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.