A major UK study to identify new ways to accurately predict if patients will develop long-term complications as a consequence of concussion has been launched, led by experts at BHP founder-member the University of Birmingham and the Defence Medical Rehabilitation Centre, in collaboration with the Defence Medical Services.

With year one funded by the Ministry of Defence (£2m) and projected to run over eight years, the multi-faceted study will include a trial involving 400 civilians and 400 military personnel aged over 18 with a new diagnosis of concussion (also known as a mild traumatic brain injury or mTBI) which has resulted in them needing hospital treatment or rehabilitation.

At specific time intervals over two years, the participants will take part in nine different areas of research using a variety of medical techniques and assessments to establish if these can be used routinely by medics as ‘biomarkers’ to indicate prognosis and long term impact of concussion. Medical techniques and assessments being trialled include brain imaging and function, analysis of blood and saliva samples, and headache measures, as well as mental health, vision, balance, and cognitive performance.

mTBI is common and has been declared a major global public health problem, with 1.4 million hospital visits due to head injury annually in England and Wales – 85% of which are classified as mTBI. It is also estimated that up to 9.5% of UK military personnel with a combat role are diagnosed with mTBI annually.

The research will involve 20 University of Birmingham experts working across disciplines, including neurology, psychology, sports medicine, mathematics and academics within the University’s Centre for Human Brain Health, and will be coordinated by Birmingham Clinical Trials Unit. It will also be driven by experts at the Defence Medical Rehabilitation Centre Stanford Hall; Aston University, Imperial College London; University of Westminster; University of Nottingham; Royal Centre for Defence Medicine; and University Hospitals Coventry & Warwickshire.

Alex Sinclair, Professor of Neurology at the University of Birmingham and Chief Investigator of the project, called mTBI-Predict, explained: “Although classified as mild, and many recover, the consequences of concussion can be profound with many patients suffering long-term disability due to persistent headaches, fatigue, imbalance, memory disturbance, and poor mental health including post-traumatic stress disorder, while it can have a significant impact on the economy through loss of working hours and demand on the health system.

“Identifying those patients most at risk of these disabling consequences is not currently possible. There is therefore a pressing need to develop accurate, reproducible biomarkers of mTBI that are practical for use in a clinical setting and can predict long-term complications. Our programme of research will deliver a step change in the care of patients with mTBI, enabling a personalised medicine approach to target early intervention for those most in need but also identifying those with a good prognosis who can return rapidly to activities of daily living.”

Co-Chief Investigator, Air Vice-Marshall Rich Withnall QHS Director of Defence Healthcare, UK Ministry of Defence said: “I am delighted that the Defence Medical Services, including the Defence Medical Rehabilitation Centre at Stanford Hall, will be working hand-in-glove with class-leading civilian colleagues and the National Rehabilitation Centre Programme. I fully support this ground-breaking research which I am confident will lead to significant clinical innovation to benefit military and civilian patients, and have translational positive impact for sporting activities from grass-roots to elite levels.”

Peter McCabe, Chief Executive of Headway – the brain injury association, said: “We know that even a seemingly minor head injury can have a major impact on a person’s life – and often the lives of those closest to them. This is particularly the case if the brain injury goes undiagnosed or its effects are mistaken for other conditions. The frustration of not having an accurate diagnosis or receiving the right support can be compounded by the lack of a clear recovery pathway or timeline. We therefore welcome this study in the hope that it can advance our understanding of concussion and mTBI.”

 

A new clinical trial being led by BHP founder-member the University of Birmingham and funded by the British Heart Foundation could help improve the recovery of children who undergo life-saving heart surgery.

The £570,000 study will compare two ways of protecting the heart when children require open heart surgery to repair congenital heart defects, to find which is most effective.

Congenital heart disease is a heart defect that develops in the womb before a baby is born. Each day in the UK, around 13 babies are diagnosed with a congenital heart condition, with more diagnoses later in life.

In severe cases, and often at a young age, open heart surgery is required to repair the defect to help improve the child’s survival and quality of life. Some children require multiple operations, and recovery from open heart surgery can take several weeks or even months.

During open heart surgery, a fluid called cardioplegia is commonly used to stop the heart beating so that the surgeon can repair it safely. Although the technique is safe, cardioplegia stops the blood flow to the heart and may cause damage to the heart muscle when the blood flow is restored, which can affect the child’s recovery.

There are many different types of cardioplegia solutions available, which work in slightly different ways – and it is not currently known which fluid works best in children of different ages.

In the United States, the most commonly used solution is called del Nido cardioplegia, which was designed specifically for use in children’s heart surgery but has not previously been available in the UK.

The new trial will compare del Nido cardioplegia with St Thomas’ cardioplegia, which has been used for many years in both adults and children and is currently the standard of care in the UK.

It will involve 220 children undergoing open heart surgery at four hospitals across the UK – Birmingham Children’s Hospital, Bristol Royal Hospital for Children, Great Ormond Street Hospital and Leeds Children’s Hospital.

Half of the patients will be assigned to receive del Nido, with the other half receiving St Thomas’ cardioplegia. Researchers will then compare the two groups by assessing how well the children recover from surgery and determining the extent of any heart damage.

The study will help to reveal whether one solution is potentially more effective than the other for children during surgery.

The research will be led by Nigel Drury, Consultant in Paediatric Cardiac Surgery at BHP member Birmingham Children’s Hospital and Hunterian Professor in the Institute of Cardiovascular Sciences at the University of Birmingham.

Mr Drury, who is also a British Heart Foundation (BHF) Intermediate Fellow, said: “By improving the way in which we protect the heart during surgery, we expect that children will recover from surgery faster and with fewer complications.

“These early benefits may also lead to better long-term outcomes, with less injury and scarring to the heart muscle. As children with severe heart defects often need multiple operations, they will have the most to gain from improving how we protect the heart during each surgery.

“If our trial is successful, this will support the need for a larger, definitive study, which could have the potential to change the way children are treated around the world.”

Dr Shannon Amoils, Senior Research Advisor at the British Heart Foundation, said: “Heart defects are the most common congenital anomaly in babies born in the UK, so it’s important that we continue to refine treatments for these conditions to help improve the lives of young patients.

“This multi-centre trial, held at four leading UK children’s hospitals, will compare how well these two solutions can protect the hearts of children undergoing open heart surgery. If the study reveals important differences between the two solutions, a larger clinical trial would be needed to further investigate the findings. Ultimately, this important research could result in heart surgery becoming even safer for children.

“The BHF can only fund vital research like this thanks to the generous support of the public, in driving forward our mission to beat heartbreak forever.”

Alfie Donnelly, aged nine and from Erdington, was born with various complex congenital heart diseases and has had to undergo three open heart surgeries at Birmingham Children’s Hospital.

Mum Claire Donnelly, aged 43, said: “When Alfie was a new-born, we noticed that he wasn’t feeding well, was cold all the time and wouldn’t cry. We struggled to wake him one morning and he was making a grunting noise when he was breathing, so I rang the hospital who told us to bring him in.

“Alfie became so ill that he was put on a life support machine. After several tests and scans, we were told that Alfie’s heart condition was rare and complex and that he needed open heart surgery. We were also told that if a procedure did go ahead, it was unlikely he would survive past his first birthday. The whole situation felt so bizarre, I remember feeling frozen to the spot.

“Alfie was just one week old when he had his first operation, and he was a little fighter. He has since had two more open heart surgeries, which included replacing the damaged valve in his heart with a donor valve.

“Alfie’s recovery after surgery has been slow and he has had further complications. Following his first and second surgery, Alfie had a build up of fluid in his lungs and this required several chest drains, which meant spending further time in hospital.

“With what Alfie has been through, it has made us a solid family and we all appreciate life even more. For us as a family, the research that the BHF is funding gives us hope that children and babies with congenital heart disease, like Alfie, aren’t being forgotten. So much more is needed to raise awareness of heart defects in children.”

LifeArc and PSC Support have jointly awarded £948,774 for new research into primary sclerosing cholangitis (PSC) – a rare disease where the body attacks its own liver, causing inflammation and scarring of the bile ducts.

The national study, led by Dr Palak Trivedi at BHP founder-member the University of Birmingham, is called FAecal microbiota transplantation in primaRy sclerosinG chOlangitis: The FARGO trial. The aim of the study is to explore the potential of a new treatment to slow the progression of PSC and improve the quality of life for patients.

PSC is a rare liver disease where the body attacks itself, causing inflammation and scarring of the bile ducts and liver. This causes bile to stop flowing properly, leading to repeated infections, liver failure and, in some cases, cancer. In 80% of people with PSC the body will also attack the bowel, which can lead to inflammatory bowel disease (IBD).

The combination of the two conditions results in a 15-30% lifetime risk of bowel cancer, and patients require a colonoscopy every year to look for this complication. PSC affects approximately 3,600 people in the UK. The condition can develop at any age, but has a particular impact in people under 40 years.

At present, the treatment of PSC is focused on managing the symptoms, not treating the cause. Unfortunately, there is no cure, nor any medication that has been shown to improve survival. Liver transplantation is the only lifesaving treatment. Although a very rare disease, PSC accounts for 10-15% of all liver transplants performed in the UK and is now the leading reason for transplantation in several European countries.

Transplantation is risky and costs around £1m per patient (including aftercare). Moreover, PSC returns in around 30% of people who have had a liver transplant.

The team, led by researchers at the University of Birmingham, has one of the largest PSC research programmes globally, with a dedicated PSC-IBD clinic as part of the Centre for Rare Diseases. The research team is partnering with PSC Support, the leading patient organisation for people living with primary sclerosing cholangitis, which has a wealth of experience working with medicines’ regulators on drug development for this condition.

Through this partnership the team aims to explore the potential of a new treatment to slow the progression of PSC and improve the quality of life for patients.

It has been shown that the makeup of gut microorganisms in PSC are different to that found in people without liver and bowel inflammation, and that this is associated with many abnormal immune functions, which may be a driver of disease development. The Birmingham research team will trial a novel treatment called faecal microbiota transplantation (FMT), which involves taking stool from the gut of healthy donors, refining it in a laboratory, and transferring contents to the bowel of people with PSC to reverse the imbalance of gut microorganisms.

Early research has shown that FMT is effective and safe in treating IBD. This grant, which is jointly awarded by the LifeArc philanthropic fund and PSC Support, will enable the team to accelerate and scale up their research to answer the key questions that will allow them to translate this experimental treatment, from idea to direct patient benefit across the UK PSC population.

Dr Trivedi, Associate Professor and Consultant Hepatologist at the NIHR Birmingham BRC said: “LifeArc is a self-financing charity that advances promising life science ideas into life-changing solutions for patients, particularly those living with a rare disease. I am delighted that they have chosen to support such a novel, bespoke and distinctive clinical trial, alongside the necessary translational work needed to better understand how PSC develops and progresses.

“We will test the safety and long-term effects of FMT to treat people with PSC. In parallel, this study will really help us to understand which specific consortia of gut microbes are most important, and how this information can be used to enhance the product for large scale rollout.”

Researchers will randomly allocate individuals with PSC to receive either FMT once a week for 8 weeks (group 1), or placebo (an inactive FMT equivalent; group 2). Each group will continue to receive routine standard of care for symptoms and treatment for their IBD.

Both groups will be observed for another 40 weeks, meaning the trial will run for 48 weeks. The team will then measure how successful the treatment has been in improving liver blood test results, the burden of scarring in the liver, activity of IBD and quality of life.

“Our study will lay the foundation for future work on a larger scale, with a view to making FMT available on a more global scale,” added Dr Trivedi. “In parallel, PSC Support will work with the wider study team, to support delivery of FMT as a treatment after the trial has finished.

“This will include writing and submitting the necessary trial documents to the UK medicines’ regulatory agency (the MHRA), which is a necessary step to broaden access to new treatments for people living with the disease.

“Should our trial deliver a positive efficacy signal, then PSC Support are ready to lead the conversation and advocate for patients to access FMT as early as possible. We expect patient benefit within 5-7 years after completion of this work and are working with the University of Birmingham Enterprise and Drug Discovery teams to achieve this goal.”