Tracheal Occlusion To Accelerate Lung Growth (TOTAL) Trial for Severe Pulmonary Hypoplasia (TOTAL)

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.

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.

Study Overview

• Status: Completed
• Conditions: Congenital Diseases; Pulmonary Hypoplasia; Diaphragmatic Hernia
• Intervention / Treatment: Other: watchful waiting during pregnancy; Procedure: fetal endoluminal tracheal occlusion

• Study Type: Interventional
• Enrollment (Actual): 93
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Australia
  • Queensland
    • Brisbane, Queensland, Australia, 4101
      • Mater Mother's Hospital
• Belgium
  • Leuven, Belgium, 3000
    • University Hospitals Leuven
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X5
      • Mount Sinai Hospital
• France
  • Clamart, France, 92141
    • Hôpital Antoine Béclère
• Germany
  • Bonn, Germany, 53105
    • University Hospital of Bonn
• Italy
  • Milano, Italy, 20122
    • Ospedale Maggiore Policlinico
  • Rome, Italy, 00123
    • Ospedale Pediatrico Bambino Gesù
• Japan
  • Tokyo, Japan, 157-8535
    • National Center for Child Health and Development
• Poland
  • Warsaw, Poland
    • 1st Department of Obstetrics and Gynecology, Medical University of Warsaw
• Spain
  • Catalunya
    • Barcelona, Catalunya, Spain, 08028
      • Hospital Clinic Barcelona
• United Kingdom
  • London, United Kingdom, SE5 9RS
    • King's College Hospital
• United States
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas Health Science Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: expectant management during pregnancy; watchful waiting during pregnancy	Other: watchful waiting during pregnancy; pregnancy surveillance for fetal wellbeing, development of polyhydramnios and cervical shortening
EXPERIMENTAL: fetal endoluminal tracheal occlusion; fetoscopic balloon occlusion at 27 to 29+6 weeks of gestation	Procedure: fetal endoluminal tracheal occlusion; percutaneous fetoscopy, positioning of endoluminal balloon at 27-30 weeks and whenever possible elective removal at 34 weeks; Other Names: Balt Goldbal 2 balloon

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival at discharge from neonatal intensive care unit	The baby can be discharged either alive (and then it qualifies as "surviving at discharge") or dead. Not discharged babies have not reached the primary endpoint.	at discharge from neonatal intensive care unit

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Defect size		at the time of postnatal surgery
prenatal increase in lung volume after FETO	volume of lung after occlusion	prior to balloon removal
grading of oxygen dependency		born >32 wks: between 28-56d of life; born <32wks: 36wks postmenstrual age
occurrence of pulmonary hypertension	determined by cardiac ultrasound	within first weeks of life
number of days in Neonatal Intensive Care Unit (NICU)	As long as the baby is in the hospital, it is hospitalized either in NICU or in another, less intensive care unit. The number of days in NICU is an outcome variable, expressed in days.	within hospital stay
number of days of ventilatory support		within NICU stay
presence of periventricular leucomalacia		2 months of life
presence of neonatal sepsis, intraventricular haemorrhage, retinopathy grade III or higher		within hospital stay
number of days till full enteral feeding		within first 2 years of life
presence of gastro-esophagal reflux		at discharge
day of surgery		within hospital stay
requirement for use of patch for repair		at the time of postnatal surgery
bronchopulmonary dysplasia	defined as oxygen need for at least 28 days	with the first 8 weeks
Need for Extracorporeal membrane oxygenation		during NICU admission
number of days alive in case of postnatal death		during NICU admission

Collaborators and Investigators

• Sponsor: University Hospital, Gasthuisberg
• Collaborators: The University of Texas Health Science Center, Houston; Hospital Clinic of Barcelona; Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico; University Hospital, Bonn; Mount Sinai Hospital, Canada; Medical University of Warsaw; Hopital Antoine Beclere; King's College Hospital NHS Trust (UK); Mater Mothers' Hospital; Ospedale Pediatrico Bambino Gesù, Rome (IT); National Center for Child Health and Development, Tokyo (JP)
• Investigators: Principal Investigator: Jan Deprest, MD, Universitaire Ziekenhuizen KU Leuven

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, 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.
• 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.
• 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.
• 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 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 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 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Helpful Links

• opens only end 2010

Study record dates

Study Major Dates

• Study Start: November 1, 2011
• Primary Completion (ACTUAL): March 1, 2020
• Study Completion (ACTUAL): December 1, 2020

Study Registration Dates

• First Submitted: August 4, 2010
• First Submitted That Met QC Criteria: November 12, 2010
• First Posted (ESTIMATE): November 15, 2010

Study Record Updates

• Last Update Posted (ACTUAL): May 4, 2021
• Last Update Submitted That Met QC Criteria: May 3, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: Fetal Surgery; Isolated Congenital Diaphragmatic Hernia; Pulmonary Hypoplasia
• Additional Relevant MeSH Terms: Congenital Abnormalities; Pathological Conditions, Anatomical; Internal Hernia; Hernia; Hernias, Diaphragmatic, Congenital; Hernia, Diaphragmatic
• Other Study ID Numbers: ML 6277; B32220108118 (OTHER: UZ Gasthuisberg KU Leuven (Belgium))