'TOTAL' (Tracheal Occlusion To Accelerate Lung Growth) Trial

Phase 2

Completed

Conditions: Hernia
Congenital Diaphragmatic Hernia
Hernia, DIaphragmatic, Congenital
Pulmonary Hypoplasia
Hernia, Diaphragmatic
Pathological Conditions, Anatomical
Congenital Abnormalities
Fetal Anomaly
Fetal Surgery

Interventions: Device: GoldBal2 detachable balloon
Device: Baltaccidbpe100 Delivery Catheter
Other: Standardized postnatal care

Registration Number: NCT02875860

Lead Sponsor: Michael A Belfort

Brief Summary: This trial will test whether temporary fetoscopic endoluminal tracheal occlusion (FETO) rather than expectant management during pregnancy, followed by standardized postnatal management, increases survival at discharge and decreases oxygen need at 6 months in case of survival till discharge.

Detailed Description: This is a multi-center, non-blinded randomized controlled trial in fetuses with isolated moderate CDH, i.e. moderate lung hypoplasia (as determined by prenatal assessment of lung development). It essentially compares fetal therapy added to conventional postnatal care, versus expectant prenatal management during pregnancy followed by conventional postnatal care.

Enrollment:

Following completion of an inclusion/exclusion criteria checklist and obtaining informed consent, the subject will be randomized into two groups ("FETO" and "expectant").

Procedures:

Group I: Standardized postnatal care (expectant group): mothers will be expectantly managed during pregnancies and babies receive standardized postnatal care at a tertiary center used to manage babies with CDH. The recommendation is that they adhere to consensus guidelines published on the study website.

Group II: Prenatal intervention (FETO group): patients will undergo fetoscopic tracheal occlusion and ideally prenatal reversal of the occlusion followed by standardized postnatal care as in I. In this study FETO is to be done between 30 weeks plus 0 day and 31 weeks plus 6 days and removal of the balloon at 34 weeks plus 0 day to 34 weeks plus 6 days.

This study trial is a pragmatical or efficacy trial: ideally mothers will deliver after removal of the balloon at those tertiary centers, typically offering postnatal care for the patient involved. In group II (FETO-group), mothers will, in between placement and removal of the balloon, thus carrying a fetus with obstructed airways, ideally remain under the care of our local fetal treatment center (further referred to as FETO center). As many as possible precautions are taken to avoid problems with balloon removal in case of earlier than expected delivery.

* Balloons are to be electively removed prior to 35 weeks. FETO centers will provide 24/24 hours and 7/7 days services for management of fetuses with obstructed airways, either in utero or during labor and delivery.

* Patients in the study and randomized to FETO, will be encouraged to stay near the FETO center. After reversal of the occlusion the patient will be referred to the tertiary care center where delivery and postnatal care will be undertaken. If the patient is not remaining at or close to the FETO center, the postnatal treatment center should organize likewise EXIT services.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 5

Inclusion Criteria

Patients aged 18 years or more, who are able to consent,
Singleton pregnancy,
Chromosomally normal fetus,
Gestation at randomization prior to 31 weeks plus 5 days or so that occlusion is done at the latest on 31 weeks plus 6 days,
Fetus is estimated to have moderate pulmonary hypoplasia, defined prenatally as:

• O/E LHR 25-34.9% (included; irrespective of the position of the liver) • O/E LHR 35-44.9% (included) with intrathoracic liver herniation as determined by ultrasound or MRI.

The O/E LHR will be determined by the FETO centers as follows:
- Measurement of the contralateral lung area preferentially by the tracing method at the 4-chamber view of the heart; if by other method adjusted normative ranges must be used.
- Measurement of the head circumference at the standard biparietal view of the head
- The observed lung area: calculation of the LHR as the ratio of the measurements of the lung area to head circumference
- The expected lung area is the lung area of a normal gestational age match, as determined by the head circumference of the index case in a normogram established for the same measurement method (tracing method in this case). A calculator for this will be available on the website of the study.
- Calculation of the observed over expected lung area,
Acceptance of randomization and the consequences for the further management during pregnancy and thereafter, this includes the required observation following FETO surgery, which lasts up to 4 weeks after balloon is in place,
The patients must undertake the responsibility for either remaining close to, or at the FETO center, or being able to travel swiftly and within acceptable time interval to the FETO center until the balloon is removed. Intended postnatal treatment center must subscribe to suggested guidelines for "standardized postnatal treatment," and
Provide written consent to participate.
Fetus with no major anomalies that would impact the clinical course or outcomes.

Exclusion Criteria

Maternal contraindication to fetoscopic surgery or severe medical condition in pregnancy that make fetal intervention risky,
Technical limitations precluding fetoscopic surgery, such as severe maternal obesity, uterine fibroids or potentially others, not anticipated at the time of writing this protocol,
Preterm labor, cervix shortened (<15 mm at randomization) or uterine anomaly strongly predisposing to preterm labor, placenta previa,
Patient age less than 18 years,
Psychosocial ineligibility, precluding consent,
Diaphragmatic hernia: right-sided or bilateral, major anomalies, isolated left-sided outside the O/E LHR limits for the inclusion criteria, and
Patient refusing randomization, to comply with required 4-week observation after balloon placement, or to comply with return to FETO center during the time period the airways are occluded or for elective removal of the balloon.
Patient allergic to latex.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Prenatal Intervention (FETO)	Standardized postnatal care	Patients will undergo fetoscopic endoluminal tracheal occlusion and ideally prenatal reversal of the occlusion followed by standardized postnatal care as in the expectant . In this study FETO (where GoldBal2 detachable balloon and Baltaccidbpe100 Delivery Catheter are used) is to be done between 30 weeks plus 0 day and 31 weeks plus 6 days and removal of the balloon at 34 weeks plus 0 day to 34 weeks plus 6 days.
Prenatal Intervention (FETO)	Baltaccidbpe100 Delivery Catheter	Patients will undergo fetoscopic endoluminal tracheal occlusion and ideally prenatal reversal of the occlusion followed by standardized postnatal care as in the expectant . In this study FETO (where GoldBal2 detachable balloon and Baltaccidbpe100 Delivery Catheter are used) is to be done between 30 weeks plus 0 day and 31 weeks plus 6 days and removal of the balloon at 34 weeks plus 0 day to 34 weeks plus 6 days.
Standardized postnatal care (Expectant)	Standardized postnatal care	Mothers will be expectantly managed during pregnancies and babies receive standardized postnatal care at a tertiary center used to manage babies with CDH. The recommendation is that they adhere to consensus guidelines published on the study website.
Prenatal Intervention (FETO)	GoldBal2 detachable balloon	Patients will undergo fetoscopic endoluminal tracheal occlusion and ideally prenatal reversal of the occlusion followed by standardized postnatal care as in the expectant . In this study FETO (where GoldBal2 detachable balloon and Baltaccidbpe100 Delivery Catheter are used) is to be done between 30 weeks plus 0 day and 31 weeks plus 6 days and removal of the balloon at 34 weeks plus 0 day to 34 weeks plus 6 days.

Primary Outcome Measures

Name	Time	Method
Proportion of Neonate Survival at Discharge From Hospital	At hospital discharge, an average of 1.5 months	The null hypothesis to be tested is that there is no difference in survival between fetuses managed expectantly during pregnancy versus those undergoing antenatal therapy (FETO).
Participants Requiring Supplemental Oxygen	At 6 months of age	The number of survivors requiring supplemental oxygen at 6 months of age

Secondary Outcome Measures

Name	Time	Method
ECMO (Extracorporeal Membrane Oxygenation) Support	Neonatal period (during the first 4 weeks of life)	Need for extracorporeal membrane oxygenation (ECMO) in the neonatal period
Grade of Oxygen Dependency	at 6 months of age	Measured as FiO2 (oxygen) amount required as a grade (0-III) with Grade 0 indicating the best outcome and Grade III indicating the worst outcome. Grade 0 = No Bronchopulmonary Dysplasia (BPD); Grade I = FiO2 21% or room air; Grade II = FiO2 22-29%; Grade III = FiO2 \>29%, CPAP or mechanical ventilation.
Occurrence of Severe Pulmonary Hypertension	During the first 4 weeks of life (neonatal period).	Occurrence of severe pulmonary hypertension in the neonatal period.
CDH Defect Size	Measured in neonate at delivery by MRI and/or ultrasound	Postnatal grade classification (A-D) using CDH study group standardized system with A being the smallest defects and D being the largest defects. A = Defect entirely surrounded by muscle; B = Small (\<50%) portion of the chest wall devoid of diaphragm tissue; C = Large (\>50%) portion of the chest wall devoid of diaphragm tissue; D = Complete or near complete absence of the diaphragm.
Number of Days in the NICU	At the time of discharge from the NICU, an average of 1.5 months	Length of stay in the neonatal intensive care unit measured in days
Ventilatory Support	During the first 4 weeks of life (neonatal period)	Length of time participants required ventilator support measured in days.
Number of Subjects With Periventricular Leukomalacia (PVL)	During first 2 months of life	As measured by presence in medical record ≤ 2 months postnatally by ultrasound (yes/no)
Neonatal Sepsis	During the first 4 weeks of life (neonatal period)	As measured by presence in medical record
Intraventricular Hemorrhage	During first month of life	Measured as presence in neonate during first month by MRI and/or ultrasound.
Retinopathy of Prematurity	At the time of discharge from the NICU, an average of 1.5 months	Postnatal grade classification presence of grade III or higher using standardized system (yes/no)
Days to Full Enteral Feeding	At hospital discharge, an average of 1.5 months	The number of days until full enteral feeding
Gastroesophageal Reflux	At the time of discharge from the NICU, an average of 1.5 months	Presence of reflux above 1/3 of esophagus on clinically indicated radiologic exam
CDH (Congenital Diaphragmatic Hernia) Surgery Repair	From the time of birth until discharge from the NICU	How many days from birth until the surgery is performed to repair the defect.
Use of Patch in CDH Repair	At the time of the surgical repair postnatally, up to 3 days postnatal	The number of participants who had a patch used in the repair of the CDH defect.
Survival	At 24 months of age	The number of participants that survived to 24 months of age