E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Oxygen shortage during birth resulting in insufficient oxygen supply to the brain |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10004943 |
E.1.2 | Term | Birth asphyxia |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10003500 |
E.1.2 | Term | Asphyxia neonatal |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To provide an early evaluation of the efficacy using magnetic resonance spectroscopy [MRS] and the combination of survival with amplitude-integrated electroencephalogram [aEEG]) of 2-IB |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the short term safety and tolerability of 2-IB;
• To evaluate the pharmacokinetic profile of 2-IB;
• To gather preliminary evidence on the long term efficacy of 2-IB, as measured by neurodevelopmental outcome at 24 months after birth;
• To gather preliminary evidence on the long term safety of 2-IB, as measured by serious adverse events reports up to 24 months after birth.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects must meet all of the following requirements prior to inclusion in the study:
1. Neonates with ≥ 36 and <44 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 6 hours after birth.
3. Presence in hospital and ability to start treatment within 6 hours after birth.
4. Informed Consent Form signed before first study-related activity according to local law. The Law on Ethics of Biomedical research of the Republic of Lithuania Lithuanian law art. 7 para.2 , states that both parents of the minor should give informed consent before a minor can be included in a study. If there is only a mother (i.e. divorce, unknown father), the Informed Consent Form should be signed by the mother.
5. Receiving standard therapy without hypothermia.
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E.4 | Principal exclusion criteria |
Subjects meeting one or more of the following criteria cannot be included
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). |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary efficacy parameters as assessed by the Medical Adjudication Committee:
• The Lac/NAA ratio in the basal ganglia as measured by single or multiple voxel 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).
• 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 CRF. The aEEG will be classified as normal or abnormal at 48h after the start of treatment. The aEEG will be scored in five categories using pattern-recognition (Hellstrom-Westas et al, 2006): continuous normal voltage (CNV) and discontinuous normal voltage (DNV) being classified as normal (Thoresen et al, 2010), and burst suppression (BS), continuous extremely low voltage (CLV) and flat trace (FT) classified as abnormal.
To prevent bias due to death before 48h after start treatment, survival is added as parameter. 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.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
MRS will evaluated between 3 and 7 days after start treatment.
aEEG/mortality will evaluated at 48 hours after start of treatment |
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E.5.2 | Secondary end point(s) |
Secondary efficacy parameters
• 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):
o Moderate or severe score in basal ganglia and thalamus
o Abnormal PLIC
o Severe white matter abnormalities
• MRI: DWI (diffusion weighted images): apparent diffusion coefficient (ADC) in basal ganglia and PLIC
• aEEG. Additional parameters derived from the aEEG recording will be assessed:
o aEEG at 36h after start of study drug administration (classified the same way as described for the primary endpoint at 48h)
o aEEG at 4-hour intervals until 48h after start of study drug administration (classified the same way as de described for the primary endpoint at 48h)
o Time to normal aEEG, defined as the first time a normal aEEG is seen after birth
o Time until the aEEG shows sleep-wake-cycling (Osredkar et al, 2005)
o Presence of (sub)clinical seizures (Glass et al, 2009, Bjorkman, 2010)
• Full neurological examination at discharge from level III NICU (see Table 4)
• Mortality during first 7 days after birth
• Length of stay at the level III NICU
Safety parameters: vital signs, clinical laboratory parameters, clinical evaluation and adverse events and local tolerance.
Pharmacokinetic parameters to be determined 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)
• Tend of infusion (time at maximum plasma concentration).
• t1/2 (terminal elimination half-life)
• CL (clearance)
• V (volume of distribution)
In addition metabolomics will be done on blood samples.
The Primary efficacy outcome parameter of the follow-up period is a composite of mortality and severe neurodevelopmental disability in survivors at 24 months of age. Severe neurodevelopmental disability will be defined as the presence of at least one of:
1. BSID MDI<70,
2. The GMFCS level III-V,
3. Bilateral cortical visual impairment.
For safety the primary outcome parameters during the follow-up period are frequency and nature of SAEs, survival and growth parameters. Sub-analyses will be performed for moderate and severe asphyxia and gender. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Time points for Secondary parameters during hospitalization period:
MRI(incl DWI):3-7 days after birth
aEEG: will be recorded as soon as possible after birth (at least before first administration study medication) till at least 72 hours after birth.
Neurological examination will be performed at the end of the level III NICU stay.
Safety parameters will be followed up continously during the hospiatlization period. For Pharmacokinetics six samples will be taken, and for metabolomics three samples.
Follow-up period will have visits at 3,6,12,18 and 24 months of age. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
The design will include an open label pilot phase before main phase. |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 4 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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LVLS, or earlier if subject has dropped out or died.The trial has two parts: the hospitalization period and the follow-up period, with two separate data sets. after the hospitalization period has been completed the data set for that period will be closed and analysed. This is expected to be around 1 year after the start of the trial.
The follow-up period will continue another two years. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |