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Terminated Prematurely due to COVID-19
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| Name | Class |
|---|---|
| Amgen | INDUSTRY |
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The primary goal is to assess the impact of Evolocumab therapy on platelet function of familial hypercholesterolemia (FH) patients in a randomized, double blind study. Evolocumab is a humanized monoclonal antibody that targets circulating PCSK9, increases hepatic LDL receptor, decreases plasma LDL cholesterol and reduces risk of cardiovascular events. Evolocumab (brand name Rapatha) has been approved by FDA along with diet and maximally tolerated statin therapy in adults with FH or atherosclerotic heart or blood vessel problems, who need additional lowering of LDL cholesterol.
The secondary goal is to determine if platelet activation or the response to Evolocumab therapy is modified by rs3184504 polymorphism. The investigators believe that these investigations will complement ongoing studies to demonstrate that Evolocumab reduces athero-thrombotic risk and aid the decision-making as to whether Evolocumab can reduce the atherothrombotic risk in acute coronary syndrome (ACS) patients.
Hyperlipidemia as exemplified by familial hypercholesterolemia is associated with increased platelet activation and an underlying pro-coagulant state. Hyperlipidemia primes platelets and increases platelet activation in response to various agonists. Plasma cholesterol levels appear to have a critical role in modulating platelet activity as hypercholesterolemia increases platelet activation more potently than hypertriglyceridemia. Increased platelet reactivity may contribute to the increased risk of atherothrombosis associated with hypercholesterolemia. Plasma levels of platelet activation markers such as thrombin-antithrombin complex (TAT), soluble P-selectin (sP-selectin), soluble CD40L (sCD40L) or P-selectin exposure at surface of platelets are increased in hypercholesterolemic patients. Increased levels of the platelet activation markers are associated with increased platelet membrane cholesterol content in hypercholesterolemia.Statins may show antithrombotic properties.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Evolocumab | Active Comparator | Subjects will start with placebo and will receive Evolocumab 140 mg every 14 days starting Day 14 until Day 196. |
|
| Placebo | Placebo Comparator | Subjects will start with placebo and will receive Evolocumab 140 mg every 14 days starting Day 28 until Day 196. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Evolocumab | Drug | 140 mg every 14 days A monoclonal antibody designed for the treatment of hyperlipidemia |
|
| Measure | Description | Time Frame |
|---|---|---|
| Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (P2Y12 Reaction Units (PRU)) | ADP- or arachidonic acid-stimulated platelet aggregation as assessed by the commercially-available VerifyNow P2Y12 (VerifyNow PRUTest) will be performed. Unit: PRU | Day 7, Day 14, Day 21, Day 28, Day 84 |
| Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (Aspirin Reaction Unit (ARU)) | ADP- or arachidonic acid-stimulated platelet aggregation as assessed by the commercially-available VerifyNow Aspirin assay (Accriva Diagnostics) will be performed. Unit: Aspirin Reaction Unit (ARU) | Day 7, Day 14, Day 21, Day 28, Day 84 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Henry Ginsberg, MD | Columbia University | Study Director |
| Nan Wang, PhD | Columbia University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Columbia University Medical Center | New York | New York | 10032 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 4359434 | Background | Carvalho AC, Colman RW, Lees RS. Platelet function in hyperlipoproteinemia. N Engl J Med. 1974 Feb 21;290(8):434-8. doi: 10.1056/NEJM197402212900805. No abstract available. | |
| 14022629 | Background | CONNOR WE, HOAK JC, WARNER ED. Massive thrombosis produced by fatty acid infusion. J Clin Invest. 1963 Jun;42(6):860-6. doi: 10.1172/JCI104778. No abstract available. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Evolocumab | Subjects will start with placebo and will receive Evolocumab 140 mg every 14 days starting Day 14 until Day 196. Evolocumab: 140 mg every 14 days A monoclonal antibody designed for the treatment of hyperlipidemia |
| FG001 | Placebo | Subjects will start with placebo and will receive Evolocumab 140 mg every 14 days starting Day 28 until Day 196. Evolocumab: 140 mg every 14 days A monoclonal antibody designed for the treatment of hyperlipidemia |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Patients who have a clinical diagnosis of familial hypercholesterolemia and are referred for treatment with PCSK9 inhibitor, with LDL cholesterol levels ≥70 mg/dl on baseline treatment with statins and/or ezetimibe or intolerant to statin and/or ezetimibe.
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| ID | Title | Description |
|---|---|---|
| BG000 | Evolocumab | Subjects will start with placebo and will receive Evolocumab 140 mg every 14 days starting Day 14 until Day 196. Evolocumab: 140 mg every 14 days A monoclonal antibody designed for the treatment of hyperlipidemia |
| BG001 | Placebo |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| 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 | Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (P2Y12 Reaction Units (PRU)) | ADP- or arachidonic acid-stimulated platelet aggregation as assessed by the commercially-available VerifyNow P2Y12 (VerifyNow PRUTest) will be performed. Unit: PRU | Adult male and female subjects who have a clinical diagnosis of familial hypercholesterolemia and referred for treatment with PCSK9 inhibitor, with LDL cholesterol levels ≥70 mg/dl on baseline treatment with statins and/or ezetimibe or intolerant to statin and/or ezetimibe. Of the four participants reported in this study, one participant per arm had ADP assessed by PRU Test (evolocumab and placebo arms) and one participant per arm had ADP assessed by Aspirin assay (evolocumab and placebo arms). | Posted | Number | PRU | Day 7, Day 14, Day 21, Day 28, Day 84 |
|
4 months
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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 | Evolocumab | Subjects will start with placebo and will receive Evolocumab 140 mg every 14 days starting Day 14 until Day 196. Evolocumab: 140 mg every 14 days A monoclonal antibody designed for the treatment of hyperlipidemia |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Nan Wang | Columbia University Irving Medical Center | 212-342-1761 | nw30@cumc.columbia.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | May 29, 2019 | Feb 9, 2021 | Prot_SAP_004.pdf |
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| ID | Term |
|---|---|
| D006938 | Hyperlipoproteinemia Type II |
| D006949 | Hyperlipidemias |
| D006937 | Hypercholesterolemia |
| D013927 | Thrombosis |
| ID | Term |
|---|---|
| D008052 | Lipid Metabolism, Inborn Errors |
| D008661 | Metabolism, Inborn Errors |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
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| ID | Term |
|---|---|
| C577155 | evolocumab |
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| 22214850 | Background | Owens AP 3rd, Passam FH, Antoniak S, Marshall SM, McDaniel AL, Rudel L, Williams JC, Hubbard BK, Dutton JA, Wang J, Tobias PS, Curtiss LK, Daugherty A, Kirchhofer D, Luyendyk JP, Moriarty PM, Nagarajan S, Furie BC, Furie B, Johns DG, Temel RE, Mackman N. Monocyte tissue factor-dependent activation of coagulation in hypercholesterolemic mice and monkeys is inhibited by simvastatin. J Clin Invest. 2012 Feb;122(2):558-68. doi: 10.1172/JCI58969. Epub 2012 Jan 3. |
| 3524709 | Background | Harmon JT, Tandon NN, Hoeg JM, Jamieson GA. Thrombin binding and response in platelets from patients with dyslipoproteinemias: increased stimulus-response coupling in type II hyperlipoproteinemia. Blood. 1986 Aug;68(2):498-505. |
| 8266915 | Background | Wada H, Mori Y, Kaneko T, Wakita Y, Nakase T, Minamikawa K, Ohiwa M, Tamaki S, Tanigawa M, Kageyama S, et al. Elevated plasma levels of vascular endothelial cell markers in patients with hypercholesterolemia. Am J Hematol. 1993 Oct;44(2):112-6. doi: 10.1002/ajh.2830440208. |
| 9529262 | Background | Davi G, Romano M, Mezzetti A, Procopio A, Iacobelli S, Antidormi T, Bucciarelli T, Alessandrini P, Cuccurullo F, Bittolo Bon G. Increased levels of soluble P-selectin in hypercholesterolemic patients. Circulation. 1998 Mar 17;97(10):953-7. doi: 10.1161/01.cir.97.10.953. |
| 11705814 | Background | Garlichs CD, John S, Schmeisser A, Eskafi S, Stumpf C, Karl M, Goppelt-Struebe M, Schmieder R, Daniel WG. Upregulation of CD40 and CD40 ligand (CD154) in patients with moderate hypercholesterolemia. Circulation. 2001 Nov 13;104(20):2395-400. doi: 10.1161/hc4501.099312. |
| 12534449 | Background | Puccetti L, Pasqui AL, Pastorelli M, Bova G, Cercignani M, Palazzuoli A, Angori P, Auteri A, Bruni F. Time-dependent effect of statins on platelet function in hypercholesterolaemia. Eur J Clin Invest. 2002 Dec;32(12):901-8. doi: 10.1046/j.1365-2362.2002.01086.x. |
| 23319813 | Background | Violi F, Calvieri C, Ferro D, Pignatelli P. Statins as antithrombotic drugs. Circulation. 2013 Jan 15;127(2):251-7. doi: 10.1161/CIRCULATIONAHA.112.145334. No abstract available. |
| 16226162 | Background | Ray KK, Cannon CP, McCabe CH, Cairns R, Tonkin AM, Sacks FM, Jackson G, Braunwald E; PROVE IT-TIMI 22 Investigators. Early and late benefits of high-dose atorvastatin in patients with acute coronary syndromes: results from the PROVE IT-TIMI 22 trial. J Am Coll Cardiol. 2005 Oct 18;46(8):1405-10. doi: 10.1016/j.jacc.2005.03.077. |
| 12135935 | Background | Cipollone F, Mezzetti A, Porreca E, Di Febbo C, Nutini M, Fazia M, Falco A, Cuccurullo F, Davi G. Association between enhanced soluble CD40L and prothrombotic state in hypercholesterolemia: effects of statin therapy. Circulation. 2002 Jul 23;106(4):399-402. doi: 10.1161/01.cir.0000025419.95769.f0. |
| 16907931 | Background | Undas A, Brummel-Ziedins KE, Potaczek DP, Stobierska-Dzierzek B, Bryniarski L, Szczeklik A, Mann KG. Atorvastatin and quinapril inhibit blood coagulation in patients with coronary artery disease following 28 days of therapy. J Thromb Haemost. 2006 Nov;4(11):2397-404. doi: 10.1111/j.1538-7836.2006.02165.x. Epub 2006 Aug 14. |
| 25861297 | Background | Pawelczyk M, Chmielewski H, Kaczorowska B, Przybyla M, Baj Z. The influence of statin therapy on platelet activity markers in hyperlipidemic patients after ischemic stroke. Arch Med Sci. 2015 Mar 16;11(1):115-21. doi: 10.5114/aoms.2015.49216. Epub 2015 Mar 14. |
| 22615342 | Background | Pignatelli P, Carnevale R, Pastori D, Cangemi R, Napoleone L, Bartimoccia S, Nocella C, Basili S, Violi F. Immediate antioxidant and antiplatelet effect of atorvastatin via inhibition of Nox2. Circulation. 2012 Jul 3;126(1):92-103. doi: 10.1161/CIRCULATIONAHA.112.095554. Epub 2012 May 21. |
| 24678979 | Background | Blom DJ, Hala T, Bolognese M, Lillestol MJ, Toth PD, Burgess L, Ceska R, Roth E, Koren MJ, Ballantyne CM, Monsalvo ML, Tsirtsonis K, Kim JB, Scott R, Wasserman SM, Stein EA; DESCARTES Investigators. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014 May 8;370(19):1809-19. doi: 10.1056/NEJMoa1316222. Epub 2014 Mar 29. |
| 25773607 | Background | Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, Ballantyne CM, Somaratne R, Legg J, Wasserman SM, Scott R, Koren MJ, Stein EA; Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015 Apr 16;372(16):1500-9. doi: 10.1056/NEJMoa1500858. Epub 2015 Mar 15. |
| 27046161 | Background | Writing Committee; Lloyd-Jones DM, Morris PB, Ballantyne CM, Birtcher KK, Daly DD Jr, DePalma SM, Minissian MB, Orringer CE, Smith SC Jr. 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2016 Jul 5;68(1):92-125. doi: 10.1016/j.jacc.2016.03.519. Epub 2016 Apr 1. No abstract available. |
| 23428009 | Background | Leoncini M, Toso A, Maioli M, Angiolillo DJ, Giusti B, Marcucci R, Abbate R, Bellandi F. High-dose atorvastatin on the pharmacodynamic effects of double-dose clopidogrel in patients undergoing percutaneous coronary interventions: The ACHIDO (Atorvastatin and Clopidogrel HIgh DOse in stable patients with residual high platelet activity) study. JACC Cardiovasc Interv. 2013 Feb;6(2):169-79. doi: 10.1016/j.jcin.2012.09.013. |
| 23852152 | Background | Leoncini M, Toso A, Maioli M, Angiolillo DJ, Giusti B, Marcucci R, Abbate R, Bellandi F. Pharmacodynamic effects of adjunctive high dose atorvastatin on double dose clopidogrel in patients with high on-treatment platelet reactivity depending on diabetes mellitus status. J Thromb Thrombolysis. 2014 May;37(4):427-34. doi: 10.1007/s11239-013-0966-0. |
| 24049520 | Background | Sikora J, Kostka B, Marczyk I, Krajewska U, Chalubinski M, Broncel M. Effect of statins on platelet function in patients with hyperlipidemia. Arch Med Sci. 2013 Aug 30;9(4):622-8. doi: 10.5114/aoms.2013.36905. Epub 2013 Aug 8. |
Subjects will start with placebo and will receive Evolocumab 140 mg every 14 days starting Day 28 until Day 196. Evolocumab: 140 mg every 14 days A monoclonal antibody designed for the treatment of hyperlipidemia |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | Placebo | Subjects will start with placebo and will receive Evolocumab 140 mg every 14 days starting Day 28 until Day 196. Evolocumab: 140 mg every 14 days A monoclonal antibody designed for the treatment of hyperlipidemia |
|
|
| Primary | Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (Aspirin Reaction Unit (ARU)) | ADP- or arachidonic acid-stimulated platelet aggregation as assessed by the commercially-available VerifyNow Aspirin assay (Accriva Diagnostics) will be performed. Unit: Aspirin Reaction Unit (ARU) | Adult male and female subjects who have a clinical diagnosis of familial hypercholesterolemia and referred for treatment with PCSK9 inhibitor, with LDL cholesterol levels ≥70 mg/dl on baseline treatment with statins and/or ezetimibe or intolerant to statin and/or ezetimibe. Of the four participants reported in this study, one participant per arm had ADP assessed by PRU Test (evolocumab and placebo arms) and one participant per arm had ADP assessed by Aspirin assay (evolocumab and placebo arms). | Posted | Number | ARU | Day 7, Day 14, Day 21, Day 28, Day 84 |
|
|
|
| 0 |
| 2 |
| 0 |
| 2 |
| 0 |
| 2 |
| EG001 | Placebo | Subjects will start with placebo and will receive Evolocumab 140 mg every 14 days starting Day 28 until Day 196. Evolocumab: 140 mg every 14 days A monoclonal antibody designed for the treatment of hyperlipidemia | 0 | 2 | 0 | 2 | 0 | 2 |
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| D006951 | Hyperlipoproteinemias |
| D050171 | Dyslipidemias |
| D052439 | Lipid Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D016769 | Embolism and Thrombosis |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| Aspirin Test, Day 21 |
|
| Aspirin Test, Day 28 |
|
| Aspirin Test, Day 84 |
|