Condition category
Respiratory
Date applied
26/05/2020
Date assigned
22/07/2020
Last edited
23/07/2020
Prospective/Retrospective
Retrospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
COVID-19 is a condition caused by the coronavirus (called SARS-CoV-2) that was first identified in late 2019. This virus can infect the respiratory (breathing) system. Some people do not have symptoms but can carry the virus and pass it on to others. People who have developed the condition may develop a fever and/or a continuous cough among other symptoms. This can develop into pneumonia. Pneumonia is a chest infection where the small air pockets of the lungs, called alveoli, fill with liquid and make it more difficult to breathe.

In 2020, the virus has spread to many countries around the world and neither a vaccine against the virus or specific treatment for COVID-19 has yet been developed. As of March 2020, it is advised that people minimize travel and social contact, and regularly wash their hands to reduce the spread of the virus.

Groups who are at a higher risk from infection with the virus, and therefore of developing COVID-19, include people aged over 70 years, people who have long-term health conditions (such as asthma or diabetes), people who have a weakened immune system and people who are pregnant. People in these groups, and people who might come into contact with them, can reduce this risk by following the up-to-date advice to reduce the spread of the virus.

The key clinical feature is rapid respiratory failure requiring mechanical ventilation (MV). There are no known treatments for COVID-19. The most vulnerable in society may not survive or be suitable for MV. The pandemic is overwhelming health systems across the globe and has the potential to devastate regions of the world with poor public health and underdeveloped critical care. The anticipated scale of the epidemic is such that hospitals, and particularly intensive care facilities, may be massively overstretched and overwhelmed.

This study aims to support the re-purposing of promising pharmaceutical assets with prior use in humans through performing rapid experimental medicine feasibility studies in small groups of COVID-19 patients. The results of these studies will support further evaluation in existing national and international trial networks. The key interception is to prevent the lung damage in patients with COVID-19 that leads to respiratory failure.

Who can participate?
Patients aged 16 years or above who are COVID-19 positive.

What does the study involve?
Two treatments will be compared to standard care. Nafamostat (anti-viral and anti-coagulant) given for 7 days and TD139 (galectin 3 inhibitor) given for 14 days. Participants will be placed into groups randomly.

What are the possible benefits and risks of participating?
Benefits - There is no direct benefit. However, we believe the results of this research may bring potential benefits for similar patients in the future.
Risks - Blood sampling carries a small risk of bruising and discomfort, our doctors and nurses are very experienced in taking blood and will attempt to minimise this. If possible, the research team will use an existing line to minimise any discomfort.
Collecting samples from the throat and nasal passages can be a bit uncomfortable, this will be done as smoothly as possible and by doctors and nurses experienced in obtaining these samples.
All participants randomised to a treatment will be observed carefully for any side effects; however, there may be potential side-effects that have not previously been seen. These side effects may be mild or serious. Although the team do not anticipate this, in some cases, these side effects might be long lasting or permanent and may even be life threatening. If any negative change in the health of the patient is seen which may have an association with the treatment, the team will stop the treatment.
This trial will also involve up to two chest x-rays and CT scans. The scan of your heart and lungs are additional to those that would normally be taken. The scan uses ionising radiation to form images of the body. Ionising radiation can cause cell damage that may, after many years or decades, turn cancerous. In patients with COVID-19, the chance of this happening is extremely small.

Where is the study run from?
University of Edinburgh (UK)

When is the study starting and how long is it expected to run for?
March 2020 to December 2021.

Who is funding the study?
Life Arc (UK)

Who is the main contact?
Dr Annya Bruce, Annya.Bruce@ed.ac.uk

Trial website

Contact information

Type

Public

Primary contact

Dr Annya Bruce

ORCID ID

Contact details

Queen's Medical Research Institute
Little France Crescent
Edinburgh
EH16 4TJ
United Kingdom
+44 (0)131 2429180
Annya.Bruce@ed.ac.uk

Additional identifiers

EudraCT number

2020-002230-32

ClinicalTrials.gov number

Nil known

Protocol/serial number

20/SS/0060, IRAS 282934

Study information

Scientific title

Rapid Experimental Medicine for COVID-19

Acronym

DEFINE

Study hypothesis

This trial aims to support the repurposing of promising therapeutic assets with prior use in humans but without prior information on use in COVID-19, to determine the PK-PD profile of the agent, compared to standard of care supportive therapy, in small cohorts of COVID-19 patients. The results are intended to provide initial safety, pharmacokinetic and pharmacodynamic data and experimental medicine data to support further evaluation in existing national and international trial networks for candidates demonstrating appropriate impact on the dynamic marker of interest. The key interception is to mitigate the lung damage in patients with COVID-19 that leads to respiratory failure. As such, the assets in this programme will focus on abrogating putative mechanisms implicated in COVID-19 respiratory disease.

Ethics approval

Approved 03/07/2020, Scotland A REC (2nd Floor Waverley Gate, 2-4 Waterloo Place, Edinburgh, EH1 3EG, UK; +44 (0)131 4655678; manx.neill@nhslothian.scot.nhs.uk), ref: 20/SS/0066

Study design

Phase II interventional randomized controlled single centre

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use contact details to request a participant information sheet.

Condition

Prevention of lung injury in patients with COVID-19 (SARS-CoV-2 infection)

Intervention

Patients will be divided into cohorts, a) community b) hospitalised requiring supplemental oxygen and c) hospitalised requiring assisted ventilation.

Two treatments will be compared to standard care. Nafamostat (anti-viral and anti-coagulant) and TD139 (galectin 3 inhibitor). For Nafamostat, it is intended that the licensed dose (0.2 mg/kg/h) in Japan will be used. Patients randomised to Nafamostat will receive a continuous intravenous infusion at 0.2 mg/kg/h for 7 days. If a participant is discharged from hospital or can no longer receive this treatment, the treatment will be stopped. For TD139, patients will inhale 5 mg x 2 (10 mg) twice daily for the first 48 h and then subsequently 5 mg x 2 (10 mg) once daily for the remaining 12 days. Unless a participant is discharged from hospital or can no longer use an inhaler – in which case treatment will be stopped at such time.

Randomisation will be performed using a web-based randomisation system (built in REDCap) hosted at the Edinburgh Clinical Trials Unit (ECTU) at the University of Edinburgh (a fully registered UKCRC CTU (registration #15)). Since these studies are designed to be small, this study will balance underlying risk across the allocations using the method of minimisation.

Follow up will be at 30, 60 and 90 days post treatment.

Intervention type

Drug

Phase

Phase II

Drug names

Nafamostat, TD139

Primary outcome measure

Safety of candidate agents as add-on therapy to SoC in patients with COVID-19 measured at 30, 60 and 90 days post-treatment using:
1. Haematological and biochemical safety laboratory investigations:
1.1. Haematology: Full blood count and differential white cell count
1.2. Coagulation: D-dimer, fibrinogen, activated partial thromboplastin time (aPTT), prothrombin time (PT), international normalised ratio (INR), Cd39, ecto-ADPase, nitrous oxide, PGI2, antithrombin, Thrombomodlin, protein c, EPCR, kallikrein.
1.3. Biochemistry: Random glucose, Urea and electrolytes (urea, sodium, potassium, chloride, magnesium, bicarbonate, creatinine); liver function tests (Total protein, albumin, globulin, total bilirubin, SGOT(AST), SGPT(ALT), GGT, LDH, alkaline phosphatase); C-reactive protein (CRP); ferritin; triglycerides; troponin; creatine kinase (MB fraction)
2. Physical examination performed at screening, including assessment of presenting symptoms. At subsequent assessments, a symptom-directed (targeted) physical examination will be performed as required by the condition of the patient and the presenting complaint
3. Vital signs (blood pressure/heart rate/temperature and respiratory rate)
4. Daily electrocardiogram (ECG) readings
5. Adverse events that are not related to the patient’s underlying condition or clinical interventions will be recorded following consent. In the case of an AE, the Investigator should initiate the appropriate treatment according to their medical judgment

Secondary outcome measures

1. Pharmacokinetic (PK)/ pharmacodynamic (PD) information measured using daily blood samples
2. Response of key exploratory biomarkers during treatment period, namely IL-1β, IL-6, IL-8 and TNF-α, CXCL-10 and IL-1ra. Due to the nature of this research additional analytical tests may be developed or required in order to profile COVID-19 and develop therapies
3. Improvement or deteroriation of patients measured using WHO ordinal scale and NEWS2 score at 30, 60 and 90 days post treatment
4. Number of oxygen-free days measured at 30, 60 and 90 days post treatment.
5. Ventilator-free days and incidence and duration of any form of new ventilation use measured at 30, 60 and 90 days post treatment
6. SpO2/FiO2, measured daily from randomisation to Day 15, hospital discharge, or death
7. SARS-CoV-2 viral load measured using qualitative and quantitative polymerase chain reaction (PCR) determination of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in oropharyngeal/nasal/saliva swab while hospitalised on Days 1, 3, 5, 8, 11, 15
8. Time to discharge (days)
9. The use of renal dialysis or haemofiltration (not used/used and duration of use) at 30, 60 and 90 days post treatment

Overall trial start date

01/03/2020

Overall trial end date

01/12/2021

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Provision of informed consent from the patient or representative
2. Aged at least 16 years
3. If the patient is of childbearing potential*, the patient, and their partner(s), agree to use medically-accepted double-barrier methods of contraception (eg, barrier methods, including male condom, female condom or diaphragm with spermicidal gel) during the study and for at least 90 days after the termination of study therapy. A vasectomised partner would be considered an appropriate birth control method provided that the partner is the sole male sexual partner and the absence of sperm has been confirmed.
4. COVID-19 positive

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

100

Participant exclusion criteria

1. Current or recent history, as determined by the Investigator, of severe, progressive, and/or uncontrolled cardiac disease (NYHA class IV), uncontrolled renal disease (eGFR < 30 mL/min/1.73 m²), severe liver dysfunction (ALT/AST > 5x ULN) or bone marrow failure (Hb < 8g/dL AND ANC < 0.5 mm³ AND platelet count <50,000 µL)
2. Women who are pregnant or breastfeeding.
3. Participation in another clinical trial of an investigational medicinal product (CTIMP)
4. Known hypersensitivity to the IMP or excipients.
5. Pre-existing or concomittant use of off-label treatments for COVID-19

Recruitment start date

03/07/2020

Recruitment end date

22/06/2021

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Western General Hospital
NHS Lothian
Edinburgh
EH4 2XU
United Kingdom

Trial participating centre

Royal Infirmary Edinburgh
NHS Lothian
Edinburgh
EH16 4SA
United Kingdom

Trial participating centre

St John's Hospital
NHS Lothian Howden W Rd Howden
Livingston
EH54 6PP
United Kingdom

Sponsor information

Organisation

University of Edinburgh

Sponsor details

Queen's Medical Research Institute
Little France Crescent
Edinburgh
EH16 4TJ
United Kingdom
+44 (0)131 242 3330
ACCORD@nhslothian.scot.nhs.uk

Sponsor type

University/education

Website

http://www.accord.ed.ac.uk

Organisation

NHS Lothian

Sponsor details

Queen's Medical Research Institute
Little France Crescent
Edinburgh
EH16 4TJ
United Kingdom
+44 (0)131 242 3330
ACCORD@nhslothian.scot.nhs.uk

Sponsor type

Hospital/treatment centre

Website

http://www.nhslothian.scot.nhs.uk/Pages/default.aspx

Funders

Funder type

Charity

Funder name

Life Arc

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Scientific publications and the sharing of clinical data generated as part of this trial is crucial to better understanding COVID-19 and developing new treatments. As such, the results of each nested study detailed in the relevant appendices will be published as soon as the treatment arm has finished recruitment, data has been cleaned and any outstanding patient safety follow-ups completed.

IPD sharing statement:
The current data sharing plans for this study are unknown and will be available at a later date.

Intention to publish date

10/10/2021

Participant level data

Not provided at time of registration

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

23/07/2020: Internal review. 09/07/2020: Trial’s existence confirmed by NHS Scotland.