Evolocumab Plus Ezetimibe in Haemodialized Statin-intolerant Patients With Hypercholesterolemia

Sponsor

Policlinico Casilino ASL RMB (Other)

Overall Status

Recruiting

CT.gov ID

NCT04659525

Collaborator

IRCCS San Raffaele (Other)

Enrollment

Location

Arms

13.9

Anticipated Duration (Months)

3.6

Patients Per Site Per Month

Study Details

Study Description

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 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).

Condition or Disease	Intervention/Treatment	Phase
Hypercholesterolemia CKD Stage 5 Chronic Kidney Disease Requiring Chronic Dialysis	Drug: Evolocumab Drug: Ezetimibe Drug: Placebo	Phase 4

Study Design

Study Type:

Interventional

Anticipated 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 :

Nov 1, 2020

Anticipated Primary Completion Date :

Nov 30, 2021

Anticipated Study Completion Date :

Dec 30, 2021

Arms and Interventions

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

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

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

Outcome Measures

Primary Outcome Measures

LDL cholesterol change dichotomic [24 weeks]
proportion of patients that achieve an LDL cholesterol level < 55 mg/dL

Secondary Outcome Measures

LDL cholesterol change time-points [4 weeks, 12 weeks, 24 weeks]
change in LDL cholesterol levels from baseline
HDL cholesterol change [24 weeks]
change in HDL cholesterol levels from baseline
non-HDL cholesterol change [24 weeks]
change in non-HDL cholesterol levels from baseline
Triglycerides change [24 weeks]
change in triglycerides levels from baseline

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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, ﬁbrates 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