TOTAL Trial (H-39398)

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

This is a multicenter, 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. Subjects will be randomized into two groups (“FETO” and “expectant”) after assessment in a FETO center. 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 day 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.

Fetuses:

1. Left-sided diaphragmatic hernia

2. Fetuses presenting at the latest at 31 weeks plus 5 days gestation (intervention at the latest on 31 weeks plus 6 days)

3. Severity: Predicted moderate pulmonary hypoplasia. 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 percent (included: irrespective of the position of the liver) OR

• O/E LHR 35-44.9 percent (included) with intrathoracic herniation of the liver. In this group there is a predicted risk for postnatal death of 40 percent or higher and the risk of bronchopulmonary dysplasia in case of survival is 33 percent or higher.

Mother Subjects:

1. Patients aged 18 years or more, who are able to consent

2. Singleton pregnancy

3. Anatomically and chromosomally normal fetus

4. Gestation at randomization prior to 31 weeks plus 5 days or so that occlusion is done at the latest at 31 weeks plus 6 days

5. Estimated to have moderate pulmonary hypoplasia, defined prenatally as:

• O/E LHR 25-34.9 percent (included: irrespective of the position of the liver)

• O/E LHR 35-44.9 percent (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).

• Calculation of the observed over expected lung area

6. 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 four weeks after balloon is in place, until balloon is removed.

7. 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.” See Standardized Postnatal Management of Infants with Congenital Diaphragmatic Hernia in Europe: The CDH EURO Consortium Consensus.

8. Provide written consent to participate.

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 4week 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