E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Neonatal hypoxia-ischaemia (HI). There is no exact MedDRA term for this. The closest MedDRA terms matching this are neonatal asphyxia and neonatal hypoxia. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028923 |
E.1.2 | Term | Neonatal asphyxia |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10028923 |
E.1.2 | Term | Neonatal asphyxia |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10028946 |
E.1.2 | Term | Neonatal hypoxia and asphyxia |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10050081 |
E.1.2 | Term | Neonatal hypoxia |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10050081 |
E.1.2 | Term | Neonatal hypoxia |
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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 study is designed to explore the technical feasibility of delivering the inhaled gas xenon in neonatal intensive care and to detect the unlikely event of derangement of body function not previously detected in its use with adults during anaesthesia and in the newborn of two animal species. |
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E.2.2 | Secondary objectives of the trial |
No secondary research questions but the pilot study is essential for the planning of a randomised trial to assess the effectiveness of this intervention. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Infants will be eligible for xenon if the St Michael’s standard inclusion criteria for cooling are met Standard Hypothermia Treatment Criteria for 72 hrs of cooling — all of criteria A, B, and C.
A Infants > 36.0 weeks gestation (clinical assessment) with at least ONE of the following: 1 Apgar score of <5 at ten (10) minutes after birth 2 Continued need for resuscitation, including endotracheal or mask ventilation, at ten minutes after birth 3 Acidosis defined as either umbilical cord pH or any arterial, venous or capillary pH within 60 minutes of birth less than pH 7.00 4 Base deficit greater than or equal to 16 mmol/L in umbilical cord blood sample or any blood sample within 60 minutes of birth (arterial or venous blood). If the infant meets criterion A then assess for neurological abnormality using criterion B and C (by trained personnel):
B Moderate or Severe encephalopathy as evidenced by any of the following -- 1 Altered state of consciousness (reduced or absent responses or pathological irritability and hyper responsive and at least ONE or more of the following: 2 Hypotonia 3 Abnormal reflexes including oculomotor or pupillary abnormalities 4 Absent or weak suck 5 Clinical seizures, as recorded by trained personnel And C At least 30 minutes duration of amplitude-integrated electroencephalography (aEEG) recording that shows abnormal background aEEG activity. The decision to cool is based on the worst section of the aEEG, not the best (al Naqeeb, et al, 1999) or seizures (clinical or electrical) thus meeting ONE of the following: 1 Normal background with some electrical seizure activity 2 Moderately abnormal activity (upper margin of trace >10μV and lower margin <5μV) 3 Suppressed activity (upper margin of trace <10μV and lower margin of trace <5μV) 4 Definite seizure activity
Additional inclusion criteria for xenon: Before being considered for additional inhaled xenon therapy via the breathing gas mixture, the infant would need to meet further additional entry criteria: 1) Intubated, ventilated, sedated, being cooled. 2) Any seizures under control. 3) Weight > 2.3 kg. 4) No evidence of infection. 5) Stable cardiovascular parameters; Mean arterial pressure >45mmHg. 6) Oxygen requirement via mechanical ventilator < 35%. 7) Positive End Expiratory Pressure (PEEP) requirement < 6mmHg 8) Arterial pCO2 within the accepted range (4.5-6.5 kPa) 9) Postnatal age <18 hours 10) Major congenital abnormalities, imperforate anus and congenital abnormalities suggestive of chromosomal anomaly or other syndromes that include brain dysgenesis.
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E.4 | Principal exclusion criteria |
Exclusion criteria for cooling 1. Infants expected to be greater than 12 hours of age at the time of starting cooling treatment. 2. Futility. Where prognosis is considered to be hopeless e.g. no cardiac output for 20 minutes.
Failure to meet the additional inclusion criteria for xenon: Before being considered for additional inhaled xenon therapy via the breathing gas mixture, the infant would need to meet further additional entry criteria: 1) Intubated, ventilated, sedated, being cooled. 2) Any seizures under control. 3) Weight > 2.3 kg. 4) No evidence of infection. 5) Stable cardiovascular parameters; Mean arterial pressure >45mmHg. 6) Oxygen requirement via mechanical ventilator < 35%. 7) Positive End Expiratory Pressure (PEEP) requirement < 6mmHg 8) Arterial pCO2 within the accepted range (4.5-6.5 kPa) 9) Postnatal age <18 hours 10) Major congenital abnormalities, imperforate anus and congenital abnormalities suggestive of chromosomal anomaly or other syndromes that include brain dysgenesis.
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E.5 End points |
E.5.1 | Primary end point(s) |
This is a feasibility study of adding xenon inhalation to the the established treatment of cooling the body down to 33.5 C for days. 1)Our hypothesis is that we will observe no changes in those clinical and biochemical markers that we routinely monitor in infants who receive cooling therapy. We have local comparable data (infants recruited with same entry criteria) from 50 cooled infants (in the anomyised database described in REC09/Ho106/3).
2)We will monitor a number of variables: Gas exchange: Oxygen saturation, end-tidal carbon dioxide concentration, blood gas data, mechanical ventilation requirements (rate, peak inspiratory pressure, PEEP settings). Alveolar-arterial oxygen gradient [P(A - a)O2].
Haemodynamic: Mean arterial pressure, heart rate.
Any problems during weaning and extubation, such as post-extubation stridor.
In addition we have looked at other variables in our own cooled babies which we also intend to record in this study: 1] Inotrope requirement, TroponinI 2] Hepatic impairment, [raised Alanine aminotransferase > 40, Alkaline phospatase > 100] 3] Renal impairment, oliguria [urine output < 1 ml/kg/h, raised creatinine > 100] 4] Infection [culture proven, need for antibiotics ~ 5 days, raised CRP ~ within 4 days of life] 5] Length of hospital stay 6] Coagulopathy [INR >2, APTT> 50] 7] Seizures (from EEG recording)
The study is designed to explore the technical feasibility of delivering the inhaled gas xenon in neonatal intensive care and to detect the unlikely event of derangement of body function not previously detected in its use with adults during anaesthesia and in the newborn of two animal species. |
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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 | No |
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) | No |
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 |
Xenon is licenced in UK for use in adults as anaesthetic. However this will be first use in neonates |
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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 | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
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 | No |
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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
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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Once last case has been recruited and left the Special Care Baby Unit the main trial will be completed. Long term follow up is routine practice in these neonates and all aspects of the trial will be completed when last baby enrolled is seen in clinic at 18m follow up visit. Enrollment period is up to 2 years and if a neonate is enrolled at 2 years they will still be followed up until 18 months. Therefore maximum potential trial duration is 3 years 6 months, so this is the value we have given. |
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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 | 6 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |