For Trial Participants

The ECUSTEC trial will assess whether eculizumab reduces the severity of Shiga-toxin producing Escherichia coli Haemolytic Uraemic Syndrome (STEC HUS) in children and young people.

Shiga-Toxin producing E. Coli Haemolytic Uraemic Syndrome (STEC HUS) is a sudden illness that develops in some people (often children and young people) after a gut infection caused by bacteria called STEC (Shiga-toxin producing E.Coli). People with STEC HUS often develop acute kidney injury – when the kidneys suddenly stop working properly – and some of these people need dialysis (artificial kidney treatment). Sometimes STEC HUS can cause complications in other parts of the body. Most people fully recover from STEC HUS but some will have long-term consequences and may need long-term specialist care.

Eculizumab is a medicine that blocks part of the immune (infection-fighting) system that seems to play a part in causing STEC HUS. Some doctors have given eculizumab to people with severe STEC HUS but not in a systematic way that can tell us whether it worked. We are testing eculizumab in a trial to see if it can make STEC HUS better.

The purpose of this trial is to see whether giving two doses of eculizumab to children and young people with STEC HUS reduces the severity of their disease. 134 children and young people with STEC HUS will be selected by kidney specialists at children’s kidney units around the UK over a four year period. In addition to their normal care, they will receive either eculizumab or placebo (dummy treatment) within 36 hours of arriving at the children’s kidney unit and a second dose of the same medicine a week later. In order to find out if eculizumab has been effective, information about each child’s progress over the following 12 months will be collected by the team at the children’s kidney unit and sent to the ECUSTEC trial co-ordination centre at the Birmingham Clinical Trials Unit (BCTU).

STEC HUS can cause a number of serious health problems. The kidneys may suddenly fail or stop working properly needing dialysis (artificial kidney treatment). Other rare but serious complications in other parts of the body include diabetes (raised blood sugar, usually temporary), colitis (inflamed bowel, occasionally needing surgery), seizures (fits), problems with vision or a stroke. Most people fully recover from STEC HUS, but some will have long-term consequences and may need long-term specialist care.

We are testing eculizumab to see if it can reduce the severity of STEC HUS, for example result in less time on dialysis or fewer children developing complications in other parts of the body. Half the children in the trial will receive two doses of eculizumab and half will receive two doses of placebo (dummy medicine) so that we can compare the outcome in both groups.

Children and young people aged 6 months to 18 years, inclusive, with STEC HUS.

If you agree for your child to take part in the trial a computer will decide whether they receive active eculizumab or a placebo – a bit like tossing a coin. Neither you nor your doctor will know whether your child has been given the eculizumab or the placebo, though this information can be found out if it is absolutely essential in an emergency. This is to make the trial the best possible test of which treatment is better.

The first injection will be given within 36 hours of your child arriving at the children’s kidney unit. This is because we think that the earlier eculizumab is given, the more effect it might have. Your child will receive a second injection of the same treatment (eculizumab or placebo) a week later. All participants, whether given eculizumab or placebo, will receive vaccination against “meningococcus”, an organism that causes meningitis (infection of the linings of the brain), and septicaemia (blood infection) and will receive an 8 week course of twice daily low dose antibiotic by mouth to help prevent meningococcal infection (see “what are the side effects of the treatment” below).

All participants will be assessed regularly until discharge from hospital (the time until discharge varies depending on the course of the illness) and then at 1, 2, 6 and 12 months from enrolment to assess their progress. At each visit, information will be collected on your child’s clinical progress, treatments they have required and complications experienced.

If your child experiences any signs or symptoms of brain involvement (such as fits, problems with vision, a stroke) during their time in hospital, a full examination of the central nervous system (brain) including vision, hearing and psychological (child behaviour) assessments, will be undertaken at the 2 month visit. These will involve clinic assessments (possibly over more than one visit) with an audiologist, ophthalmologist, and paediatric neurologist. You will also be asked to complete a questionnaire about your child’s behaviour.

The progress of STEC HUS is usually monitored with regular blood tests in hospital and during follow up. Children in the trial will have daily routine blood tests whilst in hospital and with each follow up visit, in keeping with usual practice. Between day 1 and day 8, all children will have a 4-5ml, 1 teaspoon, sample of blood (containing their DNA – the chemical that contains genes) sent to Bristol University to analyse the genes associated with HUS to help interpret the results of the trial. At 12 months a blood sample will be taken to look at your child’s kidney function, this would be sent for analysis at East Kent Hospitals University NHS Foundation Trust.

At the 1 month assessment you will be asked to bring in a stool (poo) sample from your child. You will be provided with a pot to collect the sample in and instructions on how to collect the sample. This sample will be sent to Public Health England Microbiological Reference Laboratory.

Optional blood and urine samples

In addition to routine blood tests, at several of the study visits, an optional research blood sample and a sample of urine (if available) will be collected from your child to look for further evidence of what causes STEC HUS. We will only collect the research blood samples at a time when your child is having blood tests for routine monitoring. Your child can still take part in the study without giving a research blood or urine sample. The amount of extra blood needed for the research blood sample depends upon how much your child weighs. For children weighing less than 15kg, each research sample would be 3ml (less than one teaspoon), for children weighing between 15 and 30kg, each research sample would be 5ml (one teaspoon) and for children weighing more than 30kg each research sample would be 9ml (less than two teaspoons). The blood samples will be processed and stored at your local centre and then sent to Bristol University and Cardiff University for analysis. The urine samples will be processed and stored at your local centre and then sent to Bristol University for analysis. A small number of participants at Bristol may be asked to give an additional, optional, one-off 10ml blood sample (two teaspoons) to undertake experiments to see how white blood cells from a patient affect with kidney cells in the laboratory. These experiments on the samples would take place in Bristol.

If you agree, the DNA sample used to test genes associated with HUS will undergo further optional detailed analysis, at an approved laboratory, of all potentially relevant genes (by a process called whole exome sequencing), to look for additional genes that might be involved in STEC HUS, which may give clues to develop additional treatments in the future. We will not feedback results from this testing unless it is directly relevant to your child’s STEC HUS illness.

We will ask you to complete two short questionnaires about your child’s quality of life at six of the visits. This will take less than 20 minutes on each occasion. These will only be identified by your child’s unique trial number and date of birth in the month/year format. At the 2 month visit, there will be an optional feedback questionnaire to help us see if we can make improvements to the trial for future participants.

The rest of your child’s treatment will be the usual treatment for STEC HUS.

Eculizumab is generally well tolerated, although the following side effects have been reported: stomach upsets, cough, loss of appetite, runny nose, sore throat, headache, dizziness, tiredness, altered taste, pain in the joints or muscles, relatively few platelets in blood (thrombocytopenia), low white blood cell count (leukopenia), hair loss, itching, rash and flu-like symptoms. Allergic reactions are uncommon. People with STEC HUS may develop many of these symptoms during the usual course of their illness.

Special warning – Please note

Importantly, eculizumab treatment may reduce your child’s natural resistance to infections, especially against “meningococcus”, an organism that causes meningitis (infection of the linings of the brain) and septicaemia (blood infection). The risk of this infection is low – from information about patients treated with eculizumab for other conditions we estimate the risk of developing meningococcal infection is around one in 4,000 per patient receiving eculizumab in the trial.

 To ensure the risk of meningococcal infection is as low as possible, your child will be vaccinated against meningococcus. Since some younger children will have received a particular meningococcal vaccination as part of the UK vaccination schedule (“meningitis B vaccine”), the research team will liaise with your child’s GP to determine which vaccines are necessary. Your child will also receive 8 weeks of penicillin (given twice daily by mouth, or an alternative if they are allergic to penicillin) and the first dose will be given before receiving the trial treatment (eculizumab or placebo). To make this trial the best possible test of which treatment is better, it is important to keep all treatments the same in both groups except eculizumab. Therefore people in both groups will receive vaccination and penicillin/alternative.

 Side effects of meningococcal vaccination include sleepiness, headache, nausea, vomiting, diarrhoea, rash, pains in muscles and joints, irritability, injection site pain and redness. Side effects of penicillin include stomach upsets, stomach ache and allergy (rash, cough, wheeze, tightness in throat).

 We will also give you information to recognise the signs and symptoms of meningococcal infection and advice about what to do in the unlikely event that you suspect your child may have meningococcal infection.

Potential harm to the unborn child

For Girls
The effect of eculizumab on the development of an embryo, foetus or unborn child is currently unknown. Therefore, if your child is a sexually active female of child-bearing potential, she must agree to not become pregnant for 6 months from enrolment into the trial. In addition, your daughter must agree to use an effective and reliable method of birth control that has been agreed upon by the trial doctor  for 6 months from enrolment into the trial. Some birth control methods that are acceptable for this trial are abstinence, the consistent use of an approved oral contraceptive (birth control pill or “the pill”), an intrauterine device (IUD), hormonal implants, contraceptive injection or a double barrier method (diaphragm with spermicidal gel or condom with contraceptive foam). The trial doctor will need to approve the method chosen. If your daughter should become pregnant during the trial, the trial doctor should immediately be notified. No further doses of trial drug will be given and the progress of her pregnancy will be monitored until the outcome of the pregnancy is known.

For Boys
If your son is a sexually active male, he must inform his partner(s) (if she/they are female of child-bearing potential), that the effects of eculizumab on sperm are unknown. Your son or his partner(s) should use acceptable methods of birth control (as above), to avoid his partner(s) becoming pregnant for 6 months from enrolment into the trial.

People who take part in research trials such as this receive very regular and careful medical attention from a research team that includes doctors, nurses, and other health professionals. Although your child may not receive any individual benefit from taking part in the trial the information we get from the trial may help us to improve the treatment of all people with STEC HUS in the future. If eculizumab is found to be effective then your child’s health may improve as a result of receiving a treatment which is not currently widely available.

 Children may develop side-effects of eculizumab (see ‘What are the side effects of the treatment?’ section) or of the vaccination and antibiotics given to prevent meningococcal infection. All children will be monitored for side-effects and if there is any concern that these are in any way associated with the trial then your child could be withdrawn from the trial.

The ECUSTEC trial is being co-ordinated by the Birmingham Clinical Trials Unit at the University of Birmingham and is sponsored by the Newcastle Upon Tyne Hospitals NHS Foundation Trust. The Chief Investigator is Dr Sally Johnson at the Great North Children’s Hospital. The trial is supported by the British Association for Paediatric Nephrology and the Children Specialty of the UK Clinical Research Network. The trial is being funded by National Institute for Health Research, Efficacy and Mechanism Evaluation Programme (NIHR EME) Ref: 14/48/43. Funding for the eculizumab is provided by the NHS, not the manufacturer. The research has been reviewed and approved by all these organisations. Your child’s doctor will not be paid for including your child in this trial. The research is also supported by Haemolytic Uraemic Syndrome Help (HUSH) - The UK E-coli Support Group.
The ECUSTEC trial co-ordinating centre is located at the Birmingham Clinical Trials Unit, College of Medical & Dental Sciences, Institute of Applied Health Research, University of Birmingham, Edgbaston, Birmingham B15 2TT. Tel 0121 415 9132, Fax: 0121 415 9135, web address: www.birmingham.ac.uk/ECUSTEC and email: Ecustec@Trials.bham.ac.uk.