Cambridge CRF receives new funding boost for delivery of early stage clinical research
The NIHR Cambridge Clinical Research Facility (CRF) has been awarded new funding to support its research over the next 5 years, including an uplift on historical funding levels.
The CRF supports studies which test new treatments in patients for the very first time (first-in-human trials), through to early, (Phase IIa) trials evaluating drug efficacy or mechanisms of disease. They provide specialist facilities and staff expertise to support research studies funded by the NIHR, Charities, the life sciences industry and other organisations. NIHR Cambridge CRF works closely with other NIHR infrastructure on the Cambridge Biomedical Campus, including the NIHR Cambridge Biomedical Research Centre and NIHR BioResource, to support ‘translational research’ (sometimes called experimental medicine) that takes scientific discoveries from the pre-clinical stage to new diagnostics, preventive medicine and treatments that can be used in the NHS.
Professor Krishna Chatterjee, Director of NIHR Cambridge Clinical Research Facility, pictured left, stated: “We are delighted to have received an increase in funding with which we will continue to translate discovery science into improved health for patients and people across diverse populations”.
Professor Lucy Chappell, Chief Executive of the NIHR and Chief Scientific Adviser to the Department of Health and Social Care, said: “NIHR’s CRFs scheme has been a key force in translational research across England, helping to position the nation as internationally competitive in early stage clinical research. This new funding, a 43% increase, will allow the CRFs to continue to drive forward innovation in experimental medicine and support translation of exciting discoveries into new treatments for patients.”
More than a decade of delivering innovative research
Since first funded by the NIHR in 2012, the research delivered by CRFs has provided faster access for patients to novel treatments and supported growth in early stage research in England, translating new advances into patient benefit and wider economic gain.
Cambridge CRF has supported an impressive array of research studies that have made a dramatic impact on healthcare locally, and across the country. Innovations such as the artificial pancreas for treatment of diabetes, a device (cytosponge) for diagnosis of oesophageal precancer and alemtuzumab therapy for multiple sclerosis are amongst the lifechanging advances, made possible through the facility.
At the forefront of early stage COVID-19 research
The CRFs were a crucial component of the nation’s COVID-19 response, supporting the delivery of early phase experimental medicine studies and Urgent Public Health studies. The CRFs’ knowledge and expertise, as well as the availability of existing facilities and networks, ensured studies were delivered quickly, safely and in an efficient and coordinated way. Throughout the pandemic, Cambridge CRF has played a key role in local, COVID-19 research efforts on the Cambridge Biomedical Campus. In the earliest days of the pandemic, the CRF led testing and validation of a new diagnostic (SAMBA II test), enabling rapid diagnosis of SARS-CoV-2 infections in patients needing admission to Cambridge University Hospitals (CUH), helping to keep other patients and staff safe. Their staff and facilities have also played a key role in supporting key, national studies (e.g. RECOVERY) of COVID therapies and trials (e.g. ChadOx, COVBOOST) evaluating COVID vaccines.
New research suggests COVID-19 severity can be predicted in hospitalised patients
Research conducted at Addenbrooke’s hospital and supported by the NIHR Cambridge Biomedical Research Centre has found it may be possible to predict which patients will go on to develop severe or long-term COVID symptoms (sometimes known as ‘long COVID’). The results have been released as a pre-print, due to their implications for public health.
Most people with COVID-19 will experience mild to moderate symptoms without needing medical treatment, but some – most commonly older people or those with underlying health conditions –become seriously ill and may have long-term complications.
In this study, Cambridge researchers looked at blood samples taken at regular intervals over three months from more than 200 people, ranging from COVID patients who were severely ill and needed ventilation to asymptomatic NHS staff who had tested positive for the virus but showed no symptoms.
They compared the samples with those taken from 45 healthy controls.
The samples showed that people’s immune response to COVID-19 determined how sick they were from the virus.
The immune systems in patients who were the sickest showed early evidence of an abnormal inflammatory response, leading to a flood of immune cells which damaged healthy cells as well as the virus. This can cause serious problems such as lung damage and organ failure, and even death.
Worryingly these cells remained in this fighting state even after the virus has been cleared, causing chronic (long-lasting) inflammation.
Crucially evidence of this inflammation was present in the earliest blood samples taken, suggesting that this could help doctors to identify and predict patients who will develop severe COVID.
Doctors could then treat them quickly to prevent long-term damage, using some of the treatments identified in studies such as RECOVERY.
In contrast, the immune responses in patients with mild or asymptomatic symptoms quickly recognised and fought off the infection. This response decreased once the virus was gone, with no chronic inflammation which damages the organs.
Dr Paul Lyons, senior co-author, from the Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), said: “Our evidence suggests that the journey to severe COVID-19 may be established immediately after infection, or at the latest, around the time that they begin to show symptoms.
“This finding could have major implications as to how the disease needs to be managed, as we would need to begin treatment to stop the immune system causing damage very early on.”
Long COVID
The study also indicated a way to help identify which patients may develop ‘long COVID’ – where they no longer have the virus but are still experiencing symptoms of the disease, including fatigue, for several weeks or even months after infection.
In these patients, researchers found that their immune cells still showed signs of abnormalities long after they no longer have the virus and had been discharged from hospital.
Researcher Dr Laura Bergamaschi said: “[These cells] are likely to be of huge importance in long COVID…The more we understand about this, the more likely we will be able to better treat patients whose lives continue to be blighted by the after-effects of COVID-19.”
This research was made possible through the participants in the NIHR COVID-19 BioResource. Professor John Bradley, Chief Investigator of the NIHR BioResource, said: “The NIHR BioResource is a unique resource made possible by the strong links that exist in the UK between doctors and scientists in the NHS and at our universities. It’s because of collaborations such as this that we have learnt so much in such a short time about SARS-CoV-2.”
The research was supported by CVC Capital Partners, the Evelyn Trust, UK Research & Innovation COVID Immunology Consortium, Addenbrooke’s Charitable Trust, the NIHR Cambridge Biomedical Research Centre and Wellcome.
Reference
Bergamaschi, L et al. Early immune pathology and persistent dysregulation characterise severe COVID-19. MedRXiV; 15 Jan 2021; DOI: 10.1101/2021.01.11.20248765
• You can read more on this research on the University of Cambridge website.
Phased re-start of non-COVID-19 research
15 June 2020
In line with NIHR guidance, we are beginning the process of phased re-opening of some non-COVID-19 research studies, while maintaining our contribution to local and nationally prioritised urgent public health studies for COVID-19.
As COVID-19 related admissions continue to fall across our hospital trusts, local research studies will be prioritised as detailed below. However, as and when this situation changes, this process may need to be further adjusted or paused. Delivery of front-line care and COVID-19 research remains our priority, and all research delivery teams working within CUH will be allocated studies on this basis.
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Prioritisation of Studies
Level 1
Existing COVID-19 related research – nationally prioritised COVID-19 Urgent Public Health Research studies and CUH COVID-19 related research trials.
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Level 2
Existing clinical trials and studies that are currently suspended, which offer potential therapeutic benefit to patients via improved diagnosis and/or a treatment/intervention improving or extending life.
Longitudinal follow-up studies of previous interventions; online staff research studies and studies where ALL participant study visits can be integrated with routine clinical management or conducted remotely without imposing major, immediate demand on research workforce and facilities.
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Level 3
All other existing and new clinical research studies.
We anticipate that Level 3 studies will not be able to re-open until the national lockdown has been fully eased. When this occurs, we will provide further information and advice to this effect.
Urgent applications may be considered on a case by case basis.
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Application for re-start
All studies must have Capacity and Capability (C&C) formally re-confirmed by R&D prior to recommencement. R&D sign off is in addition to other approvals required (for example, from the CRF or CCTU).
Principal investigators and study teams wanting to have their studies assessed for re-start need to complete the risk assessment form here.
R&D will assess the information provided in the risk assessment form to establish which studies are eligible for Level 1 or 2 prioritisation, and can therefore re-start/start all research activities. The availability of necessary supporting services (Pharmacy, Radiology, Labs, CRF, etc) and research staff will also contribute to the assessment.
NIHR centrally will monitor restart across England to identify and help to resolve any cross-cutting issues that may arise. To this end, a cross-Centre ‘NIHR Restart Implementation Group’ has been established, which will be chaired by Dr William van’t Hoff, CEO of the NIHR Clinical Research Network and Senior Responsible Officer for the NIHR Restart Programme.
Read more on the NIHR website.
Cambridge trial targets immune response to treat COVID-19 patients
A new national study, supported by the NIHR Cambridge Biomedical Research Centre and the Cambridge Clinical Trials Unit will test whether two drugs that are already in use to treat other immune-related conditions can prevent the development of severe COVID-19 infection.
The TACTIC-R trial (mulTiArm therapeutiC sTudy in pre-Icu patients admitted with Covid-19 – Repurposed drugs) will target patients as they are admitted to hospital, and test whether drugs that suppress the immune system can prevent the so-called ‘cytokine storm’ that is thought to lead to severe COVID-19 disease.
For the majority of people who have COVID-19, the infection causes only mild symptoms including a fever and cough. However, around 15% of patients develop severe disease, which includes serious damage to the lungs and multiple organ failure. This lung and organ damage appears to be mostly caused by the body’s own immune system responding to the presence of infected cells and ‘over-reacting’, destroying healthy cells as well as virus-infected ones. Researchers hope that preventing the immune ‘over-reaction’ using drugs that stop or ‘suppress’ the immune response will stop patients developing the severest form of COVID-19, preventing the need for intensive care.
Repurposing medicines to treat COVID-19
The immune system has several ways to attack viruses and other infections, and TACTIC will initially test two drugs that target different aspects of the immune response and are already in use to treat other conditions caused by an overactive immune system.
One of the first systems triggered when the immune system spots a pathogen (a bacteria or virus) is known as the complement system. Parts of the complement system are constantly circulating in the blood, ready to spot infections. When activated, it acts as a ‘first responder’ setting off a rapid chain of events that alerts the rest of the immune system and can label infected cells for destruction. Excessive activity by the complement system is thought to be responsible for the organ damage seen in COVID-19, and this trial will test a drug called ravulizumab that is usually used to treat a condition where the complement system destroys red blood cells.
The cells in the body that fight infection ‘talk’ to each other using tiny chemical messages known as cytokines. Different cytokines give different instructions to other immune cells, telling them to make more cytokines, multiply themselves to make more immune cells or to destroy other cells showing signs of infection. The right amount of the right cytokines gives the best immune response – but too much of the wrong cytokines causes inflammation that can damage healthy cells and tissues. This is known as a ‘cytokine storm’ and is thought to be another contributor to severe COVID-19 responses. The TACTIC trial aims to test whether baricitinib, a drug that is regularly used to ‘dial down’ excessive cytokines in people with rheumatoid arthritis, can effectively reduce the cytokine storm experienced by patients with severe COVID-19 symptoms.
Dr Frances Hall, Consultant Rheumatologist, Cambridge University Hospitals NHS Foundation Trust (CUH) and TACTIC Chief Investigator, explained: “With no proven treatments for Covid-19, the quickest route to a cure is through trying drugs already used for other illnesses that affect the body in a similar way. There is good reason to believe that these two drugs could help prevent severe organ failure and even death. I want to thank all of the patients taking part in this important trial – you have made a vital contribution to finding the solution to Covid-19.”
The two drugs that will be tested in TACTIC have been carefully selected by a consortium of doctors and scientists with expertise in treating immune-mediated diseases, and are thought to have a high chance of reducing the immune ‘over-reactions’ seen in very sick patients with COVID-19. However, the TACTIC trial has been designed so that if further drugs are identified that calm the immune response seen in these patients, they can easily and safely be tested in the study.
Similarly, if the trial shows evidence that a drug is not effective, it can quickly be removed so that other options can be tested. This is known as a ‘platform’ study, and will ensure that the knowledge that is gained through this study (whether the drugs are effective or not) is quickly adopted into medical care to improve outcomes for patients.
This trial will be delivered with support from our partners in the life sciences industry. This will enable drugs that treat COVID-19 to quickly and safely be tested through this study, so that any drugs that are shown to be effective can rapidly be licenced for use internationally. Partnering with Alexion for ravulizumab and Lilly for baricitinib will ensure that, if either is successful, production is ready to be scaled up to ensure that there is a suitable supply available to treat those who need it.
“We look forward to working with Cambridge University Hospitals NHS Foundation Trust to explore whether inhibiting complement with ravulizumab (Ultomiris) can help to reduce the progression to severe COVID-19 in high-risk hospitalised patients who do not yet require ventilatory support”, said John Orloff, M.D., Executive Vice-President and Head of Research and Development at Alexion. “This study will provide important controlled clinical data to determine whether earlier-stage treatment can reduce the severe organ damage associated with COVID-19 as well as the need for admission to the intensive care unit and use of ventilation.”
Dr Arash Tahbaz, Lilly Senior Medical Director for Northern Europe, said: “During this challenging time, Lilly is focused on ensuring a reliable supply of medicines, keeping our employees safe and pushing scientific efforts at top speed to defeat COVID-19. Supporting the TACTIC-R trial is one of the ways we are doing this and we are very pleased to be able to support the Cambridge team in their work to find effective treatments for COVID-19.”
Professor Ian Wilkinson, Director of the Cambridge Clinical Trials Unit, said: “This is a time of huge national effort in the fight against Coronavirus and I am delighted that Cambridge is playing a key role in this. TACTIC will test the effectiveness of a number of existing and new drugs in patients admitted to hospital with COVID-19, in a similar way to the RECOVERY trial, but with a strong focus on modulating the immune response and collecting high quality data that can be used by our partner pharmaceutical companies to seek the necessary approvals for widespread international use.”
Support This study is one of a number of COVID-19 studies that have been given urgent public health research status by the Department of Health and Social Care.
This trial is being supported by the NIHR Cambridge BRC and NIHR Guy’s and St. Thomas’ BRC.
First Addenbrooke’s Patient in National COVID-19 Trial
Today, Addenbrooke’s Hospital has enrolled our first patient into the national RECOVERY trial, led by Oxford researchers, which is hoping to identify potential treatments for COVID-19. The Randomised Evaluation of COVid-19 thERapY (RECOVERY) trial, will test several medications that are safely used for other conditions, and that have shown promise in other countries.
The opportunity to join this trial will be offered to adults who are hospitalised with COVID-19 at Addenbrooke’s, and other participating NHS hospitals across the country, and who do not have health conditions that would interact with the trial drugs. There are 3 drugs being tested in the first stages of the trial, including hydroxychloroquine, which is similar to a drug used to treat malaria and some rheumatic diseases. However, the trial follows an ‘adaptive’ design, which means that if further drugs show promise, they can be added to the treatments being tested.
The trial results will be regularly reviewed so that any treatments that are found to be effective can be made available to all patients.
Participation in this national trial is part of Cambridge’s wider contribution to COVID-19 research. Local principal investigator Dr Martin Knolle said “this is an example of Cambridge researchers, as part of a national effort, pulling together to deliver potentially life-saving treatments in record time in the most difficult of circumstances. I am very proud of our team and research community for this response.”