Treatment of high blood pressure in the lungs in newborns with a defect in the diaphragm; inhaled Nitric Oxide compared to intravenous Sildenafil.

• Register: EUCTR
• Last refreshed on: 23 July 2018
• Main ID: EUCTR2017-000421-13-AT
• Date of registration: 08/05/2018
• Prospective Registration: Yes
• Primary sponsor: Erasmus MC
• Public title: Treatment of high blood pressure in the lungs in newborns with a defect in the diaphragm; inhaled Nitric Oxide compared to intravenous Sildenafil.
• Scientific title: Newborns with Congenital Diaphragmatic hernia: inhaled Nitric Oxide versus intravenous Sildenafil: an international randomized controlled trial - CoDiNOS trial
• Date of first enrolment: 13/07/2018
• Target sample size: 330
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2017-000421-13
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: no; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): yes

Countries of recruitment

Austria, Netherlands

Contacts

• Name: project leader
• Affiliation: Erasmus MC

• Name: project leader
• Affiliation: Erasmus MC

Key inclusion & exclusion criteria

Inclusion criteria:
• Diagnosis of CDH and pulmonary hypertension defined as 2 of the following 4 criteria:
I. PAP> 2/3 systemic pressure estimated by echocardiography
II. RV dilatation/septal displacement, RV dysfunction +/- LV dysfunction
III. Pre-post ductal SpO2 difference > 10%
IV. OI>20.
• Parental informed consent
• Children born at or after a gestational age of 34 weeks
• Newborns who received a fetal intervention may be included

Are the trial subjects under 18? yes
Number of subjects for this age range: 330
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
• Severe chromosomal anomaly, like trisomy 18 or trisomy 13, which may imply a decision to stop or not to start life-saving medical treatment
• Severe cardiac anomaly, expected to need corrective surgery in the first 60 days of life (such as transposition of the great arteries, truncus arteriosus, coarctation aortae or double outlet right ventricle)
• Renal anomalies associated with oligohydramnios
• Severe orthopaedic and skeletal deformities, which are likely to influence thoracic, and / or lung development (such as chest wall deformities and spine anomalies)
• Severe anomalies of the central nervous system




Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Congenital diaphragmatic hernia with pulmonary hypertension

Therapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Intervention(s)

Trade Name: revatio 0.8mg/ml solution for injection
Pharmaceutical Form: Solution for injection/infusion
INN or Proposed INN: Sildenafil
CAS Number: 171599-83-0
Concentration unit: mg/kg milligram(s)/kilogram
Concentration type: equal
Concentration number: 0.4-

Trade Name: INOmax 800ppm mol/mol inhalatiegas
Pharmaceutical Form: Medicinal gas, compressed
INN or Proposed INN: NITRIC OXIDE
CAS Number: 10102-43-9
Concentration unit: PPM part per million
Concentration type: equal
Concentration number: 20-

Primary Outcome(s)

Main Objective: The primary objective of this study is to determine if there is a difference in the incidence of pulmonary hypertension in the absence of pulmonary vasodilator therapy on day 14 on echocardiography and/or death within the first 28 days of life between CDH patients treated with iNO versus those treated with intravenous sildenafil.

Primary end point(s): The main study endpoint is pulmonary hypertension in the absence of pulmonary vasodilator therapy on echocardiography on day 14 and/or death within the first 28 days of life

Timepoint(s) of evaluation of this end point: Day 14 and day 28

Secondary Objective: The secondary objectives are:
• To compare the change in oxygenation index before and after start treatment
• To compare overall mortality
• To compare the incidence of treatment failure (see paragraph 6.5)
• To compare the time on intervention drug
• To compare the need for ECMO
• To compare the number of ventilator free days at day 28
• To compare the vasoactive-inotropic support score before and after starting the intervention drug
• To compare laboratory markers for pulmonary vascular endothelial damage and pulmonary hypertension (see paragraph 6.3)
• To compare the use of other medication given for pulmonary hypertension
• To compare the use of pulmonary and/or cardiac medication after discharge
• To compare the incidence of long-term pulmonary hypertension at the age of 1 year
• To compare the incidence of chronic lung disease

Secondary Outcome(s)

Secondary end point(s): • Change in oxygenation index after 12 hours of treatment
• Overall mortality in the first year of life
• Requirement of ECMO (only for ECMO centres)
• Treatment failure (see paragraph 6.5, failure criteria)
• Severity and presence of pulmonary hypertension on day 1 and/or just before starting the study drug, on day 14, on day 28 or at discharge (whatever comes first), at 6 months and 1 year according to the following echocardiographic parameters as described by the cardiologist: PAP < or > 2/3 systemic pressure, RV dilatation/septal displacement, RV dysfunction +/- LV dysfunction. (see Case Record Form)
• Number ventilator free days on day 28 (deaths are counted as worst outcome)
• Number of intervention drug free days on day 14
• Fraction of days requiring medical treatment for pulmonary hypertension during the hospital admission, described as the use of iNO, sildenafil, prostanoids, endothelin 1 antagonists, and/or other medication for pulmonary hypertension
• The level of specific laboratory markers and urine, up to day 28, to describe the severity and presence of pulmonary hypertension.
• Vasoactive-inotropic support score before and 12 hours after starting study medication.
This score is calculated with: (dopamine (mcg/kg/min) + dobutamine (mcg/kg/min) + 100x adrenaline (mcg/kg/min) + 10x milrinone (mcg/kg/min) + 10.000x vasopressin (U/kg/min) + 100x noradrenaline (mcg/kg/min)) [31]
• Requirement of PH medication, described as oral sildenafil, bosentan and/or a prostanoid at discharge and/or during the first year of life.
• Severity of chronic lung disease using need for oxygen on day 28 and 56.
• Long-term pulmonary hypertension using echocardiography at the age of 6 and 12 months.
• The development of neurological abnormalities evaluated with an ultrasound of the brain before start of intervention drug, after surgery and before discharge.

Timepoint(s) of evaluation of this end point: 12 and 24 hours
day of surgery and day after surgery
day of starting ECMO and day after ECMO
day 14 and day 28 or at discharge (whichever comes first)
day 56
6 and 12 months

Secondary ID(s)

2017-000421-13-NL

NL60229.078.17

Source(s) of Monetary Support

CDH UK Sparks

SSWO