Ignite Creation Date:
2024-05-06 @ 1:49 PM
Last Modification Date:
2024-10-26 @ 1:20 PM
Study NCT ID:
NCT04130243
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2022-10-18
First Post:
2017-05-01
Brief Title:
Biomarkers in Pediatric Congenital Heart Disease and PAH
Sponsor:
University Medical Center Groningen
Organization:
University Medical Center Groningen
Study Overview
Official Title:
Biomarkers in Congenital Heart Diseases and Pulmonary Arterial Hypertension
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2022-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Nowadays biomarkers are broadly used in clinical practice Blood-derived biomarkers fulfil an important role in the field of cardiology However most biomarkers have been investigated for adult left ventricular disease In congenital heart diseases CHD and pulmonary arterial hypertension PAH which involves children and mostly the right ventricle less is known about the clinical and predictive value of blood-derived biomarkers Since the group of survivors of CHD and PAH is growing because of the improved techniques nowadays development of better tools to maintain the quality of life for the longer term in these patients is urgently needed Blood-derived biomarkers are minimally invasive biomarkers are quantitative and have shown to be able to reveal pathological processes in an early stage Hence blood-derived biomarkers may be a good addition to current diagnostic means in CHD and PAH
Objective The primary objective of this study is to investigate cross-sectionally the association between various emerging blood-derived biomarkers and right ventricular RV functiondefined as tricuspid annular plane systolic excursion TAPSE measured with echocardiography in children with a history of an abnormally loaded volume andor pressure loaded right ventricle associated with CHD andor PAH
Objective The primary objective of this study is to investigate cross-sectionally the association between various emerging blood-derived biomarkers and right ventricular RV functiondefined as tricuspid annular plane systolic excursion TAPSE measured with echocardiography in children with a history of an abnormally loaded volume andor pressure loaded right ventricle associated with CHD andor PAH
Detailed Description:
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 functiondefined as tricuspid annular plane systolic excursion TAPSE measured with echocardiography in children with a history of an abnormally loaded volume andor pressure loaded right ventricle associated with CHD andor 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 heartlung transplantation
STUDY POPULATION All patients with a history of an abnormally loaded right ventricle associated with CHD andor 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 hisher parentslegal representatives by letter and telephone When the patient or hisher parentslegal 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 hisher 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 heshe 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 100Functional class will be clearly documented in most included patients 80MRI will be performed in a subpopulation of included patients 50CPET 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 Childrens 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 sponsorinvestigator 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 wwwtoetsingonlinenl and clintrailgov
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 SAEs 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 -03 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 coefficientsRepeated 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 eg biomarkers with skewed distribution will be if appropriate log-transformed prior to inclusion in the regression models
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 functiondefined as tricuspid annular plane systolic excursion TAPSE measured with echocardiography in children with a history of an abnormally loaded volume andor pressure loaded right ventricle associated with CHD andor 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 heartlung transplantation
STUDY POPULATION All patients with a history of an abnormally loaded right ventricle associated with CHD andor 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 hisher parentslegal representatives by letter and telephone When the patient or hisher parentslegal 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 hisher 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 heshe 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 100Functional class will be clearly documented in most included patients 80MRI will be performed in a subpopulation of included patients 50CPET 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 Childrens 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 sponsorinvestigator 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 wwwtoetsingonlinenl and clintrailgov
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 SAEs 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 -03 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 coefficientsRepeated 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 eg biomarkers with skewed distribution will be if appropriate log-transformed prior to inclusion in the regression models
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None