E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Neonatal asphyxial encephalopathy |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12 |
E.1.2 | Level | SOC |
E.1.2 | Classification code | 10028946 |
E.1.2 | Term | neonatal hypoxia and asphyxia |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The principal research question is: does the combination of xenon and hypothermia reduce the pathophysiological process that leads to neurological impairment after perinatal asphyxia.
The objectives of the study are to compare the effects of xenon and hypothermia with hypothermia alone, and to measure the effects within the brain using two biomarkers: (i) proton magnetic resonance spectroscopy (MRS) to measure the cerebral lactate to N acetylaspartate ratio (Lac/NAA); and (ii) quantitative magnetic resonance imaging (MRI) of cerebral white matter, especially the posterior limb of the internal capsule (PLIC). The biomarkers are: mechanistically relevant; clinically prognostic of severe neurological impairment; affected by therapy; and MRS is a bridging biomarker which detects the effect of neuroprotective therapy in animal studies. The prognostic characteristics of these biomarkers mean that the effects of the intervention may be analysed shortly after treatment, avoiding the need |
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E.2.2 | Secondary objectives of the trial |
We will also determine the safety of inhaled xenon gas by assessing several secondary outcomes prior to hospital discharge, comparing their incidence in the intervention and control groups. Impaired circulatory and blood-clotting function will be studied by comparing the rates of: Intracranial haemorrhage; Persistent hypotension; Pulmonary haemorrhage; Pulmonary hypertension; Prolonged blood coagulation time; Cardiac arrhythmia; Thrombocytopenia; Major venous thrombosis; Renal failure treated with dialysis. Incidence of infection will be assessed by comparing rates of culture proven sepsis, necrotising enterocolitis and pneumonia. Respiratory function will be assessed by comparing rates of pneumonia and pulmonary airleak. The mortality rate and the neurological examination score at discharge will be compared between groups. Comparing duration of hospitalisation for each group provides an overall indication of the level and severity of disease.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
A Infants 36 to 43 weeks gestation with at least one of the following: (a) Apgar score of < or =5 at 10 minutes after birth; (b) Continued need for resuscitation, including endotracheal or mask ventilation, at 10 minutes after birth; (c) Acidosis defined as pH <7.00 and/or base deficit >15 mmol/L in umbilical cord blood sample or any blood sample within 60 minutes of birth (arterial or venous blood). B Moderate to severe encephalopathy consisting of altered state of consciousness (reduced or absent response to stimulation) and hypotonia, and abnormal primitive reflexes (weak or absent suck or Moro response). Clinical severity of HIE will be assessed by Thompson encephalopathy score, and modified Sarnat score. C At least 30 minutes duration of amplitude integrated EEG (aEEG) recording that shows moderately abnormal or suppressed background aEEG activity or seizures.
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E.4 | Principal exclusion criteria |
• If treatment with hypothermia is delayed beyond 6 hours, or infants are expected to be >12 hours of age at the time of randomisation; • Infants with ventilatory oxygen requirement > 70%; • Attending clinician considers infant not suitable to participate because of other serious congenital abnormalities, or the infant’s condition appears terminal.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome will be: reduction in Lac/NAA ratio on magnetic resonance spectroscopy or preserved apparent diffusion coefficients or fractional anisotropy measured by tract based spatial statistics (TBSS) on diffusion weighted magnetic resonance imaging. |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | Information not present in EudraCT |
E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
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 | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Ventilation with air or oxygen as needed |
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E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
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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Last MRI examination in the last subject undergoing the trial |
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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 |