TOTAL TRIAL: 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
Phase: PHASE2
Conditions: Hernia, Hernia, Diaphragmatic, Hernia, DIaphragmatic, Congenital, Pathological Conditions, Anatomical, Congenital Abnormalities, Congenital Diaphragmatic Hernia, Fetal Anomaly, Fetal Surgery, Pulmonary Hypoplasia
Sponsor: Michael A Belfort

TOTAL Trial 
 
PI: Michael Belfort 
IDE# G160187 
 
Baylor IRB: H-39398 
 
 
 
 
 
 
TITLE: RANDOMIZED TRIAL OF FETOSCOPIC ENDOLUMINAL 
TRACHEAL OCCLUSION (FETO) VERSUS EXPECTANT 
MANAGEMENT DURING PREGNANCY IN FETUSES WITH 
LEFTSIDED AND ISOLATED CONGENITAL DIAPHRAGMATIC 
HERNIA AND MODERATE PULMONARY HYPOPLASIA 
 
NCT02875860 
 
Document Date: August 24, 2017 

 
 
 
 
 
 
 
 
TOTAL TRIAL 
 
 
 
 
 
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 
 
 
Principal Investigator: 
Michael A Belfort, MD, PhD, MBBCH, FACOG, FRCOG, FRCSC 
Texas Children’s Hospital Pavilion for Women 
Baylor College of Medicine 
6651 Main Street 
Houston, TX 77030 
 
 
 
 
Sub-investigators: 
 
Oluyinka Olutoye, MB, ChB, PhD 
Olutoyin A. Olutoye, MB, ChB 
Jimmy Espinoza, MD 
Christopher Cassady, MD  
Timothy Lee, MD 
Magdalena Sanz Cortes, MD, PhD 
Alireza Abdollah Shamshirsaz, MD 
Sundeep Keswani, MD 
Wesley Lee, MD 
 
 
 
 
IDE #G160187 
Baylor H-39398 
 
 
 
 
 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
2 
 
Table Contents 
1.0 
PURPOSE .................................................................................................................................... 5 
1.1 
Primary Objectives ..................................................................................................................... 5 
1.2 
Secondary Objectives ................................................................................................................. 5 
2.0 
BACKGROUND AND RATIONALE ................................................................................................ 5 
2.1 
Report of Prior Investigations .................................................................................................... 6 
2.2 
Current Rationale for Prenatal Treatment of Moderate CDH ................................................... 8 
2.3 
Justification for the Investigation .............................................................................................. 8 
3.0 
INVESTIGATIONAL DEVICE INFORMATION ................................................................................ 8 
3.1 
Intended Use of the Device........................................................................................................ 8 
4.0 
STUDY DESIGN............................................................................................................................ 8 
5.0 
PATIENT ELIGIBILITY ................................................................................................................. 11 
5.1 
Patient Recruitment and Enrollment ....................................................................................... 11 
5.2 
Inclusion Criteria ...................................................................................................................... 12 
5.3 
Exclusion Criteria ...................................................................................................................... 13 
6.0 
TREATMENT PLAN .................................................................................................................... 14 
6.1 
Study Schedule – Prior to Delivery for Group I (standard of care) and Group II (FETO 
procedure)…………………………………………………………………………………………………………………………………………..15 
6.2 
Study Schedule – Neonate ....................................................................................................... 15 
6.3 
Procedure ................................................................................................................................. 16 
6.4.1 
Preoperative............................................................................................................................. 16 
6.4.2 
Anesthesia ................................................................................................................................ 17 
6.4.3 
Balloon Placement ................................................................................................................... 17 
6.4.4 
Postoperative Care ................................................................................................................... 18 
6.5 
Balloon Removal ...................................................................................................................... 18 
6.6 
Delivery .................................................................................................................................... 20 
6.7 
Postnatal .................................................................................................................................. 20 
Postnatal Death ........................................................................................................................................ 20 
7.0 
RISKS ......................................................................................................................................... 21 
7.1 
Mother ..................................................................................................................................... 21 
7.2 
Fetus and Neonate ................................................................................................................... 22 
7.3 
Steps to Minimize Risks............................................................................................................ 23 
7.4 Risk Balance Summary ....................................................................................................................... 24 
8.0 
BENEFITS .................................................................................................................................. 24 
9.0 
STATISTICAL CONSIDERATIONS ................................................................................................ 24 
9.1 
Sample Size and Precision ........................................................................................................ 24 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
3 
 
9.2 
Proposed Analysis .................................................................................................................... 26 
9.3 
SAFETY EVENTS/Reporting ....................................................................................................... 30 
9.3.2 
Definition of Safety Event ........................................................................................................ 31 
9.4 
Not Device or Procedure Related – Adverse Event (AE) .......................................................... 31 
9.5 
Device or Procedure Related – Adverse Device Effect (ADE) .................................................. 31 
9.6 
Definitions of Serious Safety Events ........................................................................................ 31 
9.7 
Not Device or Procedure Related – Serious Adverse Event (SAE) ........................................... 31 
9.8 
Device or Procedure Related – Serious Adverse Device Effect (SADE) .................................... 32 
9.9 
Unanticipated – Unanticipated Adverse Device Effect (UADE) ............................................... 32 
9.10 
Safety Event Assessments ........................................................................................................ 32 
9.11 
Assessment of Causality ........................................................................................................... 32 
9.12 
Investigational Product ............................................................................................................ 32 
9.13 
Procedure ................................................................................................................................. 33 
9.14 
Serious Safety Events, Reporting Requirements ..................................................................... 33 
9.15 
Unanticipated Safety Event Reporting Requirements ............................................................. 33 
9.16 
Follow-up of Safety Events....................................................................................................... 33 
10.0 
INFORMED CONSENT and RISKS .............................................................................................. 34 
10.1 
Changes to the protocol and/or informed consent form ........................................................ 34 
10.2 
Withdrawal of informed consent ............................................................................................. 34 
11.0 
TRIAL MONITORING PROCEDURES .......................................................................................... 34 
11.1 
Institutional Monitoring ........................................................................................................... 34 
11.2 
Written Monitoring Procedures .............................................................................................. 34 
11.3 
Monitoring, Audits and Inspections ......................................................................................... 35 
12.0 
REPORTING REQUIREMENTS ................................................................................................... 35 
12.1 
Registration .............................................................................................................................. 35 
12.2 
Each Case ................................................................................................................................. 35 
12.3 
Access to Original Records ....................................................................................................... 36 
12.4 
Records Retention .................................................................................................................... 36 
12.5 
Data Security ............................................................................................................................ 36 
12.6 
Storage ..................................................................................................................................... 36 
13.0 
REGULATORY REQUIREMENTS ................................................................................................. 36 
13.1 
Ethical conduct of the study and regulatory review ................................................................ 36 
13.2 
Study Management .................................................................................................................. 37 
13.3 
Training of study site personnel............................................................................................... 37 
13.4 
Financial Disclosure .................................................................................................................. 37 
13.5 
Confidentiality .......................................................................................................................... 37 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
4 
 
Appendix A: Medications Used in this Protocol....................................................................................... 38 
REFERENCES ……………………………………………………………………………………………………………………………………….39 
 
 
 
 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
5 
 
1.0 
PURPOSE 
 
This trial will test whether temporary fetoscopic tracheal occlusion rather than expectant 
management during pregnancy, followed by standardized postnatal management, increases 
survival at discharge and decreases oxygen need at 6 months in case of survival till discharge. 
 
The target group are fetuses with isolated moderate CDH hence predicted rates of survival rate of 
60% or lower and predicted rates of bronchopulmonary dysplasia of 33% or higher. 
 
The rationale is that FETO triggers lung growth and maturation to such an extent that the chances 
of neonatal survival are significantly increased as compared to standard postnatal care in the same 
severity group. Further, we hypothesize that improved lung development lessens the need for 
ventilatory assistance, hence decreases pulmonary morbidity and therefore might improve quality 
of life of survivors. 
 
A precondition for such an assumption is that both FETO and postnatal treatment are undertaken 
in specialist centers with extensive experience in the management of affected fetuses. We impose 
adherence to the consensus guidelines drafted after a meeting of several leading European centers 
(Mannheim, 2006) and updated after the completion of the VICI trial (demonstrating no added 
value of primary high frequency oscillatory ventilation). 1, 2. 
 
 
1.1 Primary Objectives 
 
To determine if  FETO added to standardized postnatal management increases survival at 
discharge and decreases oxygen need at 6 months in survivors, as compared to what is observed 
after standard postnatal management alone. 
 
1.2 Secondary Objectives 
 
To determine whether FETO improves additional morbidity indicators. The subjects will be 
followed up for long-term neurodevelopmental and pulmonary functional outcomes, if the 
necessary funding can be secured. 
 
 
2.0 
BACKGROUND AND RATIONALE 
 
Congenital Diaphragmatic Hernia (CDH) is associated with major chromosomal and other 
abnormalities in about 30% of cases and in this group the mortality rate is higher than 85%. In 
the case of isolated CDH there is a high risk of perinatal death and morbidity mainly because of 
pulmonary hypoplasia and pulmonary hypertension. These complications can be predicted 
prenatally by the ultrasonographic measurement of the lung area to head circumference ratio 
(LHR). In the case of fetuses with severe CDH (defined by a ratio of the observed to the expected 
normal mean for gestation (O/E) LHR of less than about 25% and intrathoracic herniation of the 
fetal liver) the predicted survival rate with the traditional expectant antenatal management and 
postnatal ventilatory support for stabilization followed by surgery is less than 30% 3. In addition, 
in the survivors there is a high rate of morbidity with evidence of bronchopulmonary dysplasia 
in more than 70% of cases, which also relates to prenatally measured LHR.4 
 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
6 
 
In the last seven years the members of the applying consortium have pioneered, developed and 
applied in more than 150 cases of severe CDH an intrauterine therapeutic approach, which 
consists of percutaneous fetoscopic endoluminal tracheal occlusion (FETO) typically performed 
at 26-29 weeks of gestation, with removal of the balloon at about 34 weeks 5. This has been 
shown to be safe for the mother and to improve the estimated survival from less than 30% (most 
centres obtain <15%) to about 55%. In addition, the improved survival with FETO was 
associated with 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 
group6. Also this consortium has 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 size7. As 
of 2009, the FETO consortium has performed over 200 of these procedures, with steady results, 
i.e. a 50% survival rate after FETO. FETO is also associated with a consistent risk for PPROM 
(15% within 3 weeks) and an earlier gestational age at delivery (mean: 35.3 weeks) 8. Also the 
fetal lung response is more vigorous when occlusion is made earlier, rather than later in 
pregnancy 9. 
 
In 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) managed expectantly the 
estimated rate of postnatal survival is 60% or lower and the rate of broncho-pulmonary dysplasia 
in survivors is 33% or higher. It is not known whether percutaneous fetoscopic tracheal 
occlusion in this group would improve survival and reduce morbidity. 
 
 
2.1 Report of Prior Investigations 
 
Fetuses  with  CDH  presenting  with  liver  herniation  and  a  lung  area-to-head circumference 
ratio (LHR) of less than 1.0 have a high chance for neonatal death due to pulmonary hypoplasia. 
Fetal tracheal occlusion (TO) prevent egress of lung liquid, and this has been shown to trigger 
lung growth. Initially animal experiments showed that a minimally invasive technique for 
Fetoscopic Endoluminal Tracheal Occlusion (FETO) with a detachable balloon was possible and 
effective in reducing lung hypoplasia from CDH.2 
 
In 2001, Deprest et al10 demonstrated the feasibility of FETO by percutaneous access, using a 
fetoscope, in fetuses with severe CDH. In a retrospective multicenter review, the same group 
obtained LHR measurements and noted the position of the liver in 134 babies with isolated left-
sided CDH between 26 and 28 weeks gestation.10, 11 The overall survival of the live born babies 
was 47% (58/123). The LHR and position of the liver both had a direct correlation with 
subsequent survival.12.13 A combination of both variables best predicted neonatal outcome: the 
presence of the liver in the chest and a LHR < 1.0 predicted a survival of 9%. When the LHR was 
< 0.6, there were no survivors irrespective of liver position. Deprest’s group successfully 
performed endotracheal placement of the FETO balloon in 20 cases at a median gestational age 
of 26 weeks. The mean duration of the operation was 22 (range 5-54) minutes. In 11 (55%) of 
these patients, there was postoperative preterm (i.e.,<37 weeks) rupture of the membranes 
(PPROM). The membranes ruptured before 32 weeks in 35% of cases, with a decreasing trend as 
experience increased. Ultrasound scans after FETO demonstrated an increase in the echogenicity 
of the lungs within 48 hours and improvement in the LHR from a median 0.7 (range 0.4-0.9) 
before FETO to 1.8 (range 1.1- 2.9) within 2 weeks after surgery. The median gestation at delivery 
was 33.2 (range 27-38) weeks, and in 14 (70%) this occurred after 32 weeks.10 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
7 
 
 
Postpartum surgical repair of the diaphragmatic hernia was achieved in 13 babies, and in all but 
1 the defect was extensive and required the insertion of a patch. Survival to discharge was 50%. 
At the time of publication in 2005 the 10 long-term surviving babies were aged 7 to 26 (median 
19) months without known neurologic morbidity. Eight babies died in the neonatal period due to 
complications of the underlying disease. Two non-survivors died from other causes but with 
appropriately developed lungs. Improved survival coincided with increasing experience, in turn 
related to a reduced incidence of postoperative PPROM, later delivery, and a change in the policy 
on the timing of removal of the balloon from intrapartum to the prenatal period. Survival in 
eligible contemporary controls was 1/12 (8%). They concluded that the presence of liver 
herniation and a low lung-to-head ratio (LHR <1.0) is a good predictor of poor prognosis at 
different tertiary centers around the world, and that severe CDH may be successfully treated with 
FETO, which is minimally invasive and may improve postnatal survival.4, 14 
 
Another group working in Spain has assessed the postnatal outcomes of a group of babies treated 
with the FETO procedure. They studied twelve babies who were born at 34 weeks after having 
been treated with FETO in the early third trimester and concluded that CDH patients with a poor 
prognosis undergoing FETO had postnatal outcomes similar to non- prenatally studied cases and 
CDH cases that did not have FETO but who had a good prognosis predicted by a LHR > 1.0.3  
Harrison, et al (2003) conducted the only randomized controlled trial done in the USA. Although 
the results failed to show benefit from prenatal therapy, there were a number of problems with 
this study design and statistical analysis. This study lacked power to document the potential 
advantage of prenatal therapy in severe cases because the data were stratified and the individual 
data groups were too small to accurately assess small benefits. In addition, the fetal obstruction 
surgery included a number of different procedures such  as tracheal  clipping with  open fetal  
surgery  (through a  uterine incision) and an exteriorized fetus, balloon procedures done via a 
maternal laparotomy, and fetoscope placement through an exposed uterus, all of which were all 
done under general anesthesia.15 
 
This is very different to the current European approach, 16 which is minimally invasive and all 
done through a fetoscope under regional or local anesthesia. The plug-unplug sequence has been 
refined and the benefits of FETO on pulmonary vascular function are now appreciated to a much 
greater extent.17, 18 Maternal risks have been minimized and PPROM rate and need for tocolytics 
therapy have been lessened. This fact has been well appreciated by the Fetal Surgery community 
in the USA. The same group that published the USA RCT experience applied for, and was 
granted, an IDE to perform a research trial on the FETO procedure using the same methodology 
as practiced by the European groups.19 We follow these guidelines and use more stringent criteria 
and procedures as already approved by the FDA for the University of California – San Francisco 
IDE granted to Dr. Lee and currently used in Europe.20 
 
In 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) managed expectantly the estimated 
rate of postnatal survival is 60% or lower and the rate of broncho-pulmonary dysplasia in 
survivors is 33% or higher. It is not known whether percutaneous fetoscopic tracheal occlusion 
in this group would improve survival and reduce morbidity. Although the FETO procedure has 
shown promise as an intervention for severe and extremely severe CDH, moderate CDH has not 
been studied adequately in the United States. This study will help extend current trials of FETO to 
include the population of the United States. 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
8 
 
2.2 Current Rationale for Prenatal Treatment of Moderate CDH 
 
The rationale is that FETO triggers lung growth and maturation to such an extent that the chances 
of neonatal survival are significantly increased as compared to standard postnatal care in the same 
severity group.  Further,  we  hypothesize  that  improved  lung  development  lessens  the  need  
for  ventilatory assistance, hence decreases pulmonary morbidity and therefore might improve 
quality of life of survivors. A precondition for such an assumption is that both FETO and 
postnatal treatment are undertaken in specialist centers with extensive experience in the 
management of affected fetuses. We impose adherence to the consensus guidelines drafted 
after a meeting of several leading European centers (Mannheim, 2006) which is attached as a 
separate document, and was updated after the completion of the VICI trial (demonstrating no 
added value of primary high frequency oscillatory ventilation). 
 
 
2.3 
Justification for the Investigation 
 
 
The hypothesis is that prenatal intervention will improve morbidity (increase survival rate until 
discharge) and decrease the number of survivors requiring oxygen at six months of age in patients 
with isolated, moderate CDH. 
 
3.0 
INVESTIGATIONAL DEVICE INFORMATION 
 
 
The device is a detachable latex balloon (called the “GoldBal”), delivered with a 1mm diameter 
catheter (called the “BALTACCIPBPE 100” Microcatheter). The current manufacturer is Balt 
Extrusion located in Montmorency, France.  The balloon was originally designed to treat Carotid-
Cavernous Fistulas via a less-invasive catheter procedure under fluoroscopic guidance and it was 
called Goldvalve. The Goldvalve Balloon has been approved for this indication and marketed in 
Europe for over 15 years. Nfocus Neuromedical acquired the device and submitted it for US FDA 
clearance via the Class II (510(k)) application. This device did not receive approval for the 
vascular indication as Nfocus Neuromedical was bought by Acta Vascular Systems, Inc. and they 
did not want to pursue approval.   
 
3.1 
Intended Use of the Device 
 
The deflated Goldbal Balloon, mounted on the catheter tip, is introduced into the trachea of the 
affected fetus through intrauterine endoscopy and endotracheal intubation of the fetus. Once 
positioned, the balloon is inflated with saline, delivered through the catheter, and detached from 
the catheter tip. The inflated balloon is compliant enough to prevent deformation of the fetal 
trachea, yet provides adequate and complete obstruction. While the present study will utilize this 
device for an indication not anticipated during the design or previous testing of the GoldBal 
Balloon, the sizes and soft, compliant nature of the balloon have proven useful for fetal tracheal 
occlusion in the hands of other investigators. 
 
4.0 
STUDY DESIGN 
 
This is a multi-center, non-blinded randomized controlled trial in fetuses with isolated moderate 
CDH, i.e. moderate lung hypoplasia (as determined by prenatal assessment of lung development). 
It essentially compares fetal therapy added to conventional postnatal care, versus expectant 
prenatal management during pregnancy followed by conventional postnatal care. 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
9 
 
There are currently 11 participating centers, of which seven see moderate only cases, one sees 
severe only cases, and three see both severe and moderate cases. Dr. H. Sago in Tokyo, Japan is 
preparing to join the study.  As sites are added to the study, they are updated in the main study’s 
website, http://www.totaltrial.eu and at www.ClinicalTrials.gov (NCT00763737). 
 
Lead Investigator 
Institution(s) 
Case Type 
Country 
Dr. Jan Deprest 
University Hospitals Leuven 
Severe and Moderate 
Belgium 
Dr. Michael Belfort 
Baylor College of Medicine  
   Texas Children’s Hospital 
Moderate 
United States of 
America 
Dr. Eduard Gratacos 
Hospital Clínic, University of 
Barcelona 
Moderate 
Spain 
Dr. Alexandra Benachi 
Hôpital Antoine Béclère 
Severe and Moderate 
France 
Dr. Yves Ville 
Hôpital Necker – Enfants Malades 
Severe and Moderate 
France 
Dr. Kypros Nicolaides 
King's College Hospital 
Moderate 
United Kingdom 
Dr. Christoph Berg 
University Hospital of Bonn 
Moderate 
Germany 
Dr. Glenn Gardener 
Mater Mother's Hospital 
Moderate 
Australia 
Dr. Nicola Persico 
Ospedale Maggiore Policlinico 
Moderate 
Italy 
Dr. Pietro Bagolan 
Ospedale Pediatrico Bambino Gesù 
Moderate 
Italy 
Dr. Greg Ryan 
Mount Sinai Hospital 
Severe 
Canada 
 
 
Subjects will be randomized into two groups (“FETO” and “expectant”) after assessment in a 
FETO center. In the event that the potential participant is unable to travel to our Fetal Center, we 
will accept appropriate images within three weeks of the date of randomization. As long as the 
quality of the images are appropriate enough to make the necessary measurements, they can be 
accepted by the Fetal Center staff for decision-making purposes. If a screening ultrasound or MRI 
(standard of care diagnostic exams) takes place outside of TCH, it will also be read by TCH 
physicians responsible for the trial. If possible, the participants should be assessed at TCH. In the 
FETO group the balloon will be introduced between 30 weeks plus 0 day and 31 weeks plus 6 
days and whenever clinically feasible, removed at 34 weeks plus 0 d to 34 weeks plus 6 days. 
Following completion of an inclusion/exclusion criteria checklist on the internet 
(www.eurocdh.org) and obtaining informed consent, the subject will be randomized over the 
internet with equal likelihood to either arm of the study. Randomization lists will be computer 
generated consisting of an initial block of 80 patients which were used as an internal pilot, since 
there were no data on the outcomes of percutaneous FETO in moderate hypoplasia. This group 
was analyzed for efficacy (as foreseen in initial protocol) and an adjusted sample size was 
calculated. It showed that in total 98 patients were required to demonstrate an increase in survival 
from 40 to 60%. Using a sequential design with an overall one-sided alpha of 2.5% and power of 
80%, five interim analyses for efficacy are planned after 40, 60, 70, 80, and 90% of the sample 
size at the final analysis (59, 69, 79, 89 and 98 patients in each arm respectively). 
 
GROUPS: 
 
 I. Standardized postnatal care (expectant group): mothers will be expectantly managed during 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
10 
 
pregnancies and babies will receive standardized postnatal care at a tertiary center used to manage 
babies with CDH. The recommendation is that they adhere to consensus guidelines published on 
the study website at www.eurocdh.org. 
 
II. Prenatal intervention (FETO group): patients will undergo fetoscopic tracheal occlusion and 
ideally prenatal reversal of the occlusion followed by standardized postnatal care as in group I. 
In this study FETO is to be done between 30 weeks plus 0 day and 31 weeks plus 6 days and 
removal of the balloon at 34 weeks plus 0 day to 34 weeks plus 6 days. 
 
This study trial is a pragmatical or efficacy trial: ideally mothers will deliver after removal of the 
balloon at those tertiary centers, typically offering postnatal care for the patient involved. In group 
II (FETO-group), mothers will, in between placement and removal of the balloon, thus carrying 
a fetus with obstructed airways, ideally remain under the care of our local fetal treatment center 
(further referred to as FETO center). As many as possible precautions are taken to avoid problems 
with balloon removal in case of earlier than expected delivery. 
 
• 
Balloons are to be electively removed prior to 35 weeks. FETO centers will provide 24/24 
hours and 7/7 days services for management of fetuses with obstructed airways, either in 
utero or during labor and delivery. 
 
• 
Patients in the study and randomized to FETO, are required to stay within 30 minutes of 
the FETO center while the fetus' airway is blocked by the balloon. After reversal of the 
occlusion, the patient will be referred to the tertiary care center where delivery and 
postnatal care will be undertaken. 
 
• 
Preterm Labor: 
 
In the event of progressive and unremitting preterm labor in a patient who has a FETO balloon in 
situ, the balloon will be removed emergently using the same procedure described above, time 
permitting. If this is not possible the baby will be delivered by cesarean section using the EXIT 
(ex utero intrapartum therapy) procedure. In this procedure, only the fetal head will be delivered 
initially through a cesarean section incision while the mother is under general anesthesia. Once the 
head is delivered, a neonatologist or pediatric surgeon will perform bronchoscopy and the balloon 
occluding the trachea will be deflated and removed. The airway will be suctioned, an endotracheal 
tube inserted, and exogenous surfactant (Exosurf Neonatal, Glaxo Wellcome) will be administered 
at a dose of 3 ml/kg body weight, and assisted ventilation will be started before the umbilical cord 
is divided. Once the baby is ventilated the body of the child will be delivered and the umbilical 
cord will be cut. This procedure allows the baby to be oxygenated while the balloon is removed 
and the endotracheal tube is placed. In the event that the baby delivers precipitously without the 
EXIT procedure being possible, a pediatric surgeon will be in the operating room to puncture the 
balloon and remove it as soon as possible after the delivery. Patients will be counseled as to the 
importance of returning for care if there is any possibility of progressive preterm labor and delivery 
so the necessary preparations can be made. 
 
III. Postnatal: 
 
Neonates will be assessed at discharge, 6 months, 1 year, and 2 years after delivery with regard to 
their need for supplemental oxygen. 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
11 
 
 
Postnatal Death:  Permission should be requested for full postmortem examination in all cases of 
fetal or postnatal death. If this is not granted then permission for an MRI or CT examination and 
histological examination of open lung biopsies should be requested. If none of the above is 
possible the cause of death will be determined on the basis of clinical findings. 
 
5.0 
PATIENT ELIGIBILITY 
 
5.1 
Patient Recruitment and Enrollment  
 
This study involves the enrollment of pregnant women, and so precautions will be taken to protect 
this vulnerable population. Potential subjects will be approached by the PI or coinvestigator and 
informed about the study. Interested individuals will be counseled extensively. Interpreters will 
be used as necessary. 
 
Patients with a fetus that has been diagnosed with a CDH that meets the eligibility criteria for 
moderate left sided and isolated CDH will be offered the FETO procedure at Texas Children's 
Hospital (TCH). The PI and co-investigator fetal surgeon will be the primary contacts at TCH 
and the team who will make the initial assessment of whether the patient is a candidate or not. 
We will enroll eligible subjects in the United States for this study diagnosed prenatally with 
moderate left sided and isolated CDH. Subjects will be randomized to either receive the FETO 
procedure or standard of care. Outcome data will be compared between the two groups. 
 
Patients may be referred to our center from their primary physician anywhere in the country. We 
will be contacted by the referring physicians to determine whether the patient is a suitable 
candidate. If this is determined to be the case (after discussion with the referring physician) the 
patient will be contacted and the proposed surgery and our study will be discussed. 
 
Once the patient has had sufficient opportunity to read and understand the consent form, the PI 
and/or the study staff will answer any and all questions to the satisfaction of the potential subject. 
 
The study staff will obtain informed consent of both, the pregnant mother and the father of the 
baby (unless the father is unable to consent because of unavailability, incompetence, or 
temporary incapacity or the pregnancy resulted from rape or incest), and after all of the parent’s 
questions have been answered to the their satisfaction.  
  
Written consent will be signed by each participant as well as an appropriate witness if necessary. 
At all stages, it will be emphasized that enrollment is strictly voluntary and that a refusal to 
participate will in no way influence the willingness or ability of her providers to care for her. 
Cognitively impaired patients will not be enrolled. 
 
This study begins with enrollment of a pregnant mother and includes later follow up on the 
newborn to two years of life. Thus, this study involves the enrollment of children. Parents will be 
counseled about the follow-up checks that will be done on their child to assess neuromotor and 
mental development and will consent to the enrollment of their children. 
 
After signing the informed consent document, the participant will complete release of information 
forms (one for her and one for the child) which will allow study staff to gather data from their 
medical records. The participant (mother) may be contacted by phone, email, and/or mail by the 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
12 
 
study staff to sign a medical record release every year if necessary to allow this to occur. She may 
also be contacted by study staff regarding any changes to the study while she is a participant. 
 
In the event that the potential participant is unable to travel to our Fetal Center, she and the father 
of the baby will be counseled over the phone by our multidisciplinary team, which may also 
include the family meeting, prior to signing the informed consent. This conversation will include 
the purpose of the trial ,the aspects of the trial that are experimental, the inclusion/exclusion 
criteria, the random assignment to each treatment, the subjects responsibilities, the alternative 
procedures or courses of treatment that may be available, the anticipated expenses. It will also 
provide the subject the opportunity to inquire about details of the trial and to decide whether or 
not to participate in the trial. All questions about the trial will be answered before informed 
consent is obtained. The consent form will be mailed or securely emailed to them. 
 
The subject will undergo a detailed ultrasound assessment performed by a maternal fetal 
medicine specialist, who is trained to perform the assessment. If, after ultrasound and physical 
examination, the subject still meets all of the criteria, she will be randomized to either receive 
standard care or undergo the FETO intervention. Subjects who meet the eligibility criteria will 
be extensively counseled for each arm. 
 
Neonatal treatments for CDH (such as hernia repair) are not part of the study. Parents will be 
asked to consent on behalf of their child (for neonatal follow-up) before the child is born. 
 
 
5.2 
Inclusion Criteria 
 
FETUSES: 
 
1. Left-sided diaphragmatic hernia 
 
2. Fetuses presenting at the latest at 31 weeks plus 5 days (intervention at the latest on 31 weeks 
plus 6 days). 
 
3. Severity: Predicted moderate pulmonary hypoplasia10. The degree of hypoplasia will be 
determined by the ultrasonographic measurement of the observed to expected lung area to head 
circumference ratio (O/E LHR) in a FETO center at entry to the study, at the latest the day before 
occlusion, but ideally between 26 and 31 weeks for practical reasons. (The O/E LHR is a measure 
that is gestational age independent.) 
 
The following criteria for moderate pulmonary hypoplasia will be used: • O/E LHR 25-34.9% 
(included) irrespective of the liver position, or • O/E LHR 35-44.9% (included) with intrathoracic 
herniation of the liver. 
 
In this group there is a predicted risk for postnatal death of 40% or higher and the risk of 
broncho-pulmonary dysplasia in case of survival is 33% or higher. 
 
4. Chromosomally normal fetus. 
 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
13 
 
5.  Fetus with no major anomalies that would impact the clinical course or outcomes.  
 
MOTHER SUBJECTS: 
 
1. Patients aged 18 years or more, who are able to consent. 
 
2. Singleton pregnancy. 
 
3. Gestation at randomization prior to 31 weeks plus 5 days or so that occlusion is done at the latest 
on 31 weeks plus 6 days. 
 
4. 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. 
 
• 
The O/E LHR will be determined by the FETO centers as follows: 
 
- 
Measurement of the contralateral lung area preferentially by the tracing method at the 
4-chamber view of the heart; if by other method adjusted normative ranges must be used. 
 
- 
Measurement of the head circumference at the standard biparietal view of the head. 
 
- 
The observed lung area: calculation of the LHR as the ratio of the measurements of the 
lung area to head circumference. 
 
- 
The expected lung area is the lung area of a normal gestational age match, as determined 
by the head circumference of the index case in a normogram established for the same 
measurement method (tracing method in this case). A calculator for this will be available 
on the website of the study. 
 
- 
Calculation of the observed over expected lung area. 
 
5. Acceptance of randomization and the consequences for the further management during 
pregnancy and thereafter, this includes the required observation following FETO surgery, which 
lasts approximately 4 weeks after balloon is in place, until balloon is removed. 
 
6. The patients must undertake the responsibility for either remaining close to, or at the TCH FETO 
center, or being able to travel swiftly and within acceptable time interval (within 30 minutes) to 
the TCH FETO center until the balloon is removed. Intended postnatal treatment center must 
subscribe to suggested guidelines for “standardized postnatal treatment.” 
 
7. Provide written consent to participate. 
 
 
5.3 
Exclusion Criteria 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
14 
 
 
1. Maternal contraindication to fetoscopic surgery or severe medical condition in pregnancy that 
make fetal intervention risky. 
 
2. Technical limitations precluding fetoscopic surgery, such as severe maternal obesity, uterine 
fibroids or potentially others, not anticipated at the time of writing this protocol. 
 
3. Preterm labor, cervix length of ≤ 15 mm at randomization or uterine anomaly strongly 
predisposing to preterm labor, placenta previa. 
 
4. Patient age less than 18 years. 
 
5. Psychosocial ineligibility, precluding consent. 
 
 
6. Diaphragmatic hernia: right-sided or bilateral, major anomalies, isolated left-sided outside the 
O/E LHR limits for the inclusion criteria. 
 
7. Patient refusing randomization, to comply with required 4-week observation after balloon 
placement, or to comply with return to FETO center during the time period the airways are 
occluded or for elective removal of the balloon. 
 
8. Patient allergic to latex. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.0 
TREATMENT PLAN 
 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
15 
 
6.1 
Study Schedule – Prior to Delivery for Group I (standard of care) and Group II 
(FETO procedure) 
 
 
 
Study Procedure 
Up until 31w 
+6d (before any 
intervention) 
GROUP I & II 
Plug Procedure 
30w- 31w+6d 
 
GROUP II 
Postsurgical 
 
 
GROUP II 
Monitoring 
between PLUG 
and UNPLUG 
GROUP II 
UNPLUG 
34w- 
34w+6d 
GROUP II 
Monitoring 
after 
UNPLUG 
GROUP II 
Delivery5,6 
 
GROUP   
I & II 
Postnatal 
 
GROUP  
 I & II 
Eligibility 
X 
CDH counseling 
X 
Maternal History 
X 
Maternal Physical 
exam, vital signs 
X 
X 
X 
X 
X 
 
X 
X 
Measurement of 
cervix length 
X 
Family Meeting 
X 
Informed Consent 
X 
Randomization 
X 
Patient Education 
X 
Patient randomized 
to FETO procedure 
Clearance by 
Anesthesia and 
Obstetrical staff 
X 
 
X 
Surgery 
 
X 
 
 
X 
 
 
Hospitalization 
 
X 
X 
 
X 
 
X 
Ultrasound 
X2 
X2 
X2 
X2 
X2 
X2 
 
Comprehensive 
Ultrasound 
X4 
 
 
X4 
 
X4 
 
MRI 
X 
 
 
 
 
 
 
Fetal surveillance by 
biophysical profiles 
and Doppler studies 
 
 
X1,3 
X1,3 
 
X1,3 
 
 
1Fetal surveillance will be performed weekly post balloon placement. 
 
2Serial measurements of sonographic lung volume and LHR will begin within 24-48 hours following surgery and continue weekly 
by targeted ultrasound evaluation. 
 
3Amniotic fluid level and membrane status will also be monitored at weekly intervals. 
 
4Comprehensive ultrasonography for fetal growth will be performed every 1-2 weeks. 
 
5After removal of the balloon, patients will have the choice of delivering at Texas Children’s Hospital Pavilion for Women with 
the CDH managed and repaired at TCH, or returning to their obstetrician for delivery with subsequent repair of the CDH by the 
pediatric surgeons at their referring facility. 
 
6Delivery will be ideally scheduled at term 
6.2 
Study Schedule – Neonate 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
16 
 
 
Age of Neonate 
6 weeks 
Age at Discharged 
6 months 
1 year 
2 years 
Assessing with 
regards to need for 
supplemental O2 
 
X 
X 
X 
X 
Developmental 
Testing 2 
 
X 
 
X 
X 
Pulmonary function 
and volume testing1 
X 
X 
 
X 
 
 
 
1Pulmonary function and volume testing before and after CDH repair, at discharge and one year of age if the necessary funding 
can be secured 
 
2Developmental testing will start at 3 months old 
 
 
In case of fetal or neonatal death: 
 
Permission should be requested for full postmortem examination in all cases of fetal or postnatal 
death. If this is not granted then permission for an MRI or CT examination and histological 
examination of open lung biopsies should be requested. If none of the above is possible the cause 
of death will be determined on the basis of clinical findings. 
 
6.3 
Procedure 
 
EXPECTANT MANAGEMENT GROUP PROCEDURES: 
 
Participants in this arm will not undergo any operation during their pregnancy. The management 
of patients will be at the discretion of the treating physicians and may be decided by clinical needs, 
which may include (but not limited to) ultrasound scans and/or magnetic resonance imaging. Study 
staff will also monitor signs of increased fluid around the baby that might need to be drained in 
order to avoid premature delivery 
 
FETO GROUP PROCEDURES: 
 
Participants in this arm will undergo the FETO procedure as follows: 
 
6.4.1 
Preoperative 
 
Prior to surgery the mother will be given an antibiotic (such as Cefazolin 2 g IV x1, Clindamycin 
900 mg IV, Azithromycin 500 mg IV, and/or Metronidazole 500 mg IV) and if indicated will be 
treated with indomethacin (50mg orally), nifedipine (10 mg orally), Magnesium Sulfate, 
Terbutaline, and pain killers (such as Acetaminophen (500 mg - 1 g orally) and 
Acetaminophen/Hydrocodone). 
 
 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
17 
 
 
 
6.4.2 Anesthesia 
 
The procedure will be performed under spinal anesthesia (2% Chloroprocaine 11mg/kg/dose for 
a maximum of 800mg, Ropivacaine 2.5mg/kg/dose for a maximum of 300 mg) or local anesthesia 
(0.25% Marcaine) with intravenous sedation (Fentanyl or Remifentanil). Regional anesthesia 
choices will be made by the attending anesthesiologist according to standard of care. 
 
The fetus will receive an intramuscular injection of narcotic, anticholinergic (Fentanyl 15 mcg/kg 
and Atropine 20 mcg/kg) and a muscle relaxant (Vecuronium 0.1mg/kg) into her buttocks or any 
extremity using a 22G needle that passes through the maternal abdominal and uterine walls in 
order to provide muscle relaxation, sedation, and analgesia to the fetus. 
 
Depending on the amniotic fluid volume in the uterus an amnioinfusion using a maximum of 1L 
normal saline given by manual injection may or may not be employed to optimize access to the 
fetal nose and mouth. 
 
6.4.3 Balloon Placement 
 
Using standard technique, a 9-12 Fr Teflon cannula will be inserted into the amniotic cavity using 
either a pyramidal trocar or the needle and guidewire Seldinger technique and a Storz endoscope 
or Storz fetoscope will be passed through the cannula into the amniotic fluid.  
 
The scope will be guided into the fetal larynx either through a nostril and then via the nasal 
passage or through the fetal mouth, and then through the fetal vocal cords with the aid of both 
direct vision through the scope and cross-sectional ultra-sonographic visualization. 
 
A detachable latex balloon will be placed in the fetal trachea midway between the carina and the 
vocal cords. 
 
In the event of difficult access to the fetal larynx we will make reasonable attempts to visualize 
the correct area for deployment of the balloon as long as this, in the judgment of the surgeon, is 
safe for both mother and baby. If there is difficulty in accessing the fetal mouth or nose, 
repositioning of the baby or fetoscope/endoscope may be required. 
 
If there is difficulty in seeing the vocal cords, despite having adequate access to the larynx, 
reasonable attempts to reposition the scope within the larynx will be made without exposing 
mother or baby to excessive risk. A maximum of 4 attempts will be made based on a risk benefit 
analysis and medical judgement. Ultimately, this is a difficult situation to quantify and the 
feasibility of the procedure will fall into the realm of the judgment and experience of the surgeon. 
For this multicenter study, however, failure to access the fetal trachea to achieve tracheal occlusion 
has so far been less than 4%; this was solved by a second attempt. If the trachea cannot be accessed 
due to fetal position, the procedure may need to be rescheduled. 
 
The balloon can dislodge spontaneously either by deflation or increasing tracheal diameter. 
Reinsertion of a balloon will be considered if this complication occurs within 10 days of the 
initial insertion. This has so far been very uncommon (4%). 
 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
18 
 
The balloon will be inflated with isosmotic contrast material so that it fills the fetal trachea 
(approximate diameter, 2.2 mm) for a length of at least 2 cm. Studies have shown that this 
maneuver effectively occludes the fetal trachea. In the case of an anterior placenta, every effort 
will be made to avoid placing the sheath and fetoscope/endoscope through the placenta. The 
region of insertion will be visualized with ultrasound prior to insertion to ensure that the placental 
integrity remains intact. Using a combination of amnioinfusion, fetal manipulation (external 
version), and careful placement of the fetoscope/endoscope, avoidance of an anterior placenta can 
be achieved in almost all cases. 
 
In the event that it is impossible to place the fetoscope/endoscope without intentionally 
perforating the placenta, the procedure will be abandoned and attempted at a later time when 
conditions have changed such that the placenta will not be damaged (fetal position change). This 
procedure will not be done transplacentally. 
 
6.4.4 Postoperative Care 
 
Tocolysis: Postoperative tocolysis will be given as needed with either nifedipine (10 mg every 4 
hours orally- for a maximum of two days), indomethacin (25 mg every 6 hours orally), Magnesium 
Sulfate and/or Terbutaline. 
 
If necessary, tocolytic drugs will be administered until 34 weeks. 
 
The mothers will be discharged once stable. Mothers may be contacted weekly by phone for follow 
up. 
 
Patients will be on modified bed rest for the first 2 weeks post discharge, but subsequently allowed 
to graduate to moderate activity if the uterus is quiescent. 
 
All discharged patients will stay within 30 minutes of TCH to permit standardized postoperative 
management and emergent retrieval of the balloon in the event of preterm labor or premature 
rupture of membranes prior to the scheduled removal. 
 
Fetal Monitoring: Fetal surveillance will be performed weekly post balloon placement. 
 
Serial measurements of sonographic lung volume and LHR will begin within 24-48 hours 
following surgery and continue weekly by targeted ultrasound evaluation. 
 
Amniotic fluid level and membrane status will also be monitored at weekly intervals. 
Comprehensive ultrasonography for fetal growth will be performed every 1-2 weeks. 
 
6.5 
Balloon Removal 
 
Balloon retrieval will be planned at between 34+0/7 and 34+6/7 weeks; at the discretion of the 
FETO center. 
 
In the event of a patient relocating after having the balloon placed, despite having committed to 
remain in the area during consent process, she will be asked to return for the removal. Every effort 
to make arrangements for her to be managed by the nearest center capable of an EXIT procedure 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
19 
 
or balloon retrieval (San Francisco or Philadelphia) will be made. 
 
The optimal method for balloon retrieval (fetoscopic versus ultrasound guided percutaneous) will 
be decided case by case by the FETO team based on fetal position and fetal lung response. 
 
Betamethasone (12 mg IM, 2 doses given 24 hours apart) will be given to the mother 
preoperatively to improve fetal lung compliance prior to removal if indicated. 
 
Anesthesia, sedation, and tocolysis for the balloon retrieval will be as described above for the 
balloon placement. 
 
Endoscopic balloon removal: 
 
• 
As with placement of the balloon, fetoscopic/endoscopic retrieval will use a 9-12 Fr 
Teflon cannula loaded with a pyramidal trocar that is inserted into the amniotic cavity. 
 
• 
A Storz endoscope or Storz fetoscope will be passed through the cannula into the 
amniotic fluid and maneuvered into the fetal larynx as noted above. 
 
• 
The balloon will be visualized, punctured, grasped, and removed. 
 
• 
The fetoscope/endoscope and cannula will be then removed. 
 
 
 Ultrasound guided balloon removal: 
• 
Using a 22G needle and continuous ultrasound guidance the balloon will be 
punctured. 
 
• 
The deflated balloon will be flushed from the trachea by the egress of pulmonary 
secretions distal to the occlusion. Recovery post balloon removal: 
• 
The mother will then recover in the usual way and be discharged once stable. 
 
• 
After removal of the balloon, patients will have the choice of delivering at Texas 
Children’s Hospital Pavilion for Women with the CDH managed and repaired at TCH, or 
returning to their obstetrician for delivery with subsequent repair of the CDH by the pediatric 
surgeons at their referring facility. 
 
• 
Given the severity of the CDH, the baby will need to be delivered in a facility that has 
the capability of immediate pediatric surgery services. 
 
Balloon retrieval reattempts:  
In the event of a failed attempt to remove a balloon, depending on the reason for the failure, the 
patient will remain in-house and a re-attempt may be contemplated. If the reason for failure to even 
attempt an endoscopic removal (i.e. no placement of instruments in the amniotic cavity) is inability 
to position the fetus in such a way that access to the mouth is possible, a further attempt may be 
performed the next day or whenever the fetus is in an ideal position in the next 3 days. If fetal 
positioning remains impossible an ultrasound directed needle puncture of the balloon will be 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
20 
 
attempted. In the event that the balloon has not been removed or punctured within the time period 
mandated by the protocol (< 35 weeks) despite reasonable attempts, further attempts will be 
undertaken at the discretion of the PI to remove or puncture the balloon up until the time of delivery. 
The patient will remain in-house until such time as the balloon is removed or punctured. In the 
event that the balloon is still in place at the time of labor or scheduled delivery a planned 
non-emergent EXIT procedure will be performed. 
 
6.6 Delivery 
 
Delivery will be ideally scheduled at term and the baby will be handed off to the pediatric 
surgery team for further management after delivery. 
 
6.6.1  
Scheduled Delivery 
 
Delivery will be elective because of the need to have pediatric subspecialists at the delivery and 
this will be managed according to obstetric principles. A 24 hours a day, 7 days a week, on-call 
team consisting of one of the fetal interventionists and a pediatric surgeon will be available in the 
event of an unscheduled delivery or need for balloon retrieval. If the balloon cannot be removed 
by an in-utero procedure prior to delivery, the on-call team will be present at delivery and will 
coordinate a plan with on- call neonatology for immediate balloon removal at the time of the baby’s 
birth. A neonatal intensive care team is always available at TCH given that the NICU is staffed 24 
hours/day by a neonatologist. Delivery will be vaginal unless cesarean section is indicated. 
 
6.6.2 Unscheduled Delivery for PPROM or Preterm Labor 
 
Should preterm premature rupture of membranes (PPROM) occur prior to 34 weeks, standardized 
practice would entail administration of latency prolongation antibiotics and consideration for 
delivery at 34 completed weeks of gestation. In the event that the membranes rupture prior to 
retrieval or puncture of the balloon the patient will be admitted to TCH for monitoring of her 
status. If she is not contracting prolongation of the pregnancy will be attempted according to 
standard of care. If the balloon can be punctured using a sonographically guided needle this will 
be done at the appropriate time. If it is not possible to do this, and retrieval of the balloon is not 
feasible using the usual fetoscopic technique, the baby will be delivered by EXIT procedure at 
34 weeks or at the time that she goes into labor. Final decisions on management of PPROM will 
be at the discretion of the attending physician, and the decision on delivery would be based on 
standard, accepted maternal and fetal indications. 
 
 
6.7 
Postnatal 
 
Neonates will be assessed at discharge, 6 months, 1 year, and 2 years after delivery with regard 
to their need for supplemental oxygen. 
 
 
    6.7.1 Postnatal Death 
 
Permission should be requested for full postmortem examination in all cases of fetal or postnatal 
death. If this is not granted then permission for an MRI or CT examination and histological 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
21 
 
examination of open lung biopsies should be requested. If none of the above is possible the cause 
of death will be determined on the basis of clinical findings. 
 
 
 
 
 
 
 
7.0 
RISKS 
 
Potential maternal and fetal risks associated with the FETO procedure are outlined below. 
 
7.1 
Mother 
 
Wound infection: Because this is an invasive procedure, there is always the risk of infection 
at the puncture site, or other wound infection. 
 
Chorioamnionitis: Because an instrument is passed from the outside into the cavity of the 
uterus there is always the risk that there could be infection in the amniotic fluid. 
 
Amniotic fluid leak: Puncturing the uterus and membranes could cause amniotic fluid to leak 
out and decrease the overall fluid level. 
 
Pseudomembranous colitis: Certain antibiotics given throughout the procedure may result in 
a slight risk of developing pseudomembranous colitis. 
 
Side effects of tocolytic agents: Tocolytic agents will be given to decrease any uterine 
contractions and the risk for going into preterm labor. The type of tocolytic agent given will 
determine the number and type of side effects that could occur including low blood pressure, 
headache, flushing, dizziness, weakness, depressed deep tendon reflexes, other cardiovascular 
risks, and pulmonary edema. 
 
Placental abruption: Because an instrument will be placed through the abdominal wall into 
the uterus, there is a risk of placental abruption. 
 
Side effects of general and epidural anesthesia: these will be explained in greater detail by the 
anesthesiologist. 
 
Bleeding: Because an instrument will be placed through the abdominal wall and into the uterus 
there is always a risk of significant bleeding from any of the structures that the instrument is placed 
through. 
 
Open surgery: If the procedure caused significant bleeding or damage to internal organs, the 
uterus, or abdominal wall then open surgery might be required to stop bleeding or to repair an 
injury. 
 
Cesarean section: There may be a need to deliver the baby immediately if the baby does not 
tolerate the balloon procedure and develops bradycardia or cardiac decompensation not amenable 
to in-utero resuscitation. 
 
Hysterectomy: If there is bleeding or some injury to the uterus that cannot be controlled, the 
uterus may have to be removed. 
 
Brain Damage: Injury or an anesthetic reaction may cause brain damage.  The risk of this is 
very low. 
 
Death: The procedure or the anesthesia could cause death. The risk of this is very low and to 
date, no woman, to our knowledge, has died from fetoscopic CDH surgery. 
 
Damage to other organs in the abdomen: If there is a need for open surgery, cesarean section 
or other procedures, there could be damage to other organs such as the bowel or bladder. 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
22 
 
 
Failure of balloon positioning: The failure rate of entering the uterus or trachea, or positioning 
the balloon is currently estimated to be 2%. In most cases this can be anticipated, by assessing the 
fetal position and the degree of amniotic fluid volume. It might be wise to delay the procedure in 
such cases. 
 
7.2 
Fetus and Neonate 
 
Placental perforation: Because placental perforation can lead to significant bleeding of the 
mother there is a risk to the fetus. When a mother loses a lot of blood she could die or could have 
such low blood pressure that the baby may not get enough oxygen and may develop brain damage 
or die. 
 
Placental abruption: Membrane separation – anytime an instrument is passed through the 
uterine wall there is a small risk that it could cause bleeding between the membranes and the 
uterine wall. Most commonly a small abruption will not result in a need for delivery, but if there 
is a significant separation, there may be a need to perform a cesarean section and deliver the baby. 
There may also be a need for a blood transfusion for the mother. 
 
Bradycardia and cardiac decompensation: The fetus may not tolerate the FETO procedure and 
may develop bradycardia and cardiac decompensation not amendable to in-utero resuscitation so 
a cesarean surgery may be required.  
 
Intrauterine bleeding: Whenever an instrument passes through the uterine wall, there is an 
increased risk for bleeding which may result in the need to perform a cesarean section and deliver 
the baby. 
 
 Chorioamnionitis: Because an instrument is passed from the outside into the cavity of the 
uterus there is always the risk that there could be infection in the amniotic fluid. 
 
Prematurity/preterm premature rupture of membranes/preterm labor: A 2009 study22 showed 
a risk of Preterm Premature Rupture of Membranes ranging from 11% to 35% depending on 
duration of the FETO procedure. Although the risk of preterm birth and preterm rupture of 
membranes are increased with this procedure, experience to-date suggests that the chance of the 
baby’s survival in cases of severe or extremely severe CDH (as defined by inclusion criteria of 
this study) is significantly increased with a successful tracheal occlusion procedure. 
 
Bronchial perforation – in the event that the balloon migrates into the bronchus during 
inflation there is a risk that the bronchus can be perforated or ruptured and the balloon extruded 
into the pleural space. This has happened once in our experience and the bronchus healed without 
complication. 
 
Bronchial abrasion – the endoscope or instruments placed through the scope (needle or 
grasper) could cause abrasions or perforation of the bronchus. 
 
Pleural effusion – irrigating the airways to keep them open could cause a pleural effusion if 
there is a bronchial rupture or communication between the bronchus and the pleural cavity. 
 
Vocal cord paresis/paralysis: Placing the balloon through the trachea creates the risk of 
damage to the developing vocal cords. 
 
Tracheomalacia (the collapse of the breathing tube) tracheomegaly (abnormally enlarged 
trachea): There is a risk of deformation of the fetal trachea and a theoretical risk of rupture of the 
fetal trachea from the balloon. There is also a risk of weakness to the cartilage of the airway that 
may create a floppy and/or unstable airway.  
 
Fetal hydrops: There is a theoretical risk that the baby could become hydropic from significant 
lung expansion. If this does occur, the balloon will be removed.i 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
23 
 
 
Chorioamniotic separation: Occasionally there may be leakage between the amnion and the 
chorion, which would allow amniotic fluid between the two which can increase the risk of leakage 
of fluid vaginally. Usually this will resolve spontaneously without complication but occasionally 
this may result in premature rupture of membranes. 
 
Failure of the balloon to work: There is a chance that the balloon could migrate from the place 
in which it was placed and be ejected from the windpipe. 
 
Migration of the balloon: It is possible that the balloon could move further into the baby’s 
lungs than where it was placed. If this happens it will not work and will have to be removed after 
the baby is born. 
 
Inability to remove the balloon before delivery or after birth: There is a risk the baby could 
be delivered without there being time or opportunity for the balloon to be removed before delivery. 
There is the risk that there may be a delay in removing or an inability to remove the balloon that 
could results in long term brain damage or death of the baby. In a 2009 study22, the incidence of 
death due to complications of balloon removal was 5%. All of the failures where when the retrieval 
was attempted in a non-FETO center. We, and investigators cited, believe this risk can be reduced 
by elective balloon removal at or before 34 weeks gestation, anticipation of the need to puncture 
the balloon externally, and having the patient reside near the hospital throughout the duration of 
the tracheal occlusion. 
 
Brain Damage: The procedure could cause injury to the brain. 
 
Death: There is always the risk that the procedure could cause injury to the baby and cause 
him or her to die. 
 
7.3 
Steps to Minimize Risks 
 
Fetal risks: 
 
The fetal procedures will be performed by specialists in fetal medicine with extensive experience 
in fetoscopy as well as FETO. 
 
This is not an open study and eventual extension of the study consortium will be made dependent 
on a decision of the steering committee. 
 
Maternal risks: 
 
 
Maternal infectious complications: prophylactic administration of intravenous antibiotics. 
 
 
Complications and side effects of epidural analgesia (if applied): the procedure will be 
carried out or under the direct supervision of an expert in this procedure. 
 
 
Preterm labor induced by the intervention: prophylactic administration of tocolytics. 
 
 
Maternal uterine / placental bleeding: ultrasound guidance of trocar insertion.  
 
The FETO procedure and neonatal management of the patients will be undertaken in major 
university hospitals with multidisciplinary teams of experts familiar with both pre- and postnatal 
management of CDH and FETO. 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
24 
 
 
 
 
7.4 Risk Balance Summary 
 
Severe CDH (O/E LHR of less than 25%) is associated with high rates of mortality (more than 
70%) and morbidity. In such cases FETO has been introduced as an alternative to the options of 
termination of pregnancy and expectant management. There is evidence from experience of more 
than 150 cases treated by FETO that the survival rate is improved. There is also evidence that this 
increased survival is not at the expense of an increased short term morbidity. In contrast survivors 
seem to have less morbidity than can be expected based on severity (O/E LHR). 
 
The rationale for the proposed study is that in cases of moderate CDH, FETO in the third trimester 
would reduce morbidity and may increase survival. 
 
On the basis of our current experience with FETO there is no apparent serious risk for the mother. 
The main risk for the fetus is iatrogenic prematurity which in this study is minimized by performing 
the procedure in the third trimester. 
 
A randomized clinical trial is the only way to answer this question. If the results are favorable, we 
will offer a new therapeutic modality to future patients. If not favorable, we will have prevented 
untimely spread of this new operation that would have claimed benefits without scientific basis. 
 
By  
8.0 
BENEFITS 
 
The hypothesis is that prenatal intervention will improve morbidity, lung development and growth 
or survival in patients with isolated, moderate CDH. We do not know at this stage of the trial 
whether in fetuses with moderate diaphragmatic hernia FETO is beneficial or not. The results of 
this study will help us to manage moderate diaphragmatic hernia better in the future. 
 
Although the FETO procedure has shown promise as an intervention for severe and extremely 
severe CDH, moderate CDH has not been studied adequately in the United States. This study will 
help extend current trials of FETO to include the population of the United States. 
 
Even though the FETO procedure creates risks, the chance of the baby's survival is still probably 
much better with a successful FETO procedure. We believe the benefits will outweigh the risks. 
Risk to benefit ratio is favorable. 
 
9.0 
STATISTICAL CONSIDERATIONS 
 
9.1 
Sample Size and Precision 
 
Primary endpoint has been changed to survival at discharge. Initially, it was estimated that 55% of 
patients in control arm would be alive at discharge. Given that we have decided that an absolute 
increase in survival rate of 20% in FETO arm would be an improvement, clearly clinically relevant 
and realistic, we'd then assume a survival rate of 75% in FETO arm to determine sample size. An 
absolute increase of 15% would still be acceptable. Although it is of importance in this trial to 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
25 
 
avoid continuation when there is evidence of effectiveness of FETO, it'd be undesired to 
underestimate the required sample size because of an overestimated survival rate in control arm. 
Therefore, we decided to use data from administrative review to estimate sample size. This 
resembles the internal pilot study method by Friede and Kieser.23 Using the overall average 
survival rate over the two groups (blinded data), which was 50.1%, we'd therefore use 40% vs 60% 
survival rate in control vs FETO arm. Based on blinded procedure, the size of the ‘internal pilot’, 
and the fact that an overall response rate of 50% maximizes required sample size 24 there is no 
need to adjust type I and II error rates. 
 
We use a group sequential design with overall one-sided alpha of 2.5% and a power of 80%. 
Formal interim analyses are scheduled for efficacy only, although the DMC retains the right to 
stop the trial for clear futility. We adopted the O’Brien-Fleming method25 to derive critical 
boundaries to stop the trial for efficacy. Five interim analyses are planned, after 40, 60, 70, 80, and 
90% of sample size at final analysis. Using the abovementioned parameters and z-test for the 
difference in proportions, critical boundaries are obtained using PROC SEQDESIGN in SAS v9.3 
(SAS Institute, Cary, USA). 
 
 
 
Analysis 
N per arm 
Efficacy boundary 
Difference in 
survival rates 
p-value 
Interim 1 
40 
0.365 
0.0005 
Interim 2 
59 
0.243 
0.0036 
Interim 3 
69 
0.209 
0.0064 
Interim 4 
79 
0.182 
0.0099 
Interim 5 
89 
0.162 
0.0140 
Final 
98 
0.146 
0.0186 
 
 
When deriving a sample size plan including formal boundaries to stop for futility, the overall 
sample size hardly changed. As a result, we left stopping for futility at the discretion of the Data 
Safety Monitoring Committee (DSMC). 
 
The main secondary endpoint is survival without oxygen dependency at 6 months. A hierarchical 
testing procedure is suggested, where a formal hypothesis test for this endpoint will be undertaken 
only when statistical significance for the primary endpoint has been declared. Given the 
assumption of 40% vs 60% survival at discharge, we define 35% vs 55% as a related relevant 
difference between the groups. Then, 96 patients per group are needed to obtain 80% power at an 
upper one-sided alpha of 2.5%. Given that the above group-sequential method allows early 
stopping for efficacy, this number of patients may not be reached. Therefore, the DSMC retains 
the right to continue including patients in the FETO arm after an interim bound for efficacy has 
been reached in order to secure power at a chosen level. Given the O’Brien- Fleming boundaries 
described above, we computed for each interim analysis the number of patients required in the 
FETO arm to achieve 70, 75, or 80% power. The number of patients in the control arm is fixed at 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
26 
 
the number that is included at the interim analyses where the efficacy boundary was reached. For 
example when the trial reached the efficacy boundary for the primary endpoint at the third interim 
analysis, there are 69 patients in each arm. Then, to achieve 80% power for the main secondary 
endpoint, 89 additional patients are needed in the FETO arm. In total, there would then be 69 
patients in the control arm and 158 patients in the FETO arm. When the trial would be stopped at 
the first interim analysis, numbers show that it is not feasible to continue with the FETO arm in 
order to obtain an acceptable power level. In case no additional patients are needed, there is at 
least 80% power for the main secondary endpoint is desired. 16 more patients are needed in FETO 
arm. 
 
 
 
Analysis where 
stopped for efficacy 
N per arm 
Additional patients needed in FETO arm 
80% power 
75% power 
70% power 
Interim 1 
40 
>1000 
>1000 
601 
Interim 2 
59 
195 
94 
48 
Interim 3 
69 
89 
43 
16 
Interim 4 
79 
44 
13 
0 
Interim 5 
89 
16 
0 
0 
Final 
98 
0 
0 
0 
 
 
 
9.2 
Proposed Analysis 
 
Achieved significance rule: 
 
The initially anticipated increase in survival at discharge was 20%, yet at the moment of design of 
the trial no data on outcomes on percutaneous FETO with a balloon for moderate hypoplasia were 
known. 
 
There is no stratification prior to or post randomization. 
 
Null Hypothesis: The null hypothesis to be tested is that there is no difference in survival and in 
number of survivors requiring supplemental oxygen at the age of 6 months between fetuses 
managed expectantly during pregnancy versus those undergoing antenatal therapy. 
 
Stopping rule: 
 
The trial will be discontinued if there is a significant difference for the primary outcome measure 
(survival at discharge) at the foreseen time points of analysis. The DSMC, however, may consider 
continuation of the study in an adapted design to determine whether significance can be achieved 
for the co-primary variable (oxygen need at 6 months of life). 
 
The DSMC is a group of physician and ethicist experts from Baylor College of Medicine who are 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
27 
 
not otherwise involved with the study. The DSMC will assess, on an ongoing basis, the study 
conduct and monitor the safety of current and future patients as well as the validity and scientific 
integrity of the trial. The DSMC will meet to review data and will recommend continuation, 
modifications to the study design or discontinuation of the study. The DSMC will advise the 
Principal Investigator (PI) and study staff of any issues after the meetings. 
 
Primary Analysis:  
 
The primary analysis will compare the proportion of subjects who are surviving till discharge and 
the survivors requiring no oxygen at 6 months of age. The primary analysis will be based on the 
intent-to-treat principle. 
 
 
Secondary Analyses: 
 
A secondary analysis will compare the proportion of subjects that survived until discharge from 
the hospital in the two treatment groups, and those free of oxygen need at 6 months of age with an 
as-treated (“per protocol”) analysis. 
 
Data will also be analyzed depending on the case load at each postnatal treatment center, i.e. 
treatment centers with a case load above, respectively under 6/year. 
 
Whenever possible, analysis of outcomes of non-randomized subjects will be made to provide the 
most complete synthesis of the data. We will keep data from any non-randomized patient that 
receives a FETO balloon on a compassionate basis and we will analyze the data in a separate 
analysis. 
 
Methods of analysis 
 
We will analyze the primary and co-primary endpoints with the z-test for unpaired proportions 
(equal to the Pearson chi-square test) using a one-sided alpha of 2.5%. To control for multiplicity, 
we will use a hierarchical approach. If the trial is stopped for efficacy for the primary endpoint 
(survival at discharge) at one of the interim analyses based on the z-test, we will evaluate the co-
primary endpoint (survival without oxygen dependency at 6 months) with the same test. As 
explained in the sample size section, the DSMC first decides whether more patients in the FETO 
arm have to be recruited in order to reach the required sample size. If it is not feasible to reach the 
required sample size, we will not perform the z-test for the co-primary endpoint. 
For the primary and co-primary endpoints, we will compute the difference in proportions between 
the study arms as well as the relative risk, both with a standard two-sided 95% CI. These results 
are at least as important as the determination of statistical significance based on the z-test. 
For the secondary endpoints, we will not perform statistical testing. For categorical endpoints, we 
will compute relative risks and differences in proportion with their respective 95% confidence 
intervals. For continuous endpoints, we will compute 95% confidence intervals on the difference 
in medians using the percentile bootstrap method. We will analyze time-to-event outcomes (days 
to discharge from neonatal intensive care unit, days until end of ventilatory support, days until 
release from ECMO support, days until full enteral feeding) with a 95% confidence interval for 
the median cumulative incidence of the event, with death used as a competing event 26 
 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
28 
 
  
 
 
 
Sources of error:  
 
 
The power of the study will be adversely affected by patient’s non-compliance with the 
randomly assigned regimen. 
 
 
The number of centers recruiting for postnatal treatment cannot be anticipated at this time. 
This will by definition be uncontrollable, and it may influence the outcome in either group. This 
is an accepted source of error by the investigators because it is a clinical reality (this is an 
effectiveness or pragmatic trial). The organizers do not have funding, neither the power nor 
logistics for having all postnatal management at one location. Guidelines for standardization of 
postnatal treatment are therefore being issued (Appendix I), which will reduce the impact of this 
source of error. An important source of error may also be case load at each of these participating 
centers. For that reason a post hoc analysis will be made according to the case load during the 
study period. 
 
 
Subjects randomized to postnatal care who seek fetal intervention elsewhere, may reduce 
study power. The consortium of FETO centers will not perform FETO in patients eligible for the 
present study, outside the herein described RCT. This seems ethical as FETO-treatment for this 
particular severity group so far has not been offered by the FETO consortium, and to their 
knowledge neither elsewhere. 
 
 
The extent to which non-FETO centers will carry out FETO in patients that are eligible 
for the herein proposed RCT cannot be estimated. Maximum efforts will be done to reduce the 
number of such centers. One method is to include those centers based on the criteria outline below. 
During the course of this study, other prenatal treatment centers have expressed their interest to 
join this study. If they are not or less experienced, this may be a source of error. The steering 
committee has met on this issue and has defined empirically criteria for eligibility for study 
participation, following which they may apply locally for ethics committee approval and 
ultimately they may participate to the present study under the same conditions as herein. 
 
 
Preterm pre-labor rupture of the membranes and as a consequence preterm labor prior to 
in utero reversal of the occlusion, with as a consequence “incomplete” prenatal therapy as well as 
problems directly due to the inability or difficulties to remove the balloon, may result in lower 
than expected survival chances. When this happens, it will cause delivery at one of the FETO 
centers, therefore leading to a higher than expected number of babies delivered at these 
institutions. However this is inherent to the prenatal therapy and not avoidable. A separate 
secondary analysis may be done as to judge on the biological effect of the complete course of 
prenatal therapy (balloon insertion and balloon removal followed by birth in the un-occluded 
state), but again, results will be reported on an intention to treat - basis. 
 
 
In the fetal treatment arm there is the potential of patients not complying during the period 
the airways are plugged, presenting in an emergency at their local center, or for whatever reason 
not returning to the FETO center for balloon removal. This may adversely affect the outcome in 
the treatment group, lead to a higher than expected death rate in that arm. It could only be 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
29 
 
discounted by post hoc exclusion. This will however not be done, as it is considered as an inherent 
risk of prenatal therapy. Such an effect may however be documented in a secondary analysis as 
described above. 
 
 
Prenatal medical imaging techniques may fail to recognize a concomitant congenital 
anomaly that is therefore only diagnosed after birth. Since serious associated anomalies are an 
independent predictor of outcome, and their numbers should be low, patients may not be equally 
distributed in both treatment arms. These patients will be excluded post hoc from analysis. It will 
include patients with serious genetic anomalies (not known at the time of FETO), undiagnosed 
structural cardiac or other structural anomalies that directly compromise neonatal outcome. 
Analysis of cases to be excluded will be overseen by the Data Monitoring and Safety Committee 
(also referred to as Oversight Committee). 
 
 
Adjustments for error sources: The aforementioned error sources will be dealt with, in 
part, by following all subjects eligible for the primary outcome regardless of whether the subject 
consents to randomization or refuses to comply with the assigned randomization. Since the 
magnitude of these effects cannot be known in advance, the Steering Committee will be charged 
with examining randomization refusal rates and refusal of randomized treatment. They may 
suggest to modify the sample size, the study design, or terminate the study for inadequate 
accrual/power/data quality/safety issues in consultation with the Oversight Committee, who has 
the final word about this. 
 
 
Missing data for the primary endpoints are very unlikely. In addition, the DSMC will 
review data entry and quality at every interim analysis such that we will detect eventual issues 
quickly such that we can act appropriately to ensure complete data. Inspection of data quality at 
the first two interim analyses confirms that missing values are very rare. If there is a missing value 
for the primary endpoint of survival at discharge, we will exclude the case from the study. If there 
is a missing value for the co-primary endpoint of survival without oxygen dependency at 6 
months, we will not use the case for the analysis of the co-primary endpoint. 
 
 
If there is a missing value or for any secondary endpoint, we will exclude the case for the 
analysis of that specific endpoint. If we observe more than 10% missing values for a secondary 
endpoint, we will not analyze this endpoint. There is no need for statistical imputation of missing 
data. 
 
Outcome measures 
 
Primary outcome measures: 
 
• Survival until discharge 
 
• Supplemental oxygen at 6 months of age. 
 
 Secondary postnatal outcome measures: 
 
• Grade of oxygen dependency (grade 0-III; definition as above) 
 
• Occurrence of severe pulmonary hypertension (yes / no; based on evidence on cardiac ultrasound 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
30 
 
of predominant unidirectional right to left shunt) in the neonatal period 27 
 
• Need for ECMO support for centers offering it (yes / no) 28 
 
• Defect size as per classification by the CDH study group 
 
• Number of days in neonatal intensive care unit (days); (if death occurs; day of death) 
 
• Number of days of ventilatory support (days) ; 
 
• Presence of periventricular leucomalacia at ≤2 months postnatally (yes / no) 
 
• Presence of neonatal sepsis (yes/no) 
 
• Presence of intraventricular hemorrhage (grade 0-III) 
 
• Presence of retinopathy of prematurity (grade III or higher) 
 
• Number of days till full enteral feeding (days) 
 
• Presence of gastro-esophageal reflux (above one third of the esophagus on clinically indicated 
radiologic study) 
 
• Day of surgery (days) 
 
• Use of a patch (yes/no) 
 
Secondary prenatal outcome measure: 
 
• Lung volume as serially measured by 2D-ultrasound and/or fetal MRI (o/e LHR, o/e total lung 
volume) 
 
• Liver position; in case of liver herniation, the liver-to-thorax volume.  
 
Secondary longer term outcome variables: 
 
• Pulmonary function and volume testing before and after repair, at discharge, and at one year of 
age 
 
• Neurodevelopmental milestones at discharge, 12 months and 2 years (AGES and STAGES, 
validated English and Spanish questionnaires). Use of this questionnaire does not depend on 
additional funding. 
 
• Death at 2 years (due to either primary illness or other causes) 
 
9.3 
SAFETY EVENTS/Reporting 
 
The Investigator is responsible for the detection, documentation and follow-up of all safety events 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
31 
 
meeting the criteria and definitions outlined below in subjects enrolled on this protocol. For 
purposes of this protocol subjects can be mother, fetus, and/or infant/child up to 2 years of age. 
 
9.3.2 
Definition of Safety Event 
 
A safety event is any untoward medical occurrence, unintended disease or injury or any untoward 
clinical sign (including a clinically significant abnormal laboratory finding) in subjects whether or 
not related to the investigational devices or to the procedures involved (including any procedure 
in the clinical study protocol). 
 
9.4 
Not Device or Procedure Related – Adverse Event (AE) 
 
Safety events which are not related to the investigational device or the procedure to place the 
balloon are referred to as Adverse Events (AEs). 
 
9.5 
Device or Procedure Related – Adverse Device Effect (ADE) 
 
An Adverse Device Effect (ADE) is a safety event related to the use of an investigational medical 
device. This includes any safety event resulting from insufficiencies or inadequacies in the 
Instructions for use, the deployment, placement, operation, or any malfunction of the 
investigational medical device(s). This includes any event that is a result of a use error or 
intentional misuse. 
 
9.6 
Definitions of Serious Safety Events 
 
A safety event is serious if the event: 
 Led to a death. 
 Led to a serious deterioration in health that either: 
 Resulted in a life-threatening illness or injury, or 
 Resulted in an injury or permanent impairment of a body structure or a body function, or 
 Required in-subject hospitalization or prolongation of existing hospitalization, or 
 Resulted in medical or surgical intervention to prevent life threatening illness. 
 Led to fetal distress, fetal death or a congenital abnormality or birth defect. 
 
This includes deficiencies that might have led to a serious adverse event if: 
 
 
Suitable action had not been taken or 
 
Intervention had not been made or 
 
A planned hospitalization for a pre-existing condition, or a procedure required or described as a 
possibility by the protocol as part of procedures performed in regular clinical care, without a 
serious deterioration in health, is not considered to be a serious safety event. Events that occur 
after birth that are related to the underlying condition (CDH) and which are unrelated to this 
protocol (such as a complication with ECMO or other forms of neonatal treatment for CDH) will 
not be considered to be a serious safety event of the balloon placement. 
 
9.7 
Not Device or Procedure Related – Serious Adverse Event (SAE) 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
32 
 
 
A Serious Adverse Event (SAE) is a safety event that has resulted from a serious safety event as 
assessed by the investigator and is not device or procedure related. 
 
9.8 
Device or Procedure Related – Serious Adverse Device Effect (SADE) 
 
A Serious Adverse Device Effect (SADE) is a device or procedure related safety event that has 
resulted from a serious safety event and is an event by its nature, incidence, severity or outcome 
that has been previously identified in the Risks section (Section 7.0) of this protocol. 
 
9.9 
Unanticipated – Unanticipated Adverse Device Effect (UADE) 
 
An Unanticipated Adverse Device Effect (UADE) is defined as any serious adverse effect on 
health or safety or any life-threatening problem or death caused by, or associated with, the 
Investigational device(s), if that effect, problem, or death was not previously identified in nature, 
severity, or degree of incidence in the clinical study protocol, Report of Prior Investigations, or 
application (including a supplementary plan or application), or any other unanticipated serious 
problem associated with an investigational product that relates to the rights, safety, or welfare of 
subjects (21 CFR 812.3(s)). 
 
9.10 
Safety Event Assessments 
 
All safety events will be monitored in conjunction with the study assessment schedule and will be 
reported to the IRB and FDA on an annual basis in the IDE Progress Report. 
 
Unanticipated events will be collected, assessed and reported according to SOP P-15-XX-
Documentation and Reporting of Serious Adverse Events and Unanticipated Problems.     
 
The Sponsor (IDE holder) will be responsible for reporting all reportable unanticipated events to 
the appropriate regulatory agencies (e.g., IRB, FDA) as per each agency’s individual reporting 
requirements and within that agency’s required time frame. 
 
 
9.11 
Assessment of Causality 
 
The Investigator will assess the relationship between each safety event and both the device and the 
procedure using the definitions listed below. Note that a safety event may be related to the device 
or the procedure or both. The Investigator should assess causality of each safety event to the device 
independent from the procedure and to the procedure independent from the device. 
 
9.12 
Investigational Product 
 
 
Definitely Related: The safety event has a strong temporal relationship to the device. The 
safety event is most likely explained by device. The safety event is consistent with a known 
response to the device. Another etiology is unlikely or significantly less likely. 
 
Probably Related: The safety event has a strong temporal relationship to the device. The 
safety event is more likely explained by the device than by another cause. 
 
Possibly Related: The safety event has a reasonable temporal relationship to the device. 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
33 
 
The safety event could have been due to another equally likely cause. 
 
Not Related: The subject did not receive the device OR the safety event has no temporal 
relationship to the device OR the safety event has a much more likely alternate etiology OR the 
safety event is due to an underlying or concurrent illness or effect of another drug. 
 
9.13 
Procedure 
 
 
Definitely Related: The safety event has a strong temporal relationship to the procedure. 
The safety event is most likely explained by the procedure. 
 
The safety event is consistent with a known response to the procedure. Another etiology is 
unlikely or significantly less likely. 
 
Probably Related: The safety event has a strong temporal relationship to the procedure. 
The safety event is more likely explained by the procedure than by another cause. 
 
Possibly Related: The safety event has a reasonable temporal relationship to the procedure. 
The safety event could have been due to another equally likely cause. 
 
Not Related: The subject did not have the procedure OR the safety event has no temporal 
relationship to the procedure OR the safety event has a much more likely alternate etiology OR 
the safety event is due to an underlying or concurrent illness or effect of another drug. 
 
Even in situations in which minimal information is available for the initial safety event, it is 
important that the Investigator always make an assessment of causality for every event. The 
causality assessment is one of the criteria used when determining regulatory reporting 
requirements. The Investigator may change his or her opinion of causality in light of follow-up 
information and amend the report accordingly. 
 
All safety events must be followed until they are resolved, the condition stabilizes, the events are 
otherwise explained, or the subject is lost to follow-up. 
 
9.14 
Serious Safety Events, Reporting Requirements 
 
Once the Investigator determines that a safety event meets the definition of serious (SAE or 
SADE), the Sponsor-Investigator will provide an assessment within 5 days of becoming aware of 
the event. 
 
9.15 
Unanticipated Safety Event Reporting Requirements 
 
If the Investigator determines that a safety event meets the definition of unanticipated (UADE), 
the Investigator or their designee must notify the IRB and FDA within 10 days of becoming aware 
of the event. 
 
An evaluation of a UADE will be immediately conducted and results of the evaluations will be 
reported to FDA and all reviewing IRBs in accordance with the applicable national and local 
regulations.  
 
9.16 
Follow-up of Safety Events 
 
SAE/SADE/UADEs will be followed until the event resolves, the condition stabilizes, the event is 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
34 
 
otherwise explained, the subject is lost to follow-up or death occurs.  
 
New or updated information will be recorded on a follow up Serious Adverse Event Report. 
 
10.0 
INFORMED CONSENT and RISKS  
 
All subjects must sign an informed consent document consistent with local institutional and 
Federal guidelines stating that they are aware of the investigational nature of this protocol and of 
the possible risks of treatment.  Further, subjects must be informed that no efficacy of this therapy 
is guaranteed, and that unforeseen risks may occur.  Full confidentiality of patients and patient 
records will be provided according to institutional guidelines. The subjects or their families will 
not receive any payment for participation in this study. No charge will be made for the FETO 
procedure being performed as part of this study. 
 
10.1 
Changes to the protocol and/or informed consent form 
 
Changes to the research covered by this protocol must be implemented by a formal protocol 
amendment. Protocol amendments must not be implemented without prior IRB and FDA approval. 
When the change(s) involve only logistic or administrative aspects of the study, the IRB only needs 
to be notified. During the course of the study, in situations where a departure from the protocol is 
unavoidable, the Investigator will contact the FDA for approval. Except in emergency situations, 
this contact should be made before implementing any departure from the protocol. 
 
10.2 
Withdrawal of informed consent 
 
Withdrawal of consent from a study means that the subject does not wish to receive further 
protocol-required therapies or procedures, and the subject does not wish to or is unable to continue 
further study participation in the study. The investigator is to discuss with the subject appropriate 
procedures for withdrawal from the study.  
 
11.0 
TRIAL MONITORING PROCEDURES 
 
11.1 
Institutional Monitoring 
 
The study will be monitored by the Fetal Therapy Board at Texas Children’s Hospital.  The Fetal 
Therapy Board is an institutional board established to examine ethical and clinical aspects of this 
type of procedures. The Board provides written concurrence after cases are reviewed to proceed 
with these activities. None of the members of the Fetal Therapy Board are professionally involved 
in the cases under consideration. The Board membership is comprised of physicians who have the 
education, training and expertise needed to monitor this protocol and data as well as a medical 
ethicist. 
 
11.2 
Written Monitoring Procedures 
 
Case report forms are utilized to record study related data, including any procedural complications 
such as failed balloon placement or failed balloon retrieval, as well as surgical or anesthesia 
complications.  Summary statistics of these data will be reviewed by the Fetal Therapy Board on 
an annual basis. 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
35 
 
 
Maternal and neonatal outcomes will be recorded. Neonatal outcomes will include survival of the 
fetus, short-term measures of neonatal pulmonary morbidity, including the need for extracorporeal 
membrane oxygenation and the duration of neonatal ventilatory support and administration of 
supplemental oxygen; gastrointestinal morbidity; neurologic morbidity; survival to discharge from 
the hospital; and the duration of hospitalization. Assessments of other measures of long-term 
morbidity, including the need for supplemental oxygen, rates of recurrent infection, the need for 
repeated hospitalization, as well as neurodevelopmental outcomes, will be performed. 
 
Maternal morbidity will also be assessed in terms of incidence of preterm delivery (spontaneous 
or indicated), cesarean section rate, length of hospitalization after the FETO procedure, length of 
hospitalization after balloon removal, post procedure vaginal bleeding, incidence of placental 
abruption, incidence of post-procedure rupture of membranes, incidence of oligohydramnios, and 
incidence of chorioamnionitis. 
 
The Fetal Therapy Monitoring Board will monitor this study to ensure that the investigation is in 
accordance with the principles of Good Clinical Practice and that the investigators follow the 
protocol without any major deviations. The Fetal Therapy Monitoring Board will follow the 
progress of the trial including patient recruitment, data collection, management, and patient/infant 
outcomes. 
 
The Fetal Therapy Monitoring Board will also review the annual and final IDE progress reports 
prior to submission to the FDA. 
 
 
11.3 
Monitoring, Audits and Inspections 
 
The Investigator will assure that local study staff cooperate with monitoring and audits. The 
Investigator agrees to allow auditing of all essential clinical study documents and inspection by 
the FDA or other appropriate regulatory authorities. Auditing visits will be scheduled with the 
appropriate staff at mutually agreeable times as applicable. 
 
 
12.0 
REPORTING REQUIREMENTS 
 
12.1 
Registration 
 
The research coordinator registers all subjects in the CDH-TOTAL enrollment log. The following 
forms/actions are completed: 
 
Eligibility Checklist 
 
Informed Consent 
 
Case Report Form (CRF) 
 
As part of the randomization process, patient data are entered in the centralized electronic 
database at www.eurocdh.org. 
 
12.2 
Each Case 
 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
36 
 
There will be a report generated on each case within 2 days of each procedure and within 90 days 
of delivery setting forth the circumstances and outcomes of mother and baby. If there are no serious 
adverse events, this information will be reported at the time of the annual IDE report. 
 
12.3 
Access to Original Records 
Regulatory authorities expect that monitors, auditors, and representatives of national and 
international government regulatory agency bodies have access to original source documentation 
to ensure data integrity. “Original” in this context is defined as the first documentation of an 
observation and does not differentiate between hard-copy and electronic records. 
 
12.4 
Records Retention 
 
Health Insurance Portability and Accountability Act of 1996 - The Investigator agrees to comply 
with all applicable federal, state, and local laws and regulations relating to the privacy of subjects’ 
health information, including, but not limited to, the Standards for Individually Identifiable Health 
Information, 45CFR Parts160 and164 (the Health Insurance Portability and Accountability Act of 
1996 privacy regulation). The Investigator shall ensure that study subjects authorize the use and 
disclosure of protected health information in accordance with the privacy regulations of the Health 
Insurance Portability and Accountability Act. 
 
12.5 
Data Security 
 
Access to the data will be strictly controlled. 
 
 
12.6 
Storage 
 
Investigational devices must be received by a designated person at the study locations, handled 
and stored safely and properly, and kept in a secured location to which only the investigator and 
designated staff have access to. Upon receipt, all Investigational Devices should be stored in a 
locked and secured location. 
 
The investigator or designated staff must maintain an accurate record of the shipment and use of 
the research system in an accountability ledger. Monitoring of the study accountability will be 
performed periodically and at the completion of the trial. 
 
Medical records of research study participants are securely stored according to federal and legal 
requirements.  
 
13.0 
REGULATORY REQUIREMENTS 
 
13.1 
Ethical conduct of the study and regulatory review 
 
The Investigator agrees to adhere to the instructions and procedures described in the protocol and 
to conduct the study in accordance with the Code of Federal Regulations (21 CFR Parts 11, 50, 
54, 56, 312, 314, and 320), which originate from the ethical principles laid down in the current 
revision of the Declaration of Helsinki, GCP, and policies and procedures as outlined by the ethical 
requirements for IRB review and informed consent forms. 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
37 
 
 
A copy of the protocol, proposed informed consent form and other written subject information, 
must be submitted to the IRB for written approval before recruitment of subjects into the study 
and shipment of investigational devices can begin. 
  
The Investigator must submit and, where necessary, obtain approval from the IRB for all 
subsequent protocol amendments and changes to the informed consent document. Subjects who 
may have already been consented with the older consent form and for whom an amended consent 
form is relevant must be re-consented using the approved, amended forms. The investigator is to 
notify the IRB of deviations from the protocol or serious adverse events occurring at the site and 
other adverse event reports received from the device manufacturer (if applicable), in accordance 
with local procedures.  
 
The Investigator is responsible for obtaining annual IRB approval /renewal throughout the duration 
of the study. 
 
13.2 
Study Management 
 
The Investigator will assure proper implementation and conduct of the study will be performed 
according to the currently approved study protocol.  
 
 
13.3 
Training of study site personnel 
 
The Investigator will assure research activities, including those study-related duties delegated, will 
be performed by appropriately qualified individuals. The Investigator will assure that study staff 
will demonstrate due diligence in recruiting and screening study patients. 
 
13.4 
Financial Disclosure 
 
Participating Investigators will provide a signed Financial Disclosure Form and Investigator 
Agreement. 
 
13.5 
Confidentiality 
 
All information provided by and all data and information generated as part of the study (other than 
a subject’s medical records) will be kept confidential by the Investigator and other site staff. This 
information and data will not be used by the Investigator or other site personnel for any purpose 
other than conducting the study. These restrictions do not apply to the following: 
 
1) Information that becomes publicly available through no fault of the Investigator or site staff;  
2) Information that must be disclosed in confidence to an IRB solely for the evaluation of the study 
results; 
3) Information that must be disclosed in order to provide appropriate medical care to a study 
subject; or  
4) Study results that may be published. 
 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
38 
 
 
 
Appendix A: Medications Used in this Protocol 
 
Mother: 
 
Balloon placement and removal: 
 
Cefazolin 2 gm IV x1  
 
Clindamycin 900 mg IV 
 
Azithromycin 500 mg IV 
 
Indomethacin (50 mg orally)  
 
Nifedipine (10 mg orally) 
 
Chloroprocaine 2% (11mg/kg/dose to a maximum of 800 mg) 
 
Ropivacaine (2.5 mg/kg/dose to a maximum of 300 mg) 
 
Marcaine (0.25% local anesthesia) with intravenous sedation of either Fentanyl IV or 
Remifentanil IV sedation 
 
Betamethasone (12 mg IM, 2 doses given 24 hours apart) may be given to the mother 
preoperatively to improve fetal lung compliance prior to removal only. 
 
Post-Surgery after balloon placement and removal: 
 
Postoperative tocolysis will be given as needed with either nifedipine (10 mg every 4 hours 
orally) or indomethacin (25 mg every 6 hours orally) for a maximum of two days 
 
 
Neonate: 
 
Balloon placement and removal: 
 
Fentanyl 15 mcg/kg narcotic, Atropine 20 mg/kg anticholinergic and Vecuronium 0.1 
mg/kg Muscle relaxant  given as one time intramuscular injection 
 
1L isotonic solution 
 
If Pre-term delivery: 
 
Exogenous surfactant (Exosurf Neonatal, Glaxo Wellcome) administered at a dose of 3 
ml/kg of body weight 
 
 
 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
39 
 
REFERENCES 
 
1- 
Reiss I, Schaible T, van den Hout L, Capolupo I, Allegaert K, van Heijst A, Gorett Silva 
M, Greenough A, Tibboel D; CDH EURO Consortium. Standardized postnatal management of 
infants with congenital diaphragmatic hernia in Europe: the CDH EURO Consortium consensus. 
Neonatology. 2010;98(4):354- 64. doi: 10.1159/000320622. Epub 2010 Oct 27.  PubMed ID: 
20980772 
 
2- 
Snoek KG, Capolupo I, van Rosmalen J, Hout Lde J, Vijfhuize S, Greenough A, Wijnen 
RM, Tibboel D, Reiss IK; CDH EURO Consortium. Conventional Mechanical Ventilation 
Versus High-frequency Oscillatory Ventilation for Congenital Diaphragmatic Hernia: A 
Randomized Clinical Trial (The VICI- trial). Ann Surg. 2016 May;263(5):867-74. doi: 
10.1097/SLA.0000000000001533.  PubMed ID: 26692079 
 
3- 
 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.  PubMed 
ID: 17587219 
 
4- 
 Jani JC, Benachi A, Nicolaides KH, Allegaert K, Gratacós 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.  PubMed ID: 18844275 
 
5- 
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. Erratum in: Ultrasound Obstet 
Gynecol. 2004 Oct; 24(5):594. PubMed ID: 15287047 
 
6- 
Jani J, Nicolaides K, Gratacos E, et al. 558: Short term neonatal morbidity in severe left-
sided congenital diaphragmatic hernia treated by tracheal occlusion before 30 weeks. Am J Obstet 
Gynecol Dec;197(6),Supplement:S162. 
 
7- 
Jani JC, Nicolaides KH, Gratacós E, Vandecruys H, Deprest JA; FETO Task Group. Fetal 
lung-to-head ratio in the prediction of survival in severe left-sided diaphragmatic hernia treated by 
fetal  endoscopic tracheal occlusion (FETO). Am J Obstet Gynecol. 2006 Dec;195(6):1646-50. 
Epub 2006 Jun 12.  PubMed ID: 16769018 
  
8- 
Jani JC, Nicolaides KH, Gratacós E, Valencia CM, Doné 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.  PubMed ID: 
19658113 
 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
9- 
Cannie MM, Jani JC, De Keyzer F, Allegaert K, Dymarkowski S, Deprest J. Evidence and 
patterns in lung response after fetal tracheal occlusion: clinical controlled study. Radiology. 2009 
Aug;252(2):526-33. doi: 10.1148/radiol.2522081955. Epub 2009 Jun 9.  PubMed ID: 19508989 
 
10- 
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. 
 
11- 
Jani J, Van Schoubroeck D, Cannie M, Gallot D, Dymarkowski S, Fryns JP, Naulaers G, 
Gratacos E, Nicolaides K. Current consequences of prenatal diagnosis of congenital diaphragmatic 
hernia. J Pediatr Surg. 2006;41:423-30. J Pediatr Surg. 2006 Jul;41(7):1344- 5; author reply 1345-
6. 
 
12- 
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.  
PubMed ID: 17587219 
 
13- 
Yang SH, Nobuhara KK, Keller RL, Ball RH, Goldstein RB, Feldstein VA, Callen PW, 
Filly RA, Farmer DL, Harrison MR, Lee H. Reliability of the lung-to-head ratio as a predictor of 
outcome in fetuses with isolated left congenital diaphragmatic hernia at gestation outside 24-26 
weeks. Am J Obstet Gynecol. 2007 Jul; 197(1):30.e1-7. 
 
14- 
Deprest, J., Jani, J., Gratacos, E., Vandecruys, H., Naulaers, G., Delgado, J., ... & Group, 
T. F. T. (2005, April). Fetal intervention for congenital diaphragmatic hernia: the European 
experience. In Seminars in perinatology (Vol. 29, No. 2, pp. 94-103). WB Saunders.. 2005 
Apr;29(2):94-103 
 
15- 
Harrison MR, Keller RL, Hawgood SB, Kitterman JA, Sandberg PL, Farmer DL, Lee H, 
Filly RA, Farrell JA, Albanese CT. A randomized trial of fetal endoscopic tracheal occlusion for 
severe fetal congenital diaphragmatic hernia. N Engl J Med. 2003 Nov13; 349(20):1916-24. 
 
16- 
Deprest J, Jani J, Cannie M, Debeer A, Vandevelde M, Done E, Gratacos E, Nicolaïdes K. 
Prenatal intervention for isolated congenital diaphragmatic hernia. Curr Opin Obstet Gynecol. 
2006;18:203-15. 
 
17- 
Chiba T, Albanese CT, Farmer DL, Dowd CF, Filly RA, Machin GA, Harrison M. 
Balloon tracheal occlusion for congenital diaphragmatic hernia: experimental studies. J Pediatr 
Surg. 2000 Nov;35 (11):1566-70.  PubMed ID: 11083424 
 
18- 
Papadakis K, De Paepe ME, Tackett LD, Piasecki GJ, Luks FI. Temporary tracheal 
occlusion causes catch-up lung maturation in a fetal model of diaphragmatic hernia. J Pediatr Surg. 
1998;33:1030-7. 
 
19- 
Dr. Hanmin Lee. Percutaneous Endoscopic Tracheal Plug/Unplug for CDH. 

IDE# G160187  
TOTAL Trial  H-39398  
Version 1.1, 24 AUG 2017 
 
 
www.ClinicalTrial.gov. NCT00768703 
 
20- 
Doné 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;28:581-91. 
 
21- 
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. PubMed ID: 18845492 
 
22- 
Jani JC, Nicolaides KH, Gratacós E, Valencia CM, Doné 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. 
 
23- 
 Friede, T., & Kieser, M. (2006). Sample size recalculation in internal pilot study designs: 
a review. Biometrical Journal, 48(4), 537-555. 
 
24-  
Friede, T., Mitchell, C., & Müller‐Velten, G. (2007). Blinded Sample Size Reestimation 
in Non‐Inferiority Trials with Binary Endpoints. Biometrical Journal, 49(6), 903-916. 
 
25-  
O'Brien, P. C., & Fleming, T. R. (1979). A multiple testing procedure for clinical 
trials. Biometrics, 549-556. 
 
26-  
Wolbers, M., Koller, M. T., Stel, V. S., Schaer, B., Jager, K. J., Leffondré, K., & Heinze, 
G. (2014). Competing risks analyses: objectives and approaches. European heart 
journal, 35(42), 2936-2941. 
 
27- 
Ostrea EM, Villanueva-Uy ET, Natarajan G, Uy HG. Persistent pulmonary hypertension 
of the newborn: pathogenesis, etiology, and management. Paediatr Drugs. 2006;8(3):179-88. 
Review. PubMed ID: 16774297 
 
28- 
Congenital Diaphragmatic Hernia Study Group, Lally KP, Lally PA, Lasky RE, Tibboel 
D, Jaksic T, Wilson JM, Frenckner B, Van Meurs KP, Bohn DJ, Davis CF, Hirschl RB. Defect 
size determines survival in infants with congenital diaphragmatic hernia. Pediatrics. 2007 
Sep;120(3):e651-7.  PubMed ID: 1776650