Clinical Trials Register

Summary
EudraCT Number:	2013-004478-80
Sponsor's Protocol Code Number:	Issue1
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2014-04-04
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2013-004478-80

A.3

Full title of the trial

XENON AND COOLING THERAPY IN BABIES AT HIGH RISK OF BRAIN INJURY FOLLOWING POOR CONDITION AT BIRTH: A RANDOMISED OUTCOME STUDY (COOLXENON3 STUDY)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Randomised outcome study of cooling therapy (standard treatment) versus inhaled xenon gas in combination with cooling, in babies at high risk of brain injury following poor condition at birth.

A.3.2

Name or abbreviated title of the trial where available

CoolXenon3

A.4.1

Sponsor's protocol code number

Issue1

A.5.4

Other Identifiers

Name:	Sponsor - UHBristol NHS Trust	Number:	CH/2013/4414
Name:	Central Bristol Research Ethics Committee	Number:	13/SW/0300

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	University Hospital Bristol NHS Foundation Trust
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	The Moulton Charitable Foundation
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University Hospitals Bristol
B.5.2	Functional name of contact point	Professor Marianne Thoresen
B.5.3	Address:
B.5.3.1	Street Address	St Michael's Hospital, Level D, Southwell Street
B.5.3.2	Town/ city	Bristol
B.5.3.3	Post code	BS2 8EG
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	01173425226
B.5.5	Fax number	01173425751
B.5.6	E-mail	marianne.thoresen@bris.ac.uk

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	LENOXe
D.2.1.1.2	Name of the Marketing Authorisation holder	AIR LIQUIDE Medical GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Germany
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	LENOXe
D.3.4	Pharmaceutical form	Emulsion for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Inhalation use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Xenon
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	% (V/V) percent volume/volume
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100%
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	Yes
D.3.11.13.1	Other medicinal product type	Xenon is an elemental noble gas extracted from atmospheric air during the process of oxygen manufacture by fractional distillation of air. It is known to have anaesthetic and analgesic effects.

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes

E. General Information on the Trial

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.

E.1.1.1

Medical condition in easily understood language

Lack of blood flow and oxygen delivery to the brain of a baby at or around the time of birth. Causes can be multifactorial.

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	16.1
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

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.1
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	100000004868

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.1
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

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

This is a randomised two group pilot outcomes study comparing Bayley neurodevelopmental outcome scores between;
i) the established treatment of cooling the body down to 33.5 °C for 3 days; to
ii) Xenon inhalation for 18 hours in combination with whole body cooling 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 the Bayley Scales of Infant and Toddler Development (Bayley III) scores at 18m of age will show a trend towards an enhanced neuroprotective effect of the Xenon-cooling combination over cooling alone.

E.2.2

Secondary objectives of the trial

The following potential predictors of outcome will be used:
a. Time to recovery after birth of a normal aEEG1
b. MRI scan before 14 days of life2,35
c. Peak LDH value within 72h of life4,36
d. Resistance Index (RI).
We will also collect data on:
e. Plasma glucose at birth (in cord blood)
f. Age in hours after birth when plasma lactate has fallen to 5mmol/L
g. Different inotropic drugs needed and the total duration in hours of any inotropic support
h. Number of anticonvulsants given
i. Amount and duration of sedation (e.g. morphine)
j. Age at full oral feeds (breast or bottle or tube)
k. Neonatal hearing screening result before 14 days of life
l. Clinical examination at birth, at 7 days of age and at discharge including weight and head circumference

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Infants will be eligible for Xenon 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 (estimated or clinical assessment) with at least ONE of the following:
i. Apgar score of ≤5 at ten (10) minutes after birth
ii. Continued need for resuscitation, including tracheal or mask ventilation, at ten minutes after birth
iii. Acidosis defined as either umbilical cord pH or any arterial, venous or capillary pH within 60 minutes of birth less < 7.00
iv. Base deficit ≥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:
i. Altered state of consciousness (reduced or absent responses or pathological irritability and hyper responsive and at least ONE or more of the following:
ii. Hypotonia
iii. Abnormal reflexes including oculomotor or pupillary abnormalities
iv. Absent or weak suck
v. 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 30 min section of the aEEG, not the best, or seizures (clinical or electrical) thus meeting ONE of the following:
i. Normal background with some (> 5 min) electrical seizure activity
ii. Moderately abnormal activity (upper margin of trace >10μV and lower margin <5μV)
iii. Suppressed activity (upper margin of trace <10μV and lower margin of trace <5μV)
iv. 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 (all must be met):
i. Intubated, ventilated, sedated, being cooled.
ii. ≤5 hours old
iii. Any seizures under control.
iv. Weight > 2nd centile for gestational age
v. Stable cardiovascular parameters; Mean arterial pressure >40mmHg.
vi. Oxygen requirement via mechanical ventilator < 40%.
vii. Positive End Expiratory Pressure (PEEP) requirement ≤ 8cm H2O
viii. Arterial/capillary/venous pCO2 <7.0kPa (ideally arterial). Venous can be higher if peri-arrest and tissues have been very recently Ischaemic
ix. Postnatal age ≤5 hours
x. 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. Congenital syndromes affecting the brain should be excluded when diagnosed.

E.4

Principal exclusion criteria

Exclusion criteria for cooling in the CoolXenon3 study
a. Infants expected to be greater than 3 hours of age at the time of starting cooling treatment.
b. Futility. Where prognosis is considered to be hopeless e.g. no cardiac output for 20 minutes.

E.5 End points

E.5.1

Primary end point(s)

This is a randomised two group pilot outcomes study comparing Bayley scores between;
1) Xenon inhalation for 18 hours in combination with whole body cooling to 33.5 °C for 3 days, and
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.

E.5.1.1

Timepoint(s) of evaluation of this end point

18 months

E.5.2

Secondary end point(s)

The following potential predictors of outcome will be used:
a. Time to recovery after birth of a normal aEEG1
b. MRI scan before 14 days of life
c. Peak LDH value within 72h of life
d. Resistance Index (RI).
We will also collect data on:
e. Plasma glucose at birth (in cord blood)
f. Age in hours after birth when plasma lactate has fallen to 5mmol/L
g. Different inotropic drugs needed and the total duration in hours of any inotropic support
h. Number of anticonvulsants given
i. Amount and duration of sedation (e.g. morphine)
j. Age at full oral feeds (breast or bottle or tube)
k. Neonatal hearing screening result before 14 days of life
l. 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:
m. Bayley III Cognitive Composite score less than 85.
n. Bayley III Motor Composite score less than 85
Bayley scores will also be expressed as a Developmental Quotient (DQ) calculated from developmental age scores as this allows a larger range of scores for those functioning at a low level.
o. Bilateral cortical visual impairments
p. Hearing loss needing amplification > 40dB.

In addition any Adverse Events will be recorded and criteria have been devised for stopping the study early if necessary. The IDRG will review data after when 8, 16 and 24 infants have undergone Xenon treatment.

E.5.2.1

Timepoint(s) of evaluation of this end point

14 days

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

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

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Cooling for 72h (the conventional treatment for this condition)

E.8.2.4

Number of treatment arms in the trial

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

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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

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 thelast 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.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1