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
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 6
- 试验地点
- 2
- 主要终点
- The Lac/NAA ratio in the basal ganglia as measured by single or multiple voxel Magnetic Resonance Spectroscopy (MRS).
研究概览
简要总结
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- — 至 6 Hours（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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).
- •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.
- •Presence in hospital and ability to start treatment within 6h after birth.
- •Informed Consent Form signed before first study-related activity according to local law.
- •Receiving standard therapy without hypothermia.
排除标准
- •Major antenatally known- or congenital abnormalities, such as hernia diaphragmatica requiring ventilation.
- •Major antenatally known chromosomal abnormalities, such as trisomy 13 or 18 or neonates with evident syndromal appearances including brain dysgenesis.
- •Severe growth restriction with a birth weight below the 3rd percentile.
- •Inability to insert an indwelling catheter (umbilical venous catheter or percutaneously inserted central catheter, preferably multiple lumen).
研究组 & 干预措施
2-Iminobiotin
干预措施: 2-Iminobiotin (Drug)
结局指标
主要结局
The Lac/NAA ratio in the basal ganglia as measured by single or multiple voxel Magnetic Resonance Spectroscopy (MRS).
时间窗: The MRS will be performed between 3-7 days after birth
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
时间窗: 48h after start treatment
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.
次要结局
- Mortality(first 7 days after birth)
- MRI: pattern of injury score(The MRI will be performed between 3-7 days after birth)
- MRI: DWI (diffusion weighted images): apparent diffusion coefficient (ADC) in basal ganglia and PLIC(The MRI will be performed between 3-7 days after birth)
- aEEG. Background pattern(Every 4 hours until 48 hours after start treatment)
- Length of stay at the level III NICU(On the average this is expected to be 4-14 days after birth)
- Neurodevelopmental status(3,6,12,18 and 24 months after treatment)
- Long term safety(3,6,12,18,24 months)
- Safety during hospitalization period(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)
- Pharmacokinetics during the treatment phase(From start of treatment untill right after last treatment has been given (20h15min after start treatment))
- Neurological status as assessed by full neurological examination(at discharge from level III NICU on the average this will 7-14 days after birth.)
- aEEG. Time to normal aEEG(Up to 72 hours after start treatment)
- aEEG. Seizures (clinical and sub-clinical)(48 hours after start treatment)
- aEEG. Time to normal sleep-wake cycling(up to 72 hours after start treatment)