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

Study Overview
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Brief Summary
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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
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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.

Official Title
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TOTAL TRIAL: Randomized Trial of Fetoscopic Endoluminal Tracheal Occlusion (FETO) Versus Expectant Management During Pregnancy in Fetuses With Left-Sided and Isolated Congenital Diaphragmatic Hernia and Moderate Pulmonary Hypoplasia

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

Intervention / Treatment
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* Device: GoldBal2 detachable balloon
* Device: Baltaccidbpe100 Delivery Catheter
* Other: Standardized postnatal care


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Standardized postnatal care (Expectant)<br>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. | Other: Standardized postnatal care<br>* After birth, the babies will 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. For detailed description on this please visit https://www.karger.com/Article/Abstract/320622<br>|
| Experimental: Prenatal Intervention (FETO)<br>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. | Device: GoldBal2 detachable balloon<br>* Placement of the balloon using the plug/unplug method.<br>Device: Baltaccidbpe100 Delivery Catheter<br>* The catheter assists with implanting the balloon in the plug/unplug method.<br>Other: Standardized postnatal care<br>* After birth, the babies will 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. For detailed description on this please visit https://www.karger.com/Article/Abstract/320622<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Neonate Survival at Discharge From Hospital | 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). | At hospital discharge, an average of 1.5 months | 
| Participants Requiring Supplemental Oxygen | The number of survivors requiring supplemental oxygen at 6 months of age | At 6 months of age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Grade of Oxygen Dependency | 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. | at 6 months of age | 
| Occurrence of Severe Pulmonary Hypertension | Occurrence of severe pulmonary hypertension in the neonatal period. | During the first 4 weeks of life (neonatal period). | 
| ECMO (Extracorporeal Membrane Oxygenation) Support | Need for extracorporeal membrane oxygenation (ECMO) in the neonatal period | Neonatal period (during the first 4 weeks of life) | 
| CDH Defect Size | 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. | Measured in neonate at delivery by MRI and/or ultrasound | 
| Number of Days in the NICU | Length of stay in the neonatal intensive care unit measured in days | At the time of discharge from the NICU, an average of 1.5 months | 
| Ventilatory Support | Length of time participants required ventilator support measured in days. | During the first 4 weeks of life (neonatal period) | 
| Number of Subjects With Periventricular Leukomalacia (PVL) | As measured by presence in medical record ≤ 2 months postnatally by ultrasound (yes/no) | During first 2 months of life | 
| Neonatal Sepsis | As measured by presence in medical record | During the first 4 weeks of life (neonatal period) | 
| Intraventricular Hemorrhage | Measured as presence in neonate during first month by MRI and/or ultrasound. | During first month of life | 
| Retinopathy of Prematurity | Postnatal grade classification presence of grade III or higher using standardized system (yes/no) | At the time of discharge from the NICU, an average of 1.5 months | 
| Days to Full Enteral Feeding | The number of days until full enteral feeding | At hospital discharge, an average of 1.5 months | 
| Gastroesophageal Reflux | Presence of reflux above 1/3 of esophagus on clinically indicated radiologic exam | At the time of discharge from the NICU, an average of 1.5 months | 
| CDH (Congenital Diaphragmatic Hernia) Surgery Repair | How many days from birth until the surgery is performed to repair the defect. | From the time of birth until discharge from the NICU | 
| Use of Patch in CDH Repair | The number of participants who had a patch used in the repair of the CDH defect. | At the time of the surgical repair postnatally, up to 3 days postnatal | 
| Survival | The number of participants that survived to 24 months of age | At 24 months of age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CDH, Congenital Diaphragmatic Hernia, Fetal Tracheal Occlusion, FETO, plug-unplug, GoldBal2, Balloon, Goldvalve Balloon, TOTAL