search
Back to results

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

Primary Purpose

Congenital Diseases, Diaphragmatic Hernia, Pulmonary Hypoplasia

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
fetal endoluminal tracheal occlusion
watchful waiting during pregnancy
Sponsored by
University Hospital, Gasthuisberg
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Congenital Diseases focused on measuring Isolated Congenital Diaphragmatic Hernia, Fetal Surgery, Pulmonary Hypoplasia

Eligibility Criteria

18 Years - 50 Years (Adult)FemaleDoes not accept healthy volunteers

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

Sites / Locations

  • University of Texas Health Science Center
  • Mater Mother's Hospital
  • University Hospitals Leuven
  • Mount Sinai Hospital
  • Hôpital Antoine Béclère
  • University Hospital of Bonn
  • Ospedale Maggiore Policlinico
  • Ospedale Pediatrico Bambino Gesù
  • National Center for Child Health and Development
  • 1st Department of Obstetrics and Gynecology, Medical University of Warsaw
  • Hospital Clinic Barcelona
  • King's College Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Experimental

Arm Label

expectant management during pregnancy

fetal endoluminal tracheal occlusion

Arm Description

watchful waiting during pregnancy

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

prenatal increase in lung volume after FETO
volume of lung after occlusion
grading of oxygen dependency
occurrence of pulmonary hypertension
determined by cardiac ultrasound
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.
number of days of ventilatory support
presence of periventricular leucomalacia
presence of neonatal sepsis, intraventricular haemorrhage, retinopathy grade III or higher
number of days till full enteral feeding
presence of gastro-esophagal reflux
day of surgery
requirement for use of patch for repair
bronchopulmonary dysplasia
defined as oxygen need for at least 28 days
Need for Extracorporeal membrane oxygenation
Defect size
number of days alive in case of postnatal death

Full Information

First Posted
August 4, 2010
Last Updated
May 3, 2021
Sponsor
University Hospital, Gasthuisberg
Collaborators
King's College Hospital NHS Trust (UK), Hospital Clinic of Barcelona, Hopital Antoine Beclere, University Hospital, Bonn, Mater Mothers' Hospital, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Ospedale Pediatrico Bambino Gesù, Rome (IT), Mount Sinai Hospital, Canada, National Center for Child Health and Development, Tokyo (JP), The University of Texas Health Science Center, Houston, Medical University of Warsaw
search

1. Study Identification

Unique Protocol Identification Number
NCT01240057
Brief Title
Tracheal Occlusion To Accelerate Lung Growth (TOTAL) Trial for Severe Pulmonary Hypoplasia
Acronym
TOTAL
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

2. Study Status

Record Verification Date
May 2021
Overall Recruitment Status
Completed
Study Start Date
November 2011 (undefined)
Primary Completion Date
March 2020 (Actual)
Study Completion Date
December 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University Hospital, Gasthuisberg
Collaborators
King's College Hospital NHS Trust (UK), Hospital Clinic of Barcelona, Hopital Antoine Beclere, University Hospital, Bonn, Mater Mothers' Hospital, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Ospedale Pediatrico Bambino Gesù, Rome (IT), Mount Sinai Hospital, Canada, National Center for Child Health and Development, Tokyo (JP), The University of Texas Health Science Center, Houston, Medical University of Warsaw

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Congenital Diseases, Diaphragmatic Hernia, Pulmonary Hypoplasia
Keywords
Isolated Congenital Diaphragmatic Hernia, Fetal Surgery, Pulmonary Hypoplasia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
93 (Actual)

8. Arms, Groups, and Interventions

Arm Title
expectant management during pregnancy
Arm Type
Placebo Comparator
Arm Description
watchful waiting during pregnancy
Arm Title
fetal endoluminal tracheal occlusion
Arm Type
Experimental
Arm Description
fetoscopic balloon occlusion at 27 to 29+6 weeks of gestation
Intervention Type
Procedure
Intervention Name(s)
fetal endoluminal tracheal occlusion
Other Intervention Name(s)
Balt Goldbal 2 balloon
Intervention Description
percutaneous fetoscopy, positioning of endoluminal balloon at 27-30 weeks and whenever possible elective removal at 34 weeks
Intervention Type
Other
Intervention Name(s)
watchful waiting during pregnancy
Intervention Description
pregnancy surveillance for fetal wellbeing, development of polyhydramnios and cervical shortening
Primary Outcome Measure Information:
Title
Survival at discharge from neonatal intensive care unit
Description
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.
Time Frame
at discharge from neonatal intensive care unit
Secondary Outcome Measure Information:
Title
prenatal increase in lung volume after FETO
Description
volume of lung after occlusion
Time Frame
prior to balloon removal
Title
grading of oxygen dependency
Time Frame
born >32 wks: between 28-56d of life; born <32wks: 36wks postmenstrual age
Title
occurrence of pulmonary hypertension
Description
determined by cardiac ultrasound
Time Frame
within first weeks of life
Title
number of days in Neonatal Intensive Care Unit (NICU)
Description
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.
Time Frame
within hospital stay
Title
number of days of ventilatory support
Time Frame
within NICU stay
Title
presence of periventricular leucomalacia
Time Frame
2 months of life
Title
presence of neonatal sepsis, intraventricular haemorrhage, retinopathy grade III or higher
Time Frame
within hospital stay
Title
number of days till full enteral feeding
Time Frame
within first 2 years of life
Title
presence of gastro-esophagal reflux
Time Frame
at discharge
Title
day of surgery
Time Frame
within hospital stay
Title
requirement for use of patch for repair
Time Frame
at the time of postnatal surgery
Title
bronchopulmonary dysplasia
Description
defined as oxygen need for at least 28 days
Time Frame
with the first 8 weeks
Title
Need for Extracorporeal membrane oxygenation
Time Frame
during NICU admission
Title
Defect size
Time Frame
at the time of postnatal surgery
Title
number of days alive in case of postnatal death
Time Frame
during NICU admission

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jan Deprest, MD
Organizational Affiliation
Universitaire Ziekenhuizen KU Leuven
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Texas Health Science Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Mater Mother's Hospital
City
Brisbane
State/Province
Queensland
ZIP/Postal Code
4101
Country
Australia
Facility Name
University Hospitals Leuven
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
Facility Name
Mount Sinai Hospital
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 1X5
Country
Canada
Facility Name
Hôpital Antoine Béclère
City
Clamart
ZIP/Postal Code
92141
Country
France
Facility Name
University Hospital of Bonn
City
Bonn
ZIP/Postal Code
53105
Country
Germany
Facility Name
Ospedale Maggiore Policlinico
City
Milano
ZIP/Postal Code
20122
Country
Italy
Facility Name
Ospedale Pediatrico Bambino Gesù
City
Rome
ZIP/Postal Code
00123
Country
Italy
Facility Name
National Center for Child Health and Development
City
Tokyo
ZIP/Postal Code
157-8535
Country
Japan
Facility Name
1st Department of Obstetrics and Gynecology, Medical University of Warsaw
City
Warsaw
Country
Poland
Facility Name
Hospital Clinic Barcelona
City
Barcelona
State/Province
Catalunya
ZIP/Postal Code
08028
Country
Spain
Facility Name
King's College Hospital
City
London
ZIP/Postal Code
SE5 9RS
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
19658113
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.
Results Reference
background
PubMed Identifier
20352401
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.
Results Reference
background
PubMed Identifier
19559323
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.
Results Reference
background
PubMed Identifier
19125386
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.
Results Reference
background
PubMed Identifier
18845492
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.
Results Reference
background
PubMed Identifier
18844275
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.
Results Reference
background
PubMed Identifier
17587219
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.
Results Reference
background
PubMed Identifier
16374756
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.
Results Reference
background
PubMed Identifier
15287047
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. Erratum In: Ultrasound Obstet Gynecol. 2004 Oct;24(5):594.
Results Reference
background
PubMed Identifier
21484841
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.
Results Reference
background
PubMed Identifier
35032132
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.
Results Reference
derived
PubMed Identifier
34808130
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.
Results Reference
derived
PubMed Identifier
34106556
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.
Results Reference
derived
Links:
URL
http://www.totaltrial.eu
Description
opens only end 2010

Learn more about this trial

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

We'll reach out to this number within 24 hrs