Mechanistic Clinical Trial of PCSK9 Inhibition for AAA

Abdominal Aortic Aneurysm Clinical Trial

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06081153
• Other study ID #: 852428
• Secondary ID: R01HL166991
• Status: Not yet recruiting
• Phase: Early Phase 1
• Start date: July 1, 2024
• Est. completion date: November 1, 2028

Study information

• Verified date: March 2024
• Source: University of Pennsylvania
• Contact: Kevin Dougherty, MPH
• Phone: 215-662-2243
• Email: kevin.dougherty[@]pennmedicine.upenn.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 44
• Est. completion date: November 1, 2028
• Est. primary completion date: November 1, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Abdominal aortic aneurysm (AAA) requiring open surgical repair

2. Age > 18

3. Provision of signed and dated informed consent form

4. Stated willingness to comply with all study procedures and availability for the duration of the study

Exclusion Criteria:

1. Prior use of a PCSK9 inhibitor (evolocumab, alirocumab, inclisiran) within 6 months of the baseline visit

2. LDL-C < 40 mg/dL (within 3 months of baseline visit)

3. Known allergy to PCSK9 inhibitor

4. Aortic dissection

5. Vascular connective tissue disorders

6. Type I-III or V Thoraco-abdominal Aortic Aneurysm

7. Vasculitis or inflammatory aneurysm

8. Pregnant or lactating women

9. Poorly controlled diabetes (A1C > 10%)

10. Chronic kidney disease Stage 4/5 or End Stage Renal Disease (ESRD) on hemodialysis (HD)

11. Liver Disease (alanine transaminase [ALT] or aspartate aminotransferase [ALT] > 3.0 x upper limits of normal) (within 3 months of baseline visit)

12. Known latex or naturally rubber allergy

13. 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.

14. Any other condition that the Investigator feels prohibits participants' ability to comply with study or follow up.

Related Conditions & MeSH terms

• Abdominal Aortic Aneurysm
• Aneurysm
• Aortic Aneurysm
• Aortic Aneurysm, Abdominal

Intervention

Drug:
• Evolocumab
See arm description.
• Placebo
See arm description.

Locations

Country	Name	City	State
n/a

Sponsors (3)

Lead Sponsor	Collaborator
University of Pennsylvania	Amgen, National Heart, Lung, and Blood Institute (NHLBI)

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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)
Secondary	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)
Secondary	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)