Clinical trial NCT00763737: Fetal Surgery for Moderate Left Sided Congenital Diaphragmatic Hernia.
Official title: 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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Congenital Diaphragmatic Hernia
Fetal Surgery
Pulmonary Hypoplasia
Keywords: congenital diaphragmatic hernia
fetal surgery
pulmonary hypoplasia
observed/expected lung to head ratio
liver position
feto
fetoscopic endoluminal tracheal occlusion
standardized neonatal care
Lead sponsor: University Hospital, Gasthuisberg
Sponsor class: OTHER
Collaborators: name: King's College Hospital NHS Trust (UK)
name: Hospital Clinic of Barcelona
name: Hopital Antoine Beclere
name: Hôpital Necker-Enfants Malades
name: University Hospital, Bonn
name: Mater Mothers' Hospital
name: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
name: Ospedale Pediatrico Bambino Gesù, Rome (IT)
name: Mount Sinai Hospital, Canada
name: Baylor College of Medicine
name: The University of Texas Health Science Center, Houston
name: Medical University of Warsaw
First posted: 2008-10-01
Enrollment: 196
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Isolated Congenital Diaphragmatic Hernia (CDH) can be diagnosed in the prenatal period, and remains associated with a 30 % chance of perinatal death and morbidity mainly because of pulmonary hypoplasia and pulmonary hypertension. In addition, in the survivors there is a high rate of morbidity with evidence of bronchopulmonary dysplasia in more than 70% of cases. The risk for these can be predicted prenatally by the ultrasonographic measurement of the observed/expected lung area to head circumference ratio (O/E LHR) which is a measure of pulmonary hypoplasia. Also position of the liver is predictive of outcome.

The proposing consortium has developed a prenatal therapeutic approach, which consists of percutaneous fetoscopic endoluminal tracheal occlusion (FETO) with subsequent removal of the balloon. Both procedures are performed percutaneously, there is now experience with more than 150 cases and it has been shown to be safe for the mother. We have witnessed an improvement of survival in fetuses with a predicted chance of survival of less than 30% (referred to as fetuses with severe pulmonary hypoplasia; O/E LHR \<25% and liver herniation) to 55% on average. Also there is an apparent reduction in morbidity with the rate of bronchopulmonary dysplasia decreasing from the estimated rate of more than 70% to less than 40% in the same severity group.

Further we have shown that results of FETO are predicted by LHR measurement prior to the procedure, so that better results can be expected in fetuses with larger lung size. Therefore we now aim to offer FETO to fetuses with moderate CDH (=O/E LHR 25-34.9%, irrespective of the liver position as well as O/E LHR 35-44.9% with intrathoracic herniation of the liver). When managed expectantly the estimated rate of postnatal survival is 55%.

This trial will test whether temporary fetoscopic tracheal occlusion rather than expectant management during pregnancy, both followed by standardized postnatal management increases survival or decrease oxygen dependency at 6 months of age. The balloon will be placed between 30 and 31+6 weeks, and will be removed between 34 and 34+6 weeks.


Eligibility criteria: Inclusion Criteria:

* Patients aged 18 years or more, who are able to consent
* Singleton pregnancy
* Anatomically and chromosomally normal fetus
* Left sided diaphragmatic hernia
* Gestation at randomization prior to 31 wks plus 5 d (so that occlusion is done at the latest on 31 wks plus 6 d)
* 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
* Acceptance of randomization and the consequences for the further management during pregnancy and thereafter.
* 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".
* Provide written consent to participate in this RCT

Exclusion Criteria:

* Maternal contraindication to fetoscopic surgery or severe medical condition in pregnancy that make fetal intervention risk full
* 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 labour, cervix shortened (\<15 mm at randomization) or uterine anomaly strongly predisposing to preterm labour, 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
* Patient refusing randomization or to comply with return to FETO center during the time period the airways are occluded or for elective removal of the balloon

Primary outcomes:
measure: Survival at discharge
timeFrame: at the time of discharge from NICU, approximately 2 months
measure: Supplemental oxygen at 6 months of age
timeFrame: at 6 months of age
Secondary outcomes:
measure: Grading of oxygen dependency
timeFrame: between 28 and 56 days of life if born >32 weeks; at 36 weeks postmenstrual age if born <32 weeks
measure: Pulmonary hypertension
timeFrame: during NICU admission
measure: Use of extracorporeal membrane oxygenation
timeFrame: during NICU admission
measure: Change in O/E LHR after FETO
timeFrame: prior to unplug
measure: NICU days
timeFrame: during NICU admission
measure: days of ventilatory support
timeFrame: during NICU admission
measure: Periventricular leucomalacia
timeFrame: during NICU admission
measure: Neonatal sepsis
timeFrame: during NICU admission
measure: Intraventricular hemorrhage
timeFrame: during NICU admission
measure: Retinopathy of prematurity
timeFrame: during NICU admission
measure: Days until full enteral feeding
timeFrame: during NICU admission
measure: Gastroesophageal reflux
timeFrame: during NICU admission
measure: Day of postnatal surgery
timeFrame: during NICU admission
measure: Use of patch
timeFrame: at the time of postnatal surgery
measure: Defect size
timeFrame: at the time of postnatal surgery
measure: Number of days alive in case of postnatal death
timeFrame: during NICU admission
Other outcomes:
Locations:
city: Houston
country: United States
facility: Baylor College of Medicine/Texas Children's Hospital
state: Texas
city: Houston
country: United States
facility: University of Texas Health Science Center
state: Texas
city: Brisbane
country: Australia
facility: Mater Mother's Hospital
state: Queensland
city: Leuven
country: Belgium
facility: University Hospitals Leuven
city: Toronto
country: Canada
facility: Mount Sinai Hospital
state: Ontario
city: Clamart
country: France
facility: Hôpital Antoine Béclère
city: Paris
country: France
facility: Hôpital Necker - Enfants Malades
city: Bonn
country: Germany
facility: University Hospital of Bonn
city: Milan
country: Italy
facility: Ospedale Maggiore Policlinico
city: Rome
country: Italy
facility: Ospedale Pediatrico Bambino Gesù
city: Warsaw
country: Poland
facility: 1st Department of Obstetrics and Gynecology, Medical University of Warsaw
city: Barcelona
country: Spain
facility: Hospital Clinic Barcelona
state: Catalunya
city: London
country: United Kingdom
facility: King's College Hospital
Study officials:
affiliation: Universitaire Ziekenhuizen KU Leuven
name: Jan A Deprest, MD PhD
role: STUDY_CHAIR
References:
citation: 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.
citation: Done E, Gucciardo L, Van Mieghem T, Jani J, Cannie M, Van Schoubroeck D, Devlieger R, Catte LD, Klaritsch P, Mayer S, Beck V, Debeer A, Gratacos E, Nicolaides K, Deprest J. Prenatal diagnosis, prediction of outcome and in utero therapy of isolated congenital diaphragmatic hernia. Prenat Diagn. 2008 Jul;28(7):581-91. doi: 10.1002/pd.2033.
citation: Deprest J, Jani J, Gratacos E, Vandecruys H, Naulaers G, Delgado J, Greenough A, Nicolaides K; FETO Task Group. Fetal intervention for congenital diaphragmatic hernia: the European experience. Semin Perinatol. 2005 Apr;29(2):94-103. doi: 10.1053/j.semperi.2005.04.006.
citation: 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.
citation: 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.
citation: Deprest JA, Gratacos E, Nicolaides K, Done E, Van Mieghem T, Gucciardo L, Claus F, Debeer A, Allegaert K, Reiss I, Tibboel D. Changing perspectives on the perinatal management of isolated congenital diaphragmatic hernia in Europe. Clin Perinatol. 2009 Jun;36(2):329-47, ix. doi: 10.1016/j.clp.2009.03.004.
citation: Deprest JA, Hyett JA, Flake AW, Nicolaides K, Gratacos E. Current controversies in prenatal diagnosis 4: Should fetal surgery be done in all cases of severe diaphragmatic hernia? Prenat Diagn. 2009 Jan;29(1):15-9. doi: 10.1002/pd.2108. No abstract available.
citation: Gregoir C, Engels AC, Gomez O, DeKoninck P, Lewi L, Gratacos E, Deprest JA. Fertility, pregnancy and gynecological outcomes after fetoscopic surgery for congenital diaphragmatic hernia. Hum Reprod. 2016 Sep;31(9):2024-30. doi: 10.1093/humrep/dew160. Epub 2016 Jul 4.
citation: Snoek KG, Reiss IK, Greenough A, Capolupo I, Urlesberger B, Wessel L, Storme L, Deprest J, Schaible T, van Heijst A, Tibboel D; CDH EURO Consortium. Standardized Postnatal Management of Infants with Congenital Diaphragmatic Hernia in Europe: The CDH EURO Consortium Consensus - 2015 Update. Neonatology. 2016;110(1):66-74. doi: 10.1159/000444210. Epub 2016 Apr 15.
citation: Nawapun K, Eastwood MP, Diaz-Cobos D, Jimenez J, Aertsen M, Gomez O, Claus F, Gratacos E, Deprest J. In vivo evidence by magnetic resonance volumetry of a gestational age dependent response to tracheal occlusion for congenital diaphragmatic hernia. Prenat Diagn. 2015 Nov;35(11):1048-56. doi: 10.1002/pd.4642. Epub 2015 Sep 29.
citation: Deprest J, Brady P, Nicolaides K, Benachi A, Berg C, Vermeesch J, Gardener G, Gratacos E. Prenatal management of the fetus with isolated congenital diaphragmatic hernia in the era of the TOTAL trial. Semin Fetal Neonatal Med. 2014 Dec;19(6):338-48. doi: 10.1016/j.siny.2014.09.006. Epub 2014 Nov 11.
citation: Done E, Debeer A, Gucciardo L, Van Mieghem T, Lewi P, Devlieger R, De Catte L, Lewi L, Allegaert K, Deprest J. Prediction of neonatal respiratory function and pulmonary hypertension in fetuses with isolated congenital diaphragmatic hernia in the fetal endoscopic tracleal occlusion era: a single-center study. Fetal Diagn Ther. 2015;37(1):24-32. doi: 10.1159/000364805. Epub 2014 Nov 8.
citation: DeKoninck P, Gomez O, Sandaite I, Richter J, Nawapun K, Eerdekens A, Ramirez JC, Claus F, Gratacos E, Deprest J. Right-sided congenital diaphragmatic hernia in a decade of fetal surgery. BJOG. 2015 Jun;122(7):940-6. doi: 10.1111/1471-0528.13065. Epub 2014 Sep 17.
citation: Windrim R, Ryan G, Lebouthillier F, Campisi P, Kelly EN, Baud D, Yoo SJ, Deprest J. Development and use of a high-fidelity simulator for fetal endotracheal balloon occlusion (FETO) insertion and removal. Prenat Diagn. 2014 Feb;34(2):180-4. doi: 10.1002/pd.4284. Epub 2013 Dec 27.
citation: Engels AC, DeKoninck P, van der Merwe JL, Van Mieghem T, Stevens P, Power B, Nicolaides KH, Gratacos E, Deprest JA. Does website-based information add any value in counseling mothers expecting a baby with severe congenital diaphragmatic hernia? Prenat Diagn. 2013 Nov;33(11):1027-32. doi: 10.1002/pd.4190. Epub 2013 Aug 29.
citation: Dekoninck P, Gratacos E, Van Mieghem T, Richter J, Lewi P, Ancel AM, Allegaert K, Nicolaides K, Deprest J. Results of fetal endoscopic tracheal occlusion for congenital diaphragmatic hernia and the set up of the randomized controlled TOTAL trial. Early Hum Dev. 2011 Sep;87(9):619-24. doi: 10.1016/j.earlhumdev.2011.08.001.
citation: Deprest J, Flake A. How should fetal surgery for congenital diaphragmatic hernia be implemented in the post-TOTAL trial era: A discussion. Prenat Diagn. 2022 Mar;42(3):301-309. doi: 10.1002/pd.6091. Epub 2022 Jan 22.
citation: Van Calster B, Benachi A, Nicolaides KH, Gratacos E, Berg C, Persico N, Gardener GJ, Belfort M, Ville Y, Ryan G, Johnson A, Sago H, Kosinski P, Bagolan P, Van Mieghem T, DeKoninck PLJ, Russo FM, Hooper SB, Deprest JA. The randomized Tracheal Occlusion To Accelerate Lung growth (TOTAL)-trials on fetal surgery for congenital diaphragmatic hernia: reanalysis using pooled data. Am J Obstet Gynecol. 2022 Apr;226(4):560.e1-560.e24. doi: 10.1016/j.ajog.2021.11.1351. Epub 2021 Nov 19.
citation: Deprest JA, Benachi A, Gratacos E, Nicolaides KH, Berg C, Persico N, Belfort M, Gardener GJ, Ville Y, Johnson A, Morini F, Wielgos M, Van Calster B, DeKoninck PLJ; TOTAL Trial for Moderate Hypoplasia Investigators. Randomized Trial of Fetal Surgery for Moderate Left Diaphragmatic Hernia. N Engl J Med. 2021 Jul 8;385(2):119-129. doi: 10.1056/NEJMoa2026983. Epub 2021 Jun 8.