Specifying the Anti-inflammatory Effects of Ziltivekimab (SPIDER)

Specifying the Anti-inflammatory Effects of Ziltivekimab With Diverse Imaging Modalities and In-depth Cellular Phenotyping

The goal of this randomized, double blind, placebo controlled trial is to study whether ziltivekimab therapy reduces arterial wall inflammation as assessed by imaging, and reduces the systemic inflammatory tone as assessed by circulating monocytes, inflammatory biomarkers and proteomics.

Study Overview

• Status: Not yet recruiting
• Conditions: Inflammation; Atherosclerosis
• Intervention / Treatment: Drug: Placebo; Drug: Ziltivekimab

Detailed Description

Considering that ziltivekimab is currently undergoing a phase 3 CVOT trial, it is of great importance to elucidate its mechanistic effects. The objective of this study is to research whether ziltivekimab therapy for 20 weeks reduces arterial wall inflammation, as assessed by state-of-the-art imaging modalities, and reduces systemic inflammatory tone, as assessed by in depth phenotyping of circulating monocytes, inflammatory biomarkers and proteomics. The imaging modalities used in this study are 68Ga-DOTATATE PET/CT and CCTA. This study is designed as a single center, randomized, double-blinded, placebo-controlled intervention study in 40 atherosclerotic patients of 50 years and older with hsCRP levels of 2 mg/L and above.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: R.F. Oostveem, MD; Phone Number: +312052268791; Email: r.oostveen@amsterdamumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Aged 50 years and older.
• Multi-vessel coronary artery disease (defined as CAD-RADS ≥2).
• Serum hsCRP level ≥2 mg/L.

Exclusion Criteria:

• Coronary stents in situ.
• Chronic or recent (<1 month) (serious) infections and/or clinical signs of acute (serious) infection.
• History of severe auto-immune diseases, or other (severe) (recurrent or chronic) inflammatory disorders.
• Use of preventive systemic antibiotics (antibiotics used to treat latent tuberculosis are exempted).
• Stable lipid lowering treatment for less than 4 weeks, including statins, ezetimibe and PCSK9 inhibition.
• Untreated latent tuberculosis, active hepatitis B (positive HBsAg and/or positive anti-HBc with detectable HBV DNA) or C, human immunodeficiency virus (HIV) not on stable antiretroviral regimen
• Uncontrolled diabetes (HbA1c >90 mmol/mol).
• Renal insufficiency, defined as eGFR <45 ml/min/1.73 m2.
• Platelet count <120,000 and >450,000 /mm3.
• Elevated liver enzymes (>3 ULN of liver transaminases), acute liver failure or known (severe) liver disease.
• Premenopausal women not using birth-control.
• History of gastrointestinal perforation, active diverticulitis (within 5 years) or active inflammatory bowel disease (within 12 months).
• Uncontrolled hypertension (systolic >180 mmHg; diastolic >110 mmHg).
• Diagnosis of (active) malignancy in last 5 years.
• Standard contra-indications to 68Ga-DOTATATE PET, and CT based on physician's experience and current practices.
• Inability or unwillingness to comply with the protocol requirements, or deemed by investigator to be unfit for the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ziltivekimab; 15 mg ziltivekimab subcutaneously once per month for 5 months	Drug: Ziltivekimab; Monoclonal antibody targeting IL-6; Other Names: no other intervention name
Placebo Comparator: Placebo; Placebo, subcutaneously, once per month for 5 months	Drug: Placebo; Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
TBRmax coronary arteries	mean percentage change in coronary arteries target to background ratio (TBRmax)	5.5 months
monocyte activation marker protein expression	The impact of ziltivekimab on a mass cytometry monocyte phenotype panel; expression markers such as CD14 and CD16.	5.5 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
delta PCAT	Difference in PCAT (CCTA derived) after ziltivekimab treatment.	5.5 months
Correlation delta TBRmax and CCTA derived plaque characteristics	Correlation between changes in coronary 68Ga-DOTATATE uptake and anatomical plaque changes on CCTA.	5.5 months
delta SUVmax bone marrow	Difference in 68Ga-DOTATATE SUVmax of bone marrow after treatment.	5.5 months
delta TBRmax ascending aorta	Difference in 68Ga-DOTATATE TBRmax of ascending aorta after treatment	5.5 months
changes monocyte phenotype	The impact of ziltivekimab on monocyte phenotype in transendothelial migration (TEM) capacity and transcriptome profile.	5.5 months
changes in hsCRP	hsCRP (high-sensitivity C-reactive protein): mg/L	5.5 months
changes plasma cytokine and chemokine levels (pg/mL)	TNF-α (Tumor Necrosis Factor alpha): pg/mL IL-8 (Interleukin-8): pg/mL MCP-1 (Monocyte Chemoattractant Protein-1): pg/mL	5.5 months
changes plasma cytokine and chemokine levels (ng/mL)	sICAM (soluble Intercellular Adhesion Molecule): ng/mL sVCAM (soluble Vascular Cell Adhesion Molecule): ng/mL	5.5 months

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Investigators: Principal Investigator: E.S.G. Stroes, Prof.dr., Amsterdam UMC

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2024
• Primary Completion (Estimated): March 1, 2025
• Study Completion (Estimated): April 1, 2025

Study Registration Dates

• First Submitted: August 3, 2023
• First Submitted That Met QC Criteria: February 8, 2024
• First Posted (Actual): February 16, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2024
• Last Update Submitted That Met QC Criteria: March 22, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Inflammation; PET/CT; Monocytes; DOTATATE; CCTA; Ziltivekimab
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Inflammation; Atherosclerosis
• Other Study ID Numbers: NL83403.018.22

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 drug product: No
• Studies a U.S. FDA-regulated device product: No