Immunomodulatory Effects of PCSK9 Inhibition

NCT05720156 | Withdrawn

• 1 other identifier: 2022P002214
• Study Type: observational
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

Cardiovascular disease (CVD) represents the leading cause of death worldwide. While medications, such as statins, significantly reduce atherosclerotic CVD (ASCVD) risk by lowering low density lipoprotein levels, they may also have pleiotropic effects on inflammation. The immunomodulatory effects of these medications are relevant to ASCVD risk reduction given that inflammation plays a central role in atherosclerotic plaque formation (atherogenesis) and influences the development of vulnerable plaque morphology. Patients on statins, however, may have residual inflammation contributing to incident ASCVD despite the potent LDL-lowering effects of statins. While new therapies, such as proprotein convertase subtilisin/kexin type 9 (PSCK9) inhibitors, further reduce incident ASCVD and drastically reduce LDL-C below that achieved by statin therapy alone, PCSK9 inhibitors may also have pleiotropic effects on inflammation. Thus, PCSK9 inhibitors may help reduce arterial inflammation to a level closer to that of patients without ASCVD. This study will apply a novel targeted molecular imaging approach, technetium 99m (99mTc)-tilmanocept SPECT/CT, to determine if residual macrophage-specific arterial inflammation is present with statin therapy and the immunomodulatory effects of PSCK9 inhibition. Given the continued high mortality and morbidity attributable to ASCVD, strong imperatives exist to better understand the immunomodulatory effects of lipid lowering therapies and residual inflammatory risk. This understanding, in turn, will inform the development of new ASCVD preventative and treatment strategies as well as elucidate other indications for established therapies.

Conditions

Atherosclerotic Cardiovascular Disease; Cardiovascular Diseases; Atherosclerosis; Arterial Inflammation; Vascular Diseases; Vascular Disease, Peripheral; Vascular Calcification; High Cholesterol/Hyperlipidemia; Heart Diseases; Heart Attack; Stroke; Cerebrovascular Accident; Carotid Artery Diseases; Carotid Atherosclerosis; Transient Ischemic Attack

Outcome Measures

Primary Outcomes (2)

• Between-group difference (case participants versus control participants) in percent volume with aortic 99mTc-tilmanocept uptake across different uptake thresholds

  Baseline

• Change in the percent volume with aortic 99mTc-tilmanocept uptake across different uptake thresholds after PCSK9 inhibitor therapy for 12 months (case participants only)

  Baseline and 12 Months

Secondary Outcomes (6)

• Relationship between baseline immune cell subpopulations (cells/µL) and aortic volume with 99mTc-tilmanocept uptake

  Baseline and 12 Months

• Relationship between baseline markers of immune activation/ systemic inflammation and aortic volume with 99mTc-tilmanocept uptake

  Baseline and 12 Months

• Relationship between change in macrophage-specific arterial infiltration with PCSK9 inhibitors and change in immune cell subpopulations (cells/µL)

  Baseline and 12 Months

• Relationship between change in macrophage-specific arterial infiltration with PCSK9 inhibitors and change in markers of immune activation/ systemic inflammation

  Baseline and 12 Months

• Relationship between change in macrophage-specific arterial infiltration with PCSK9 inhibitors and baseline immune cell subpopulations (cells/µL)

  Baseline and 12 Months

Study Arms (2)

Case group: History of ASCVD, on high-intensity statins and initiating PCSK9 inhibitor therapy

History of ASCVD, on high-intensity statins and initiating PCSK9 inhibitor therapy

Other: 99mTc-tilmanocept SPECT/CT scanning

Control group: No history of ASCVD, not on statins or initiating PCSK9 inhibitor therapy

No history of ASCVD, not currently on high-intensity statins, other lipid lowering therapy or initiating PCSK9 inhibitor therapy

Other: 99mTc-tilmanocept SPECT/CT scanning

Interventions

99mTc-tilmanocept SPECT/CT scanning OTHER

99mTc-Tilmanocept SPECT/CT allows for visualization of macrophage-specific arterial infiltration

Case group: History of ASCVD, on high-intensity statins and initiating PCSK9 inhibitor therapy; Control group: No history of ASCVD, not on statins or initiating PCSK9 inhibitor therapy

Eligibility Criteria

• Age: 18 Years - 85 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Case: People with known ASCVD, on high-intensity statin therapy for at least 6 months and about to initiate PCSK9 inhibitor therapy Control: Healthy controls with no known ASCVD and not on statin

You may qualify if:

• to 85 years of age
• CASE PARTICIPANTS ONLY: History of ASCVD (including a history of coronary artery disease, carotid artery disease, peripheral artery disease, acute coronary syndrome, percutaneous coronary intervention, coronary bypass surgery, carotid endarterectomy, stroke or TIA)
• CASE PARTICIPANTS ONLY: High-intensity statin therapy for at least 6 months prior enrollment and without an interruption of \>1 month
• CASE PARTICIPANTS ONLY: Initiation of PCSK9 inhibition with either evolocumab or alirocumab (and not inclisiran - PSCK9 inhibition through small interfering RNA)

You may not qualify if:

• pregnancy or breastfeeding
• CONTROL PARTICIPANTS ONLY: No known history of ASCVD (including a history of coronary artery disease, carotid artery disease, peripheral artery disease, acute coronary syndrome, percutaneous coronary intervention, coronary bypass surgery, carotid endarterectomy, stroke or TIA)
• current treatment with prescription, systemic (oral, IV, IM or intra-articular) steroids or anti-inflammatory/immune suppressant medical therapies (excluding topical therapies, UV therapy, ASA-derivative therapies, or NSAIDS) for autoimmune/inflammatory diseases (psoriasis, RA, IBD, lupus), post-transplant care, asthma, or pain syndromes
• use of oral steroids or prescription oral anti-inflammatory/immune suppressant medication for \> 7 days within the past 1 month
• use of IV, IM or intra-articular steroids or IV, IM or intra-articular anti-inflammatory/immune suppressant medication within the past 3 months
• Any prior use of PCSK9 inhibitors including both monoclonal antibodies or small interfering RNA
• CONTROL PARTICIPANTS ONLY: use of cholesterol lowering therapy (including statins, ezetimibe, bempedoic acid, PCSK9 inhibitors including both monoclonal antibodies or small interfering RNA, niacin, fibrates) or other lipid lowering agents associated with ASCVD risk reduction such as Vascepa. Cholesterol lowering therapies that that predominantly target triglycerides including over the counter omega-3 fatty acids and Lovaza are permitted.
• known allergy to dextrans and/or DTPA and/or radiometals
• significant radiation exposure (\>2 CT angiograms) received within the past 12 months
• concurrent enrollment in another research study judged by the study investigators to interfere with the current study

Sponsors & Collaborators

• Massachusetts General Hospital: lead

Study Sites (1)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

MeSH Terms

Conditions

Atherosclerosis; Cardiovascular Diseases; Arteritis; Vascular Diseases; Peripheral Vascular Diseases; Vascular Calcification; Hypercholesterolemia; Hyperlipidemias; Heart Diseases; Myocardial Infarction; Stroke; Carotid Artery Diseases; Ischemic Attack, Transient

Condition Hierarchy (Ancestors)

Arteriosclerosis; Arterial Occlusive Diseases; Vasculitis; Calcinosis; Calcium Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Dyslipidemias; Lipid Metabolism Disorders; Myocardial Ischemia; Infarction; Ischemia; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Necrosis; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Brain Ischemia

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: January 20, 2023
• First Posted: February 9, 2023
• Study Start: April 4, 2024
• Primary Completion: March 1, 2026
• Study Completion: March 1, 2026
• Last Updated: September 26, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)