DEFINE is a clinical study which aims to test promising new therapies in small numbers of COVID-19 patients.
This clinical study will compare promising additional treatments against standard care (i.e. only treatments given routinely by your doctor/nurse) in patients who are experiencing different symptoms of COVID-19, either in the community or in a hospital environment. In order to assess how well the treatments are working, the study team will look at how safe and tolerable certain treatments are, and also measure small molecules in the blood and other samples called biomarkers. Biomarkers are molecules normally found in blood, other body fluids, or tissues and can be a sign of a normal or abnormal process, or of a condition or disease. In addition, knowing how certain biomarkers change (or not) with certain treatments will help us to understand how to tailor therapies for future COVID-19 patients.
The DEFINE clinical study is an Urgent Public Health (UPH) badged study which means this research will have an impact on public health within 12 months and that the science underpinning the proposed study is compelling.
You can learn more about the different aspects of the study by using the links below.
The following documents contain information provided to participants in the DEFINE study.
About the study
COVID-19 is a community acquired pneumonia caused by infection with the new coronavirus (SARS-CoV-2). It is a serious condition which currently has limited treatment options other than standard care. Urgent investigation of potential treatments for this condition is required.
In order to treat COVID-19, the scientific community need to develop an understanding of how the body’s immune system responds to the virus and to new treatments. It is hoped that this information could help develop new ways to treat the virus and assess if they are more effective than standard care. Comparing how patients with and without new treatments respond to COVID-19 will allow a greater understanding about the virus and if the new treatments should be tested in larger groups of patients.
Whilst other researchers are working to develop a COVID-19 vaccine, there is a need to find effective treatments as soon as possible to treat the infection now. There may be some of the population who cannot have the vaccine or for whom the vaccine is not effective. Current vaccines are in the early stages of development, and so will take time to test and distribute.
There are no drugs of proven value against COVID-19, but there are several which may turn out to be effective when added to the usual medical treatment people receive. By using drugs already shown to be safe for use in people, we can respond quickly to this need.
DEFINE now has Urgent Public Health (UPH) priority from the Department of Health and Social Care (DHSC) at UK government level. The DEFINE clinical study started at the start of July 2020. In the first instance, we will test two therapeutic drugs, Nafamostat and TD139. These will be compared to patients who are receiving standard care.
The research study team is based at the Queen's Medical Research Institute (QMRI) on the Edinburgh BioQuarter site and works across hospitals in Lothian. Patients asked to take part in this study will include hospital- and community-based COVID-19 positive patients. This study hasn’t identified a community drug at present. Additional therapies will be added to this study when they are identified and have been approved by the study Trial Steering Committee and a number of other independent committees.
We anticipate that the study will be active for at least the next year.
The DEFINE study will recruit small numbers of COVID-19 patients to each treatment arm and we will compare how effective these therapies are in COVID-19 patients to those receiving standard care. How a patient is allocated to a treatment or standard care is random, like rolling a dice. The doctor or the study team cannot decide what the patient is allocated to as this is done by a computer.
Regardless of whether patients are randomly allocated to receive a trial treatment or not, they will also receive the usual high standard of care in hospital. Taking the study treatment does not mean any other treatment in hospital that the patient needs are withheld.
Participants will be fully informed as to how the treatment they are allocated to (if they are allocated to a treatment) will be administered and any assistance they need provided. Treatments will be suitable for the current clinical condition of the patient and the patients’ physical location, whether in hospital or in the community.
Participants will be asked to provide blood samples and other clinical samples (such as nasal swabs and saliva samples). They may also be asked to have scans and heart monitoring carried out.
All participants in the study will be closely monitored and fully advised of any of the risks of taking part.
All the treatments have been studied in patients before and have shown to be safe.
Nafamostat is an antiviral drug which has been shown to prevent unwanted blood clots from forming.
Nafamostat has been used routinely in clinical settings in Japan since 1985 to treat blood clotting in disseminated intravascular coagulation (DIC). It is thought that Nafamostat can inhibit part of the mechanism used by coronavirus (SARS-CoV-2) and other viruses to gain entry to cells. The outer coat of viruses are covered with very small molecules called proteins. The virus enters cells in the human body by binding to the Spike protein, and it is thought that Nafamostat can stop this binding process and prevent the virus from entering human cells and infecting someone.
Severe COVID-19 disease can cause small blood clots to develop throughout the bloodstream, blocking small blood vessels. This increased clotting can deplete platelets and clotting factors that would normally control excessive bleeding. Nafamostat has been shown to inactivate this clotting pathway, thus preventing blood clot formation. In patients in Wuhan, where the virus broke out, an increase in blood clotting defects were seen in patients with COVID-19.
When the human body fights a virus such as COVID-19 the way the body responds includes an inflammatory response. Pathogens such as SARS-CoV-2 can cause acute and/or chronic inflammatory responses in the body which could lead to tissue damage or disease. Inflammation can show up as swelling, pain and loss of function in the affected areas. Nafamostat has also been shown to reduce inflammation in the body.
TD139 is a small molecule drug which can be inhaled by patients. It inhibits a protein called galectin-3, which has been shown to play an important role in the way the body responds to viruses. Protein molecules are complex molecules that have critical roles in the body. They do most of the work in the body’s cells and are required for the structure, function, and regulation of the body’s tissues and organs. It is thought that by inhibiting the galectin-3 protein, the excessive immune response seen in some patients with COVID-19 can be controlled.
TD139 has already been tested in healthy volunteers and patients with a lung disease called idiopathic lung fibrosis (IPF) which causes lung scarring. The results of these studies suggest that it might be useful in addressing COVID-19 related lung tissue inflammation. It may also have direct antiviral effects.
If a patient is suitable for the study they will be approached by their clinical care team within the hospital or community. If a drug is suitable for patients who are unable to consent to take part - for example, if they are on a ventilator - we may ask to speak to their legal representative about them taking part in the study.
You can find out more about how researchers involve adults with incapacity in research studies on the Scottish Government website.
If you would like to ask about this study, please contact us.
Funders and collaborators
This adaptive trial platform is funded by LifeArc.
The study is sponsored by the University of Edinburgh and NHS Lothian through ACCORD.
The study has been given a favourable ethical opinion by the Scotland A ethics committee, the regulator and local Research and Development Departments.