Extensive CArdioVAscular Characterization and Follow-up of Patients Receiving Immune Checkpoint Inhibitors (CAVACI)

May 30, 2023 updated by: Prof. Dr. Christof Vulsteke, Algemeen Ziekenhuis Maria Middelares

Extensive CArdioVAscular Characterization and Follow-up of Patients Receiving Immune Checkpoint Inhibitors: a Prospective Multicentre Study

The goal of this prospective, multicentre study is to investigate short- and long-term cardiovascular effects in cancer patients treated with immune checkpoint inhibitors (ICIs).

The main question[s] it aims to answer are:

  • To investigate troponin and NT-proBNP values in patients receiving ICIs and their association with ICI-induced CV abnormalities and MACEs.
  • Study the calcium score, systolic, and diastolic (dys)function.
  • Evaluate associations between patient/disease characteristics / transthoracic echocardiography parameters / electrocardiography parameters and troponin / NT-proBNP levels.

Participants will be closely monitored by performing the following additional visits and testing:

  • Chest CT scan prior to treatment start, after 12 and 24 months.
  • Consultation with a cardiologist at baseline, 3, 6, 12 and 24 months, who will perform an electrocardiogram and echocardiogram.
  • One additional blood sample prior to treatment start, after 3, 6, 12 and 24 months. An extra blood sample could be taken in case of sudden heart problems.
  • Non-invasive endothelial function tests prior to treatment start, after 12 and 24 months.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

The increasing use of immune checkpoint inhibitors (ICIs) in the treatment of both advanced and early stages of various malignancies has resulted in a substantial increase in the incidence of cardiovascular immune related adverse events (irAEs). The current guidelines are based on anecdotal evidence and expert opinions due to the lack of solid data and prospective studies. Therefore, cardiac monitoring, in patients receiving ICIs, is often not implemented by oncologists as many questions remain unanswered. Hence, the urgent need to investigate the possible short and long term cardiovascular effects of ICIs.

The investigators developed a multicentre, prospective study in which patients with a solid tumour eligible for ICI treatment will be enrolled. The study exists of routine investigations of blood parameters (troponin and (N-terminal) brain-type natriuretic peptide levels in particular) and a thorough cardiovascular follow-up on fixed time points during a period of two years. The cardiovascular follow-up consists of continuous remote patient monitoring, routine cardiology consultations including electrocardiograms, transthoracic echocardiograms, CT-scans for calcium scoring and non-invasive endothelial function tests. Associations between these blood parameters and short and long term cardiovascular irAEs will be statistically analysed.

This project will allow for a better estimate of the incidence of both short and long-term cardiovascular irAEs in a 'real world' patient population receiving ICIs. If the investigators are able to accurately predict and detect short- and long-term cardiovascular irAEs in an early (and subclinical) stage by correct implementation and interpretation of existing cardiac markers, they could be managed early on in a more effective manner.

Study Type

Interventional

Enrollment (Estimated)

276

Phase

  • Not Applicable

Contacts and Locations

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

Study Contact

Study Contact Backup

Study Locations

  • Belgium
      • Antwerp, Belgium, 2650
        • Recruiting
        • Antwerp University Hospital
        • Contact:
        • Contact:
        • Principal Investigator:
          • Hans Prenen, Prof
        • Sub-Investigator:
          • Constantijn Franssen, Dr
    • East-Flanders
      • Deinze, East-Flanders, Belgium, 9800
      • Ghent, East-Flanders, Belgium, 9000
      • Zottegem, East-Flanders, Belgium, 9620

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 and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Have a solid tumour and will receive one of the following therapies based on current evidence based clinical guidelines: anti-programmed cell death protein-1 (PD-1), anti-programmed cell death ligand-1 (PD-L1) and/or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) therapy
  • Be literate in Dutch or English

Exclusion Criteria:

  • Prior treatment with immunotherapy (immune checkpoint inhibitors, T-cell transfer therapy, cancer treatment vaccines or immune system modulators).
  • Patients who will receive ICIs in combination with an additional systemic anti-cancer regimen (chemotherapy, tyrosine kinase inhibitors,…).
  • Having a known history of human immunodeficiency virus (HIV) infection.
  • Having a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as detectable RNA via qualitative nucleic acid testing) infection.
  • Having a diagnosis of immunodeficiency or is receiving chronic/active systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent)

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

  • Primary Purpose: Prevention
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: Cancer patients with a solid tumour eligible for treatment with immune checkpoint inhibitors
Patients are treated as standard of care
Procedure: Non-invasive endothelial function tests
  • FMD
  • PAT

This aspect of the study will only be performed in the patients included by the Antwerp University Hospital due to organizational/practical issues.

Other Names:
  • Flow mediated dilatation (FMD)
  • Peripheral arterial tonometry (PAT)
Procedure: Electrocardiogram
An ECG will be taken prior to each ICI cycle during the first three months of treatment.
Other Names:
  • ECG
Diagnostic test: Extra serum sample (7.5 mL)
An extra serum sample will be taken at baseline, 3, 6, 12, 24 months and in case of sudden cardiac problems. This will subsequently be analysed to determine high-sensitivity troponin I, high-sensitivity troponin T and NT-proBNP.
Procedure: Cardiology consultation
  • Electrocardiogram (ECG).
  • Echocardiogram: A comprehensive evaluation of systolic and diastolic function, ventricular and atrial geometry will be performed. Special attention will be given to acquire a 3D measurement of left ventricular ejection fraction (LVEF) and to perform deformation imaging of left ventricle (global longitudinal strain (GLS)). The right ventricular function will be evaluated by tricuspid annular plane systolic excursion (TAPSE) and peak systolic velocity S' derived from color coded tissue Doppler imaging (TDI). Diastolic dysfunction will be based on average E/e' ratio > 15 and left atrial (LA) area > 30 cm2.
Diagnostic test: Chest Computed Tomography (CT) without contrast
Calcium score. This will be performed at baseline, 12 and 24 months. The scans at 12 and 24 months will be combined, if possible, with standard of care scans for cancer treatment.
Other Names:
  • Cardiac CT

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The incidence of an elevated hs-TnT above the ULN if the baseline value was normal; or 1.5 ≥ times baseline if the baseline value was above the ULN within the first three months of treatment. The maximum measured value will be taken into account.
Time Frame: Preliminary analysis once 50 patients have reached their 3-month cardiac follow-up visit and 3 months after last patient is included.
For the primary endpoint, the cumulative incidence of troponin elevation will be calculated with death as a competing risk. Cumulative incidences and corresponding 95% confidence intervals will be reported and a cumulative incidence plot will be used to visualize the results.
Preliminary analysis once 50 patients have reached their 3-month cardiac follow-up visit and 3 months after last patient is included.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Calcium score at baseline, 12 months, and 24 months.
Time Frame: Through study completion, an average of 1 year
Proportions and 95% confidence interval
Through study completion, an average of 1 year
Peripheral vascular function at baseline, 3 months, 6 months, 12 months and 24 months.
Time Frame: Through study completion, an average of 1 year

Flow mediated dilatation: dilatation % from baseline to maximal post-occlusion diameter.

Peripheral arterial tonometry ratio: based on the response to reactive hyperemia using post and pre-occlusion values
Through study completion, an average of 1 year
The incidence of hs-TnT/NT-proBNP elevations at 6, 12, and 24 months.
Time Frame: Through study completion, an average of 1 year
Cumulative incidences and 95% confidence intervals, considering death as a competing event.
Through study completion, an average of 1 year
The incidence of hs-TnT/NT-proBNP elevations at baseline, 3, 6, 12, and 24 months.
Time Frame: Preliminary analysis once 50 patients have reached their 3-month cardiac follow-up visit and through study completion, an average of 1 year
Cumulative incidences and 95% confidence intervals, considering death as a competing event.
Preliminary analysis once 50 patients have reached their 3-month cardiac follow-up visit and through study completion, an average of 1 year
Evolution of hs-TnT/NT-proBNP in 24 months compared to baseline.
Time Frame: Through study completion, an average of 1 year
Linear mixed effects model with a random intercept per subject to account for the correlation measurements coming from the same individual.
Through study completion, an average of 1 year
Evolution of transthoracic 3D echocardiography parameters (dimensions, diastolic function, valvular abnormalities, LVEF, strain analysis) at baseline, 3, 6, 12, and 24 months.
Time Frame: reliminary analysis once 50 patients have reached their 3-month cardiac follow-up visit and through study completion, an average of 1 year
Linear mixed effects model with a random intercept per subject to account for the correlation measurements coming from the same individual.
reliminary analysis once 50 patients have reached their 3-month cardiac follow-up visit and through study completion, an average of 1 year
Evolution of electrocardiography parameters (rhythm, heart axis, PQ interval, QRS duration, bundle branch block, QT interval, RR interval, pathological Q's, left ventricular hypertrophy and STT segments) at baseline, 3, 6, 12, and 24 months.
Time Frame: reliminary analysis once 50 patients have reached their 3-month cardiac follow-up visit and through study completion, an average of 1 year
Linear mixed effects model with a random intercept per subject to account for the correlation measurements coming from the same individual.
reliminary analysis once 50 patients have reached their 3-month cardiac follow-up visit and through study completion, an average of 1 year
Association between the evolution of troponin/NT-proBNP and transthoracic echocardiography parameters at baseline, 3, 6, 12, and 24 months.
Time Frame: reliminary analysis once 50 patients have reached their 3-month cardiac follow-up visit and through study completion, an average of 1 year
Linear mixed effects model with a random intercept per subject to account for the correlation measurements coming from the same individual.
reliminary analysis once 50 patients have reached their 3-month cardiac follow-up visit and through study completion, an average of 1 year
Association between the evolution of troponin/NT-proBNP and electrocardiography (rhythm, heart axis, PQ, QRS, bundle branch block, QT, RR, pathological Q's, left ventricular hypertrophy and STT segments) parameters at baseline, 3, 6, 12, and 24 months.
Time Frame: reliminary analysis once 50 patients have reached their 3-month cardiac follow-up visit and through study completion, an average of 1 year
Linear mixed effects model with a random intercept per subject to account for the correlation measurements coming from the same individual.
reliminary analysis once 50 patients have reached their 3-month cardiac follow-up visit and through study completion, an average of 1 year
Cumulative incidence of cardiovascular (CV) abnormalities at 3, 6, 12, and 24 months based on the CARDIOTOX classification system of Sendón et al., with the inclusion of pericardial effusion and new arrhythmias.
Time Frame: Through study completion, an average of 1 year
Cumulative incidences and 95% confidence intervals, considering death as a competing event.
Through study completion, an average of 1 year
Association between the evolution of troponin/NT-proBNP and CV abnormalities (as classified based on the CARDIOTOX classification for myocardial injury including cardiac biomarkers, symptoms, LVEF, LA area, LVESV, GLS and diastolic function).
Time Frame: Through study completion, an average of 1 year
Joint model combining a linear mixed model for troponin and a sub-distributional proportional hazards model for the time-to-event taking into account death as a competing event for CV abnormality and MACE.
Through study completion, an average of 1 year
Cumulative incidence of MACEs at 3, 6, 12, and 24 months. MACEs were defined as the composite outcome of nonfatal stroke, nonfatal myocardial infarction, hospital admission for heart failure (HF) and cardiac revascularization, and CV death.
Time Frame: Through study completion, an average of 1 year
Cumulative incidences and 95% confidence intervals, considering death as a competing event.
Through study completion, an average of 1 year
Overall survival.
Time Frame: reliminary analysis once 50 patients have reached their 3-month cardiac follow-up visit and through study completion, an average of 1 year
Cumulative incidences and 95% confidence intervals
reliminary analysis once 50 patients have reached their 3-month cardiac follow-up visit and through study completion, an average of 1 year
Association between the evolution of troponin/NT-proBNP and MACEs over a period of two years. Nonfatal stroke, nonfatal myocardial infarction, hospital admission for heart failure, cardiac revascularization and CV death will be combined to report MACEs.
Time Frame: Through study completion, an average of 1 year
Joint model combining a linear mixed model for troponin and a sub-distributional proportional hazards model for the time-to-event taking into account death as a competing event for CV abnormality and MACE.
Through study completion, an average of 1 year
The difference in the evolution of hs-TnT/NT-proBNP between combination therapy and monotherapy over a period of two years.
Time Frame: Through study completion, an average of 1 year
Linear mixed effects model with a random intercept per subject to account for the correlation measurements coming from the same individual. This model will be extended with patient and treatment characteristics and their interaction with time, to evaluate their impact on the evolution of these parameters.
Through study completion, an average of 1 year
The difference in the evolution of transthoracic echocardiography parameters (dimensions, diastolic function, valvular abnormalities, LVEF, strain analysis) between combination therapy and monotherapy over a period of two years.
Time Frame: Through study completion, an average of 1 year
Linear mixed effects model with a random intercept per subject to account for the correlation measurements coming from the same individual. This model will be extended with patient and treatment characteristics and their interaction with time, to evaluate their impact on the evolution of these parameters.
Through study completion, an average of 1 year
The difference in the evolution of electrocardiography parameters (rhythm, heart axis, PQ, QRS, bundle branch block, QT, RR, pathological Q's, left ventricular hypertrophy and STT segments) between combination therapy and monotherapy.
Time Frame: Through study completion, an average of 1 year
Linear mixed effects model with a random intercept per subject to account for the correlation measurements coming from the same individual. This model will be extended with patient and treatment characteristics and their interaction with time, to evaluate their impact on the evolution of these parameters.
Through study completion, an average of 1 year
Association between patient characteristics (demographics, medical history, current oncological disease, prior cancer history, prior/concomitant medication and other relevant parameters) and troponin.
Time Frame: Through study completion, an average of 1 year
Linear mixed effects model with a random intercept per subject to account for the correlation measurements coming from the same individual. This model will be extended with patient and treatment characteristics and their interaction with time, to evaluate their impact on the evolution of these parameters.
Through study completion, an average of 1 year
Association between patient characteristics (demographics, medical history, current oncological disease, prior cancer history, prior/concomitant medication and other relevant parameters) and NT-proBNP.
Time Frame: Through study completion, an average of 1 year
Linear mixed effects model with a random intercept per subject to account for the correlation measurements coming from the same individual. This model will be extended with patient and treatment characteristics and their interaction with time, to evaluate their impact on the evolution of these parameters.
Through study completion, an average of 1 year
Agreement between hs-TnT and hs-TnI levels at baseline, 3, 6, 12, and 24 months.
Time Frame: reliminary analysis once 50 patients have reached their 3-month cardiac follow-up visit and through study completion, an average of 1 year
Bland-Altman curves and intraclass correlation coefficient (ICC) based on a two-way mixed effects model. The ICC and 95% confidence interval will be reported.
reliminary analysis once 50 patients have reached their 3-month cardiac follow-up visit and through study completion, an average of 1 year
The proportion of severe immune-related non-CV toxicities (grades 3-5).
Time Frame: Through study completion, an average of 1 year
Proportions and 95% confidence interval
Through study completion, an average of 1 year
Association between the evolution of troponin/NT-proBNP and severe immune-related non-CV toxicities (grades 3-5, e.g. pneumonitis, colitis, thyroiditis, etc. according to the CTCAE criteria).
Time Frame: Through study completion, an average of 1 year
Linear mixed effects model with a random intercept per subject to account for the correlation measurements coming from the same individual. This model will be extended with patient and treatment characteristics and their interaction with time, to evaluate their impact on the evolution of these parameters.
Through study completion, an average of 1 year
Association between the evolution of troponin/NT-proBNP and overall survival.
Time Frame: Through study completion, an average of 1 year
Joint model combining a linear mixed model for troponin and a sub-distributional proportional hazards model for the time-to-event taking into account death as a competing event for CV abnormality and MACE.
Through study completion, an average of 1 year
Association between the evolution of troponin and diastolic function (based on the recommendations listed in https://doi.org/10.1016/j.echo.2016.01.011, mitral inflow, tissue doppler imaging parameters).
Time Frame: Through study completion, an average of 1 year
Linear mixed effects model with a random intercept per subject to account for the correlation measurements coming from the same individual. This model will be extended with patient and treatment characteristics and their interaction with time, to evaluate their impact on the evolution of these parameters.
Through study completion, an average of 1 year
Association between the evolution of troponin and calcium score.
Time Frame: Through study completion, an average of 1 year

Flow mediated dilatation: dilatation % from baseline to maximal post-occlusion diameter.

Peripheral arterial tonometry ratio: based on the response to reactive hyperemia using post and pre-occlusion values
Through study completion, an average of 1 year

Collaborators and Investigators

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

Sponsor

Algemeen Ziekenhuis Maria Middelares

Investigators

  • Principal Investigator: Christof Vulsteke, Prof, Algemeen ziekenhuis Maria Middelares

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)

January 7, 2022

Primary Completion (Estimated)

November 30, 2024

Study Completion (Estimated)

November 30, 2026

Study Registration Dates

First Submitted

December 9, 2022

First Submitted That Met QC Criteria

January 24, 2023

First Posted (Actual)

January 26, 2023

Study Record Updates

Last Update Posted (Actual)

June 1, 2023

Last Update Submitted That Met QC Criteria

May 30, 2023

Last Verified

May 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • MMS.2021.058

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

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.

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