Clinical trial NCT01626924: A Study of 2-Iminobiotin in Neonates With Perinatal Asphyxia
Official title: A Multi-centre, Randomised, Double-blind, Placebo-controlled Phase II Study to Evaluate the Efficacy, Safety, Tolerability and Pharmacokinetics of 2-Iminobiotin (2-IB) in Neonates With ≥36 Weeks GA With Moderate to Severe Perinatal Asphyxia
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Perinatal Asphyxia
Keywords: Perinatal Asphyxia
Neonatal encephalopathy
Oxygen shortage at birth
Antenatal asphyxia
hypoxia-ischaemia
birth asphyxia
asphyxia neonatorum
Lead sponsor: Neurophyxia B.V.
Sponsor class: INDUSTRY
First posted: 2012-06-25
Enrollment: 6
Sex: ALL
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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).


Eligibility criteria: 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).

Primary outcomes:
measure: The Lac/NAA ratio in the basal ganglia as measured by single or multiple voxel Magnetic Resonance Spectroscopy (MRS).
timeFrame: The MRS will be performed between 3-7 days after birth
measure: The composite endpoint of survival at 48h with a normal aEEG
timeFrame: 48h after start treatment
Secondary outcomes:
measure: MRI: pattern of injury score
timeFrame: The MRI will be performed between 3-7 days after birth
measure: MRI: DWI (diffusion weighted images): apparent diffusion coefficient (ADC) in basal ganglia and PLIC
timeFrame: The MRI will be performed between 3-7 days after birth
measure: aEEG. Background pattern
timeFrame: Every 4 hours until 48 hours after start treatment
measure: Mortality
timeFrame: first 7 days after birth
measure: Length of stay at the level III NICU
timeFrame: On the average this is expected to be 4-14 days after birth
measure: Neurodevelopmental status
timeFrame: 3,6,12,18 and 24 months after treatment
measure: Long term safety
timeFrame: 3,6,12,18,24 months
measure: Safety during hospitalization period
timeFrame: Participants will be followed up for the duration of stay at hospital after birth (hospitalization period), on the average this will be 2-4 weeks
measure: Pharmacokinetics during the treatment phase
timeFrame: From start of treatment untill right after last treatment has been given (20h15min after start treatment)
measure: Neurological status as assessed by full neurological examination
timeFrame: at discharge from level III NICU on the average this will 7-14 days after birth.
measure: aEEG. Time to normal aEEG
timeFrame: Up to 72 hours after start treatment
measure: aEEG. Seizures (clinical and sub-clinical)
timeFrame: 48 hours after start treatment
measure: aEEG. Time to normal sleep-wake cycling
timeFrame: up to 72 hours after start treatment
Other outcomes:
Locations:
city: Izmir
country: Turkey
facility: T.R. Ministry of Health Izmir Tepecik Training and Research Hospital
city: Van
country: Turkey
facility: Yıl University Medical Faculty Hospital
Study officials:
affiliation: Neurophyxia B.V.
name: Paul Leufkens, PharmD
role: STUDY_DIRECTOR
References:
citation: Peeters-Scholte C, Koster J, Veldhuis W, van den Tweel E, Zhu C, Kops N, Blomgren K, Bar D, van Buul-Offers S, Hagberg H, Nicolay K, van Bel F, Groenendaal F. Neuroprotection by selective nitric oxide synthase inhibition at 24 hours after perinatal hypoxia-ischemia. Stroke. 2002 Sep;33(9):2304-10. doi: 10.1161/01.str.0000028343.25901.09.