Evolocumab Plus Ezetimibe in High Risk Haemodialized Statin Intolerant Patients

NCT04397653 | Unknown Phase 4

• 1 other identifier: Evolocumab01
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief 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 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).

Conditions

Hypercholesterolemia; Chronic Kidney Disease Requiring Chronic Dialysis

Keywords

PCSK9 inhibitor; Evolocumab; End-stage renal disease; Hypercholesterolemia; Low-density lipoprotein

Outcome Measures

Primary Outcomes (1)

• LDL cholesterol reduction dichotomic

  change in LDL cholesterol levels ≥ 20 mg/dL from baseline

  24 weeks

Secondary Outcomes (5)

• LDL cholesterol reduction time-points

  4 weeks, 12 weeks, 24 weeks

• HDL cholesterol reduction

  24 weeks

• non-HDL cholesterol reduction

  24 weeks

• Triglycerides reduction

  24 weeks

• LDL cholesterol target achieving

  24 weeks

Study Arms (2)

Evolocumab + Ezetimibe

EXPERIMENTAL

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; Drug: Ezetimibe

Placebo + Ezetimibe

PLACEBO COMPARATOR

Patients in this arm will receive subcutaneous placebo every two weeks plus ezetimibe 10 mg per os daily for 24 weeks

Drug: Placebo; Drug: Ezetimibe

Interventions

Evolocumab DRUG

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

Evolocumab + Ezetimibe

Placebo DRUG

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

Placebo + Ezetimibe

Ezetimibe DRUG

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)

Evolocumab + Ezetimibe; Placebo + Ezetimibe

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Policlinico Casilino ASL RMB: lead
• IRCCS San Raffaele: collaborator

Study Sites (1)

Policlinico Casilino

Rome, 00169, Italy

RECRUITING

Related Publications (4)

• 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.

  PMID: 24694531 BACKGROUND

• 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.

  PMID: 27712954 BACKGROUND

• 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.

  PMID: 24314355 BACKGROUND

• 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.

  PMID: 22555213 BACKGROUND

MeSH Terms

Conditions

Hypercholesterolemia; Kidney Failure, Chronic

Interventions

evolocumab; Ezetimibe

Condition Hierarchy (Ancestors)

Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Renal Insufficiency, Chronic; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Azetidines; Azetines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Central Study Contacts

Gennaro Cice, MD

CONTACT

0039330915294; gennarocice@hormail.com

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: May 12, 2020
• First Posted: May 21, 2020
• Study Start: May 4, 2020
• Primary Completion: November 19, 2020
• Study Completion: December 14, 2020
• Last Updated: May 26, 2020

Record last verified: 2020-05

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)