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| ID | Type | Description | Link |
|---|---|---|---|
| AI000585-26-288416 | Other Identifier | NIAID |
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| Name | Class |
|---|---|
| National Institute of Allergy and Infectious Diseases (NIAID) | NIH |
| University of Minnesota | OTHER |
| University of Melbourne | OTHER |
| Merck Sharp & Dohme LLC |
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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.
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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| vorapaxar | Experimental | 2.5mg of vorapaxar po qd |
|
| Placebo | Placebo Comparator | sugar pill po qd |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| vorapaxar | Drug | 2.5mg of vorapaxar taken orally once daily for 12 weeks |
|
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Sean Emery | University of NSW, Kirby Institute | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Georgetown University Hospital | Georgetown | Maryland | 20007 | United States | ||
| Hennepin County Medical Centre |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 30257802 | Derived | 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. |
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125 were screened and 60 were not randomised (55 ineligible, 4 lost to follow up and 1 withdrew consent prior to randomisation).
Participants were screened and randomised from 2 sites in USA and 5 sites in Australia.
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| ID | Title | Description |
|---|---|---|
| FG000 | Vorapaxar | 2.5mg of vorapaxar po qd vorapaxar: 2.5mg of vorapaxar taken orally once daily for 12 weeks |
| FG001 | Placebo | sugar pill po qd Placebo: Sugar pill taken orally once daily for 12 weeks |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
1 participant was lost to follow up immediately after randomisation and did not receive a single dose of study drug.
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| ID | Title | Description |
|---|---|---|
| BG000 | Vorapaxar | 2.5mg of vorapaxar po qd vorapaxar: 2.5mg of vorapaxar taken orally once daily for 12 weeks |
| BG001 | Placebo | sugar pill po qd Placebo: Sugar pill taken orally once daily for 12 weeks |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Posted | Mean | 95% Confidence Interval | percent | at week 8 and week 12 |
|
18 weeks
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Vorapaxar | 2.5mg of vorapaxar po qd vorapaxar: 2.5mg of vorapaxar taken orally once daily for 12 weeks |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Pneumonia | Respiratory, thoracic and mediastinal disorders | MedDRA 21.0 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Upper Respiratory Tract Injection | Respiratory, thoracic and mediastinal disorders | MedDRA 20.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Sean Emery, Chief Principal Investigator | University of New South Wales | +61 2 9385 0897 | s.emery@unsw.edu.au |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jul 12, 2016 | Sep 17, 2018 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Nov 13, 2017 | Dec 9, 2018 | SAP_001.pdf |
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| ID | Term |
|---|---|
| C530299 | vorapaxar |
| D000073893 | Sugars |
| ID | Term |
|---|---|
| D002241 | Carbohydrates |
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| INDUSTRY |
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| Placebo | Drug | Sugar pill taken orally once daily for 12 weeks |
|
|
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 |
| 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 |
| Northside Clinic | Fitzroy North | Victoria | 3068 | Australia |
| Monash Medical Centre | Melbourne | Victoria | 3168 | Australia |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Total Cholesterol | Median | Inter-Quartile Range | mmol/L |
|
| HDL Cholesterol | Median | Inter-Quartile Range | (mmol/L) |
|
| Systolic blood pressure | Median | Inter-Quartile Range | (mm Hg) |
|
| Diastolic blood pressure | Median | Inter-Quartile Range | (mm Hg) |
|
| Current smoker | Count of Participants | Participants |
|
| Framingham 10 yr CHD Risk Score | Framingham Heart Score: 10 year Coronary Heart Disease Risk Score was calculated at baseline using methods published by D'Agostino. Factors including age, sex, smoking status, Total Cholesterol, HDL Cholesterol, systolic blood pressure, treatment for blood pressure. | Median | Inter-Quartile Range | Percentage of risk |
|
| d-dimer | Median | Inter-Quartile Range | ng/mL |
|
| High sensitivity C Reactive Protein (hs-CRP) | Median | Inter-Quartile Range | ug/mL |
|
| Interleukin 6 (IL-6) | Median | Inter-Quartile Range | pg/mL |
|
| Estimated duration of HIV infection | Median | Inter-Quartile Range | years |
|
| Plasma HIV RNA | Median | Inter-Quartile Range | copies/mL |
|
| CD4 count | Median | Inter-Quartile Range | cells per uL |
|
| Time on current Anti-Retroviral Treatment regimen | Median | Inter-Quartile Range | years |
|
| Units | Counts |
|---|
| Participants |
|
|
| 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 | Posted | Count of Participants | Participants | at week 18 |
|
|
|
| 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 | Posted | Mean | Standard Deviation | cells/mm3 | at week 12 |
|
|
|
| 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 | Posted | Mean | Standard Deviation | cells/mm3 | at week 12 |
|
|
|
| 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 | Posted | Count of Participants | Participants | week 12 |
|
|
|
| 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 | Posted | Count of Participants | Participants | week 18 |
|
|
|
| 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 | Posted | Mean | 95% Confidence Interval | percent change | at week 18 |
|
|
|
| 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 | Posted | Mean | Standard Deviation | pg/mL | at week 18 |
|
|
|
| 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. | Posted | Mean | 95% Confidence Interval | Percent | week 8 and 12 |
|
|
|
| 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. | Posted | Mean | 90% Confidence Interval | percent | at week 8 and week 12 |
|
|
|
| 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 | Posted | Mean | Standard Deviation | pg/mL | at week 18 |
|
|
|
| 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 - | Posted | Count of Participants | Participants | at week 18 |
|
|
|
| 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 | Posted | Count of Participants | Participants | week 18 |
|
|
|
| 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 | Posted | Count of Participants | Participants | week 18 |
|
|
|
| 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 | Posted | Mean | Standard Deviation | ml/min/1.73m2 | at week 12 |
|
|
|
| 0 |
| 33 |
| 2 |
| 33 |
| 15 |
| 33 |
| EG001 | Placebo | sugar pill po qd Placebo: Sugar pill taken orally once daily for 12 weeks | 0 | 31 | 2 | 31 | 22 | 31 |
| Colitis | Gastrointestinal disorders | MedDRA 21.0 | Systematic Assessment |
|
| spinal stenosis | Nervous system disorders | MedDRA 20.0 | Systematic Assessment |
|
| Post Procedural haematoma | Injury, poisoning and procedural complications | MedDRA 20.0 | Systematic Assessment |
|
| Gout | Metabolism and nutrition disorders | MedDRA 20.0 | Systematic Assessment |
|
| Laceration | Injury, poisoning and procedural complications | MedDRA 20.0 | Systematic Assessment |
|
| Epistaxis | Blood and lymphatic system disorders | MedDRA 20.0 | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA 20.0 | Systematic Assessment |
|
| Contusion | Musculoskeletal and connective tissue disorders | MedDRA 20.0 | Systematic Assessment |
|
| Chest pain | General disorders | MedDRA 20.0 | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA 20.0 | Systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA 20.0 | Systematic Assessment |
|
| Pain in extremety | Musculoskeletal and connective tissue disorders | MedDRA 20.0 | Systematic Assessment |
|
| Paraesthesia | Nervous system disorders | MedDRA 20.0 | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Peripheral Swelling | General disorders | MedDRA 20.0 | Systematic Assessment |
|
| Dyspepsia | Gastrointestinal disorders | MedDRA 20.0 | Systematic Assessment |
|
| Gout | Metabolism and nutrition disorders | MedDRA 20.0 | Systematic Assessment |
|
Investigators need to submit a proposal, abstract, manuscript or other form of communication of trial results to the Protocol Steering Committee for review and approval.