Immunomodulatory Effects of PCSK9 Inhibition (INSPIRAR)

September 23, 2025 updated by: Mabel Toribio, Massachusetts General Hospital

ImmuNomodulatory EffectS of PCSK9 Inhibition: A TaRgeted Molecular Imaging AppRoach

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.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Study Type

Observational

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Massachusetts General Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 85 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

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

Description

Inclusion Criteria:

  • 18 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)

Exclusion Criteria:

  • 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
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
99mTc-Tilmanocept SPECT/CT allows for visualization of macrophage-specific arterial infiltration
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
99mTc-Tilmanocept SPECT/CT allows for visualization of macrophage-specific arterial infiltration

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Change in the percent volume with aortic 99mTc-tilmanocept uptake across different uptake thresholds after PCSK9 inhibitor therapy for 12 months (case participants only)
Time Frame: Baseline and 12 Months
Baseline and 12 Months
Between-group difference (case participants versus control participants) in percent volume with aortic 99mTc-tilmanocept uptake across different uptake thresholds
Time Frame: Baseline
Baseline

Secondary Outcome Measures

Outcome Measure
Time Frame
Relationship between baseline immune cell subpopulations (cells/µL) and aortic volume with 99mTc-tilmanocept uptake
Time Frame: Baseline and 12 Months
Baseline and 12 Months
Relationship between baseline markers of immune activation/ systemic inflammation and aortic volume with 99mTc-tilmanocept uptake
Time Frame: Baseline and 12 Months
Baseline and 12 Months
Relationship between change in macrophage-specific arterial infiltration with PCSK9 inhibitors and change in immune cell subpopulations (cells/µL)
Time Frame: Baseline and 12 Months
Baseline and 12 Months
Relationship between change in macrophage-specific arterial infiltration with PCSK9 inhibitors and change in markers of immune activation/ systemic inflammation
Time Frame: Baseline and 12 Months
Baseline and 12 Months
Relationship between change in macrophage-specific arterial infiltration with PCSK9 inhibitors and baseline immune cell subpopulations (cells/µL)
Time Frame: Baseline and 12 Months
Baseline and 12 Months
Relationship between change in macrophage-specific arterial infiltration with PCSK9 inhibitors and baseline markers of immune activation/ systemic inflammation
Time Frame: Baseline and 12 Months
Baseline and 12 Months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Massachusetts General Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 4, 2024

Primary Completion (Estimated)

March 1, 2026

Study Completion (Estimated)

March 1, 2026

Study Registration Dates

First Submitted

January 20, 2023

First Submitted That Met QC Criteria

January 30, 2023

First Posted (Actual)

February 9, 2023

Study Record Updates

Last Update Posted (Estimated)

September 26, 2025

Last Update Submitted That Met QC Criteria

September 23, 2025

Last Verified

September 1, 2025

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2022P002214

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Heart Diseases

Clinical Trials on 99mTc-tilmanocept SPECT/CT scanning

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Dominican Republic

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe