Perinatal AsphyxiaPhase 2NCT01626924
A Study of 2-Iminobiotin in Neonates With Perinatal Asphyxia
A Phase 2 study testing 2-Iminobiotin in people with Perinatal Asphyxia, run by Neurophyxia B.V. at 2 sites in Turkey (Türkiye).
Trial 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. Read more about this study
- Who is it for?
- Ages Up to 6 hours
- Conditions the study is for
- Perinatal Asphyxia
- What is being tested?
- 2-Iminobiotin
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 6 participants
- Where
- 2 sitesTurkey (Türkiye)
- Study dates
- Jun 2012to Mar 2016
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Up to 6 hours
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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:
Show all 15Show fewer
- 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.
Who cannot join
- 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).
Trial locations and contacts
2 sites in 1 country.
Turkey (Türkiye)2 sites
T.R. Ministry of Health Izmir Tepecik Training and Research Hospital
Izmir, 35540
Yıl University Medical Faculty Hospital
Van, 65080
About this study
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
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).
- Conditions
- Perinatal Asphyxia
- Being tested
- 2-Iminobiotin
- Keywords
- Perinatal Asphyxia, Neonatal encephalopathy, Oxygen shortage at birth, Antenatal asphyxia, hypoxia-ischaemia, birth asphyxia, asphyxia neonatorum
- Medical subject headings
- Asphyxia Neonatorum
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
2-IminobiotinDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| 2-Iminobiotin | Experimental | Not described Receives: Drug: 2-Iminobiotin |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: The MRS will be performed between 3-7 days after birth
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.
Measured: 48h after start treatment
Secondary outcomes (13)
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.
Measured: 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
Measured: The MRI will be performed between 3-7 days after birth
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.
Measured: Every 4 hours until 48 hours after start treatment
Mortality
Measured: first 7 days after birth
Length of stay at the level III NICU
Measured: On the average this is expected to be 4-14 days after birth
Neurodevelopmental status
During the follow-up visits the neurodevelopmental development is measured using age specific standardized tests, including AIMS, BSID-III, CBCL, general movements
Measured: 3,6,12,18 and 24 months after treatment
Long term safety
During the follow-up period Serious Adverse Events are reported.
Measured: 3,6,12,18,24 months
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.
Measured: 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
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)
Measured: From start of treatment untill right after last treatment has been given (20h15min after start treatment)
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
Measured: at discharge from level III NICU on the average this will 7-14 days after birth.
aEEG. Time to normal aEEG
The time to normal aEEG will be determined for each subject.
Measured: Up to 72 hours after start treatment
aEEG. Seizures (clinical and sub-clinical)
The number and severity of clinical and sub-clinical seizures will be evaluated for each subject.
Measured: 48 hours after start treatment
aEEG. Time to normal sleep-wake cycling
The time to normal sleep-wake cycling will be determined for each subject.
Measured: up to 72 hours after start treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Jun 2012 (estimated)
- Study startJun 2012
- Primary completionOct 2014
- Study completionMar 2016
Why it stopped: Recruitment too slow and site decided to use hypothermia (exclusion criteria)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Perinatal AsphyxiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 6 participants (actual)
Sponsor and investigators
- Lead sponsor
- Neurophyxia B.V.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Paul Leufkens, PharmD, Study director, Neurophyxia B.V.
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01626924
- Sponsor's protocol ID
- NEU 01-02-01
- Other IDs
- 2011-002502-74
- Status last verified
- May 2017
- First submitted
- 15 Jun 2012
- Last updated
- 25 May 2017
- Results posted
- No
- Data monitoring committee
- Yes
Publications
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.
PubMed 12215603
Study at a glance
From the registry record, last updated by the sponsor on 25 May 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01626924
- Acronym / sponsor ID
- NEU 01-02-01
- Conditions
- Perinatal Asphyxia
- Keywords
- Perinatal Asphyxia, Neonatal encephalopathy, Oxygen shortage at birth, Antenatal asphyxia, hypoxia-ischaemia, birth asphyxia, asphyxia neonatorum
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Recruitment too slow and site decided to use hypothermia (exclusion criteria)
- Enrolment
- 6 participants (actual)
- Lead sponsor
- Neurophyxia B.V.Industry (pharma, biotech, devices)
- Study start
- Jun 2012
- Primary completion
- Oct 2014 (actual)
- Study completion
- Mar 2016 (actual)
- First posted
- 25 Jun 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| 2-Iminobiotin | Experimental | Drug: 2-Iminobiotin |
Who may qualify
- Ages
- Up to 6 hours
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (15 listed)
- Neonates with ≥ 36 and <44 weeks gestation with at least one of the following:
- The presence of moderate/severe encephalopathy defined as:
- 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.
Key exclusion criteria (4 listed)
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| 2-Iminobiotin2-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. | Drug | 2-Iminobiotin |
Primary outcome
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.
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.
13 secondary outcomes
MRI: pattern of injury score
Time frame: 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
Time frame: The MRI will be performed between 3-7 days after birth
aEEG. Background pattern
Time frame: Every 4 hours until 48 hours after start treatment
Mortality
Time frame: first 7 days after birth
Length of stay at the level III NICU
Time frame: On the average this is expected to be 4-14 days after birth
Neurodevelopmental status
Time frame: 3,6,12,18 and 24 months after treatment
Long term safety
Time frame: 3,6,12,18,24 months
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
Pharmacokinetics during the treatment phase
Time frame: From start of treatment untill right after last treatment has been given (20h15min after start treatment)
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.
aEEG. Time to normal aEEG
Time frame: Up to 72 hours after start treatment
aEEG. Seizures (clinical and sub-clinical)
Time frame: 48 hours after start treatment
aEEG. Time to normal sleep-wake cycling
Time frame: up to 72 hours after start treatment
Results and safety
The study was stopped early (reason given: Recruitment too slow and site decided to use hypothermia (exclusion criteria)). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 May 2017.
- Background: PubMed 12215603Peeters-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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Paul Leufkens, PharmD study director
Neurophyxia B.V.
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing 2-Iminobiotin in people with Perinatal Asphyxia, run by Neurophyxia B.V. at 2 sites in Turkey (Türkiye).
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 15 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 25 May 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Turkey (Türkiye). Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Recruitment too slow and site decided to use hypothermia (exclusion criteria)). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01626924, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 May 2017.