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CompletedNCT02394730ADVICEUpdated Mar 6, 2019Results posted

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

A Phase 1/2 interventional study of vorapaxar and Placebo in HIV, sponsored by Kirby Institute. Completed at 7 sites in 2 countries. Open to participants aged 40 Years and older. Per ClinicalTrials.gov, last updated 2019-03-06.

Sponsored by Kirby Institute · Phase 1/2, Interventional, and Treatment

Phase
Phase 1/2
Study type
Interventional
Enrollment
65
Allocation
Randomized
Ages
40 Years and older
Sex
All
01

Study 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.

Read the 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.

02

Conditions studied

  • HIV

Keywords

  • HIV, d-dimer, hs-CRP, activated T-lymphocytes
03

In context

Lead sponsor

Kirby Institute is the lead sponsor of 94 studies on the registry; 15 are open to participants now.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
40 Years and older
Sexes eligible
All
Accepts healthy volunteers
No

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

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.
05

Study design

Phase
Phase 1 / Phase 2
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment
65 participants (actual)

Study arms

  • Experimental
    vorapaxar

    2.5mg of vorapaxar po qd

    Drug: vorapaxar

  • Placebo comparator
    Placebo

    sugar pill po qd

    Drug: Placebo

Interventions

  • Drugvorapaxar

    2.5mg of vorapaxar taken orally once daily for 12 weeks

    Also known as: Zontivity

  • DrugPlacebo

    Sugar pill taken orally once daily for 12 weeks

    Also known as: sugar pill

06

What researchers measure

Primary outcomes

  1. 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

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

07

Results

Posted Feb 28, 2019

Participant flow

Participants were screened and randomised from 2 sites in USA and 5 sites in Australia.

Participant flow — Overall Study
MilestoneVorapaxarPlacebo
Started3431
Completed3330
Not completed11
Withdrew: Lost to follow-up10
Withdrew: Withdrawal by subject01

Outcome measures

PrimaryMean 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
Reported as:
Mean · percent
Mean Percent Change From Baseline for D-dimer (ng/mL) to the Average of Weeks 8 and 12
percentVorapaxarPlacebo
Mean Percent Change From Baseline for D-dimer (ng/mL) to the Average of Weeks 8 and 12-10.8 (-23.1 to 3.4)-8.5 (-18.4 to 2.5)
SecondaryNumber 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
Reported as:
Count of participants · Participants
Number of Participants in Each Treatment Group With Plasma HIV-1 RNA <50 Copies/mL
ParticipantsVorapaxarPlacebo
Number of Participants in Each Treatment Group With Plasma HIV-1 RNA <50 Copies/mL3129
SecondaryMean 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
Reported as:
Mean · cells/mm3
Mean Change From Baseline to Week 12 in CD4+ Cell Counts
cells/mm3VorapaxarPlacebo
Mean Change From Baseline to Week 12 in CD4+ Cell Counts-21.3 ± 143.7-29.7 ± 400.3
SecondaryMean 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
Reported as:
Mean · cells/mm3
Mean Change From Baseline to Week 12 in CD8+ Cell Counts
cells/mm3VorapaxarPlacebo
Mean Change From Baseline to Week 12 in CD8+ Cell Counts3 ± 191.681.1 ± 244.7
SecondaryNumber 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
Reported as:
Count of participants · Participants
Number of Patients in Each Treatment Group With D-dimer <165ng/mL at Week 12
ParticipantsVorapaxarPlacebo
Number of Patients in Each Treatment Group With D-dimer <165ng/mL at Week 1212
SecondaryNumber 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
Reported as:
Count of participants · Participants
Number of Patients in Each Treatment Group With D-dimer > or Equal to 165ng/mL at Week 18
ParticipantsVorapaxarPlacebo
Number of Patients in Each Treatment Group With D-dimer > or Equal to 165ng/mL at Week 183229
SecondaryMean 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
Reported as:
Mean · percent change
Mean Change From Baseline in log10 D-Dimer
percent changeVorapaxarPlacebo
Mean Change From Baseline in log10 D-Dimer-2.21 (-17.9 to 16.5)-14.1 (-17.7 to 17.9)
SecondaryMean 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
Reported as:
Mean · pg/mL
Mean Change From Baseline in log10 Hs-CRP at Week 18
pg/mLVorapaxarPlacebo
Mean Change From Baseline in log10 Hs-CRP at Week 18-0.03 ± 0.39-0.10 ± 0.54
SecondaryPercent 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
Reported as:
Mean · Percent
Percent Change From Baseline Hs-CRP (ug/mL) to the Average of Week 8 and Week 12
PercentVorapaxarPlacebo
Percent Change From Baseline Hs-CRP (ug/mL) to the Average of Week 8 and Week 12-0.02 (-41.3 to 70.2)-15.7 (-40.9 to 20.2)
SecondaryMean 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
Reported as:
Mean · percent
Mean Percent Change From Baseline IL-6 (pg/mL) to the Average of Week 8 and Week 12
percentVorapaxarPlacebo
Mean Percent Change From Baseline IL-6 (pg/mL) to the Average of Week 8 and Week 1212.6 (-15.6 to 50.4)-11.6 (-29.1 to 10.3)
SecondaryDifferences 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
Reported as:
Mean · pg/mL
Differences Between Treatment Groups in Mean Change From Baseline log10 IL-6
pg/mLVorapaxarPlacebo
Differences Between Treatment Groups in Mean Change From Baseline log10 IL-60.03 ± 0.36-0.10 ± 0.25
SecondaryTotal 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
Reported as:
Count of participants · Participants
Total Number of Participants With BARC Type 1, 2, 3, 4, or 5 Bleeding Episodes
ParticipantsVorapaxarPlacebo
Total Number of Participants With BARC Type 1, 2, 3, 4, or 5 Bleeding Episodes1210
SecondaryTotal 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
Reported as:
Count of participants · Participants
Total Number of Participants With Any SAE Between Baseline and Week 18
ParticipantsVorapaxarPlacebo
Total Number of Participants With Any SAE Between Baseline and Week 1832
SecondaryTotal 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
Reported as:
Count of participants · Participants
Total Number of Participants With Any AE Between Baseline to Week 18
ParticipantsVorapaxarPlacebo
Total Number of Participants With Any AE Between Baseline to Week 182828
SecondaryChanges 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
Reported as:
Mean · ml/min/1.73m2
Changes From Baseline in Renal Function Measured by the CKD-EPI Estimate of Creatinine Clearance at Week 12
ml/min/1.73m2VorapaxarPlacebo
Changes From Baseline in Renal Function Measured by the CKD-EPI Estimate of Creatinine Clearance at Week 122.08 ± 8.382.05 ± 7.71

Adverse events

Collected over 18 weeks. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Vorapaxar0/33 (0%)2/33 (6.1%)15/33 (45.5%)
Placebo0/31 (0%)2/31 (6.5%)22/31 (71%)
Most frequent serious events
Most frequent serious events
EventVorapaxarPlacebo
PneumoniaRespiratory, thoracic and mediastinal disorders0/331/31
ColitisGastrointestinal disorders0/331/31
spinal stenosisNervous system disorders1/330/31
Post Procedural haematomaInjury, poisoning and procedural complications1/330/31
GoutMetabolism and nutrition disorders1/330/31
Most frequent other events
Showing 10 of 14
Most frequent other events
EventVorapaxarPlacebo
Upper Respiratory Tract InjectionRespiratory, thoracic and mediastinal disorders4/337/31
EpistaxisBlood and lymphatic system disorders4/332/31
HeadacheNervous system disorders4/332/31
LacerationInjury, poisoning and procedural complications3/333/31
ContusionMusculoskeletal and connective tissue disorders1/333/31
Back painMusculoskeletal and connective tissue disorders1/332/31
DizzinessNervous system disorders0/332/31
Pain in extremetyMusculoskeletal and connective tissue disorders0/332/31
ParaesthesiaNervous system disorders0/332/31
VomitingGastrointestinal disorders0/332/31

Baseline characteristics

1 participant was lost to follow up immediately after randomisation and did not receive a single dose of study drug.

Age, Continuous
Age, Continuous(years)VorapaxarPlaceboTotal
Median53 (48 to 58)52 (48 to 60)52 (48 to 60)
Sex: Female, Male
Sex: Female, Male(Participants)VorapaxarPlaceboTotal
Female235
Male312859
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)VorapaxarPlaceboTotal
White252348
Asian123
Black7512
Hispanic/Latino011
Region of Enrollment
Region of Enrollment(participants)VorapaxarPlaceboTotal
United States121022
Australia212142
Total Cholesterol
Total Cholesterol(mmol/L)VorapaxarPlaceboTotal
Median4.6 (4.0 to 5.5)4.7 (3.9 to 5.4)4.7 (4.0 to 5.4)
HDL Cholesterol
HDL Cholesterol((mmol/L))VorapaxarPlaceboTotal
Median1.2 (1.0 to 1.4)1.3 (0.9 to 1.6)1.2 (1 to 1.5)
Systolic blood pressure
Systolic blood pressure((mm Hg))VorapaxarPlaceboTotal
Median125 (115 to 133)127 (120 to 136)126.5 (117.5 to 135)
Diastolic blood pressure
Diastolic blood pressure((mm Hg))VorapaxarPlaceboTotal
Median77 (70 to 85)80 (70 to 86)78.5 (70 to 85.5)

9 further baseline measures are reported on the registry.

08

Study locations

7 sites
  • Georgetown University Hospital
    Georgetown, Maryland 20007, United States
  • Hennepin County Medical Centre
    Minneapolis, Minnesota 55415, United States
  • St Vincent's Hospital
    Darlinghurst, New South Wales 2010, Australia
  • Taylor Square Private Clinic
    Darlinghurst, New South Wales 2010, Australia
  • Melbourne Sexual Health Centre
    Carlton, Victoria 3053, Australia
  • Monash Medical Centre
    Melbourne, Victoria 3168, Australia
  • Northside Clinic
    North Fitzroy, Victoria 3068, Australia
09

References and documents

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 Dec;6(12):e815. doi: 10.1016/S2352-3018(19)30009-8. PubMed 30257802 ↗

Study documents

  • Study protocol · Jul 12, 2016
  • Statistical analysis plan · Nov 13, 2017

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Undecided

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Mar 6, 2019, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT02394730
Lead sponsor
Kirby Institute
Collaborators
National Institute of Allergy and Infectious Diseases (NIAID), University of Minnesota, University of Melbourne, Merck Sharp & Dohme LLC
Responsible party
Sponsor
First posted
Mar 20, 2015
Start date
Sep 2015
Primary completion
Nov 2017
Completion
Jan 2018
Results posted
Feb 28, 2019
Last update
Mar 6, 2019

Study contacts

Sean Emery
study director · University of NSW, Kirby Institute

Oversight

Data monitoring committee
Yes
View the source record on ClinicalTrials.gov ↗

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This study is completed, as verified in Mar 2019. You cannot join it, but the record below documents what was studied.

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