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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT00763737




Registration number
NCT00763737
Ethics application status
Date submitted
30/09/2008
Date registered
1/10/2008
Date last updated
3/12/2020

Titles & IDs
Public title
Fetal Surgery for Moderate Left Sided Congenital Diaphragmatic Hernia.
Scientific 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.
Secondary ID [1] 0 0
2008-4634
Secondary ID [2] 0 0
B32220084540
Universal Trial Number (UTN)
Trial acronym
TOTAL moderate
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Congenital Diaphragmatic Hernia 0 0
Fetal Surgery 0 0
Pulmonary Hypoplasia 0 0
Condition category
Condition code
Oral and Gastrointestinal 0 0 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Surgery - Fetoscopic Endoluminal Tracheal Occlusion

Experimental: FETO - prenatal FETO at 30-31+6 weeks and removal at 34-34+6 wks, followed by standardized postnatal care

No Intervention: Expectant management - expectant management during pregnancy followed by standardized neonatal care


Treatment: Surgery: Fetoscopic Endoluminal Tracheal Occlusion
prenatal balloon placement at 30-31+6 weeks and removal at 34-34+6 wks
Intervention code [1] 0 0
Treatment: Surgery
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Survival at discharge
Timepoint [1] 0 0
at the time of discharge from NICU, approximately 2 months
Primary outcome [2] 0 0
Supplemental oxygen at 6 months of age
Timepoint [2] 0 0
at 6 months of age
Secondary outcome [1] 0 0
Grading of oxygen dependency
Timepoint [1] 0 0
between 28 and 56 days of life if born >32 weeks; at 36 weeks postmenstrual age if born <32 weeks
Secondary outcome [2] 0 0
Pulmonary hypertension
Timepoint [2] 0 0
during NICU admission
Secondary outcome [3] 0 0
Use of extracorporeal membrane oxygenation
Timepoint [3] 0 0
during NICU admission
Secondary outcome [4] 0 0
Change in O/E LHR after FETO
Timepoint [4] 0 0
prior to unplug
Secondary outcome [5] 0 0
NICU days
Timepoint [5] 0 0
during NICU admission
Secondary outcome [6] 0 0
days of ventilatory support
Timepoint [6] 0 0
during NICU admission
Secondary outcome [7] 0 0
Periventricular leucomalacia
Timepoint [7] 0 0
during NICU admission
Secondary outcome [8] 0 0
Neonatal sepsis
Timepoint [8] 0 0
during NICU admission
Secondary outcome [9] 0 0
Intraventricular hemorrhage
Timepoint [9] 0 0
during NICU admission
Secondary outcome [10] 0 0
Retinopathy of prematurity
Timepoint [10] 0 0
during NICU admission
Secondary outcome [11] 0 0
Days until full enteral feeding
Timepoint [11] 0 0
during NICU admission
Secondary outcome [12] 0 0
Gastroesophageal reflux
Timepoint [12] 0 0
during NICU admission
Secondary outcome [13] 0 0
Day of postnatal surgery
Timepoint [13] 0 0
during NICU admission
Secondary outcome [14] 0 0
Use of patch
Timepoint [14] 0 0
at the time of postnatal surgery
Secondary outcome [15] 0 0
Defect size
Timepoint [15] 0 0
at the time of postnatal surgery
Secondary outcome [16] 0 0
Number of days alive in case of postnatal death
Timepoint [16] 0 0
during NICU admission

Eligibility
Key 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
Minimum age
18 Years
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
No
Key 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 design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/08/2010
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
1/03/2020
Sample size
Target
Accrual to date
Final
196
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 0 0
Mater Mother's Hospital - Brisbane
Recruitment postcode(s) [1] 0 0
4101 - Brisbane
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Texas
Country [2] 0 0
Belgium
State/province [2] 0 0
Leuven
Country [3] 0 0
Canada
State/province [3] 0 0
Ontario
Country [4] 0 0
France
State/province [4] 0 0
Clamart
Country [5] 0 0
France
State/province [5] 0 0
Paris
Country [6] 0 0
Germany
State/province [6] 0 0
Bonn
Country [7] 0 0
Italy
State/province [7] 0 0
Milan
Country [8] 0 0
Italy
State/province [8] 0 0
Rome
Country [9] 0 0
Poland
State/province [9] 0 0
Warsaw
Country [10] 0 0
Spain
State/province [10] 0 0
Catalunya
Country [11] 0 0
United Kingdom
State/province [11] 0 0
London

Funding & Sponsors
Primary sponsor type
Other
Name
University Hospital, Gasthuisberg
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
King's College Hospital NHS Trust (UK)
Address [1] 0 0
Country [1] 0 0
Other collaborator category [2] 0 0
Other
Name [2] 0 0
Hospital Clinic of Barcelona
Address [2] 0 0
Country [2] 0 0
Other collaborator category [3] 0 0
Other
Name [3] 0 0
Hopital Antoine Beclere
Address [3] 0 0
Country [3] 0 0
Other collaborator category [4] 0 0
Other
Name [4] 0 0
Hôpital Necker-Enfants Malades
Address [4] 0 0
Country [4] 0 0
Other collaborator category [5] 0 0
Other
Name [5] 0 0
University Hospital, Bonn
Address [5] 0 0
Country [5] 0 0
Other collaborator category [6] 0 0
Other
Name [6] 0 0
Mater Mothers' Hospital
Address [6] 0 0
Country [6] 0 0
Other collaborator category [7] 0 0
Other
Name [7] 0 0
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
Address [7] 0 0
Country [7] 0 0
Other collaborator category [8] 0 0
Other
Name [8] 0 0
Ospedale Pediatrico Bambino Gesù, Rome (IT)
Address [8] 0 0
Country [8] 0 0
Other collaborator category [9] 0 0
Other
Name [9] 0 0
Mount Sinai Hospital, Canada
Address [9] 0 0
Country [9] 0 0
Other collaborator category [10] 0 0
Other
Name [10] 0 0
Baylor College of Medicine
Address [10] 0 0
Country [10] 0 0
Other collaborator category [11] 0 0
Other
Name [11] 0 0
The University of Texas Health Science Center, Houston
Address [11] 0 0
Country [11] 0 0
Other collaborator category [12] 0 0
Other
Name [12] 0 0
Medical University of Warsaw
Address [12] 0 0
Country [12] 0 0

Ethics approval
Ethics application status

Summary
Brief 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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT00763737
Trial related presentations / publications
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.
Done 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.
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. doi: 10.1053/j.semperi.2005.04.006.
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.
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 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.
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.
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.
Nawapun K, Eastwood MP, Diaz-Cobos D, Jimenez J, Aertsen M, Gomez O, Claus F, Gratacos 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.
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.
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.
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.
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.
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.
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.
Public notes

Contacts
Principal investigator
Name 0 0
Jan A Deprest, MD PhD
Address 0 0
Universitaire Ziekenhuizen KU Leuven
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT00763737