The COllaborative Neonatal Network for the First CPAM Trial (CONNECT)

The COllaborative Neonatal Network for the First Congenital Pulmonary Airway Malformation (CPAM) Trial

The goal of this clinical trial is to compare conservative wait-and-see management to elective surgical intervention, in asymptomatic Congenital Pulmonary Airway Malformation (CPAM) children.

Children assigned to the intervention group will undergo surgical resection of the CPAM between 6 and 9 months of age. Children assigned to the control group will be monitored conservatively. The follow-up scheme will be uniform for both treatment groups and last for 5 years.

The primary outcome is the difference in maximal endurance at five years of age between the surgical and conservative group. Secondary outcome measures are molecular genetic diagnostics, validated questionnaires - on parental anxiety, quality of life and health care consumption -, repeated imaging, and pulmonary morbidity during follow-up, as well as surgical complications and histopathology.

Study Overview

• Status: Recruiting
• Conditions: Congenital Pulmonary Airway Malformation
• Intervention / Treatment: Procedure: Elective surgical resection of CPAM between 6 and 9 months of age

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 176
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: J Marco Schnater, MD, PhD; Phone Number: 0031 107036923; Email: j.schnater@erasmusmc.nl
• Study Contact Backup: Name: Rene MH Wijnen, professor; Phone Number: 0031 107036923; Email: r.wijnen@erasmusmc.nl

Study Locations

• Netherlands
  • Gelderlanf
    • Nijmegen, Gelderlanf, Netherlands, 6525GA
      • Not yet recruiting
      • Radboud University Medical Centre
      • Contact: Maarten Schurink, MD, PhD
  • Zuid-Holland
    • Rotterdam, Zuid-Holland, Netherlands, 3015GD
      • Recruiting
      • Erasmus MC Sophia Children's Hospital
      • Contact: Marco Schnater, MD, PhD; Phone Number: 0031107036923; Email: j.schnater@erasmusmc.nl
      • Contact: Rene MH Wijnen, Professor; Phone Number: 0031107036923; Email: r.wijnen@erasmusmc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 1 year (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Lesion detected during routine prenatal ultrasound screening
• Delivery at term: gestational age ≥37 weeks
• Birthweight > -2SD or >P10
• Asymptomatic at birth defined as no prolonged respiratory distress or oxygen support (< 24 hours)
• Asymptomatic up to the moment of inclusion
• Confirmation of CPAM on postnatal chest CT-scan at 3-9 months of age, according to structured report form (34)
• Unilateral lesion occupying no more than one lung lobe as assessed on chest CT-scan at 3-9 months of age

Exclusion Criteria:

• Bilateral lesion
• Development of symptoms before randomization, considered by treating physician as caused by CPAM with reasonable certainty
• Complicated pregnancy defined as (pre-)eclampsia, pregnancy diabetes in mother, foetal hydrops or severe polyhydramnios on prenatal ultrasound
• Syndrome associated anomalies on genetic analysis confirmed by genetic expert
• Major associated malformations. Anomalies include cardiac malformations requiring surgical correction or follow-up by a paediatric cardiologist, congenital malformations requiring major surgical intervention, and anomalies that affect normal lung growth and development.
• Suspicion of malignancy on chest CT scan evaluation at the age of 3-9 months
• Participation in another randomised controlled trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Conservative arm; Children assigned to this treatment arm will be conservatively managed, and will continue to be followed until the age of 5 years (end of study inclusion).
Active Comparator: Surgical arm; Children assigned to this treatment arm will undergo elective surgical resection at the age of 6-9 months, and will continue to be followed until the age of 5 years (end of study inclusion).	Procedure: Elective surgical resection of CPAM between 6 and 9 months of age; Surgical resection of the CPAM between 6 and 9 months of age

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exercise tolerance	BRUCE treadmill test protocol. Total endurance time will be converted to a sex and age matched percentile score based on pre-defined reference values.	5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pulmonary morbidity during follow-up	Infection, cough, dyspea, respiratory insufficiency etc.	through study completion, a total of 5 years
Surgical intervention due to pulmonary morbidity	Indication for surgical resection of the pulmonary lesion following the development of pulmonary morbidity during follow-up	Through study completion, a total of 5 years
CPAM characteristics on prenatal ultrasound images, according to standardized structured report	Structured report form to be added up to 1 score, in which case a higher score indicates a larger and more complicated lesion	20 weeks gestation
CPAM characteristics on postnatal CT-scan, according to standardized structured report	Structured report form to be added up to 1 score, in which case a higher score indicates a larger and more complicated lesion	3-9 months of age
CPAM development / post-surgical appearance on repeated CT imaging, according to standardized structured report	Structured report form to be added up to 1 score, in which case a higher score indicates a larger and more complicated lesion	2.5 years of age
CPAM development / post-surgical appearance on CT imaging - scored according to the Congenital Lung Abnormalities Quantification (CLAQ) method	Structured report form to be added up to 1 score, in which case a higher score indicates a larger and more complicated lesion	3-9 months of age + 2.5 years of age
Quality of life analysis	Toddler Quality of Life Questionnaire (ITQOL), transformed to a scale score from 0 (worst health) to 100 (best health)	6 months, 1 year, 2.5 years, 5 years
Quality of life analysis	Child Health Utility Index (CHU9D). Translated to total raw scores ranging from 0 (no impairment) to 36 (maximal impairment) based 9 questions in 9 different dimensions.	5 years
Parental anxiety level, assessed pre-operatively	Visual Analogue Scale for Anxiety (VAS-A), scored from 0 (no anxiety) to 10 (maximal anxiety).	6 months, 1 year, 2.5 years, 5 years
Weight	Converted to Standard Deviation score	6 months, 1 year, 2.5 years, 5 years
Height	Converted to Standard Deviation score	6 months, 1 year, 2.5 years, 5 years
Pathological characteristics of resected material, according to standardized structured report	Structured report form to be added up to 1 score, in which case this score defines specific, pre-defined pathological lesion characteristics. This score does therefore not indicate better of worse, but rather specifies the lesion characteristics.	9-12 months
Cost-effectiveness of both management strategies and comparison	The cost consequences and cost-effectiveness of surgical versus conservative management of CPAM will be analyzed through a trial-based economic evaluation. Data on health care resource consumption will be extracted from both the electronic information systems of the participating centres and the Institute for Medical Technology Assessment (iMTA) Medical Consumption Questionnaire (iMCQ). As regards the effects of the intervention, the economic evaluation will look at maximal endurance time and quality-adjusted life-years (QALYs), which is a measure of health outcome that combines quality of life with length of life. The calculation of QALYs will be based on survival data and on responses to the Child Health Utility 9D (CHU9D) questionnaire	6 months, 1 year, 2.5 years, 5 years

Collaborators and Investigators

• Sponsor: Erasmus Medical Center
• Investigators: Study Director: Rene MH Wijnen, professor, Head of department Pediatric Surgery, Erasmus MC Sophia Children's Hospital, Rotterdam

Publications and helpful links

General Publications

• Hermelijn S, Kersten C, Mullassery D, Muthialu N, Cobanoglu N, Gartner S, Bagolan P, Mesas Burgos C, Sgro A, Heyman S, Till H, Suominen J, Schurink M, Desender L, Losty P, Ertresvag K, Tiddens HAWM, Wijnen RMH, Schnater M; CONNECT study consortium COS development group; CONNECT study consortium COS development group. Development of a core outcome set for congenital pulmonary airway malformations: study protocol of an international Delphi survey. BMJ Open. 2021 Apr 12;11(4):e044544. doi: 10.1136/bmjopen-2020-044544.
• Kersten CM, Hermelijn SM, Mullassery D, Muthialu N, Cobanoglu N, Gartner S, Bagolan P, Mesas Burgos C, Sgro A, Heyman S, Till H, Suominen J, Schurink M, Desender L, Losty P, Steyaert H, Terheggen-Lagro S, Metzelder M, Bonnard A, Sfeir R, Singh M, Yardley I, Rikkers-Mutsaerts NRVM, van der Ent CK, Qvist N, Cox DW, Peters R, Bannier MAGE, Wessel L, Proesmans M, Stanton M, Hannon E, Zampoli M, Morini F, Tiddens HAWM, Wijnen RMH, Schnater JM. The Management of Asymptomatic Congenital Pulmonary Airway Malformation: Results of a European Delphi Survey. Children (Basel). 2022 Jul 30;9(8):1153. doi: 10.3390/children9081153.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2023
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2030

Study Registration Dates

• First Submitted: December 15, 2022
• First Submitted That Met QC Criteria: January 19, 2023
• First Posted (Actual): January 27, 2023

Study Record Updates

• Last Update Posted (Estimated): March 4, 2024
• Last Update Submitted That Met QC Criteria: March 1, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Randomized; Asymptomatic CPAM; Optimal management; Conservative vs surgical
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Respiratory System Abnormalities; Congenital Abnormalities; Cystic Adenomatoid Malformation of Lung, Congenital
• Other Study ID Numbers: CONNECT-study

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: all collected IPD, all IPD that underlie results in a publication
• IPD Sharing Time Frame: Starting 6 months after publication
• IPD Sharing Access Criteria: Open access
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No