Evolocumab In Advanced Chronic Kidney Disease Trial (EVO-CKD)

• ClinicalTrials.gov Identifier: NCT04510844
• Recruitment Status: Recruiting
• First Posted: August 12, 2020
• Last Update Posted: June 1, 2021
• Sponsor: NYU Langone Health
• Information provided by (Responsible Party): NYU Langone Health

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Chronic Kidney Diseases; High Cholesterol	Drug: Evolocumab; Other: Placebo	Phase 4

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 115 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: March 1, 2021
• Estimated Primary Completion Date: February 2023
• Estimated Study Completion Date: February 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Study Drug Group; 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; 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.
Placebo Comparator: Placebo group; Participants who will receive a Placebo shot at Visit 3 and self-administer the rest of the shots at visit 4-7.	Other: Placebo; 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.

Outcome Measures

Primary Outcome Measures :

1. Absolute change in LDL cholesterol concentration from baseline to end of study [ Time Frame: Baseline, Week 52 visit ]
   The primary endpoint is selected to evaluate the key pharmacologic mechanism underlying Evolocumab's cardiovascular benefits. This will be analyzed with Lipid parameters at the end of the study (Week 52)

Secondary Outcome Measures :

1. Incidence rate of serious adverse events (SAE) between baseline and end of study [ Time Frame: Baseline, Week 52 visit ]
   this is measured by the number of adverse events between baseline and week 52 at the end of the study.
2. Change in coronary flow reserve (CFR) between baseline and end of study (sub-study only) [ Time Frame: Baseline, Week 52 visit ]
   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. It is thus anticipated to provide insight into the potential for Evolocumab to impact cardiovascular health via mechanisms not directly related to a change in total burden of coronary atherosclerotic plaque.

Other Outcome Measures:

1. Change in levels of HDL Cholesterol [ Time Frame: Visit 0, Visit 4 weeks, Visit 12 weeks, Visit 24 weeks, Visit 48 weeks, Visit 52 weeks ]
   Absolute change in the levels of HDL Cholesterol will be measured by standard of care laboratory test results. High Density Lipoprotein (HDL) helps remove cholesterol from your arteries
2. Change in levels of Total cholesterol [ Time Frame: Visit 0, Visit 4 weeks, Visit 12 weeks, Visit 24 weeks, Visit 48 weeks, Visit 52 weeks ]
   Absolute change in the levels of Total Cholesterol will be measured by standard of care laboratory test results. Total cholesterol - a measure of the total amount of cholesterol in your blood. It includes both low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol.
3. Change in levels of Triglycerides [ Time Frame: Visit 0, Visit 4 weeks, Visit 12 weeks, Visit 24 weeks, Visit 48 weeks, Visit 52 weeks ]
   Absolute change in the levels of Triglycerides will be measured by standard of care laboratory test results. A triglyceride is an ester derived from glycerol and three fatty acids. Triglycerides are the main constituents of body fat in humans and other vertebrates, as well as vegetable fat
4. Change in levels of Lipoprotein(a) (Lp(a)) [ Time Frame: Visit 0, Visit 4 weeks, Visit 12 weeks, Visit 24 weeks, Visit 48 weeks, Visit 52 weeks ]
   Absolute change in the levels of Lipoprotein(a) will be measured by standard of care laboratory test results. Chr. Lipoprotein(a) is a low-density lipoprotein variant containing a protein called apolipoprotein(a).
5. Change in levels of Apolipoprotein A1(ApoA1) [ Time Frame: Visit 0, Visit 4 weeks, Visit 12 weeks, Visit 24 weeks, Visit 48 weeks, Visit 52 weeks ]
   Absolute change in the levels of Apolipoprotein A1(ApoA1) will be measured by standard of care laboratory test results. Apolipoprotein A1 is a protein that in humans is encoded by the APOA1 gene. It has a specific role in lipid metabolism.
6. Change in level of Apolipoprotein B(ApoB) [ Time Frame: Visit 0, Visit 4 weeks, Visit 12 weeks, Visit 24 weeks, Visit 48 weeks, Visit 52 weeks ]
   Absolute change in the levels of Apolipoprotein B(ApoB) will be measured by standard of care laboratory test results. Apolipoprotein B is the primary apolipoprotein of chylomicrons, VLDL, IDL, and LDL particles to all cells within all tissues.
7. Change in level of C-reactive protein (CRP) [ Time Frame: Visit 0, Visit 4 weeks, Visit 12 weeks, Visit 24 weeks, Visit 48 weeks, Visit 52 weeks ]
   Absolute change in C-reactive protein (CRP), a marker of inflammation and endothelial health measured in standard of care blood test results. C-reactive protein is an annular, pentameric protein found in blood plasma, whose circulating concentrations rise in response to inflammation. It is an acute-phase protein of hepatic origin that increases following interleukin-6 secretion by macrophages and T cells.
8. Change in level of Interleukin 6(IL-6) [ Time Frame: Visit 0, Visit 4 weeks, Visit 12 weeks, Visit 24 weeks, Visit 48 weeks, Visit 52 weeks ]
   Absolute change in Interleukin 6(IL-6), a marker of inflammation and endothelial health measured in standard of care blood test results. Interleukin 6 is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine.
9. Change in level of IPentraxin 3 (PTX3) [ Time Frame: Visit 0, Visit 4 weeks, Visit 12 weeks, Visit 24 weeks, Visit 48 weeks, Visit 52 weeks ]
   Absolute change in Pentraxin 3 (PTX3), a marker of inflammation and endothelial health measured in standard of care blood test results. Pentraxin 3 (PTX3) is an acute phase protein that is produced rapidly at local sites of inflammation
10. Change in time to cardiovascular events [ Time Frame: Visit 0, Visit 4 weeks, Visit 12 weeks, Visit 24 weeks, Visit 48 weeks, Visit 52 weeks ]
    These Cardiovascular events will be measured by the time to combined cardiovascular death or hospitalization for myocardial infarction, stroke, or revascularization. By measuring the time to the individual components of the combined cardiovascular endpoint
11. Change in the rate of cardiovascular events [ Time Frame: Visit 0, Visit 4 weeks, Visit 12 weeks, Visit 24 weeks, Visit 48 weeks, Visit 52 weeks ]
    These Cardiovascular events will be measured by the time to combined cardiovascular death or hospitalization for myocardial infarction, stroke, or revascularization. By measuring the rate of the combined cardiovascular endpoint allowing for repeated events
12. Change in the estimated glomerular filtration rate [ Time Frame: Visit 0, Visit 4 weeks, Visit 12 weeks, Visit 24 weeks, Visit 48 weeks, Visit 52 weeks ]
    Will measure the change in eGFR from baseline to end of study based on laboratory test results.
13. Increase in the Safety using Evolocumab [ Time Frame: Visit 0, Visit 4 weeks, Visit 12 weeks, Visit 24 weeks, Visit 48 weeks, Visit 52 weeks ]
    To measure the safety in the use of Evolocmab use in patients will be assessed by the decrease of adverse events
14. Number of discontinued blinded medications [ Time Frame: Visit 0, Visit 4 weeks, Visit 12 weeks, Visit 24 weeks, Visit 48 weeks, Visit 52 weeks ]
    The tolerability of use of Evolocmab use in patients will be measured by the number of discontinued blinded medications throughout the study.

Eligibility Criteria

• Ages Eligible for Study: 40 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Contacts

Contact: David Charytan, MD; 646-501-9086; David.Charytan@nyulangone.org

Locations

United States, New York

NYU Langone Nephrology Associates - Long Island; Not yet recruiting

Mineola, New York, United States, 11501

Contact: Nobuyuki Miyawaki, MD Nobuyuki.Miyawaki@nyulangone.org

Principal Investigator: Nobuyuki Miyawaki, MD

NYU Langone Health; Recruiting

New York, New York, United States, 10010

Contact: David Charytan, MD, MSc David.Charytan@nyulangone.org

Principal Investigator: David Charytan, MD, MSc

Sponsors and Collaborators

NYU Langone Health

Investigators

• Principal Investigator: David Charytan, MD; NYULangone Health

More Information

• Responsible Party: NYU Langone Health
• ClinicalTrials.gov Identifier: NCT04510844
• Other Study ID Numbers: 20-00405; 21-00455 ( Other Identifier: NYU Langone Health )
• First Posted: August 12, 2020
• Last Update Posted: June 1, 2021
• Last Verified: May 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices).
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)
• Time Frame: Beginning 9 months and ending 36 months following article publication or as required by a condition of awards and agreements supporting the research.
• Access Criteria: The investigator who proposed to use the data.Upon reasonable request. Requests should be directed to David.charytan@nyulangone.org. To gain access, data requestors will need to sign a data access agreement.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:

Kidney Diseases; Renal Insufficiency, Chronic; Hypercholesterolemia; Urologic Diseases; Renal Insufficiency; Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Evolocumab; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents