Improving Care for Children With Congenital Heart Disease by Cardiovascular Biomarker Profiling and Advanced Non-invasive Cardiac Imaging Techniques.
Phase: NA
Conditions: Heart Disease Congenital, Ventricular Septal Defect, Atrial Septal Defect, Patent Ductus Arteriosus, Partial Anomalous Pulmonary Venous Connection, Aortopulmonary Window, Cardiovascular Diseases
Sponsor: Lund University Hospital

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Unique study approval ID (Sweden):  2019-05490 
Official title: Improving care for children with congenital heart disease by cardiovascular biomarker 
profiling and advanced non-invasive cardiac imaging techniques. 
Statistical analysis plan (date): 25th of Oct. 2020 
 
Study protocol summary: 
 
Study type & outcome measure for cases:  
- Case-control study to evaluate diagnostic usefulness of non-invasive cardiac imaging measures and 
cardiovascular biomarkers in children. 
- Need for open heart surgery or cardiac catheter intervention to treat predefined congenital heart 
disease lesions leading to pulmonary over-circulation (as below). 
Enrolment:  
After local advertisement and written informed consent (dedicated healthcare regions in Sweden). 
 
Controls (0-17 years) without history or presence of cardiovascular disease at enrolment: 
Number of assessments: 1 (at enrolment) 
Type of assessments in local paediatric cardiology ambulatory / out-patient clinic settings: 
1. Clinical evaluation cardiovascular examination by paediatric cardiologist 
2. Standard 12 lead ECG recording  
3. Transthoracic echocardiography examination (predefined standard paediatric protocol including 
but not limited to 2D, Doppler, TDI)  
4. Cardiac magnetic resonance (CMR) evaluation of the heart using predefined sequence protocol 
(including 4D flow assessments) for comparison to cases reaching outcomes (matched subgroup) 
5. Peripheral blood sampling for cardiovascular biomarker batch analysis (O-link proximity extension 
assay of 96 markers and quantitative analysis of selected biomarkers, e.g. NT-pro-BNP) 
6. Optional saliva sampling at enrolment and/or retrieval of dried blood samples from neonatal 
screening laboratory if available for batch analysis and comparison to standard blood sample 
cardiovascular biomarkers (O-link proximity extension assay of 96 markers and quantitative analysis 
of selected biomarkers, e.g. NT-pro-BNP) 
 
Cases (0-17 years) without treated congenital heart disease by open heart surgery or cardiac 
catheter intervention at enrolment: 
Included lesions of congenital heart disease leading to pulmonary over-circulation: 

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- Atrial septal defect (ASD) 
- Ventricular septal defect (VSD) 
- Patent ductus arteriosus (PDA) 
- Partial anomalous pulmonary venous drainage (PAPVD) 
- Aorto-pulmonary window (APW) 
Number of assessments:  
- Minimum 2 (at enrolment and 6-12 months after outcome is reached)  
- Maximum 4 (at enrolment and annually to a max. follow-up of 3 years if not reaching outcome) 
Type of assessments in local paediatric cardiology hospital / out-patient clinic settings: 
1. Clinical evaluation cardiovascular examination by paediatric cardiologist 
2. Standard 12 lead ECG recording  
3. Transthoracic echocardiography examination (predefined standard paediatric protocol including 
but not limited to 2D, Doppler, TDI)  
4. Cardiac magnetic resonance (CMR) evaluation of the heart using predefined sequence protocol 
(including 4D flow assessments) for subjects reaching outcome (undergoing open heart surgery / 
cardiac catheter intervention) on hospital admission before treatment and 6-12 months after 
intervention in ambulatory setting. 
5. Peripheral blood sampling for later cardiovascular biomarker batch analysis (proximity extension 
assay and quantitative analysis for selected biomarkers, e.g. NT-pro-BNP) 
6. Optional saliva sampling at enrolment and/or retrieval of dried blood samples from neonatal 
screening laboratory if available as well as optional cardiovascular tissue sampling at time of open 
heart surgery  for batch analysis and comparison to standard blood sample cardiovascular 
biomarkers (O-link proximity extension assay of 96 markers and quantitative analysis of selected 
biomarkers, e.g. NT-pro-BNP) 
 
Table summarizing study protocol: 
Type of 
assessment 
Subjects  
Enrolment  
1 year 
2 years  
3 years 
Clinical 
evaluation 
Controls 
Cases  
X 
X 
- 
X 
- 
X 
- 
X 
12-lead ECG 
Controls  
Cases 
X 
X 
- 
X 
- 
X 
- 
X 
Transthoracic 
echocardiography 
Controls 
Cases  
X 
X 
- 
X 
- 
X 
- 
X 
Cardiac magnetic 
resonance * 
Controls  
Cases  
X = 1 assessment for controls at enrolment 
X = 2 assessments for cases reaching outcome  
(1st on admission for intervention & 2nd 6-12 months post intervention) 
Peripheral blood 
sampling 
Controls  
Cases  
X 
X  
- 
X 
- 
X 
- 
X 

3 
 
Optional saliva / 
dried blood 
sampling 
Controls  
Cases  
X 
X  
- 
X 
- 
X 
- 
X 
Optional 
cardiovascular 
tissue sampling 
Controls  
Cases  
-  
X   
(1 sample for subgroup of cases undergoing open heart surgery) 
*) Subgroup of cases reaching outcome during study and subgroup of matched controls.