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

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

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.

Study Overview

• Status: Completed
• Conditions: Congenital Abnormalities; Hernia; Pathological Conditions, Anatomical; Hernia, Diaphragmatic; Congenital Diaphragmatic Hernia; Fetal Anomaly; Pulmonary Hypoplasia; Hernia, DIaphragmatic, Congenital; Fetal Surgery
• Intervention / Treatment: Other: Standardized postnatal care; Device: GoldBal2 detachable balloon; Device: Baltaccidbpe100 Delivery Catheter

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.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine/Texas Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 64 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Patients aged 18 years or more, who are able to consent,
2. Singleton pregnancy,
3. Chromosomally normal fetus,
4. 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,

5. 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,
6. 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,
7. 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
8. Provide written consent to participate.
9. Fetus with no major anomalies that would impact the clinical course or outcomes.

Exclusion Criteria:

1. Maternal contraindication to fetoscopic surgery or severe medical condition in pregnancy that make fetal intervention risky,
2. Technical limitations precluding fetoscopic surgery, such as severe maternal obesity, uterine fibroids or potentially others, not anticipated at the time of writing this protocol,
3. Preterm labor, cervix shortened (<15 mm at randomization) or uterine anomaly strongly predisposing to preterm labor, placenta previa,
4. Patient age less than 18 years,
5. Psychosocial ineligibility, precluding consent,
6. Diaphragmatic hernia: right-sided or bilateral, major anomalies, isolated left-sided outside the O/E LHR limits for the inclusion criteria, and
7. 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.
8. Patient allergic to latex.

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
Other: Standardized postnatal care (Expectant); 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; 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
Experimental: Prenatal Intervention (FETO); 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.	Other: Standardized postnatal care; 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; Device: GoldBal2 detachable balloon; Placement of the balloon using the plug/unplug method.; Device: Baltaccidbpe100 Delivery Catheter; The catheter assists with implanting the balloon in the plug/unplug method.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Michael A Belfort
• Collaborators: Baylor College of Medicine; Universitaire Ziekenhuizen KU Leuven
• Investigators: Principal Investigator: Michael Belfort, MD, PhD, Baylor College of Medicine - Texas Children's Hospital

Publications and helpful links

General Publications

• Jani JC, Nicolaides KH, Gratacos E, Valencia CM, Done E, Martinez JM, Gucciardo L, Cruz R, Deprest JA. Severe diaphragmatic hernia treated by fetal endoscopic tracheal occlusion. Ultrasound Obstet Gynecol. 2009 Sep;34(3):304-10. doi: 10.1002/uog.6450.
• Deprest J, Gratacos E, Nicolaides KH; FETO Task Group. Fetoscopic tracheal occlusion (FETO) for severe congenital diaphragmatic hernia: evolution of a technique and preliminary results. Ultrasound Obstet Gynecol. 2004 Aug;24(2):121-6. doi: 10.1002/uog.1711. Erratum In: Ultrasound Obstet Gynecol. 2004 Oct;24(5):594.
• Chiba T, Albanese CT, Farmer DL, Dowd CF, Filly RA, Machin GA, Harrison M. Balloon tracheal occlusion for congenital diaphragmatic hernia: experimental studies. J Pediatr Surg. 2000 Nov;35(11):1566-70. doi: 10.1053/jpsu.2000.18311.
• Cannie MM, Jani JC, De Keyzer F, Allegaert K, Dymarkowski S, Deprest J. Evidence and patterns in lung response after fetal tracheal occlusion: clinical controlled study. Radiology. 2009 Aug;252(2):526-33. doi: 10.1148/radiol.2522081955. Epub 2009 Jun 9.
• Jani J, Nicolaides KH, Keller RL, Benachi A, Peralta CF, Favre R, Moreno O, Tibboel D, Lipitz S, Eggink A, Vaast P, Allegaert K, Harrison M, Deprest J; Antenatal-CDH-Registry Group. Observed to expected lung area to head circumference ratio in the prediction of survival in fetuses with isolated diaphragmatic hernia. Ultrasound Obstet Gynecol. 2007 Jul;30(1):67-71. doi: 10.1002/uog.4052.
• Jani JC, Benachi A, Nicolaides KH, Allegaert K, Gratacos E, Mazkereth R, Matis J, Tibboel D, Van Heijst A, Storme L, Rousseau V, Greenough A, Deprest JA; Antenatal-CDH-Registry group. Prenatal prediction of neonatal morbidity in survivors with congenital diaphragmatic hernia: a multicenter study. Ultrasound Obstet Gynecol. 2009 Jan;33(1):64-9. doi: 10.1002/uog.6141.
• Jani J, Nicolaides K, Gratacos E, et al. 558: Short term neonatal morbidity in severe left-sided congenital diaphragmatic hernia treated by tracheal occlusion before 30 weeks. Am J Obstet Gynecol Dec;197(6),Supplement:S162.
• Jani JC, Nicolaides KH, Gratacos E, Vandecruys H, Deprest JA; FETO Task Group. Fetal lung-to-head ratio in the prediction of survival in severe left-sided diaphragmatic hernia treated by fetal endoscopic tracheal occlusion (FETO). Am J Obstet Gynecol. 2006 Dec;195(6):1646-50. doi: 10.1016/j.ajog.2006.04.004. Epub 2006 Jun 12.
• Reiss I, Schaible T, van den Hout L, Capolupo I, Allegaert K, van Heijst A, Gorett Silva M, Greenough A, Tibboel D; CDH EURO Consortium. Standardized postnatal management of infants with congenital diaphragmatic hernia in Europe: the CDH EURO Consortium consensus. Neonatology. 2010;98(4):354-64. doi: 10.1159/000320622. Epub 2010 Oct 27.
• Snoek KG, Capolupo I, van Rosmalen J, Hout Lde J, Vijfhuize S, Greenough A, Wijnen RM, Tibboel D, Reiss IK; CDH EURO Consortium. Conventional Mechanical Ventilation Versus High-frequency Oscillatory Ventilation for Congenital Diaphragmatic Hernia: A Randomized Clinical Trial (The VICI-trial). Ann Surg. 2016 May;263(5):867-74. doi: 10.1097/SLA.0000000000001533.
• Deprest JA, Flemmer AW, Gratacos E, Nicolaides K. Antenatal prediction of lung volume and in-utero treatment by fetal endoscopic tracheal occlusion in severe isolated congenital diaphragmatic hernia. Semin Fetal Neonatal Med. 2009 Feb;14(1):8-13. doi: 10.1016/j.siny.2008.08.010. Epub 2008 Oct 8.
• Jani J, Benachi A, Mitanchez D, et al. 2006. Lung-to-head ratio and liver position to predict neonatal morbidity in fetuses with isolated congenital diaphragmatic hernia: A multicenter study. Am Journal Obstet Gynecol 195(6); Supplement:S60.
• Ostrea EM, Villanueva-Uy ET, Natarajan G, Uy HG. Persistent pulmonary hypertension of the newborn: pathogenesis, etiology, and management. Paediatr Drugs. 2006;8(3):179-88. doi: 10.2165/00148581-200608030-00004.
• Congenital Diaphragmatic Hernia Study Group, Lally KP, Lally PA, Lasky RE, Tibboel D, Jaksic T, Wilson JM, Frenckner B, Van Meurs KP, Bohn DJ, Davis CF, Hirschl RB. Defect size determines survival in infants with congenital diaphragmatic hernia. Pediatrics. 2007 Sep;120(3):e651-7. doi: 10.1542/peds.2006-3040.
• Gallot D, Boda C, Ughetto S, Perthus I, Robert-Gnansia E, Francannet C, Laurichesse-Delmas H, Jani J, Coste K, Deprest J, Labbe A, Sapin V, Lemery D. Prenatal detection and outcome of congenital diaphragmatic hernia: a French registry-based study. Ultrasound Obstet Gynecol. 2007 Mar;29(3):276-83. doi: 10.1002/uog.3863.
• Deprest JA, Evrard VA, Verbeken EK, Perales AJ, Delaere PR, Lerut TE, Flageole H. Tracheal side effects of endoscopic balloon tracheal occlusion in the fetal lamb model. Eur J Obstet Gynecol Reprod Biol. 2000 Sep;92(1):119-26. doi: 10.1016/s0301-2115(00)00435-8.

Helpful Links

• Information for the public and healthcare providers.
• Information for the public and healthcare providers.

Study record dates

Study Major Dates

• Study Start: January 1, 2017
• Primary Completion (Actual): October 1, 2019
• Study Completion (Actual): October 1, 2019

Study Registration Dates

• First Submitted: August 5, 2016
• First Submitted That Met QC Criteria: August 18, 2016
• First Posted (Estimate): August 23, 2016

Study Record Updates

• Last Update Posted (Actual): June 23, 2022
• Last Update Submitted That Met QC Criteria: May 31, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: Fetal Tracheal Occlusion; FETO; Congenital Diaphragmatic Hernia; Balloon; CDH; plug-unplug; GoldBal2; Goldvalve Balloon; TOTAL
• Additional Relevant MeSH Terms: Internal Hernia; Hernia; Congenital Abnormalities; Hernias, Diaphragmatic, Congenital; Hernia, Diaphragmatic; Pathological Conditions, Anatomical
• Other Study ID Numbers: H-39398

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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