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A Study of 2-Iminobiotin in Neonates With Perinatal Asphyxia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01626924
Recruitment Status : Terminated (Recruitment too slow and site decided to use hypothermia (exclusion criteria))
First Posted : June 25, 2012
Last Update Posted : May 25, 2017
Information provided by (Responsible Party):
Neurophyxia B.V.

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).

Condition or disease Intervention/treatment Phase
Perinatal Asphyxia Drug: 2-Iminobiotin Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 6 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
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
Study Start Date : June 2012
Actual Primary Completion Date : October 2014
Actual Study Completion Date : March 2016

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: 2-Iminobiotin Drug: 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.

Primary Outcome Measures :
  1. 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 ]
    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.

  2. The composite endpoint of survival at 48h with a normal aEEG [ Time Frame: 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.

Secondary Outcome Measures :
  1. MRI: pattern of injury score [ Time Frame: The MRI will be performed between 3-7 days after birth ]

    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.

  2. 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 ]
  3. aEEG. Background pattern [ Time Frame: Every 4 hours until 48 hours after start treatment ]
    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.

  4. Mortality [ Time Frame: first 7 days after birth ]
  5. Length of stay at the level III NICU [ Time Frame: On the average this is expected to be 4-14 days after birth ]
  6. Neurodevelopmental status [ Time Frame: 3,6,12,18 and 24 months after treatment ]
    During the follow-up visits the neurodevelopmental development is measured using age specific standardized tests, including AIMS, BSID-III, CBCL, general movements

  7. Long term safety [ Time Frame: 3,6,12,18,24 months ]
    During the follow-up period Serious Adverse Events are reported.

  8. 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 ]
    During the hospitalization period a number of safety parameters are measured and compared between groups, including blood tests (blood gas, haematology, biochemistry), 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.

  9. Pharmacokinetics during the treatment phase [ Time Frame: From start of treatment untill right after last treatment has been given (20h15min after start treatment) ]

    Pharmacokinetic 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)

  10. 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. ]

    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

  11. aEEG. Time to normal aEEG [ Time Frame: Up to 72 hours after start treatment ]
    The time to normal aEEG will be determined for each subject.

  12. aEEG. Seizures (clinical and sub-clinical) [ Time Frame: 48 hours after start treatment ]
    The number and severity of clinical and sub-clinical seizures will be evaluated for each subject.

  13. aEEG. Time to normal sleep-wake cycling [ Time Frame: up to 72 hours after start treatment ]
    The time to normal sleep-wake cycling will be determined for each subject.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   up to 6 Hours   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01626924

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T.R. Ministry of Health Izmir Tepecik Training and Research Hospital
Izmir, Turkey, 35540
Yıl University Medical Faculty Hospital
Van, Turkey, 65080
Sponsors and Collaborators
Neurophyxia B.V.
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Study Director: Paul Leufkens, PharmD Neurophyxia B.V.
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Responsible Party: Neurophyxia B.V. Identifier: NCT01626924    
Other Study ID Numbers: NEU 01-02-01
2011-002502-74 ( EudraCT Number )
First Posted: June 25, 2012    Key Record Dates
Last Update Posted: May 25, 2017
Last Verified: May 2017
Keywords provided by Neurophyxia B.V.:
Perinatal Asphyxia
Neonatal encephalopathy
Oxygen shortage at birth
Antenatal asphyxia
birth asphyxia
asphyxia neonatorum
Additional relevant MeSH terms:
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Asphyxia Neonatorum
Pathologic Processes
Wounds and Injuries
Infant, Newborn, Diseases