Evolocumab Plus Ezetimibe in Haemodialized Statin-intolerant Patients With Hypercholesterolemia

Hypercholesterolemia Clinical Trial

Official title:

Phase IV Study for Efficacy and Safety of Evolocumab Added to Ezetimibe (Standard of Care) in High Cardiovascular Risk Haemodialized Statin Intolerant Patients With Hypercholesterolemia

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04659525
• Other study ID #: Evolocumab02
• Status: Recruiting
• Phase: Phase 4
• Start date: November 1, 2020
• Est. completion date: December 30, 2021

Study information

• Verified date: December 2020
• Source: Policlinico Casilino ASL RMB
• Contact: Gennaro Cice, MD
• Phone: 0039330915294
• Email: gennarocice[@]hormail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol, reducing in turn the risk of cardiovascular events. Whether evolcumab is effective in haemodialized patients is uncertain. The investigators will conduct a randomized, double-blind, placebo-controlled trial to assess the feasibility, safety, and LDL-C-lowering efficacy of evolocumab in high cardiovascular risk haemodialized statin intolerant patients with hypercholesterolemia. Patients will be randomly assigned to receive evolocumab (140 mg subcutaneous every 2 weeks + ezetimibe 10 mg per os daily) or matching placebo (subcutaneous every 2 weeks + ezetimibe 10 mg per os daily) for 24 weeks. The primary efficacy end point will be the proportion of patients that will reduce LDL-C < 55 mg/dL in the evolocumab group compared to placebo at 24 weeks. The key secondary efficacy end points will be: the reduction of LDL-C from baseline at 4, 6 and 12 weeks; the reduction of HDL-C, non-HDL cholesterol and triglycerides from baseline at 24 weeks. Every adverse event (serious and non-serious) correlated to drug infusion will be recorded (safety end-point).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: December 30, 2021
• Est. primary completion date: November 30, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• high cardiovascular risk defined as patients with: Documented cardiovascular disease (CVD), clinical or unequivocal on imaging. Documented clinical CVD includes previous acute myocardial infarction, coronary revascularization and other arterial revascularization procedures, stroke and TIA, aortic aneurysm and PAD. Unequivocally documented CVD on imaging includes plaque on coronary angiography or carotid ultrasound; DM with target organ damage or with a major risk factor such as smoking or marked hypercholesterolaemia or marked hypertension.
• History of statin intolerance, demonstrated by: trial of =2 statins with intolerance of any dose or to increase statin dose above the total maximum doses because of intolerable: Myopathy or myalgia (muscle pain, ache, or weakness without CK elevation), or Myositis (muscle symptoms with increased CK levels), or Rhabdomyolysis (muscle symptoms with marked CK elevation) and Resolution or improvement of symptoms when the statin dose was decreased or discontinued
• patients with LDL-C >55 mg/dL
• end-stage renal disease on chronic hemodialysis
• Participant is willing and able to give informed consent for participation in the study.

Exclusion Criteria:

• secondary hypercholesterolemia (i.e. hypothyroidism, Primary biliary cholangitis, etc)
• Use of drugs or dietary supplements that can impact on cholesterol value (i.e. progestinic, red yeast rice, niacin >200 mg/d, lipid-regulating drugs - eg, ?brates or derivatives, ezetimibe, bile-acid sequestrants, stanols, or stanol esters - )
• Previous treatment with evolocumab or any other anti-PCSK9 therapy
• Inability to provide informed consent or to attend follow-up visits
• Unreliability as a study participant based on judgment of investigator's knowledge of the subject (eg, alcohol or other drug abuse, inability or unwillingness to adhere to the protocol, psychosis)
• Current enrollment in another investigational device or drug study or <30 d since ending another investigational device or drug study
• serum triglycerides level > 400 mg/dL at baseline
• Pregnancy, breastfeeding, or inadequate birth control in premenopausal female subjects
• Laboratory values at screening CK >3 × ULN; AST or ALT >2 × ULN

Related Conditions & MeSH terms

• Chronic Kidney Disease Requiring Chronic Dialysis
• CKD Stage 5
• Hypercholesterolemia
• Kidney Diseases
• Renal Insufficiency, Chronic

Intervention

Drug:
• Evolocumab
In the intervention arm evolocumab 140 mg subcutaneous every 2 weeks will be administered for 24 weeks to high cardiovascular risk haemodialized statin intolerant patients with hypercholesterolemia
• Ezetimibe
Ezetimibe 10 mg daily will be administered for 24 weeks to high cardiovascular risk haemodialized statin intolerant patients with hypercholesterolemia in both the placebo arm (plus placebo) and in the intervention arm (plus evolocumab)
• Placebo
In the placebo arm placebo subcutaneous every 2 weeks will be administered for 24 weeks to high cardiovascular risk haemodialized statin intolerant patients with hypercholesterolemia

Locations

Country	Name	City	State
Italy	Policlinico Casilino	Rome

Sponsors (2)

Lead Sponsor	Collaborator
Policlinico Casilino ASL RMB	IRCCS San Raffaele

Country where clinical trial is conducted

Italy, 

References & Publications (7)

Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C, Wanner C, Krane V, Cass A, Craig J, Neal B, Jiang L, Hooi LS, Levin A, Agodoa L, Gaziano M, Kasiske B, Walker R, Massy ZA, Feldt-Rasmussen B, Krairittichai U, Ophascharoensuk V, Fellström B, Holdaas H, Tesar V, Wiecek A, Grobbee D, de Zeeuw D, Grönhagen-Riska C, Dasgupta T, Lewis D, Herrington W, Mafham M, Majoni W, Wallendszus K, Grimm R, Pedersen T, Tobert J, Armitage J, Baxter A, Bray C, Chen Y, Chen Z, Hill M, Knott C, Parish S, Simpson D, Sleight P, Young A, Collins R; SHARP Investigators. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet. 2011 Jun 25;377(9784):2181-92. doi: 10.1016/S0140-6736(11)60739-3. Epub 2011 Jun 12. — View Citation

Fellström BC, Jardine AG, Schmieder RE, Holdaas H, Bannister K, Beutler J, Chae DW, Chevaile A, Cobbe SM, Grönhagen-Riska C, De Lima JJ, Lins R, Mayer G, McMahon AW, Parving HH, Remuzzi G, Samuelsson O, Sonkodi S, Sci D, Süleymanlar G, Tsakiris D, Tesar V, Todorov V, Wiecek A, Wüthrich RP, Gottlow M, Johnsson E, Zannad F; AURORA Study Group. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med. 2009 Apr 2;360(14):1395-407. doi: 10.1056/NEJMoa0810177. Epub 2009 Mar 30. Erratum in: N Engl J Med. 2010 Apr 15;362(15):1450. — View Citation

Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, Chapman MJ, De Backer GG, Delgado V, Ference BA, Graham IM, Halliday A, Landmesser U, Mihaylova B, Pedersen TR, Riccardi G, Richter DJ, Sabatine MS, Taskinen MR, Tokgozoglu L, Wiklund O; ESC Scientific Document Group. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020 Jan 1;41(1):111-188. doi: 10.1093/eurheartj/ehz455. — View Citation

Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS, Pedersen TR; FOURIER Steering Committee and Investigators. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017 May 4;376(18):1713-1722. doi: 10.1056/NEJMoa1615664. Epub 2017 Mar 17. — View Citation

Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, Edelberg JM, Goodman SG, Hanotin C, Harrington RA, Jukema JW, Lecorps G, Mahaffey KW, Moryusef A, Pordy R, Quintero K, Roe MT, Sasiela WJ, Tamby JF, Tricoci P, White HD, Zeiher AM; ODYSSEY OUTCOMES Committees and Investigators. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 2018 Nov 29;379(22):2097-2107. doi: 10.1056/NEJMoa1801174. Epub 2018 Nov 7. — View Citation

Stroes E, Colquhoun D, Sullivan D, Civeira F, Rosenson RS, Watts GF, Bruckert E, Cho L, Dent R, Knusel B, Xue A, Scott R, Wasserman SM, Rocco M; GAUSS-2 Investigators. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol. 2014 Jun 17;63(23):2541-2548. doi: 10.1016/j.jacc.2014.03.019. Epub 2014 Mar 30. — View Citation

Wanner C, Krane V, März W, Olschewski M, Mann JF, Ruf G, Ritz E; German Diabetes and Dialysis Study Investigators. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med. 2005 Jul 21;353(3):238-48. Erratum in: N Engl J Med. 2005 Oct 13;353(15):1640. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	LDL cholesterol change dichotomic	proportion of patients that achieve an LDL cholesterol level < 55 mg/dL	24 weeks
Secondary	LDL cholesterol change time-points	change in LDL cholesterol levels from baseline	4 weeks, 12 weeks, 24 weeks
Secondary	HDL cholesterol change	change in HDL cholesterol levels from baseline	24 weeks
Secondary	non-HDL cholesterol change	change in non-HDL cholesterol levels from baseline	24 weeks
Secondary	Triglycerides change	change in triglycerides levels from baseline	24 weeks