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Evolocumab Plus Ezetimibe in High Risk Haemodialized Statin Intolerant Patients

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04397653
Recruitment Status : Recruiting
First Posted : May 21, 2020
Last Update Posted : May 26, 2020
Sponsor:
Collaborator:
IRCCS San Raffaele
Information provided by (Responsible Party):
Leonardo Calò, MD, Policlinico Casilino ASL RMB

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).

Condition or disease Intervention/treatment Phase
Hypercholesterolemia Chronic Kidney Disease Requiring Chronic Dialysis Drug: Evolocumab Drug: Placebo Drug: Ezetimibe Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : May 4, 2020
Estimated Primary Completion Date : November 19, 2020
Estimated Study Completion Date : December 14, 2020

Resource links provided by the National Library of Medicine


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: 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

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)




Primary Outcome Measures :
  1. LDL cholesterol reduction dichotomic [ Time Frame: 24 weeks ]
    change in LDL cholesterol levels ≥ 20 mg/dL from baseline


Secondary Outcome Measures :
  1. LDL cholesterol reduction time-points [ Time Frame: 4 weeks, 12 weeks, 24 weeks ]
    change in LDL cholesterol levels from baseline

  2. HDL cholesterol reduction [ Time Frame: 24 weeks ]
    change in HDL cholesterol levels from baseline

  3. non-HDL cholesterol reduction [ Time Frame: 24 weeks ]
    change in non-HDL cholesterol levels from baseline

  4. Triglycerides reduction [ Time Frame: 24 weeks ]
    change in triglycerides levels from baseline

  5. LDL cholesterol target achieving [ Time Frame: 24 weeks ]
    percent of patients achieving an LDL cholesterol less than 70 mg/dL



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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04397653


Contacts
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Contact: Gennaro Cice, MD 0039330915294 gennarocice@hormail.com

Locations
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Italy
Policlinico Casilino Recruiting
Rome, Italy, 00169
Contact: Leonardo Calò, MD    0623188406    leonardocalo.doc@gmail.com   
Contact: Luca Monzo, MD, PhD    00393460242037    luca.monzo@uniroma1.it   
Principal Investigator: Gennaro Cice, MD         
Sub-Investigator: Monzo Luca, MD, PhD         
Principal Investigator: Maurizio Volterrani, MD, PhD         
Sponsors and Collaborators
Policlinico Casilino ASL RMB
IRCCS San Raffaele
Publications:
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, Syvänne 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. Erratum in: Eur Heart J. 2012 Sep;33(17):2126.

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Responsible Party: Leonardo Calò, MD, Professor, Policlinico Casilino ASL RMB
ClinicalTrials.gov Identifier: NCT04397653    
Other Study ID Numbers: Evolocumab01
First Posted: May 21, 2020    Key Record Dates
Last Update Posted: May 26, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Keywords provided by Leonardo Calò, MD, Policlinico Casilino ASL RMB:
PCSK9 inhibitor
Evolocumab
End-stage renal disease
Hypercholesterolemia
Low-density lipoprotein
Additional relevant MeSH terms:
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Kidney Diseases
Renal Insufficiency, Chronic
Hypercholesterolemia
Urologic Diseases
Renal Insufficiency
Hyperlipidemias
Dyslipidemias
Lipid Metabolism Disorders
Metabolic Diseases
Ezetimibe
Evolocumab
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents