Parent Information Leaflet A study of the neuroprotective effects of hypothermia combined with inhaled xenon following perinatal asphyxia ISRCTN08886155 /EUDRACT 200901434411 Version 7, 31/01/2013

The TOBY Xe Study We know that your baby is very unwell and that this is a very difficult time for you. We also know that your doctor will already have spoken to you about what has happened to your baby. We would like to talk to you about a research study that we are doing. We feel you may want to know about this study and have the opportunity to take part if you wish. Before you decide we would like you to understand why the research is being done and what it would involve for you. One of our team will go through the information sheet with you and answer any questions you have. Do not hesitate to ask if there is anything that is not clear or you do not understand.

What is perinatal asphyxia? Perinatal asphyxia is the word used by doctors when they suspect that the baby may have suffered from a lack of oxygen around the time of birth. We do not always know what causes perinatal asphyxia but we do know that lack of oxygen to the baby’s brain can lead to brain injury. This injury may be severe and some babies will not survive. If a baby with perinatal asphyxia does survive, there is a chance that the baby will be disabled. Disability can be severe or it can be very mild but some degree of disability occurs in about half of the babies. Until recently, the only treatment we had for perinatal asphyxia was standard intensive care. However, recent studies have shown that some benefit may result from cooling, used alongside standard intensive care. This means that the baby’s temperature is reduced by 3-4 degrees C for 3 days, and then gradually returned to normal. Your baby is suitable for treatment for cooling, and this will be started shortly if not already in place. However, we still continue to try to find ways to improve the health of babies such as yours.

What is the purpose of the study? We already know that babies with perinatal asphyxia may benefit from treatment with cooling, but there is still a chance that some babies will be disabled to some degree; in severe cases the baby may not survive. This study will find out if using inhaled Xenon gas in addition to cooling treatment

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provides added benefit, possibly improving survival and reducing disability. This study will also find out whether using inhaled Xenon with cooling is less beneficial than treating with cooling alone, or makes no difference. We will compare intensive care with cooling treatment (Cooling) to intensive care, cooling treatment plus inhaled Xenon (Cooling plus Xenon).

What is Xenon? Xenon is a gas that is present in very small quantities in the atmosphere. When breathed at concentrations above 50% it causes sedation and it is sometimes used as an anaesthetic gas. At lower concentrations it has been found in experimental studies to protect brain cells after asphyxia possibly by reducing the buildup of harmful substances in the brain.

Why is my baby suitable for this study? The specialists looking after your baby know from your baby’s condition and from tests that they have performed that your baby has perinatal asphyxia and cooling treatment is appropriate for your baby. Babies who are suitable for cooling treatment are also eligible to be included in this study.

Does my baby have to take part? Your baby does not have to take part in this study if you do not want to be involved. If you decide not to take part, your baby will receive normal intensive care treatment, which includes cooling treatment. If you do decide to take part in the study you may withdraw your baby from the study at any time without having to give a reason. Your decision whether to take part or not will not affect the care your baby receives in any way.

What will happen to my baby if I agree take part? Your baby is already receiving intensive care treatment and cooling may also have started, or will do so shortly. If you do decide to take part in the study, your baby will be treated with either ‘Cooling’ or ‘Cooling plus Xenon’. Taking part in the study does not mean that your baby will be definitely be treated with Xenon; half the babies in the study are treated with cooling alone, the other half will be treated with cooling plus inhaled Xenon. Page 2 of 10

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Following the treatment there will be some tests that will help us find out what effects it has had.

How is the treatment chosen, or ‘allocated’? This study is called a ‘randomised controlled trial’. Sometimes we do not know which way of treating patients is best. To find out, we need to compare different treatments. We put people into groups and give each group a different treatment. The results are compared to see if one is better. To try to make sure the groups are the same to start with, each patient who is suitable for the study is put into a group by chance (randomly). The decision about which treatment your baby will receive is random; this means that the decision is made by chance, in this case using a computer program. The decision is not made by your doctor choosing which babies are treated with Xenon. In this study there are two groups and your baby has an equal chance of being in either group, or a 50/50 chance. The decision about treatment needs to be made before your baby is 12 hours of age. If your baby is allocated to the ‘Cooling’ group, your baby will be looked after in the Neonatal Intensive Care Unit. Your baby’s breathing is being helped by a ventilator, which provides air with extra oxygen if required. The ventilator will be used for as long as your baby needs help with breathing. Some babies with perinatal asphyxia will have seizures, or fits, so your baby’s brain activity is monitored using a Cerebral Function Monitor, using some wires attached to the scalp. The exact treatment your baby receives will depend on what problems your baby has. In addition to difficulty breathing, babies may not be able to keep their blood pressure normal and they may have difficulties feeding. We can treat all these conditions while your baby is in the Neonatal Intensive Care Unit. If your baby is allocated to ‘Cooling plus Xenon’, your baby will receive the same intensive care as above. In addition, your baby will be given Xenon gas to breathe. This means that the ventilator that helps your baby breathe will provide air, additional oxygen if required, plus 30% Xenon gas.

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The xenon gas is used for 24 hours, and then normal air with oxygen is used. Your baby can only breathe Xenon using the ventilator; once the Xenon treatment is finished the ventilator will only be used for as long as your baby needs it. The remaining parts of the Study are the same for both groups: 1

Neurological examinations

Your baby will be examined daily by a neonatologist, who will ‘score’ specific clinical signs that indicate how your baby’s neurological system is recovering. 2 3

Magnetic Resonance Imaging (MRI) and Magnetic Resonance Spectroscopy (MRS)

These scans of your baby’s head will be performed within 15 days of birth. They are done in one procedure that will last 1-2 hours, using a magnetic resonance scanner. There are scanners located at each of the treatment centres. It is possible that the scan will need to be performed at a different centre from the one where your baby received its treatment and you will be fully informed if this is the case. If a transfer to a different centre is necessary it will be done by a specialist transfer team, and your baby will be returned to the original treatment centre once the scan has been completed. The scan will provide two important pieces of information that will be used when the study data are analysed; the people analysing the information will not know whether your baby has received Xenon or not. MRS is used to tell us about the levels of chemicals in the brain, and their relationship to each other, or their ‘ratio’. Previous research has shown that this ratio can predict with some accuracy whether future development is likely to involve some disability or not. MRI produces a series of images that will be examined by an expert for signs of specific changes within the brain resulting from perinatal asphyxia. After your baby has been scanned, the scan data and your baby’s date of birth will be uploaded to a secure computer which is compliant with the UK Data Protection Laws. This will allow us to analyse the data from all the hospitals taking part in the study. Lastly, as it is routine for babies like yours, who have been very ill at birth, to be assessed at around 2 years of age, we will ask if we may have a copy of this examination for our records and analysis.

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What will I have to do? Before we go any further you will have a chance to ask questions about the study and about anything you do not understand. It is important to us that you make your decision knowing as much as you can about what is involved. You may discuss this with your partner or other family members. As this study requires that randomisation takes place before your baby is 12 hours of age, this does limit the time you can take to make your decision. If you do agree that your baby takes part, then you will be asked to sign a consent form. You will be given a copy of this form to keep.

What are the alternatives for diagnosis or treatment? There is a slight possibility that your baby’s problems are not due to perinatal asphyxia but to some other cause, a congenital problem for example. It is unlikely that this could be diagnosed before the 12-hour age limit for joining the study has passed. Your baby has been examined by a consultant neonatologist and relevant tests performed and you will be informed of the results. Apart from providing intensive care and treating any complications as they arise there is no other treatment that can be offered. Xenon treatment is only being offered in one other hospital in the UK as part of another research study, in addition to this trial.

What are the possible disadvantages and risks of taking part? Xenon is already safely in use as an anaesthetic gas in adults; this study looks at its potential to protect the newborn brain using much lower concentrations than are used in anaesthetics. This is a new way of using Xenon and side effects may become apparent during the study. The doctors and nurses providing the treatment will be extremely vigilant; any possible side effects will be reported in detail and reviewed by an independent committee at regular intervals. If necessary the Xenon and cooling treatments can be stopped early if this is best for any of the babies in the study.

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Cooling treatment has been shown to be a safe treatment in newborns. Magnetic resonance scanning is widely used and like cooling is a noninvasive procedure.

What are the side effects of any treatment received when taking part? The slight but most likely side effect associated with Xenon is that of additional effects on your baby’s heart and circulation; however this is extremely unlikely with the dose of Xenon that will be used. All babies in this study will require intensive care, which means continuous monitoring of your baby’s heart rate, temperature, blood pressure and respiration, regular blood tests and close observation by highly skilled staff. All necessary care and treatment will be given to ensure that your baby is kept in a stable condition that will promote recovery.

What are the possible benefits of taking part? We do not know yet if there is any definite benefit from treatment with Xenon. This study will help to confirm whether or not the treatment is beneficial, or makes no difference.

What happens when the research study stops? There is no further treatment or involvement with this Study when it has finished, except that we would like your permission for us to have a copy of your child’s follow-up examination results at 2 years of age.

What if relevant new information becomes available? It is possible that other new information may become available during the course of the study, which is due to last for 3 years. It is unlikely to affect your baby’s short involvement with the study. If the study is stopped early because of new information you will be informed about this; it is unlikely to affect your baby’s ongoing care.

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What will happen if I do not want to carry on with the study? You are free to withdraw your baby from the study at any time without providing a reason; if you make this decision you will need to inform your baby’s consultant and it will be recorded in your baby’s notes. The consultant and research clinicians will also explain your options about allowing your baby’s data to be used or withdrawn from the study. This decision will not affect in any way the normal care and treatment that your baby needs.

What if there is a problem? Imperial College London holds insurance policies which apply to this study. If you experience serious and enduring harm or injury as a result of taking part in this study, you may be eligible to claim compensation without having to prove that Imperial College is at fault. This does not affect your legal rights to seek compensation. If you are harmed due to someone’s negligence, then you may have grounds for a legal action. Regardless of this, if you wish to complain, or have any concerns about any aspect of the way you have been treated during the course of this study then you should immediately inform the Investigator (name and contact details given at the end). The normal National Health Service complaint complaints mechanisms are also available to you. If you are still not satisfied with the response, you may contact the Imperial AHSC Joint Research Office.

Will my taking part in this study be kept confidential? All the information we gather about you and your baby will be stored securely and only members of the study team will be able to see it. The information we need for the study includes details about your pregnancy and about your baby’s stay in the neonatal unit, as well as details of your family doctor. This information will be collected from the medical notes and written onto the TOBY Xe study forms. These forms will be returned to the study coordinating centre in Oxford. Because we need to contact you to find out how your baby is at 2 years of age, we need your name, your address and other contact details. The NHS has an Information Centre which we will be using to keep in touch with you. They will also let us know if you or your baby leaves the NHS.

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Any personal details on paper or in electronic form will be stored in secure conditions, in locked cabinets or in password-protected files with limited access rights. We will only use your details for the conduct of the study. Your baby will be allocated a unique Study number; your baby’s data that will be used for analysis will be coded by this number. No personal identifiable data will be published. It is possible that if the conduct of this study is audited by its funder or sponsor for example, that authorised personnel will examine the study records. All will have a duty of confidentiality to you and your baby as a research participant and we will do our best to meet this duty. We will provide a summary of your infant’s care in hospital to your general practitioner.

What will happen to the results of the research study? The study will run for three years. At the end of the study the results will be made available to doctors and nurses caring for babies like yours throughout the world. Of course you and your baby will not be identified in any report or publication about the study. We will also send you a summary of the final results of the study, unless you ask us not to. This is unlikely to be before 2013.

Who is organising and funding the research? The study is being run by the Imperial College Healthcare NHS Trust, University College, Hospital and the National Perinatal Epidemiology Unit in Oxford. The study is funded by the Medical Research Council, and its sponsor is Imperial College London. Your doctor will not be paid for including you in this study, nor do participants receive payment. The original research which showed that xenon can protect the brain was carried out at Imperial College London. This work has led to the granting of patents, which name some members of the research team at Imperial College London (David Edwards, Consultant Neonatologist and Weston Professor of Neonatal Medicine; Nicholas Franks, Professor of Biophysics and Anaesthetics, and Mervyn Maze, Professor of Anaesthetics).

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Who has reviewed/approved the study? All research in the NHS is looked at by independent group of people, called a Research Ethics Committee, to protect your interests. The study has been reviewed and approved by the West London Research Ethics Committee 1. Each centre taking part in the study will also have the study approved by their Local Research Ethics Committee. Before funding was granted by the Medical Research Council, the study was also reviewed by their experts.

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Further information and contact details Data Co-ordinating Centre

Chief Investigator

NPEU Clinical Trials Unit University of Oxford Old Road Campus Headington Oxford OX3 7LF

Professor Denis Azzopardi Department of Paediatrics Faculty of Medicine, Imperial College London Hammersmith Campus, Du Cane Road London W12 0NN

Tel: 01865 289735 Fax: 01865 289740 [email protected]

Tel: 0208 383 3326 Fax: 0208 740 8281 [email protected]

Local contact details for each participating centre Queen Charlotte and Chelsea Hospital Principal Investigator: Dr Aniko Deierl 5th Floor Hammersmith House, Queen Charlotte and Chelsea Hospital Du Cane Road W12 0HS

University College Hospital Principal Investigator: Professor Nicola J Robertson Institute for Women’s Health 86-96 Chenies Mews London WC1E 6HX

Tel: 020 331 38515 [email protected]

Tel 0207 679 605 Fax 0207 679 9426 [email protected]

St Thomas Hospital

Liverpool Women’s Hospital

Principal Investigator: Dr Andrew Kapetanakis Neonatal Unit St Thomas Hospital Westminster Bridge Road London SE1 7EH

Principal Investigator: Dr Mark Turner Liverpool Women’s NHS Foundation Trust Crown Street Liverpool L8 7SS

Tel: 0207 188 7188 [email protected]

Tel: 0151 795 9558 Fax: 0151 702 4024 [email protected]