Clinical trial NCT01240057: Tracheal Occlusion To Accelerate Lung Growth (TOTAL) Trial for Severe Pulmonary Hypoplasia
Official title: Randomized Trial of Fetoscopic Endoluminal Tracheal Occlusion (FETO) Versus Expectant Management During Pregnancy in Fetuses With Left Sided and Isolated Congenital Diaphragma Hernia and Severe Pulmonary Hypoplasia.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Congenital Diseases
Diaphragmatic Hernia
Pulmonary Hypoplasia
Keywords: Isolated Congenital Diaphragmatic Hernia
Fetal Surgery
Pulmonary Hypoplasia
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: 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: National Center for Child Health and Development, Tokyo (JP)
name: The University of Texas Health Science Center, Houston
name: Medical University of Warsaw
First posted: 2010-11-15
Enrollment: 93
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This trial investigates whether prenatal intervention improves survival rate of fetuses with isolated congenital diaphragmatic hernia and severe pulmonary hypoplasia, as compared to expectant management during pregnancy, both followed by standardized postnatal care.


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 29 wks plus 5 d (so that occlusion is done at the latest on 29 wks plus 6 d)
* Estimated to have severe pulmonary hypoplasia, defined prenatally as: O/E LHR \<25 %, irrespective of the liver position
* 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 from neonatal intensive care unit
timeFrame: at discharge from neonatal intensive care unit
Secondary outcomes:
measure: prenatal increase in lung volume after FETO
timeFrame: prior to balloon removal
measure: grading of oxygen dependency
timeFrame: born >32 wks: between 28-56d of life; born <32wks: 36wks postmenstrual age
measure: occurrence of pulmonary hypertension
timeFrame: within first weeks of life
measure: number of days in Neonatal Intensive Care Unit (NICU)
timeFrame: within hospital stay
measure: number of days of ventilatory support
timeFrame: within NICU stay
measure: presence of periventricular leucomalacia
timeFrame: 2 months of life
measure: presence of neonatal sepsis, intraventricular haemorrhage, retinopathy grade III or higher
timeFrame: within hospital stay
measure: number of days till full enteral feeding
timeFrame: within first 2 years of life
measure: presence of gastro-esophagal reflux
timeFrame: at discharge
measure: day of surgery
timeFrame: within hospital stay
measure: requirement for use of patch for repair
timeFrame: at the time of postnatal surgery
measure: bronchopulmonary dysplasia
timeFrame: with the first 8 weeks
measure: Need for Extracorporeal membrane oxygenation
timeFrame: during NICU admission
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: 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: Bonn
country: Germany
facility: University Hospital of Bonn
city: Milano
country: Italy
facility: Ospedale Maggiore Policlinico
city: Rome
country: Italy
facility: Ospedale Pediatrico Bambino Gesù
city: Tokyo
country: Japan
facility: National Center for Child Health and Development
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 Deprest, MD
role: PRINCIPAL_INVESTIGATOR
References:
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 J, Breysem L, Gratacos E, Nicolaides K, Claus F, Debeer A, Smet MH, Proesmans M, Fayoux P, Storme L. Tracheal side effects following fetal endoscopic tracheal occlusion for severe congenital diaphragmatic hernia. Pediatr Radiol. 2010 May;40(5):670-3. doi: 10.1007/s00247-010-1579-9. Epub 2010 Mar 30. No abstract available.
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: 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.
citation: 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.
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: Jani J, Keller RL, Benachi A, Nicolaides KH, Favre R, Gratacos E, Laudy J, Eisenberg V, Eggink A, Vaast P, Deprest J; Antenatal-CDH-Registry Group. Prenatal prediction of survival in isolated left-sided diaphragmatic hernia. Ultrasound Obstet Gynecol. 2006 Jan;27(1):18-22. doi: 10.1002/uog.2688.
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: Rodrigues HC, Deprest J, v d Berg PP. When referring physicians and researchers disagree on equipoise: the TOTAL trial experience. Prenat Diagn. 2011 Jun;31(6):589-94. doi: 10.1002/pd.2756. Epub 2011 Apr 11.
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, Nicolaides KH, Benachi A, Gratacos E, Ryan G, Persico N, Sago H, Johnson A, Wielgos M, Berg C, Van Calster B, Russo FM; TOTAL Trial for Severe Hypoplasia Investigators. Randomized Trial of Fetal Surgery for Severe Left Diaphragmatic Hernia. N Engl J Med. 2021 Jul 8;385(2):107-118. doi: 10.1056/NEJMoa2027030. Epub 2021 Jun 8.