A Study of 2-Iminobiotin in Neonates With Perinatal Asphyxia
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.
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|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|
- The Lac/NAA ratio in the basal ganglia as measured by single or multiple voxel Magnetic Resonance Spectroscopy (MRS). [ Time Frame: The MRS will be performed between 3-7 days after birth ] [ Designated as safety issue: No ]
Proton (1H) MRS of the basal ganglia lactate/N-acetyl aspartate (Lac/NAA) peak-area ratio is considered to be an accurate quantitative biomarker for prediction of neurodevelopmental outcome after Neonatal Encephalopathy (Thayyil et al, 2010). Results will be compared between arms.
- The composite endpoint of survival at 48h with a normal aEEG [ Time Frame: 48h after start treatment ] [ Designated as safety issue: No ]Electrocortical brain activity is measured by aEEG, starting as soon as possible after birth and before study medication has been initiated and continued until at least 72h after start of treatment. Every 4h the background pattern of the aEEG and the presence of seizures will be recorded in the eCRF. The aEEG will be classified as normal or abnormal at 48h after the start of treatment. Hence, for this primary endpoint, a good outcome is defined as survival in combination with a normal aEEG at 48h. A bad outcome is either death or abnormal aEEG at 48h after start treatment.
- MRI: pattern of injury score [ Time Frame: The MRI will be performed between 3-7 days after birth ] [ Designated as safety issue: No ]
Neuro-imaging by Magnetic Resonance Imaging (MRI) between 3 and 7 days following birth. The scoring system used is the pattern of injury score (Rutherford et al, 2010, appendix) in 4 areas of the brain (cortex, basal ganglia and thalamus, white matter and posterior limb of the internal capsule (PLIC)). Abnormal MRI is reported to be a predictor of poor outcome when at least one of following occurs (Rutherford et al, 2010):
- Moderate or severe score in basal ganglia and thalamus
- Abnormal PLIC
- Severe white matter abnormalities Results will be compared between arms.
- MRI: DWI (diffusion weighted images): apparent diffusion coefficient (ADC) in basal ganglia and PLIC [ Time Frame: The MRI will be performed between 3-7 days after birth ] [ Designated as safety issue: No ]
- aEEG. Background pattern [ Time Frame: Every 4 hours until 48 hours after start treatment ] [ Designated as safety issue: No ]aEEG background will be evaluated every 4 hours until at least 48 hours after start treatment and also at time point of 48h after birth.
- Mortality [ Time Frame: first 7 days after birth ] [ Designated as safety issue: No ]
- Length of stay at the level III NICU [ Time Frame: On the average this is expected to be 4-14 days after birth ] [ Designated as safety issue: No ]
- Neurodevelopmental status [ Time Frame: 3,6,12,18 and 24 months after treatment ] [ Designated as safety issue: No ]During the follow-up visits the neurodevelopmental development is measured using age specific standarized tests, including AIMS, BSID-III, CBCL, general movements
- Long term safety [ Time Frame: 3,6,12,18,24 months ] [ Designated as safety issue: Yes ]During the follow-up period Serious Adverse Events are reported.
- Safety during hospitalization period [ Time Frame: 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 ] [ Designated as safety issue: Yes ]During the hospitalization period a number of safety parameters are measured and compared between groups, including blood tests (blood gas, haematology, biochemstry), urinalysis, vital signs, fluid balance, clinical evaluation, local tolerance, growth parameters, EEG, ECG. Also number and kind of Adverse Events and Serious Adverse Events will be compared between arms.
- Pharmacokinetics during the treatment phase [ Time Frame: From start of treatment untill right after last treatment has been given (20h15min after start treatment) ] [ Designated as safety issue: No ]
Pharmacikinetic parameters to be evaluated include:
- Cmax (observed maximum plasma concentration)
- AUC0-4h (area under the plasma concentration-time curve from time 0 to 4h after administration)
- AUC0-∞ (area under the plasma concentration-time curve from time 0 to infinity)
- T(end of infusion) (time at maximum plasma concentration).
- t1/2 (terminal elimination half-life)
- CL (clearance)
- V (volume of distribution)
- Neurological status as assessed by full neurological examination [ Time Frame: at discharge from level III NICU on the average this will 7-14 days after birth. ] [ Designated as safety issue: No ]
Full neurological examination includes:
Prechtl state, Higher cortical functions, Pupillary reflexes right,Pupillary reflexes left, corneal reflex right, corneal reflex left, optokinetic reflexes, nystagmus, facial symmetry, tone, spontaneous movements right, spontaneous movements left, tendon reflexes, ankle clonus right, ankle clonus left, sucking reflex, grasp reflex right, grasp reflex left, moro reflex right, moro reflex left, glabella reflex, snout reflex, palmomental reflex right, palmomental reflex left. Outcomes will be compared between arms
- aEEG. Time to normal aEEG [ Time Frame: Up to 72 hours after start treatment ] [ Designated as safety issue: No ]The time to normal aEEG will be determined for each subject.
- aEEG. Seizures (clinical and sub-clinical) [ Time Frame: 48 hours after start treatment ] [ Designated as safety issue: No ]The number and severity of clinical and sub-clinical seizures will be evaluated for each subject.
- aEEG. Time to normal sleep-wake cycling [ Time Frame: up to 72 hours after start treatment ] [ Designated as safety issue: No ]The time to normal sleep-wake cycling will be determined for each subject.
|Study Start Date:||June 2012|
|Estimated Study Completion Date:||October 2015|
|Estimated Primary Completion Date:||October 2013 (Final data collection date for primary outcome measure)|
|Active Comparator: 2-Iminobiotin||
2-Iminobiotin is formulated as a 0.75 mg/ml isotonic, iso-osmotic, saline solution with a pH of 4. It is administered as a solution for I.V.infusion through a central catheter. Six pulse doses will be given in 20 hours. Dosage will starts with 0.2 mg/kg/dose, but may be adapted during the study.
|Placebo Comparator: Placebo||
Placebo consists of the same solution as the active solution, but without 2-Iminobiotin. Dosage form, dosage, frequency and duration are the same as for 2-Iminobiotin
|Contact: Huibert A Tjabbes, MDfirstname.lastname@example.org|
|Contact: Paul Leufkens, PharmDemail@example.com|
|Hospital of Lithuanian University of Health Sciences||Recruiting|
|Kaunas, Lithuania, LT-50009|
|Contact: Egle Markuniene, MD 0037037326194 firstname.lastname@example.org|
|Principal Investigator: Egle Markuniene, MD|
|Study Director:||Paul Leufkens, PharmD||Neurophyxia B.V.|