Mechanistic Clinical Trial of PCSK9 Inhibition for AAA

Study Overview
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Brief Summary
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The goal of this mechanistic clinical trial is to assess whether lowering the low-density lipoprotein cholesterol (LDL-C) levels in the blood with the injections of the medication evolocumab will have any effect on the tissue or cells of patients with abdominal aortic aneurysm (AAA). Researchers will compare participants receiving evolocumab injections to participants receiving placebo injections to see how the tissue and cells of the aorta are affected by changes in LDL-C levels.

Detailed Description
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After being informed about the study and its potential risks, all patients giving informed consent will undergo a baseline visit and be randomized to received either evolocumab 140mg subcutaneously or placebo. This baseline visit includes a vital signs assessment, laboratory tests, medical history and medication review, a pregnancy test (if applicable), and training on how to perform drug injections. Participants will receive 3 doses/autoinjectors of study drug or placebo and be instructed to perform injections every 14 days starting 5 weeks prior to their scheduled AAA repair. If the baseline assessment occurs 5 weeks prior to their scheduled AAA, the first injection will be performed during this visit. Participants will have the option of coming back to the site for injections 2 and 3 or perform these injections at home under telehealth supervision. At the time of open AAA repair, participants will repeat laboratory tests and have a sample of aneurysm tissue taken. Participants will then have a follow up phone call 4 weeks after AAA repair to assess for any adverse events. At the conclusion of the study investigators will examine gene expression and protein levels in the aortic tissue to determine the impact of LDL-C lowering with evolocumab.

Official Title
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A Randomized, Placebo-Controlled Mechanistic Clinical Trial of PCSK9 Inhibition With Evolocumab in Patients Undergoing Open Abdominal Aortic Aneurysm Repair

Conditions
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Abdominal Aortic Aneurysm

Intervention / Treatment
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* Drug: Evolocumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Abdominal aortic aneurysm (AAA) requiring open surgical repair Age > 18 Provision of signed and dated informed consent form Stated willingness to comply with all study procedures and availability for the duration of the study Exclusion Criteria: Prior use of a PCSK9 inhibitor (evolocumab, alirocumab, inclisiran) within 6 months of the baseline visit LDL-C < 40 mg/dL (within 3 months of baseline visit) Known allergy to PCSK9 inhibitor Aortic dissection Vascular connective tissue disorders Type I-III or V Thoraco-abdominal Aortic Aneurysm Vasculitis or inflammatory aneurysm Pregnant or lactating women Poorly controlled diabetes (A1C > 10%) Chronic kidney disease Stage 4/5 or End Stage Renal Disease (ESRD) on hemodialysis (HD) Liver Disease (alanine transaminase [ALT] or aspartate aminotransferase [ALT] > 3.0 x upper limits of normal) (within 3 months of baseline visit) Known latex or naturally rubber allergy Treatment with another investigational product within 30 days or 5 half-lives of the investigation drug before consent (whichever is longer) that would have an impact on endpoints associated with this trial. Any other condition that the Investigator feels prohibits participants' ability to comply with study or follow up.

Ages Eligible for Study
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Minimum Age: 18 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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Evolocumab<br>Evolocumab is the drug that will be administered in this study. It will be administered as a 140mg subcutaneous injection every 14 days for 5 weeks (for a total of 3 doses). | Drug: Evolocumab<br>* See arm description.<br>|
| Placebo Comparator: Placebo<br>This arm is a matching placebo that will be administered in the same fashion as the study drug if the patient is randomized to placebo. | Drug: Placebo<br>* See arm description.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Interleukin (IL)-6 in myeloid derived monocytes/macrophages from in AAA tissue | IL-6 expression will be measured in myeloid cells in the aortic tissue specimens using single nucleus RNA sequencing and confirmed by whole tissue ELISA. | AAA Repair (Week 5) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Matrix metalloproteinase (MMP)-9 in myeloid derived monocytes/macrophages from in AAA tissue | MMP-9 expression will be measured in myeloid cells in the aortic tissue specimens using single nucleus RNA sequencing and confirmed by whole tissue ELISA and immunofluorescence activity assays. | AAA Repair (Week 5) | 
| Infiltrating immune cell composition and their activation/inflammatory states in AAA tissue | Relative numbers of infiltrating immune cell type and their activation/inflammatory state as measured by a combination of bulk and single nuclear RNA sequencing | AAA Repair (Week 5) | 
| Smooth muscle composition of AAA tissue | The relative numbers of smooth muscle cells and their contractile/proliferative state as measured by a combination of bulk and single nucleus RNA sequencing | AAA Repair (Week 5) |