The COllaborative Neonatal Network for the First CPAM Trial

Study design: prospective multicentre randomized controlled trial. Duration: the total duration of the follow-up will be 5 years Setting: collaborating centres within the COllaborative Neonatal Network for the first European Congenital Pulmonary Airway Malformation (CPAM) Trial consortium (CONNECT)

Parents expecting a child with a prenatally diagnosed CPAM will be counselled and informed about the study prenatally. At the age of 6 months, each child will undergo a chest CT with intravenous contrast in order to confirm the diagnosis, as part of the standard of care. This chest CT will be evaluated according to a structured report. If the chest CT confirms the diagnosis CPAM and the child remains asymptomatic, the child is eligible for inclusion. After having obtained informed consent from parents or caregivers, randomisation to the surgical arm or the non-surgical arm will take place. At this point, the prenatal ultrasound images will be retrospectively evaluated according to a structured report.

In case of randomisation to the surgical arm, surgical resection will take place between 6 and 9 months of age. The type and extent of the surgical procedure is dependent on the lesion characteristics, local protocol and the surgeon's preference. Preferably, small lesions are treated with a segmentectomy; i.e., sub-lobar resection. Larger lesions are generally treated with lobectomy. Wedge resection is not advised due to higher risks of post-operative air leakage and residual disease. Surgical details will be documented according to a structured report.

Resected material will be sent to the local pathology department for analysis. The local pathologist will analyse the material, and document the results according to the Structured Pathology Report for Congenital Pulmonary Airway Malformation.

Genetic testing will be offered as part of routine diagnostic procedures. Standard information leaflets and informed consent forms of the department of clinical genetics will be offered to parents. If parental consent is obtained, blood (1-4ml, depending on availability/safety) will be drawn from the study subject, at the moment when an IV-needle is placed - in order to administer the IV-contrast - just before the diagnostic CT-scan). This material will be stored in a plastic Etheylenediaminetetraacetic acid (EDTA) vacutainer blood collector tube. Similarly, blood of both parents - if possible - (10 ml) will be drawn and stored in a plastic EDTA vacutainer blood collector tube. These parental samples will be sent for DNA isolation and genetic analysis to the local departments of Clinical Genetics, where the DNA will be stored. In this diagnostic procedure, trio single nucleotide polymorphism (SNP) array / whole exome sequencing or whole genome sequencing will be performed.

The follow-up program lasts 5 years, is uniform for all patients and consists of three assessments at the ages of 1 year, 2.5 years, and 5 years (with a margin of 2 months towards the patients' age for each assessment). This follow-up structure is standard of care in the majority of the participating centres. Patients assigned to the surgical arm will visit the hospital one additional time, 2-6 weeks after the surgery has taken place, for scar inspection, postoperative complaints and evaluation of the pathology report. At the second visit (at 2.5 years) a follow-up CT-scan will be performed, and during the last visit participants will perform a standardised exercise test using the BRUCE treadmill protocol, supervised by a certified paediatric physical therapist.

Furthermore, parents will be asked to complete several questionnaires, addressing anxiety, quality of life and medical costs.

The duration of the follow-up was set to 5 years to ensure enough time to observe potential differences in clinical outcome between the two study groups (i.e., the development of post-surgical complications or the development of symptoms in the conservative group). Another consideration was that the age of 5 years is the youngest age at which standardised endurance tests have been validated.

• Pulmonary morbidity during follow-up [Time frame: through study completion, a total of 5 years]
• Surgical intervention due to pulmonary morbidity [Time frame: Through study completion, a total of 5 years]
• CPAM characteristics on prenatal ultrasound images, according to standardized structured report [Time frame: 20 weeks gestation]
• CPAM characteristics on postnatal CT-scan, according to standardized structured report [Time frame: 3-9 months of age]
• CPAM development / post-surgical appearance on repeated CT imaging, according to standardized structured report [Time frame: 2.5 years of age]
• CPAM development / post-surgical appearance on CT imaging - scored according to the Congenital Lung Abnormalities Quantification (CLAQ) method [Time frame: 3-9 months of age + 2.5 years of age]
• Quality of life analysis [Time frame: 6 months, 1 year, 2.5 years, 5 years]
• Quality of life analysis [Time frame: 5 years]
• Parental anxiety level, assessed pre-operatively [Time frame: 6 months, 1 year, 2.5 years, 5 years]
• Weight [Time frame: 6 months, 1 year, 2.5 years, 5 years]
• Height [Time frame: 6 months, 1 year, 2.5 years, 5 years]
• Pathological characteristics of resected material, according to standardized structured report [Time frame: 9-12 months]