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Immunomodulatory Effects of PCSK9 Inhibition (INSPIRAR)

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ClinicalTrials.gov Identifier: NCT05720156
Recruitment Status : Recruiting
First Posted : February 9, 2023
Last Update Posted : May 10, 2024
Sponsor:
Information provided by (Responsible Party):
Mabel Toribio, Massachusetts General Hospital

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.

Condition or disease Intervention/treatment
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 Other: 99mTc-tilmanocept SPECT/CT scanning

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Study Type : Observational
Estimated Enrollment : 40 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: ImmuNomodulatory EffectS of PCSK9 Inhibition: A TaRgeted Molecular Imaging AppRoach
Actual Study Start Date : April 4, 2024
Estimated Primary Completion Date : March 2026
Estimated Study Completion Date : March 2026

Resource links provided by the National Library of Medicine

Drug Information available for: Tilmanocept

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




Primary Outcome Measures :
  1. Between-group difference (case participants versus control participants) in percent volume with aortic 99mTc-tilmanocept uptake across different uptake thresholds [ Time Frame: Baseline ]
  2. 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 ]

Secondary Outcome Measures :
  1. Relationship between baseline immune cell subpopulations (cells/µL) and aortic volume with 99mTc-tilmanocept uptake [ Time Frame: Baseline and 12 Months ]
  2. Relationship between baseline markers of immune activation/ systemic inflammation and aortic volume with 99mTc-tilmanocept uptake [ Time Frame: Baseline and 12 Months ]
  3. 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 ]
  4. 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 ]
  5. Relationship between change in macrophage-specific arterial infiltration with PCSK9 inhibitors and baseline immune cell subpopulations (cells/µL) [ Time Frame: Baseline and 12 Months ]
  6. 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 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
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

Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05720156


Contacts
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Contact: Mabel Toribio 617-724-2826 mptoribio@mgh.harvard.edu

Locations
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United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Mabel Toribio    617-724-2826    mptoribio@mgh.harvard.edu   
Sponsors and Collaborators
Massachusetts General Hospital
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Responsible Party: Mabel Toribio, Assistant Professor, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT05720156    
Other Study ID Numbers: 2022P002214
First Posted: February 9, 2023    Key Record Dates
Last Update Posted: May 10, 2024
Last Verified: May 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Stroke
Ischemic Attack, Transient
Carotid Artery Diseases
Cardiovascular Diseases
Atherosclerosis
Vascular Diseases
Myocardial Infarction
Arteritis
Peripheral Vascular Diseases
Peripheral Arterial Disease
Hyperlipidemias
Hypercholesterolemia
Vascular Calcification
Inflammation
Pathologic Processes
Heart Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Dyslipidemias
Lipid Metabolism Disorders
Metabolic Diseases
Calcinosis
Calcium Metabolism Disorders
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Brain Ischemia
Myocardial Ischemia
Infarction