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

NCT01240057 | Completed Phase 2 DMC

• 2 other identifiers: ML 6277B32220108118
• Study Type: interventional
• Target: 93
• Locations: 11 countries
• Sites: 12

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.

Conditions

Congenital Diseases; Diaphragmatic Hernia; Pulmonary Hypoplasia

Keywords

Isolated Congenital Diaphragmatic Hernia; Fetal Surgery; Pulmonary Hypoplasia

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (15)

• prenatal increase in lung volume after FETO

  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

  within first weeks of life

• number of days in Neonatal Intensive Care Unit (NICU)

  within hospital stay

• number of days of ventilatory support

  within NICU stay

Study Arms (2)

expectant management during pregnancy

PLACEBO COMPARATOR

watchful waiting during pregnancy

Other: watchful waiting during pregnancy

fetal endoluminal tracheal occlusion

EXPERIMENTAL

fetoscopic balloon occlusion at 27 to 29+6 weeks of gestation

Procedure: fetal endoluminal tracheal occlusion

Interventions

fetal endoluminal tracheal occlusion PROCEDURE

percutaneous fetoscopy, positioning of endoluminal balloon at 27-30 weeks and whenever possible elective removal at 34 weeks

Also known as: Balt Goldbal 2 balloon

fetal endoluminal tracheal occlusion

watchful waiting during pregnancy OTHER

pregnancy surveillance for fetal wellbeing, development of polyhydramnios and cervical shortening

expectant management during pregnancy

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• University Hospital, Gasthuisberg: lead
• King's College Hospital NHS Trust (UK): collaborator
• Hospital Clinic of Barcelona: collaborator
• Hopital Antoine Beclere: collaborator
• University Hospital, Bonn: collaborator
• Mater Mothers' Hospital: collaborator
• Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico: collaborator
• Ospedale Pediatrico Bambino Gesù, Rome (IT): collaborator
• Mount Sinai Hospital, Canada: collaborator
• National Center for Child Health and Development, Tokyo (JP): collaborator
• The University of Texas Health Science Center, Houston: collaborator
• Medical University of Warsaw: collaborator

Study Sites (12)

University of Texas Health Science Center

Houston, Texas, 77030, United States

Location

Mater Mother's Hospital

Brisbane, Queensland, 4101, Australia

Location

University Hospitals Leuven

Leuven, 3000, Belgium

Location

Mount Sinai Hospital

Toronto, Ontario, M5G 1X5, Canada

Location

Hôpital Antoine Béclère

Clamart, 92141, France

Location

University Hospital of Bonn

Bonn, 53105, Germany

Location

Ospedale Maggiore Policlinico

Milan, 20122, Italy

Location

Ospedale Pediatrico Bambino Gesù

Rome, 00123, Italy

Location

National Center for Child Health and Development

Tokyo, 157-8535, Japan

Location

1st Department of Obstetrics and Gynecology, Medical University of Warsaw

Warsaw, Poland

Location

Hospital Clinic Barcelona

Barcelona, Catalonia, 08028, Spain

Location

King's College Hospital

London, SE5 9RS, United Kingdom

Location

Related Publications (13)

• 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.

  PMID: 19658113 BACKGROUND

• 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.

  PMID: 20352401 BACKGROUND

• 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.

  PMID: 19559323 BACKGROUND

• 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.

  PMID: 19125386 BACKGROUND

• 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.

  PMID: 18845492 BACKGROUND

• 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.

  PMID: 18844275 BACKGROUND

• 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.

  PMID: 17587219 BACKGROUND

• 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.

  PMID: 16374756 BACKGROUND

• 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.

  PMID: 15287047 BACKGROUND

• 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.

  PMID: 21484841 BACKGROUND

• 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.

  PMID: 35032132 DERIVED

• 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.

  PMID: 34808130 DERIVED

• 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.

  PMID: 34106556 DERIVED

Related Links

• opens only end 2010

MeSH Terms

Conditions

Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hernia, Diaphragmatic

Condition Hierarchy (Ancestors)

Internal Hernia; Hernia; Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms

Study Officials

• Jan Deprest, MD

  Universitaire Ziekenhuizen KU Leuven

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD, PhD

Study Record Dates

• First Submitted: August 4, 2010
• First Posted: November 15, 2010
• Study Start: November 1, 2011
• Primary Completion: March 1, 2020
• Study Completion: December 1, 2020
• Last Updated: May 4, 2021

Record last verified: 2021-05

Locations

DE (1); ES (1); BE (1); US (1); AU (1); FR (1); IT (2); JP (1); PL (1); GB (1); CA (1)