Fetal Surgery for Moderate Left Sided Congenital Diaphragmatic Hernia. (TOTAL moderate)

• ClinicalTrials.gov Identifier: NCT00763737
• Recruitment Status: Completed
• First Posted: October 1, 2008
• Last Update Posted: December 3, 2020
• Sponsor: University Hospital, Gasthuisberg
• Collaborators: King's College Hospital NHS Trust (UK); Hospital Clinic of Barcelona; Hopital Antoine Beclere; Hôpital Necker-Enfants Malades; University Hospital, Bonn; Mater Mothers' Hospital; Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico; Ospedale Pediatrico Bambino Gesù, Rome (IT); Mount Sinai Hospital, Canada; Baylor College of Medicine; The University of Texas Health Science Center, Houston; 1st Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw (PL)
• Information provided by (Responsible Party): Jan Deprest, Universitaire Ziekenhuizen Leuven

Tracking Information

• First Submitted Date: September 30, 2008
• First Posted Date: October 1, 2008
• Last Update Posted Date: December 3, 2020
• Study Start Date: August 2010
• Actual Primary Completion Date: March 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 30, 2020)

• Survival at discharge [ Time Frame: at the time of discharge from NICU, approximately 2 months ]
• Supplemental oxygen at 6 months of age [ Time Frame: at 6 months of age ]

• Original Primary Outcome Measures (submitted: September 30, 2008): Occurrence of broncho-pulmonary dysplasia at 28 days of life [ Time Frame: 28 days of life ]

Current Secondary Outcome Measures (submitted: November 30, 2020)

• Grading of oxygen dependency [ Time Frame: between 28 and 56 days of life if born >32 weeks; at 36 weeks postmenstrual age if born <32 weeks ]
• Pulmonary hypertension [ Time Frame: during NICU admission ]
• Use of extracorporeal membrane oxygenation [ Time Frame: during NICU admission ]
• Change in O/E LHR after FETO [ Time Frame: prior to unplug ]
• NICU days [ Time Frame: during NICU admission ]
• days of ventilatory support [ Time Frame: during NICU admission ]
• Periventricular leucomalacia [ Time Frame: during NICU admission ]
• Neonatal sepsis [ Time Frame: during NICU admission ]
• Intraventricular hemorrhage [ Time Frame: during NICU admission ]
• Retinopathy of prematurity [ Time Frame: during NICU admission ]
• Days until full enteral feeding [ Time Frame: during NICU admission ]
• Gastroesophageal reflux [ Time Frame: during NICU admission ]
• Day of postnatal surgery [ Time Frame: during NICU admission ]
• Use of patch [ Time Frame: at the time of postnatal surgery ]
• Defect size [ Time Frame: at the time of postnatal surgery ]
• Number of days alive in case of postnatal death [ Time Frame: during NICU admission ]

Original Secondary Outcome Measures (submitted: September 30, 2008)

• Survival at discharge [ Time Frame: at discharge from hospital ]
• Survival free of bronchopulmonary dysplasia at 28 days of life [ Time Frame: 28 days of life ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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.

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Congenital Diaphragmatic Hernia
• Fetal Surgery
• Pulmonary Hypoplasia

Intervention

Procedure: Fetoscopic Endoluminal Tracheal Occlusion

prenatal balloon placement at 30-31+6 weeks and removal at 34-34+6 wks

Study Arms

• Experimental: FETO
  prenatal FETO at 30-31+6 weeks and removal at 34-34+6 wks, followed by standardized postnatal care
  Intervention: Procedure: Fetoscopic Endoluminal Tracheal Occlusion
• No Intervention: Expectant management
  expectant management during pregnancy followed by standardized neonatal care

Publications *

• 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.
• Doné 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. Review.
• 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. Review.
• 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. Erratum in: Ultrasound Obstet Gynecol. 2004 Oct;24(5):594.
• Jani JC, Nicolaides KH, Gratacós E, Valencia CM, Doné 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 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. Review.
• 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.
• 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.
• 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.
• Nawapun K, Eastwood MP, Diaz-Cobos D, Jimenez J, Aertsen M, Gomez O, Claus F, Gratacós 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.
• 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. Review.
• 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.
• 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.
• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 3, 2016): 196
• Original Estimated Enrollment (submitted: September 30, 2008): 152
• Actual Study Completion Date: March 2020
• Actual Primary Completion Date: March 2020 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, Canada, France, Germany, Italy, Poland, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT00763737
• Other Study ID Numbers: B32220084540; 2008-4634 ( Other Identifier: Hospital Clinic Barcelona ); ML4999- B32220084540 ( Other Identifier: University Hospitals Leuven )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Jan Deprest, Universitaire Ziekenhuizen Leuven
• Study Sponsor: University Hospital, Gasthuisberg

Collaborators

• King's College Hospital NHS Trust (UK)
• Hospital Clinic of Barcelona
• Hopital Antoine Beclere
• Hôpital Necker-Enfants Malades
• University Hospital, Bonn
• Mater Mothers' Hospital
• Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
• Ospedale Pediatrico Bambino Gesù, Rome (IT)
• Mount Sinai Hospital, Canada
• Baylor College of Medicine
• The University of Texas Health Science Center, Houston
• 1st Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw (PL)

Investigators

• Study Chair: Jan A Deprest, MD PhD; Universitaire Ziekenhuizen Leuven

• PRS Account: University Hospital, Gasthuisberg
• Verification Date: November 2020