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A Study of 2-Iminobiotin in Neonates With Perinatal Asphyxia

Primary Purpose

Perinatal Asphyxia

Status
Terminated
Phase
Phase 2
Locations
Turkey
Study Type
Interventional
Intervention
2-Iminobiotin
Sponsored by
Neurophyxia B.V.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Perinatal Asphyxia focused on measuring Perinatal Asphyxia, Neonatal encephalopathy, Oxygen shortage at birth, Antenatal asphyxia, hypoxia-ischaemia, birth asphyxia, asphyxia neonatorum

Eligibility Criteria

undefined - 6 Hours (Child)All SexesDoes not accept healthy volunteers

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).

Sites / Locations

  • T.R. Ministry of Health Izmir Tepecik Training and Research Hospital
  • Yıl University Medical Faculty Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

2-Iminobiotin

Arm Description

Outcomes

Primary Outcome Measures

The Lac/NAA ratio in the basal ganglia as measured by single or multiple voxel Magnetic Resonance Spectroscopy (MRS).
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
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

MRI: pattern of injury score
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
aEEG. Background pattern
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
Length of stay at the level III NICU
Neurodevelopmental status
During the follow-up visits the neurodevelopmental development is measured using age specific standardized tests, including AIMS, BSID-III, CBCL, general movements
Long term safety
During the follow-up period Serious Adverse Events are reported.
Safety during hospitalization period
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.
Pharmacokinetics during the treatment phase
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)
Neurological status as assessed by full neurological examination
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
The time to normal aEEG will be determined for each subject.
aEEG. Seizures (clinical and sub-clinical)
The number and severity of clinical and sub-clinical seizures will be evaluated for each subject.
aEEG. Time to normal sleep-wake cycling
The time to normal sleep-wake cycling will be determined for each subject.

Full Information

First Posted
June 15, 2012
Last Updated
May 23, 2017
Sponsor
Neurophyxia B.V.
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1. Study Identification

Unique Protocol Identification Number
NCT01626924
Brief Title
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

2. Study Status

Record Verification Date
May 2017
Overall Recruitment Status
Terminated
Why Stopped
Recruitment too slow and site decided to use hypothermia (exclusion criteria)
Study Start Date
June 2012 (undefined)
Primary Completion Date
October 2014 (Actual)
Study Completion Date
March 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Neurophyxia B.V.

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Perinatal Asphyxia
Keywords
Perinatal Asphyxia, Neonatal encephalopathy, Oxygen shortage at birth, Antenatal asphyxia, hypoxia-ischaemia, birth asphyxia, asphyxia neonatorum

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
6 (Actual)

8. Arms, Groups, and Interventions

Arm Title
2-Iminobiotin
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
2-Iminobiotin
Intervention Description
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 Measure Information:
Title
The Lac/NAA ratio in the basal ganglia as measured by single or multiple voxel Magnetic Resonance Spectroscopy (MRS).
Description
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.
Time Frame
The MRS will be performed between 3-7 days after birth
Title
The composite endpoint of survival at 48h with a normal aEEG
Description
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.
Time Frame
48h after start treatment
Secondary Outcome Measure Information:
Title
MRI: pattern of injury score
Description
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.
Time Frame
The MRI will be performed between 3-7 days after birth
Title
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
Title
aEEG. Background pattern
Description
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.
Time Frame
Every 4 hours until 48 hours after start treatment
Title
Mortality
Time Frame
first 7 days after birth
Title
Length of stay at the level III NICU
Time Frame
On the average this is expected to be 4-14 days after birth
Title
Neurodevelopmental status
Description
During the follow-up visits the neurodevelopmental development is measured using age specific standardized tests, including AIMS, BSID-III, CBCL, general movements
Time Frame
3,6,12,18 and 24 months after treatment
Title
Long term safety
Description
During the follow-up period Serious Adverse Events are reported.
Time Frame
3,6,12,18,24 months
Title
Safety during hospitalization period
Description
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.
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
Title
Pharmacokinetics during the treatment phase
Description
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)
Time Frame
From start of treatment untill right after last treatment has been given (20h15min after start treatment)
Title
Neurological status as assessed by full neurological examination
Description
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
Time Frame
at discharge from level III NICU on the average this will 7-14 days after birth.
Title
aEEG. Time to normal aEEG
Description
The time to normal aEEG will be determined for each subject.
Time Frame
Up to 72 hours after start treatment
Title
aEEG. Seizures (clinical and sub-clinical)
Description
The number and severity of clinical and sub-clinical seizures will be evaluated for each subject.
Time Frame
48 hours after start treatment
Title
aEEG. Time to normal sleep-wake cycling
Description
The time to normal sleep-wake cycling will be determined for each subject.
Time Frame
up to 72 hours after start treatment

10. Eligibility

Sex
All
Maximum Age & Unit of Time
6 Hours
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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. Exclusion Criteria: 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).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Paul Leufkens, PharmD
Organizational Affiliation
Neurophyxia B.V.
Official's Role
Study Director
Facility Information:
Facility Name
T.R. Ministry of Health Izmir Tepecik Training and Research Hospital
City
Izmir
ZIP/Postal Code
35540
Country
Turkey
Facility Name
Yıl University Medical Faculty Hospital
City
Van
ZIP/Postal Code
65080
Country
Turkey

12. IPD Sharing Statement

Citations:
PubMed Identifier
12215603
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.
Results Reference
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A Study of 2-Iminobiotin in Neonates With Perinatal Asphyxia

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