Clinical trial NCT02394730: Attenuation of D-dimer Using Vorapaxar to Target Inflammatory and Coagulation Endpoints
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: HIV
Keywords: HIV, d-dimer, hs-CRP, activated T-lymphocytes
Lead sponsor: Kirby Institute
Sponsor class: OTHER_GOV
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
name: University of Minnesota
name: University of Melbourne
name: Merck Sharp & Dohme LLC
First posted: 2015-03-20
Enrollment: 65
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: Mean Percent Change From Baseline for D-dimer (ng/mL) to the Average of Weeks 8 and 12
timeFrame: at week 8 and week 12
Secondary outcomes:
measure: Number of Participants in Each Treatment Group With Plasma HIV-1 RNA <50 Copies/mL
timeFrame: at week 18
measure: Mean Change From Baseline to Week 12 in CD4+ Cell Counts
timeFrame: at week 12
measure: Mean Change From Baseline to Week 12 in CD8+ Cell Counts
timeFrame: at week 12
measure: Number of Patients in Each Treatment Group With D-dimer <165ng/mL at Week 12
timeFrame: week 12
measure: Number of Patients in Each Treatment Group With D-dimer > or Equal to 165ng/mL at Week 18
timeFrame: week 18
measure: Mean Change From Baseline in log10 D-Dimer
timeFrame: at week 18
measure: Mean Change From Baseline in log10 Hs-CRP at Week 18
timeFrame: at week 18
measure: Percent Change From Baseline Hs-CRP (ug/mL) to the Average of Week 8 and Week 12
timeFrame: week 8 and 12
measure: Mean Percent Change From Baseline IL-6 (pg/mL) to the Average of Week 8 and Week 12
timeFrame: at week 8 and week 12
measure: Differences Between Treatment Groups in Mean Change From Baseline log10 IL-6
timeFrame: at week 18
measure: Total Number of Participants With BARC Type 1, 2, 3, 4, or 5 Bleeding Episodes
timeFrame: at week 18
measure: Total Number of Participants With Any SAE Between Baseline and Week 18
timeFrame: week 18
measure: Total Number of Participants With Any AE Between Baseline to Week 18
timeFrame: week 18
measure: Changes From Baseline in Renal Function Measured by the CKD-EPI Estimate of Creatinine Clearance at Week 12
timeFrame: at week 12
Other outcomes:
Locations:
city: Georgetown
country: United States
facility: Georgetown University Hospital
state: Maryland
city: Minneapolis
country: United States
facility: Hennepin County Medical Centre
state: Minnesota
city: Darlinghurst
country: Australia
facility: St Vincent's Hospital
state: New South Wales
city: Darlinghurst
country: Australia
facility: Taylor Square Private Clinic
state: New South Wales
city: Carlton
country: Australia
facility: Melbourne Sexual Health Centre
state: Victoria
city: Melbourne
country: Australia
facility: Monash Medical Centre
state: Victoria
city: North Fitzroy
country: Australia
facility: Northside Clinic
state: Victoria
Study officials:
affiliation: University of NSW, Kirby Institute
name: Sean Emery
role: STUDY_DIRECTOR
References:
citation: 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.