OBJECTIVES:
Primary Objective:
The primary objective is to investigate cross-sectionally (at baseline and after one year)
the association between various emerging blood-derived biomarkers and right ventricular (RV)
function:defined as tricuspid annular plane systolic excursion (TAPSE) measured with
echocardiography, in children with (a history of ) an abnormally loaded, volume and/or
pressure loaded, right ventricle associated with CHD and/or PAH.
TIME FRAME: Baseline and after one year.
Secondary Objective:
Furthermore, the investigators aim to explore:
- - The stability, dynamic (treatment-induced) longitudinal changes of these biomarkers and
their association with RV function (defined as TAPSE).
- - The predictive value of these biomarkers measured at baseline with regard to various
clinically relevant impaired RV functioning parameters (TAPSE, RV- Fractional area
change , RV-Fractional shortening and RV function assessed with eyeballing) at long term
follow-up.
- - The predictive value of these biomarkers with regard to clinical outcome defined as the
composite of mortality, hospitalization, and or heart/lung transplantation.
STUDY POPULATION: All patients with (a history of) an abnormally loaded right ventricle
associated with CHD and/or PAH who are followed in the Center of Congenital Heart Disease
- -
University Medical Center Groningen (CHH-UMCG) from 01-12-2017 will be approached by letter
and telephone to be included.
STUDY PROCEDURES:
1. The study is introduced to the patient and his/her parents/legal representatives by
letter and telephone. When the patient or his/her parents/legal representatives are
interested the researcher will ask them to sign informed consent papers. When the
patient is admitted to the clinical ward or will come for his/her outpatient clinic
visit the researcher will check if informed consent has been given. If informed consent
has been given and the patient meets the inclusion criteria he/she will be included in
the study.
2. Study procedures with respect to primary comparison:
Echocardiography will be performed in all included patients (100%) in context of
standard care. Blood drawing in context of standard care or additional study purposes
will be performed in all included patients (100%).
3. Study procedures (all performed in context of standard care) with respect to secondary
comparisons: Mortality will be assessed in all patients (±100%).Functional class will be
clearly documented in most included patients (±80%).MRI will be performed in a
subpopulation of included patients (±50%).CPET will be performed in a subpopulation of
included patients (±40%). 6MWD will be performed in a subpopulation included patients
(±30%).
WITHDRAWAL OF INDIVIDUAL SUBJECTS: Subjects can leave the study at any time for any reason if
they wish to do so without any consequences. The investigator can decide to withdraw a
subject from the study for urgent medical reasons.
REPLACEMENT OF INDIVIDUAL SUBJECTS AFTER WITHDRAWAL: Withdrawal before the first time point
will result in exclusion. Withdrawal after the first time point will result in a smaller
sample size regarding to follow up, but the data will still be used for the available time
points.
PREMATURE TERMINATION: premature termination has no influence on the patients.
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION:
1. In this study the data will be coded according to a protected key on the general Beatrix
Children's Hospital (BKK)-disk. Data will be collected in RedCap or Utopia, which both
meet the security requirements according to legislation described by BROK and UMCG.
All included patients will get a study identification number: BioCHD001, BioCHD002, etc.
The order will be in the order of the obtained informed consent. The key will be
available at the general BKK-disk for above mentioned investigators and contains the
original patient number (UMCG-number), study identification number (study ID), and study
identification number of other studies the patient is involved in.
Data entry will be based on information from Epic, Poliplus, ECHOPAC (for
echocardiography) or Medis QMass (for MRI). The blood samples will be stored on study ID
by the central laboratory and assessments of the blood-derived biomarkers will be
performed by the central laboratory as well. Blood results will be communicated
according to study ID.
Data will be stored in the central laboratory until all the different assays have been
run. Data will be kept 15 years after end-of-study. Conditions for long-term document
storage will follow GCP, institutional and national guidelines.
2. Monitoring and Quality Assurance : Monitoring will take place according to guidelines in
Research Toolbox on UMCG-intranet.
3. Annual progress report: The sponsor/investigator will submit a summary of the progress
of the trial to the accredited METC once a year. Information will be provided on the
date of inclusion of the first subject, numbers of subjects included and numbers of
subjects that have completed the trial, serious adverse events/ serious adverse
reactions, other problems, and amendments.
4. Public disclosure and publication policy: This prospective study will be registered
prospectively at the website www.toetsingonline.nl and clintrail.gov.
The results of the study will be published without reservations at international conferences
and will be submitted for publication in international "peer-reviewed" scientific journals.
SAFETY REPORTING:
1. Temporary halt for reasons of subject safety:
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the
study if there is sufficient ground that continuation of the study will jeopardise
subject health or safety. The sponsor will notify the accredited METC without undue
delay of a temporary halt including the reason for such an action. The study will be
suspended pending a further positive decision by the accredited METC. The investigator
will take care that all subjects are kept informed.
2. Adverse events (AEs) Reporting or recording of adverse events is not applicable in this
observational follow up study.
3. The current study is a observational, non-intervention, follow up study in a population
that contains patients with possible SAEs as result of their (congenital) heart disease.
Therefore, only SAE's resulting from extra blood withdrawals will be reported by the
investigator to the sponsor without undue delay after obtaining knowledge of the events.
The sponsor will report the SAEs that are a result of extra blood withdrawal through the web
portal ToetsingOnline to the accredited METC that approved the protocol, within 7 days of
first knowledge for SAEs that result in death or are life threatening followed by a period of
maximum of 8 days to complete the initial preliminary report. All other SAEs, related to
extra blood withdrawal, will be reported within a period of maximum 15 days after the sponsor
has first knowledge of the serious adverse events.
SAMPLE SIZE CALCULATION: In this study the investigators would like to identify blood-derived
biomarkers for right ventricular disease in CHD and PAH. In this sample size calculation the
investigators have to take into account all the known references of the to be tested
biomarkers and that the levels of the biomarkers could differ with respect to age and gender.
Previous research confirmed lower levels of specific biomarkers in children compared to
adults. Published results concerns mostly significant results with respect to clinically ill
versus clinically adapted patients. The investigators would like to look at the correlation
between the level of blood-derived biomarkers and RV function. Based on the published results
with respect to biomarkers in CHD, a correlation coefficient of (-)0.3 should be sufficient.
TAPSE, gender and age are included as predictor variables. With a good prediction level this
will give a sample size of 380.
STATISTICAL ANALYSIS PLAN: For the cross-sectionally primary endpoint, the investigators will
analyze the correlations of the level of serum biomarker withRV-function (defined as the
echocardiographic measurement TAPSE), using Spearman partial correlation analyses, crude and
adjusted for age and sex. Subsequently, linear regression analysis will be used to further
explore the relationship between biomarkers with continuous RV function. This will be done at
baseline and after one year.
For the exploratory objectives, the stability of biomarkers in time will be assessed using
intraclass correlation coefficients.Repeated measures linear mixed model techniques will be
applied to explore changes of biomarkers and right ventricular function in time in which
patients will be entered as the random component of the mixed model. Binary or multinominal
logistic regression analysis will be used to assess the relationship between biomarkers and
RV function impairment.
Kaplan Meier and Cox regression analysis will be performed to compare (transplantation-free)
survival of patients with high or low baseline biomarkers and to explore the predictive value
of biomarkers on clinical outcome.
Not normally distributed continous variables (e.g. biomarkers with skewed distribution) will
be, if appropriate, log-transformed, prior to inclusion in the regression models.
