Evolocumab In Advanced Chronic Kidney Disease Trial

Study Overview
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Brief Summary
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110 individuals with stage 4-5 Chronic Kidney Disease (CKD) will be randomized to 1-year of blinded Evolocumab or placebo. Subjects will undergo evaluation of circulating lipids at baseline and end of study. A substudy including 50 subjects will assess myocardial rest and stress positron emission tomography (PET) at baseline and at 1-year.

Detailed Description
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The purpose of this study is to evaluate the effect of evolocumab (Repatha®)-a Food and Drug Administration (FDA)-approved biological drug that has been shown to reduce LDL cholesterol (bad cholesterol) Early data show that the beneftis of evolocumab may be increased as kidney function declines. This trial is therefore designed to provide additional evidence regarding the safety and cholesterol-lowering effects of evolocumab compared with placebo, a pill that has no therapeutic effect, in advanced CKD patients.

Official Title
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A Phase IV, Double-Blind, Placebo-Controlled, Multi-Center Trial To Study The Effects Of Evolocumab In Stage IV-V Chronic Kidney Disease: The Cardiovascular and Lipid-Lowering Effects Of Evolocumab In Advanced Chronic Kidney Disease Trial

Conditions
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Chronic Kidney Diseases, High Cholesterol

Intervention / Treatment
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* Drug: Evolocumab
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: CKD Stage 4-5 defined as eGFR ≤30 mL/min/1.73m2 on screening lab OR Treatment with maintenance hemodialysis for at least 30 days prior to screening LDL ≥70 mg/dL and Treatment with maximal tolerated doses of a statin OR Statin intolerance defined as any history of intolerance or allergy to ≥1 statin Age 40-80 years Individuals ≤60 years old are required to have ≥1 of the following cardiovascular risk factors: History of CV disease History of peripheral vascular disease Diabetes Smoking Baseline LDL ≥160 mg/dL Macroalbuminuria (albumin to creatinine ratio ≥300 mg/g on spot sample) Exclusion Criteria: Age >80 years Expected survival < 1 year Transplant expected within < 1 year Active liver disease (history of cirrhosis, ALT or AST > 2x ULN) CPK > 5x ULN at screening Malignancy within 5 years except for non-melanoma skin cancers, cervical in-situ carcinoma, breast ductal carcinoma in situ, or stage 1 prostate carcinoma Subject has received drugs that are strong inhibitors of cytochrome P-450 3A4 within 1 month prior to randomization or is likely to require such treatment during the study period Currently enrolled in another interventional study Female subject who has not used at least (1) effective method of birth control for at least 1 month prior to screening or (2) is not willing to use such a method during treatment and for an additional 15 weeks after the end of treatment, unless the subject is sterilized or postmenopausal. Effective measures of birth control include surgical sterilization, barrier methods, hormonal contraceptives and intrauterine devices. Pregnant or breast-feeding subjects Known sensitivity or intolerance to study medications The following additional criteria will be utilized to exclude individuals from participating in the PET substudy: Severe asthma or obstructive lung disease defined by Hospitalization for asthma or obstructive lung disease within 8 weeks Use of oral steroids for lung disease within 8 weeks Chronic oxygen therapy Use of rescue inhalers ≥three times weekly in the previous 4 weeks History of seizures Second or third-degree AV block, unless a functioning pacemaker is present Sinus node dysfunction unless a functioning pacemaker is present

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study Drug Group<br>Participants who will receive a shot of the Evolocumab at Visit 3 and self-administer the rest of the shots at visit 4-7. | Drug: Evolocumab<br>* Evolocumab is commercially available in the United States and is manufactured by Amgen. Drug and placebo, will be supplied by the manufacturer. The SureClick® pre-filled auto injector contain Evolocumab (140 mg) acetate (1.2 mg), polysorbate 80 (0.1 mg), proline (25 mg) in water for Injection. Evolocumab will be administered at a dose of 420 mg subcutaneously once monthly.<br>|
| Placebo Comparator: Placebo group<br>Participants who will receive a Placebo shot at Visit 3 and self-administer the rest of the shots at visit 4-7. | Other: Placebo<br>* Placebo will be supplied by the manufacturer. Placebo auto injectors will be identically packaged but will lack the active ingredient. Placebo will be administered at an equivalent volume to Evolocumab and given subcutaneously once monthly.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute change in LDL cholesterol concentration | The primary endpoint is selected to evaluate the key pharmacologic mechanism underlying Evolocumab's cardiovascular benefits. This will be analyzed with Lipid parameters. | Baseline, Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Serious Adverse Events (SAEs) |  | Baseline, Week 52 | 
| Change in coronary flow reserve (CFR) | Change in coronary flow reserve (CFR), the key secondary efficacy endpoint, is a measure of overall cardiovascular health.This test provides an integrative measure of myocardial microvascular supply and myocardial endothelial function as well as large vessel coronary flow. Change in coronary flow reserve over one year as measured by cardiac PET scanning. | Baseline, Week 52 |