Clinical trial NCT05699915: Extensive CArdioVAscular Characterization and Follow-up of Patients Receiving Immune Checkpoint Inhibitors
Official title: Extensive CArdioVAscular Characterization and Follow-up of Patients Receiving Immune Checkpoint Inhibitors: a Prospective Multicentre Study
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Cancer
Immune-related Adverse Event
Cardiac Abnormalities, Variable
Immune Checkpoint Inhibitor-Related Myocarditis
Diastolic Dysfunction
Atherosclerosis
Cardiotoxicity
Keywords: Cardio-oncology
Immune-related adverse event
Immune checkpoint inhibitor
Myocarditis
Troponin
Lead sponsor: Algemeen Ziekenhuis Maria Middelares
Sponsor class: OTHER
First posted: 2023-01-26
Enrollment: 105
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

Brief summary: 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.

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.

Eligibility criteria: 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)

Primary outcomes:
measure: 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.
timeFrame: Preliminary analysis once 50 patients have reached their 3-month cardiac follow-up visit and 3 months after last patient is included.
Secondary outcomes:
measure: The incidence of hs-TnT/NT-proBNP elevations at 6, 12, and 24 months.
timeFrame: Through study completion, an average of 1 year
measure: The incidence of hs-TnT/NT-proBNP elevations at baseline, 3, 6, 12, and 24 months.
timeFrame: Preliminary analysis once 50 patients have reached their 3-month cardiac follow-up visit and through study completion, an average of 1 year
measure: Evolution of hs-TnT/NT-proBNP in 24 months compared to baseline.
timeFrame: Through study completion, an average of 1 year
measure: Evolution of transthoracic 3D echocardiography parameters (dimensions, diastolic function, valvular abnormalities, LVEF, strain analysis) at baseline, 3, 6, 12, and 24 months.
timeFrame: reliminary analysis once 50 patients have reached their 3-month cardiac follow-up visit and through study completion, an average of 1 year
measure: 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.
timeFrame: reliminary analysis once 50 patients have reached their 3-month cardiac follow-up visit and through study completion, an average of 1 year
measure: Association between the evolution of troponin/NT-proBNP and transthoracic echocardiography parameters at baseline, 3, 6, 12, and 24 months.
timeFrame: reliminary analysis once 50 patients have reached their 3-month cardiac follow-up visit and through study completion, an average of 1 year
measure: 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.
timeFrame: reliminary analysis once 50 patients have reached their 3-month cardiac follow-up visit and through study completion, an average of 1 year
measure: 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.
timeFrame: Through study completion, an average of 1 year
measure: 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).
timeFrame: Through study completion, an average of 1 year
measure: 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.
timeFrame: Through study completion, an average of 1 year
measure: Overall survival.
timeFrame: reliminary analysis once 50 patients have reached their 3-month cardiac follow-up visit and through study completion, an average of 1 year
measure: 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.
timeFrame: Through study completion, an average of 1 year
measure: The difference in the evolution of hs-TnT/NT-proBNP between combination therapy and monotherapy over a period of two years.
timeFrame: Through study completion, an average of 1 year
measure: 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.
timeFrame: Through study completion, an average of 1 year
measure: 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.
timeFrame: Through study completion, an average of 1 year
measure: Association between patient characteristics (demographics, medical history, current oncological disease, prior cancer history, prior/concomitant medication and other relevant parameters) and troponin.
timeFrame: Through study completion, an average of 1 year
measure: Association between patient characteristics (demographics, medical history, current oncological disease, prior cancer history, prior/concomitant medication and other relevant parameters) and NT-proBNP.
timeFrame: Through study completion, an average of 1 year
measure: Agreement between hs-TnT and hs-TnI levels at baseline, 3, 6, 12, and 24 months.
timeFrame: reliminary analysis once 50 patients have reached their 3-month cardiac follow-up visit and through study completion, an average of 1 year
measure: The proportion of severe immune-related non-CV toxicities (grades 3-5).
timeFrame: Through study completion, an average of 1 year
measure: 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).
timeFrame: Through study completion, an average of 1 year
measure: Association between the evolution of troponin/NT-proBNP and overall survival.
timeFrame: Through study completion, an average of 1 year
measure: 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).
timeFrame: Through study completion, an average of 1 year
measure: Calcium score at baseline, 12 months, and 24 months.
timeFrame: Through study completion, an average of 1 year
measure: Peripheral vascular function at baseline, 3 months, 6 months, 12 months and 24 months.
timeFrame: Through study completion, an average of 1 year
measure: Association between the evolution of troponin and calcium score.
timeFrame: Through study completion, an average of 1 year
Other outcomes:
Locations:
city: Deinze
country: Belgium
facility: AZ Sint-Vincentius Deinze
state: East-Flanders
city: Ghent
country: Belgium
facility: Algemeen Ziekenhuis Maria Middelares
state: East-Flanders
city: Zottegem
country: Belgium
facility: AZ Sint-Elisabeth Zottegem
state: East-Flanders
city: Antwerp
country: Belgium
facility: Antwerp University Hospital
Study officials:
affiliation: Algemeen Ziekenhuis Maria Middelares
name: Christof Vulsteke, Prof
role: PRINCIPAL_INVESTIGATOR
References: