HIV
Conditions
Keywords
HIV, d-dimer, hs-CRP, activated T-lymphocytes
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.
Interventions
DRUGvorapaxar
2.5mg of vorapaxar taken orally once daily for 12 weeks
DRUGPlacebo
Sugar pill taken orally once daily for 12 weeks
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
University of Minnesota
University of Melbourne
Merck Sharp & Dohme LLC
Kirby Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
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
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Percent Change From Baseline for D-dimer (ng/mL) to the Average of Weeks 8 and 12 | 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
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline to Week 12 in CD4+ Cell Counts | at week 12 | Mean of week 12 CD4+ cell count minus mean of week 0 CD4+ cell count |
| Mean Change From Baseline to Week 12 in CD8+ Cell Counts | at week 12 | Mean of week 12 CD8+ cell count minus mean of week 0 CD4+ cell count |
| 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 \<165ng/mL at week 12 |
| Number of Patients in Each Treatment Group With D-dimer > or Equal to 165ng/mL at Week 18 | week 18 | Number of patients in each treatment group with d-dimer \> or equal to 165ng/mL at week 18 |
| Mean Change From Baseline in log10 D-Dimer | at week 18 | Differences between treatment groups in mean change from week 0 log10 d-dimer to week 18 |
| Mean Change From Baseline in log10 Hs-CRP at Week 18 | 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 |
| Number of Participants in Each Treatment Group With Plasma HIV-1 RNA <50 Copies/mL | at week 18 | Number of participants in each treatment group with plasma HIV-1 RNA \<50 copies/mL at week 18 |
| Mean Percent Change From Baseline IL-6 (pg/mL) to the Average of Week 8 and Week 12 | 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. |
| Differences Between Treatment Groups in Mean Change From Baseline log10 IL-6 | at week 18 | Differences between treatment groups in mean change from baseline log10 IL-6 at week 18 |
| Total Number of Participants With BARC Type 1, 2, 3, 4, or 5 Bleeding Episodes | 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 - |
| Total Number of Participants With Any SAE Between Baseline and Week 18 | week 18 | Total number of participants with any SAE between baseline and week 18 |
| Total Number of Participants With Any AE Between Baseline to Week 18 | week 18 | Total number of participants with any AE between week 0 to week 18 |
| Changes From Baseline in Renal Function Measured by the CKD-EPI Estimate of Creatinine Clearance at Week 12 | at week 12 | Changes from baseline in renal function measured by the CKD-EPI estimate of creatinine clearance at week 12 |
| Percent Change From Baseline Hs-CRP (ug/mL) to the Average of Week 8 and Week 12 | 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. |
Countries
Australia, United States
Participant flow
Recruitment details
Participants were screened and randomised from 2 sites in USA and 5 sites in Australia.
Pre-assignment details
125 were screened and 60 were not randomised (55 ineligible, 4 lost to follow up and 1 withdrew consent prior to randomisation).
Participants by arm
| Arm | Count |
|---|---|
| Vorapaxar 2.5mg of vorapaxar po qd
vorapaxar: 2.5mg of vorapaxar taken orally once daily for 12 weeks | 33 |
| Placebo sugar pill po qd
Placebo: Sugar pill taken orally once daily for 12 weeks | 31 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Vorapaxar | Placebo |
|---|---|---|---|
| Age, Continuous | 52 years | 53 years | 52 years |
| CD4 count | 643 cells per uL | 639 cells per uL | 698 cells per uL |
| Current smoker | 18 Participants | 9 Participants | 9 Participants |
| d-dimer | 421.9 ng/mL | 432.5 ng/mL | 391.6 ng/mL |
| Diastolic blood pressure | 78.5 (mm Hg) | 77 (mm Hg) | 80 (mm Hg) |
| Estimated duration of HIV infection | 12.5 years | 12.8 years | 12.2 years |
| Framingham 10 yr CHD Risk Score | 11.4 Percentage of risk | 10.6 Percentage of risk | 12.1 Percentage of risk |
| HDL Cholesterol | 1.2 (mmol/L) | 1.2 (mmol/L) | 1.3 (mmol/L) |
| High sensitivity C Reactive Protein (hs-CRP) | 1.58 ug/mL | 1.53 ug/mL | 1.97 ug/mL |
| Interleukin 6 (IL-6) | 0.94 pg/mL | 0.93 pg/mL | 0.99 pg/mL |
| Plasma HIV RNA | 20 copies/mL | 20 copies/mL | 20 copies/mL |
| Race/Ethnicity, Customized Asian | 3 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Black | 12 Participants | 7 Participants | 5 Participants |
| Race/Ethnicity, Customized Hispanic/Latino | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 48 Participants | 25 Participants | 23 Participants |
| Region of Enrollment Australia | 42 participants | 21 participants | 21 participants |
| Region of Enrollment United States | 22 participants | 12 participants | 10 participants |
| Sex: Female, Male Female | 5 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 59 Participants | 31 Participants | 28 Participants |
| Systolic blood pressure | 126.5 (mm Hg) | 125 (mm Hg) | 127 (mm Hg) |
| Time on current Anti-Retroviral Treatment regimen | 1.5 years | 1.3 years | 2 years |
| Total Cholesterol | 4.7 mmol/L | 4.6 mmol/L | 4.7 mmol/L |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 33 | 0 / 31 |
| other Total, other adverse events | 15 / 33 | 22 / 31 |
| serious Total, serious adverse events | 2 / 33 | 2 / 31 |
Outcome results
Primary
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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Vorapaxar | Mean Percent Change From Baseline for D-dimer (ng/mL) to the Average of Weeks 8 and 12 | -10.8 percent |
| Placebo | Mean Percent Change From Baseline for D-dimer (ng/mL) to the Average of Weeks 8 and 12 | -8.5 percent |
Secondary
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vorapaxar | Changes From Baseline in Renal Function Measured by the CKD-EPI Estimate of Creatinine Clearance at Week 12 | 2.08 ml/min/1.73m2 | Standard Deviation 8.38 |
| Placebo | Changes From Baseline in Renal Function Measured by the CKD-EPI Estimate of Creatinine Clearance at Week 12 | 2.05 ml/min/1.73m2 | Standard Deviation 7.71 |
Secondary
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vorapaxar | Differences Between Treatment Groups in Mean Change From Baseline log10 IL-6 | 0.03 pg/mL | Standard Deviation 0.36 |
| Placebo | Differences Between Treatment Groups in Mean Change From Baseline log10 IL-6 | -0.10 pg/mL | Standard Deviation 0.25 |
Secondary
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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Vorapaxar | Mean Change From Baseline in log10 D-Dimer | -2.21 percent change |
| Placebo | Mean Change From Baseline in log10 D-Dimer | -14.1 percent change |
Secondary
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vorapaxar | Mean Change From Baseline in log10 Hs-CRP at Week 18 | -0.03 pg/mL | Standard Deviation 0.39 |
| Placebo | Mean Change From Baseline in log10 Hs-CRP at Week 18 | -0.10 pg/mL | Standard Deviation 0.54 |
Secondary
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vorapaxar | Mean Change From Baseline to Week 12 in CD4+ Cell Counts | -21.3 cells/mm3 | Standard Deviation 143.7 |
| Placebo | Mean Change From Baseline to Week 12 in CD4+ Cell Counts | -29.7 cells/mm3 | Standard Deviation 400.3 |
Secondary
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Vorapaxar | Mean Change From Baseline to Week 12 in CD8+ Cell Counts | 3 cells/mm3 | Standard Deviation 191.6 |
| Placebo | Mean Change From Baseline to Week 12 in CD8+ Cell Counts | 81.1 cells/mm3 | Standard Deviation 244.7 |
Secondary
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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Vorapaxar | Mean Percent Change From Baseline IL-6 (pg/mL) to the Average of Week 8 and Week 12 | 12.6 percent |
| Placebo | Mean Percent Change From Baseline IL-6 (pg/mL) to the Average of Week 8 and Week 12 | -11.6 percent |
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vorapaxar | Number of Participants in Each Treatment Group With Plasma HIV-1 RNA <50 Copies/mL | 31 Participants |
| Placebo | Number of Participants in Each Treatment Group With Plasma HIV-1 RNA <50 Copies/mL | 29 Participants |
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vorapaxar | Number of Patients in Each Treatment Group With D-dimer <165ng/mL at Week 12 | 1 Participants |
| Placebo | Number of Patients in Each Treatment Group With D-dimer <165ng/mL at Week 12 | 2 Participants |
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vorapaxar | Number of Patients in Each Treatment Group With D-dimer > or Equal to 165ng/mL at Week 18 | 32 Participants |
| Placebo | Number of Patients in Each Treatment Group With D-dimer > or Equal to 165ng/mL at Week 18 | 29 Participants |
Secondary
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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Vorapaxar | Percent Change From Baseline Hs-CRP (ug/mL) to the Average of Week 8 and Week 12 | -0.02 Percent |
| Placebo | Percent Change From Baseline Hs-CRP (ug/mL) to the Average of Week 8 and Week 12 | -15.7 Percent |
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vorapaxar | Total Number of Participants With Any AE Between Baseline to Week 18 | 28 Participants |
| Placebo | Total Number of Participants With Any AE Between Baseline to Week 18 | 28 Participants |
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vorapaxar | Total Number of Participants With Any SAE Between Baseline and Week 18 | 3 Participants |
| Placebo | Total Number of Participants With Any SAE Between Baseline and Week 18 | 2 Participants |
Secondary
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Vorapaxar | Total Number of Participants With BARC Type 1, 2, 3, 4, or 5 Bleeding Episodes | 12 Participants |
| Placebo | Total Number of Participants With BARC Type 1, 2, 3, 4, or 5 Bleeding Episodes | 10 Participants |