Recruitment too slow and site decided to use hypothermia (exclusion criteria)

In case of insufficient oxygen supply to the brain of a newborn child (perinatal asphyxia), toxic compounds will be formed. These toxic compounds will damage the cells of the brain. 2 Iminobiotin (2 IB) is an investigational medicinal product that is related to vitamin B7. From studies in animals it has been shown that 2-IB may prevent the formation of the toxic compounds. Also it has been shown to be safe in in studies in juvenile animals and in healthy, adult male volunteers. The doctors hope that this will prevent (part of) the potential brain damage that may result from lack of oxygen to the brain.

This study is the first study in the target population: newborn with moderate to severe oxygen shortage during birth. In this study the investigators evaluate short term efficacy, safety and pharmacokinetics of 2-Iminobiotin. In the follow-up phase the investigators evaluate the long term efficacy and safety.

The study hypothesis is that 2-Iminobiotin will help to decrease the brain damage after oxygen shortage and is indeed safe. The brain damage will be measured both in the first week and during the first two years of life. The study was designed as a study with two parts an open label pilot part (6 patients) and a double-blind randomised part (60 patients). Due to lack of recruitment it was decided in September2014 to stop recruitment after the open label pilot part of the study (6 patients).

Inclusion Criteria:

1. Neonates with ≥ 36 and <44 weeks gestation with at least one of the following:

   • Apgar Score ≤ 5 at 10 minutes after birth
   • Continued need for resuscitation, including endotracheal or mask ventilation at 10 minutes after birth
   • Acidosis, defined as either umbilical cord pH or any arterial, venous, capillary pH within 60 minutes of birth pH ≤ 7.00
   • Acidosis, defined as base deficit ≥ 16 mmol/l in umbilical blood sample or any blood sample within 60 minutes of birth (arterial or venous).

2. The presence of moderate/severe encephalopathy defined as:

   • Altered state of consciousness (lethargy, stupor, coma) and at least one of the following:

     • Hypotonia
     • Abnormal reflexes including oculomotor or papillary abnormalities
     • Weak or absent suck reflex
     • Clinical seizures AND

   • Depression of the background pattern (lower margin≤ 5 µV meaning at least DNV or BS, CLV, FT) or the presence of seizure activity on the aEEG, registered for at least 30 minutes within 6h after birth.

3. Presence in hospital and ability to start treatment within 6h after birth.

4. Informed Consent Form signed before first study-related activity according to local law.

5. Receiving standard therapy without hypothermia.

Exclusion Criteria:

1. Major antenatally known- or congenital abnormalities, such as hernia diaphragmatica requiring ventilation.
2. Major antenatally known chromosomal abnormalities, such as trisomy 13 or 18 or neonates with evident syndromal appearances including brain dysgenesis.
3. Severe growth restriction with a birth weight below the 3rd percentile.
4. Inability to insert an indwelling catheter (umbilical venous catheter or percutaneously inserted central catheter, preferably multiple lumen).