| 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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| E.1.1.1 | Medical condition in easily understood language |
| Lack of blood flow and oxygen delivery to the brain of a bay at or around the time of birth. Causes can be multifactorial. |
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| E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutic techniques [E02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10050081 |
| E.1.2 | Term | Neonatal hypoxia |
| 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 | HLT |
| E.1.2 | Classification code | 10028946 |
| E.1.2 | Term | Neonatal hypoxia and asphyxia |
| E.1.2 | System Organ Class | 10036585 - Pregnancy, puerperium and perinatal conditions |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10028923 |
| E.1.2 | Term | Neonatal asphyxia |
| 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary Objective:
This is a randomised two group pilot study comparing;
i) xenon inhalation for 18 hours in combination with whole body cooling to 33.5 °C for 3 days, to
ii) the established treatment of cooling the body down to 33.5 °C for 3 days.
This will be applied in term newborn babies who are at moderate or high risk of brain injury following poor condition around the time of birth.
Our hypothesis is that during the first 2 weeks after birth using a combination of validated (in our own and others cohorts) early predictors of outcome we may observe an enhanced neuroprotective effect of the xenon-cooling combination over cooling alone and this will allow us to perform power calculations for a larger definitive neurological outcomes study of otherwise similar design.
Outcome predictors are based on a combination of:
1) Time in hours after birth when background activity as recorded by amplitude integrated EEG (aEEG: from single channel EEG) [1] and onset of sleep |
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| E.2.2 | Secondary objectives of the trial |
Secondary Objectives:
We will monitor a number of variables before/during and after the period of xenon delivery. This group of physiological and biochemical parameters includes those recorded during our recently completed xenon+cooling feasibility/safety study in neonates and a few more are added .
They are:
Gas exchange: Transcutaneous oxygen saturation, end-tidal carbon dioxide concentration, blood gas data (from arterial sample), mechanical ventilation requirements (rate, peak inspiratory pressure, PEEP settings).
Haemodynamic: Systolic, mean and diastolic arterial pressure, heart rate.
Any problems during weaning and extubation, such as post-extubation stridor, use of steroids.
We have also looked at other variables in the infants cooled in our hospital (inborn or outborn) ca 30/year since 1/12/06. We chose the best matched controls (3:1) from this cooling database and compared them with the 14 infants in the recent Xenon + cooling human feasibility study ( the |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria
Patients meeting the following criteria will be considered eligible for the study:
Infants will be eligible for inclusion in this study if the St Michael�??s hospital standard inclusion criteria for cooling are met and additional inclusion criteria for xenon administration are met.
St Michael�??s hospital standard inclusion criteria for cooling
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
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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 (all must be met):
1) Intubated, ventilated, sedated, being cooled.
2) <5 hours old
3) Any seizures under control.
4) Weight > 2nd centile for gestational age
5) Stable cardiovascular parameters; Mean arterial pressure >40mmHg.
6) Oxygen requirement via mechanical ventilator < 40%.
7) Positive End Expiratory Pressure (PEEP) requirement < 6cm H2O
8) Arterial pCO2 within the accepted range (4.0-6.5 kPa)
9) Postnatal age <5 hours
10) Absence of major congenital abnormalities, imperforate anus and in particular any bowel obstruction, congenital abnormalities suggestive of chromosomal anomaly or other syndromes that include brain dysgenesis. Neonates with congenital syndromes affecting the brain should be excluded when diagnosed (see exclusion criteria below)
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| E.4 | Principal exclusion criteria |
Exclusion Criteria
Exclusion criteria for cooling
1. Infants expected to be greater than 5 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.
Additional exclusion criteria for xenon
Failure to meet any of the additional inclusion criteria for xenon listed in section 5.1.
Patients meeting the following criteria are NOT eligible for the study:
Presence of any of:
Major congenital abnormalities, imperforate anus and in particular any bowel obstruction, congenital abnormalities suggestive of chromosomal anomaly or other syndromes that include brain dysgenesis. (Neonates with congenital syndromes affecting the brain should be excluded when diagnosed).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Objective:
This is a randomised two group pilot study comparing;
i) Adding xenon inhalation for 18 hours in combination with the (existing) whole body cooling to 33.5 °C for 3 days.
ii) The established treatment of cooling the body down to 33.5 °C for 3 days.
This will be applied in term newborn babies who are at moderate or high risk of brain injury following poor condition around the time of birth, the purpose being to reduce long term neurological impairment resulting from their condition.
Our hypothesis is that early predictors of outcome* will show a trend towards an enhanced neuroprotective effect of the xenon-cooling combination over cooling alone. The early predictors will allow us to perform power calculations for a much larger neurological outcomes study of otherwise similar design.
In addition we will examine the feasibility of earlier recruitment and start of xenon and whether we obtain the same early predictor data in the hypothermia-only group as we have in our previous hypothermia database.
(*the total clinical follow up period will be much longer than this as is already the case for cooled babies in Bristol)
2.1 Primary Endpoint
This is a randomised two group pilot study comparing;
1) xenon inhalation for 18 hours in combination with whole body cooling to 33.5 °C for 3 days, to
2) the established treatment of cooling the body down to 33.5 °C for 3 days.
This will be applied in term newborn babies who display signs indicating moderate or severe brain injury following poor condition at birth.
Our hypothesis is that we may observe an enhanced neuroprotective effect of the xenon-cooling combination over cooling alone assessed initially by early outcome predictors. This will allow us to perform power calculations for a much larger neurological outcomes study of otherwise similar design. We have tested a combination of our early predictors (using our TOBY registry cooling data in 80 infants) against Bailey outcome at 18 months and found they have a positive predictive value of 94% in cooled infants
Early predictors of outcome
For the main analysis we will use
Time to recovery after birth of a normal aEEG [1]
MRI scan before 14 days of life [32, 2]
Peak LDH value within 72h of life [4, 33]
We will also collect data on:
Plasma glucose at birth (in cord blood)
Age in hours after birth when plasma lactate is normalised
Different inotropic drugs needed and the total duration in hours of any inotropic support
Number of anticonvulsants given
Amount and duration of sedation (e.g.morphine)
Age at full oral feeds (breast or bottle)
Neonatal hearing screening before 14 days of life
Clinical examination at birth, at 7 days of age and at discharge including weight and head circumference
Neurodevelopmental follow up is a part of the routine follow up of infants with HIE, Bayley examination at 18 months of age.
Disability will be defined as any of:
Bayley II mental developmental scale (MDI) score less than 70.
Bayley II motor development scale (PDI) score less than 70. MDI and PDI will also be calculated as DQ, developmental score as this allows a larger range of score for those functioning at a low level [34]. Bilateral cortical visual impairments
Hearing loss needing amplification > 40 DB.
In addition any Adverse Events will be recorded and criteria have been devised for stopping the study early if necessary. This includes a Data Review Panel to review data when 4 xenon infants have undergone xenon treatment.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The early predictors of outcome will be completed by 2 weeks of age.
The neurodevelopmental follow up will be completed by 2 years of age. |
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| E.5.2 | Secondary end point(s) |
A series of variables that are among the most relevant for evaluation of safety (see endpoints below) were examined closely in the previous 14 baby feasibility/safety study. We will continue to routinely monitor and record the same set of physiological variables in the proposed study, for a subset of data for a longer time period until after rewarming.
�?� Endpoint 1 �?� defined as Mechanical ventilation and gas exchange parameters
�?? The following variables will be measured before (from start cooling), during and after xenon administration (for 12h or until 12h after end of cooling hours pending which variable):Transcutaneous Oxygen saturation, end-tidal carbon dioxide concentration, blood gas data, mechanical ventilation requirements (rate, peak inspiratory pressure, inspiratory time, PEEP settings),FiO2. Average percentage xenon in inspired gas mixture (when applicable). Tracheal tube cuff pressure.
�?� Endpoint 2 �?� defined as Haemodynamic parameters
�?? The following variables will be measured before, during and after xenon administration: Systolic, mean and diastolic arterial pressures, Heart rate.
�?� Endpoint 3 �?� defined as Inotropic drug requirements
�?? These (drug, dose and duration) will be recorded before, during and after xenon administration until 12h after end of cooling.
�?� Endpoint 4 �?� defined as Marker of myocardial impairment/insult
The following will be recorded before and after xenon administration: Plasma levels Troponin T (marker of myocardial cell death) recorded before and after xenon administration until 12h after end of cooling:
�?� Endpoint 5 �?� defined as timecourse and peak value of Markers of hepatic impairment
�?? These will be recorded before and after xenon administration until 12h after end of cooling: [Alanine aminotransferase , Alkaline phosphatase and Lactate Dehydrogenase]
�?� Endpoint 6 �?� defined as timecourse and peak value of Markers of renal impairment
�?? These will be recorded before, during and after xenon administration until 12h after end of cooling: oliguria is defined as [urine output < 1 ml/kg/h] from age > 24h, raised creatinine > 100 at > 24h of age.
�?� Endpoint 7 �?� defined as Evidence of infection
�?? These will be recorded: [culture proven, need for antibiotics for 5 or more days, raised CRP occurring within 24h or later.
�?� Endpoint 8 �?� defined as Length of hospital stay including duration of stay in local hospital after discharge from St Michaels hospital
�?? This will be recorded
�?� Endpoint 9 �?� defined as age when full oral feeding was achieved by breast or bottle
�?? This will be recorded
�?� Endpoint 10 �?� defined as Haematology measurements
�?? These will be recorded before and after xenon administration (these are routinely recorded 24 hrly): Coagulopathy [INR >2 and/or APTT> 50]. Full blood count.
�?� Endpoint 11 �?� defined as Serum chemistry measurements
�?? These will be recorded before and after xenon administration: Serum sodium, potassium, chloride, magnesium, phosphate, calcium, (urea, creatinine as above), glucose, (liver enzymes as above), bilirubin, albumin. Drug levels may be analysed on clinical indication (Gentamicin levels, Phenobarital levels).
�??
�?� Endpoint 12 �?� defined as aEEG background pattern and Evidence of seizures
�?? These will be recorded before, during and after xenon administration until 12h after end of cooling: Evidence from continuous aEEG/EEG recording and any anticonvulsant treatments given.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| These measures will be completed by 2 weeks 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 | No |
| 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 | 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 | Yes |
| 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 |
| Cooling for 72h (the conventional treatment for this condition) |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | No |
| 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 the 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 3.5 years 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 | 4 |
| 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 | 4 |
| 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 |
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