebo
Sugar pill taken orally once daily for 12 weeks
Other Name: sugar pill




Primary Outcome Measures :
  1. Mean Percent Change From Baseline for D-dimer (ng/mL) to the Average of Weeks 8 and 12 [ Time Frame: at week 8 and week 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.


Secondary Outcome Measures :
  1. Number of Participants in Each Treatment Group With Plasma HIV-1 RNA <50 Copies/mL [ Time Frame: at week 18 ]
    Number of participants in each treatment group with plasma HIV-1 RNA <50 copies/mL at week 18

  2. Mean Change From Baseline to Week 12 in CD4+ Cell Counts [ Time Frame: at week 12 ]
    Mean of week 12 CD4+ cell count minus mean of week 0 CD4+ cell count

  3. Mean Change From Baseline to Week 12 in CD8+ Cell Counts [ Time Frame: at week 12 ]
    Mean of week 12 CD8+ cell count minus mean of week 0 CD4+ cell count

  4. 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 <165ng/mL at week 12

  5. Number of Patients in Each Treatment Group With D-dimer > or Equal to 165ng/mL at Week 18 [ Time Frame: week 18 ]
    Number of patients in each treatment group with d-dimer > or equal to 165ng/mL at week 18

  6. Mean Change From Baseline in log10 D-Dimer [ Time Frame: at week 18 ]
    Differences between treatment groups in mean change from week 0 log10 d-dimer to week 18

  7. Mean Change From Baseline in log10 Hs-CRP at Week 18 [ Time Frame: 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

  8. Percent Change From Baseline Hs-CRP (ug/mL) to the Average of Week 8 and Week 12 [ Time Frame: week 8 and 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.

  9. Mean Percent Change From Baseline IL-6 (pg/mL) to the Average of Week 8 and Week 12 [ Time Frame: at 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.

  10. Differences Between Treatment Groups in Mean Change From Baseline log10 IL-6 [ Time Frame: at week 18 ]
    Differences between treatment groups in mean change from baseline log10 IL-6 at week 18

  11. Total Number of Participants With BARC Type 1, 2, 3, 4, or 5 Bleeding Episodes [ Time Frame: at week 18 ]
    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 -

  12. Total Number of Participants With Any SAE Between Baseline and Week 18 [ Time Frame: week 18 ]
    Total number of participants with any SAE between baseline and week 18

  13. Total Number of Participants With Any AE Between Baseline to Week 18 [ Time Frame: week 18 ]
    Total number of participants with any AE between week 0 to week 18

  14. Changes From Baseline in Renal Function Measured by the CKD-EPI Estimate of Creatinine Clearance at Week 12 [ Time Frame: at week 12 ]
    Changes from baseline in renal function measured by the CKD-EPI estimate of creatinine clearance at week 12



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Ages Eligible for Study:   40 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02394730


Locations
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United States, Maryland
Georgetown University Hospital
Georgetown, Maryland, United States, 20007
United States, Minnesota
Hennepin County Medical Centre
Minneapolis, Minnesota, United States, 55415
Australia, New South Wales
St Vincent's Hospital
Darlinghurst, New South Wales, Australia, 2010
Taylor Square Private Clinic
Darlinghurst, New South Wales, Australia, 2010
Australia, Victoria
Melbourne Sexual Health Centre
Carlton, Victoria, Australia, 3053
Monash Medical Centre
Melbourne, Victoria, Australia, 3168
Northside Clinic
North Fitzroy, Victoria, Australia, 3068
Sponsors and Collaborators
Kirby Institute
National Institute of Allergy and Infectious Diseases (NIAID)
University of Minnesota - Clinical and Translational Science Institute
University of Melbourne
Merck Sharp & Dohme Corp.
Investigators
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Study Director: Sean Emery University of NSW, Kirby Institute
  Study Documents (Full-Text)

Documents provided by Kirby Institute:
Study Protocol  [PDF] July 12, 2016
Statistical Analysis Plan  [PDF] November 13, 2017


Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Kirby Institute
ClinicalTrials.gov Identifier: NCT02394730     History of Changes
Other Study ID Numbers: 2014-01-ADV
AI000585-26-288416 ( Other Identifier: NIAID )
First Posted: March 20, 2015    Key Record Dates
Results First Posted: February 28, 2019
Last Update Posted: March 6, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Keywords provided by Kirby Institute:
HIV, d-dimer, hs-CRP, activated T-lymphocytes

Additional relevant MeSH terms:
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Vorapaxar
Platelet Aggregation Inhibitors