Fetal Surgery for Moderate Left Sided Congenital Diaphragmatic Hernia.

Congenital Diaphragmatic Hernia Clinical Trial

— TOTAL moderate  

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00763737
• Other study ID #: B32220084540
• Secondary ID: 2008-4634ML4999-
• Status: Completed
• Phase: N/A
• Start date: August 2010
• Est. completion date: March 2020

Study information

• Verified date: November 2020
• Source: University Hospital, Gasthuisberg
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 196
• Est. completion date: March 2020
• Est. primary completion date: March 2020
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Congenital Diaphragmatic Hernia
• Fetal Surgery
• Hernia
• Hernia, Diaphragmatic
• Hernias, Diaphragmatic, Congenital
• Pulmonary Hypoplasia

Intervention

Procedure:
• Fetoscopic Endoluminal Tracheal Occlusion
prenatal balloon placement at 30-31+6 weeks and removal at 34-34+6 wks

Locations

Country	Name	City	State
Australia	Mater Mother's Hospital	Brisbane	Queensland
Belgium	University Hospitals Leuven	Leuven
Canada	Mount Sinai Hospital	Toronto	Ontario
France	Hôpital Antoine Béclère	Clamart
France	Hôpital Necker - Enfants Malades	Paris
Germany	University Hospital of Bonn	Bonn
Italy	Ospedale Maggiore Policlinico	Milan
Italy	Ospedale Pediatrico Bambino Gesù	Rome
Poland	1st Department of Obstetrics and Gynecology, Medical University of Warsaw	Warsaw
Spain	Hospital Clinic Barcelona	Barcelona	Catalunya
United Kingdom	King's College Hospital	London
United States	Baylor College of Medicine/Texas Children's Hospital	Houston	Texas
United States	University of Texas Health Science Center	Houston	Texas

Sponsors (13)

Lead Sponsor

Collaborator

University Hospital, Gasthuisberg

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

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  France,  Germany,  Italy,  Poland,  Spain,  United Kingdom, 

References & Publications (16)

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. — View 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. — View 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. Review. — View 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. Erratum in: Ultrasound Obstet Gynecol. 2004 Oct;24(5):594. — View 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. Review. — View 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. Review. — View 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. — View 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. — View Citation

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. — View 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. — View 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. — View 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. — View Citation

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. — View Citation

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. — View 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. — View 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. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Survival at discharge		at the time of discharge from NICU, approximately 2 months
Primary	Supplemental oxygen at 6 months of age		at 6 months of age
Secondary	Grading of oxygen dependency		between 28 and 56 days of life if born >32 weeks; at 36 weeks postmenstrual age if born <32 weeks
Secondary	Pulmonary hypertension		during NICU admission
Secondary	Use of extracorporeal membrane oxygenation		during NICU admission
Secondary	Change in O/E LHR after FETO		prior to unplug
Secondary	NICU days		during NICU admission
Secondary	days of ventilatory support		during NICU admission
Secondary	Periventricular leucomalacia		during NICU admission
Secondary	Neonatal sepsis		during NICU admission
Secondary	Intraventricular hemorrhage		during NICU admission
Secondary	Retinopathy of prematurity		during NICU admission
Secondary	Days until full enteral feeding		during NICU admission
Secondary	Gastroesophageal reflux		during NICU admission
Secondary	Day of postnatal surgery		during NICU admission
Secondary	Use of patch		at the time of postnatal surgery
Secondary	Defect size		at the time of postnatal surgery
Secondary	Number of days alive in case of postnatal death		during NICU admission

External Links

•   same as totaltrial.eu
•   same as www.euroCDH.org
•   website of this trial on prenatal management of CDH
•   website on prenatal diagnosis and management of CDH of the FETO consortium