Evolocumab Plus Ezetimibe in High Risk Haemodialized Statin Intolerant Patients

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

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 reduction in LDL-C ≥ 20 mg/dL from baseline. 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; the number of patients achieving LDL-C <70 mg/dL. Every adverse event (serious and non-serious) correlated to drug infusion will be recorded (safety end-point).

Study Overview

• Status: Unknown
• Conditions: Hypercholesterolemia; Chronic Kidney Disease Requiring Chronic Dialysis
• Intervention / Treatment: Drug: Evolocumab; Drug: Ezetimibe; Drug: Placebo

• Study Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Phase 4

Contacts and Locations

Study Locations

• Italy
  • Rome, Italy, 00169
    • Recruiting
    • Policlinico Casilino
    • Sub-Investigator: Monzo Luca, MD, PhD
    • Principal Investigator: Maurizio Volterrani, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria (all of them must be present):

• 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 both:

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 ≥70 mg/dL
• end-stage renal disease on chronic hemodialysis

Exclusion Criteria:

• LDL-C <70 mg/dL
• NYHA class III-IV heart failure or last known LVEF <30%
• Uncontrolled serious cardiac arrhythmia, defined as recurrent and highly symptomatic VT, AF with rapid ventricular response, or SVT that are not controlled by medications, within 3 months prior to randomization Planned cardiac surgery or revascularization DM, including: Type 1 DMType 2 DM that is poorly controlled (HbA1c>8.5%) or newly diagnosed within 6 months before randomization; Laboratory evidence of DM during screening (fasting serum glucose ≥126 mg/dL [7.0 mmol/L] or HbA1c≥6.5%) without prior DM diagnosis
• Uncontrolled hypertension, defined as sitting SBP >160mmHg or DBP>100 mm Hg
• Use during the 6 months before LDL-C screening of red yeast rice, niacin >200 mg/d, prescription lipid-regulating drugs (eg, fibrates or derivatives) other than statins, ezetimibe, bile-acid sequestrants, stanols, or stanol esters
• Use during the 12 months before LDL-C screening of a CETP inhibitor such as anacetrapib, dalcetrapib, or evacetrapib
• Use during the 3 months before LDL-C screening of systemic cyclosporine, systemic steroids excluding HRT, vitamin A derivatives (excluding vitamin Ain a multivitamin), or retinol derivatives for the treatment of dermatologic conditions
• Laboratory values at screening TSH < LLN or >1.5 × ULN; CK >3 × ULN; AST or ALT >2 × ULN
• Known concurrent illness within 3 months
• Infection
• Major hematologic, renal, metabolic, GI, or endocrine dysfunction in the judgment of the investigator
• DVT or PE
• Pregnancy, breastfeeding, or inadequate birth control in premenopausal female subjects
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Evolocumab + Ezetimibe; Patients in this arm will receive subcutaneous evolocumab 140 mg every two weeks plus ezetimibe 10 mg per os daily for 24 weeks	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; Drug: 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 Comparator: Placebo + Ezetimibe; Patients in this arm will receive subcutaneous placebo every two weeks plus ezetimibe 10 mg per os daily for 24 weeks	Drug: 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); Drug: 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
LDL cholesterol reduction dichotomic	change in LDL cholesterol levels ≥ 20 mg/dL from baseline	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
LDL cholesterol reduction time-points	change in LDL cholesterol levels from baseline	4 weeks, 12 weeks, 24 weeks
HDL cholesterol reduction	change in HDL cholesterol levels from baseline	24 weeks
non-HDL cholesterol reduction	change in non-HDL cholesterol levels from baseline	24 weeks
Triglycerides reduction	change in triglycerides levels from baseline	24 weeks
LDL cholesterol target achieving	percent of patients achieving an LDL cholesterol less than 70 mg/dL	24 weeks

Collaborators and Investigators

• Sponsor: Policlinico Casilino ASL RMB
• Collaborators: IRCCS San Raffaele

Publications and helpful links

General Publications

• 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.
• Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren M, Albus C, Benlian P, Boysen G, Cifkova R, Deaton C, Ebrahim S, Fisher M, Germano G, Hobbs R, Hoes A, Karadeniz S, Mezzani A, Prescott E, Ryden L, Scherer M, Syvanne M, Scholte op Reimer WJ, Vrints C, Wood D, Zamorano JL, Zannad F; European Association for Cardiovascular Prevention & Rehabilitation (EACPR); ESC Committee for Practice Guidelines (CPG). European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J. 2012 Jul;33(13):1635-701. doi: 10.1093/eurheartj/ehs092. Epub 2012 May 3. No abstract available. Erratum In: Eur Heart J. 2012 Sep;33(17):2126.
• Anderson TJ, Gregoire J, Pearson GJ, Barry AR, Couture P, Dawes M, Francis GA, Genest J Jr, Grover S, Gupta M, Hegele RA, Lau DC, Leiter LA, Lonn E, Mancini GB, McPherson R, Ngui D, Poirier P, Sievenpiper JL, Stone JA, Thanassoulis G, Ward R. 2016 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult. Can J Cardiol. 2016 Nov;32(11):1263-1282. doi: 10.1016/j.cjca.2016.07.510. Epub 2016 Jul 25.
• Expert Dyslipidemia Panel, Grundy SM. An International Atherosclerosis Society Position Paper: global recommendations for the management of dyslipidemia. J Clin Lipidol. 2013 Nov-Dec;7(6):561-5. doi: 10.1016/j.jacl.2013.10.001. Epub 2013 Oct 22.

Study record dates

Study Major Dates

• Study Start (Actual): May 4, 2020
• Primary Completion (Anticipated): November 19, 2020
• Study Completion (Anticipated): December 14, 2020

Study Registration Dates

• First Submitted: May 12, 2020
• First Submitted That Met QC Criteria: May 18, 2020
• First Posted (Actual): May 21, 2020

Study Record Updates

• Last Update Posted (Actual): May 26, 2020
• Last Update Submitted That Met QC Criteria: May 21, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Keywords: End-stage renal disease; Hypercholesterolemia; PCSK9 inhibitor; Evolocumab; Low-density lipoprotein
• Additional Relevant MeSH Terms: Metabolic Diseases; Urologic Diseases; Renal Insufficiency; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Kidney Diseases; Renal Insufficiency, Chronic; Hypercholesterolemia; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Evolocumab; Ezetimibe
• Other Study ID Numbers: Evolocumab01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No