DEFINE - Evaluating Therapies for COVID-19

NCT04473053 | Completed Phase 1 DMC

• 1 other identifier: AC20063
• Study Type: interventional
• Target: 71
• Locations: 1 country
• Sites: 1

Brief Summary

COVID-19 is a community acquired pneumonia caused by infection with a novel coronavirus, SARS CoV2 and is a serious condition with high mortality in hospitalised patients, for which there is no currently approved treatment other than supportive care. Urgent investigation of potential treatments for this condition is required. This protocol describes an overarching and adaptive trial designed to provide safety, pharmacokinetic (PK)/ pharmacodynamic (PD) information and exploratory biological surrogates of efficacy which may support further development and deployment of candidate therapies in larger scale trials of COVID-19 positive patients receiving normal standard of care. Given the spectrum of clinical disease, community based infected patients or hospitalised patients can be included. Products requiring parenteral administration will only be investigated in hospitalised patients. Patients will be divided into cohorts, a) community b) hospitalised patients with new changes on a chest x-ray (CXR) or a computed tomography (CT) scan or requiring supplemental oxygen and c) hospitalised requiring assisted ventilation. Participants may be recruited from all three of these cohorts, depending on the experimental therapy, its route of administration and mechanism of action. The relevant cohort(s) for any given therapy will be detailed in the therapy-specific appendix. Candidate therapies can be added to the protocol and previous candidates removed from further investigation as evidence emerges. The trial will be monitored by an independent Data Monitoring Committee (DMC) to ensure patient safety. Each candidate cohort will include a small cohort of patients randomised to candidate therapy or existing standard of care management dependent on disease stage at entry. Cohort numbers will be defined in the protocol appendices. This is a Phase IIa experimental medicine trial and as such formal sample size calculations are not appropriate.

Conditions

COVID-19

Outcome Measures

Primary Outcomes (2)

• The safety of the candidate therapies in COVID-19 patients by measuring physiological changes in the circulatory and respiratory system.

  Measure vital signs (blood pressure/heart rate/temperature and respiratory rate)

  Up to 16 days post treatment

• The safety of the candidate therapies in COVID-19 patients by recording the number of treatment related adverse events.

  Record number of participants With treatment-related adverse events

  Up to 90 days post treatment

Secondary Outcomes (11)

• Measuring the PK of the proposed trial treatments in COVID-19 patients.

  6 months

• Measure a change in the expression of key coagulation biomarkers in the blood of COVID-19 patients during and after treatment period.

  6 months

• Measure a change in the expression of key cytokines in the blood of COVID-19 patients during and after treatment period.

  6 months

• To evaluate the improvement or deteroriation of patients in each treatment arm.

  16 days

• To evaluate the number of oxygen-free days.

  16 days

Study Arms (4)

Nafamostat

EXPERIMENTAL

It is intended that the licensed dose (0.2mg/kg/hr) in Japan will be used. Patients randomised to Nafamostat will receive a continuous intravenous infusion at 0.2 mg/kg/hr for 7 days. If a participant is discharged from hospital or can no longer receive this treatment, the treatment will be stopped.

Drug: Nafamostat Mesilate

TD139

EXPERIMENTAL

Patients will inhale 5mg x 2 (10 mg) twice daily for the first 48 hrs and then subsequently 5mg 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. CE marked inhalers will be provided by the Manufacturer. All patients will receive guidance on how to use the inhaler by an appropriately trained member of the research team. Two individual inhalers will be used by each patient over the course of the 14 day study period (each inhaler will be used by one patient for 7 days) and will be thoroughly cleaned with an antiseptic wipe before and after each use.

Drug: TD139

Standard of Care

ACTIVE COMPARATOR

Nafamostat and TD139 will be compared to the Standard of Care arm.

Other: Standard care

Allogeneic SARS-CoV-2 VSTs

EXPERIMENTAL

This is an early dose escalation safety trial phase Ib/IIa interventional clinical trial with SARS-CoV-2 VSTs. This is a standalone arm of the Define study and will not be compared to any other trial appendices. A dose escalation strategy from 2x104 cells/kg to 2x106 cells/kg (based on standard 75kg weight) will be administered to patients with COVID-19 infection, and patients will be followed up to ensure their safety.

Biological: Allogeneic SARS-CoV-2 VSTs

Interventions

Nafamostat Mesilate DRUG

Nafamostat has been shown to have potential antiviral effects against MERS CoV and is thought to possibly inhibit SARS CoV2 infection via inhibition of viral entry due to inhibition of TMPRSS2. In addition, nafamostat has potent anticoagulant properties which may provide benefit in patients with DIC, a common finding in serious cases of COVID-19. Nafamostat has been broadly well tolerated in clinical trials in patients with DIC and acute pancreatitis.

Nafamostat

TD139 DRUG

TD139 is a specific inhibitor of galectin-3 which has been investigated in healthy volunteers and patients with IPF. No serious drug related serious adverse events have been reported to date. TD139 had no impact on cardiac, haematological or biochemical measures of safety during trials in humans to date. Beneficial effects on biomarker measures of lung inflammation were observed in patients with IPF. It is the purpose of this investigation to examine the potential for delivery of this inhibitor in pre-ventilator patients hospitalised with COVID-19 to examine whether this may lead to detectable changes in blood biomarkers, reduce viral load and also reduce disease severity such as time to ventilation.

TD139

Standard care OTHER

Patients will receive standard care.

Standard of Care

Allogeneic SARS-CoV-2 VSTs BIOLOGICAL

The allogeneic SARS-CoV-2 VSTs are manufactured in a single stage process directly from the starting material procured from suitable post COVID-19 recovered individuals. This is an early dose escalation safety trial phase Ib/IIa interventional clinical trial with SARS-CoV-2 VSTs.

Allogeneic SARS-CoV-2 VSTs

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision of informed consent from the patient or representative
• Aged at least 16 years
• If the patient is of child bearing 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 (if randomised to a treatment arm) and for at least 90 days after 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.
• COVID-19 positive

You may not qualify if:

• 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 \<80 g/L AND ANC\<0.5 mm3 AND platelet count \<50,000 uL)
• Women who are pregnant or breastfeeding.
• Participation in another clinical trial of an investigational medicinal product (CTIMP)
• Known hypersensitivity to the IMP or excipients (e.g. lactose)
• Pre-existing or Cconcomittant use of off-label treatments for COVID-19 that are not recognised as locally approved standard care.
• Significant electrolyte disturbance (hyperkalaemia potassium \>5.0 mmol/L or hyponatraemia sodium \< 120mmol/L)
• Patient currently receiving potassium sparing diuretics that cannot be reasonably withheld
• Patient currently receiving prophylactic or therapeutic anticoagulantsanticoagulation or antiplatelet agents that cannot be reasonably withheld if randomised to Nafamostat
• Patients (or their partners) planning on donating sperm/eggs during the trial period
• Ongoing dialysis
• History of serious liver disease (Child Pugh score \> 10)
• Hemoglobin \< 80 g/L
• Any known allergy to the IMP/excipients
• Severe uncontrolled diabetes mellitus
• In the Investigator's opinion, patient is unwilling or unable to comply with drug administration plan, laboratory tests or other study procedures.

Sponsors & Collaborators

• University of Edinburgh: lead
• University of Oxford: collaborator
• Latus Therapeutics: collaborator
• Scottish National Blood Transfusion Service (SNBTS): collaborator

Study Sites (1)

NHS Lothian

Edinburgh, EH16 4TJ, United Kingdom

Location

Related Publications (5)

• Cooper RS, Fraser AR, Smith L, Burgoyne P, Imlach SN, Jarvis LM, Turner DM, Zahra S, Turner ML, Campbell JDM. Rapid GMP-Compliant Expansion of SARS-CoV-2-Specific T Cells From Convalescent Donors for Use as an Allogeneic Cell Therapy for COVID-19. Front Immunol. 2021 Jan 8;11:598402. doi: 10.3389/fimmu.2020.598402. eCollection 2020.

  PMID: 33488592 BACKGROUND

• Gaughan E, Quinn T, Bruce A, Antonelli J, Young V, Mair J, Akram A, Hirani N, Koch O, Mackintosh C, Norrie J, Dear JW, Dhaliwal K. Evaluation of new or repurposed treatments for COVID-19: protocol for the phase Ib/IIa DEFINE trial platform. BMJ Open. 2021 Dec 15;11(12):e054442. doi: 10.1136/bmjopen-2021-054442.

  PMID: 34911721 BACKGROUND

• Quinn TM, Gaughan EE, Bruce A, Antonelli J, O'Connor R, Li F, McNamara S, Koch O, MacKintosh C, Dockrell D, Walsh T, Blyth KG, Church C, Schwarze J, Boz C, Valanciute A, Burgess M, Emanuel P, Mills B, Rinaldi G, Hardisty G, Mills R, Findlay EG, Jabbal S, Duncan A, Plant S, Marshall ADL, Young I, Russell K, Scholefield E, Nimmo AF, Nazarov IB, Churchill GC, McCullagh JSO, Ebrahimi KH, Ferrett C, Templeton K, Rannard S, Owen A, Moore A, Finlayson K, Shankar-Hari M, Norrie J, Parker RA, Akram AR, Anthony DC, Dear JW, Hirani N, Dhaliwal K. Randomised controlled trial of intravenous nafamostat mesylate in COVID pneumonitis: Phase 1b/2a experimental study to investigate safety, Pharmacokinetics and Pharmacodynamics. EBioMedicine. 2022 Feb;76:103856. doi: 10.1016/j.ebiom.2022.103856. Epub 2022 Feb 11.

  PMID: 35152152 RESULT

• Gaughan EE, Quinn TM, Mills A, Bruce AM, Antonelli J, MacKinnon AC, Aslanis V, Li F, O'Connor R, Boz C, Mills R, Emanuel P, Burgess M, Rinaldi G, Valanciute A, Mills B, Scholefield E, Hardisty G, Findlay EG, Parker RA, Norrie J, Dear JW, Akram AR, Koch O, Templeton K, Dockrell DH, Walsh TS, Partridge S, Humphries D, Wang-Jairaj J, Slack RJ, Schambye H, Phung D, Gravelle L, Lindmark B, Shankar-Hari M, Hirani N, Sethi T, Dhaliwal K. An Inhaled Galectin-3 Inhibitor in COVID-19 Pneumonitis: A Phase Ib/IIa Randomized Controlled Clinical Trial (DEFINE). Am J Respir Crit Care Med. 2023 Jan 15;207(2):138-149. doi: 10.1164/rccm.202203-0477OC.

  PMID: 35972987 RESULT

• Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, Neidhardt M, Piechotta V, Salomon S, Valk SJ, Monsef I, Schmaderer C, Wood EM, So-Osman C, Roberts DJ, McQuilten Z, Estcourt LJ, Skoetz N. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev. 2021 Sep 2;9(9):CD013825. doi: 10.1002/14651858.CD013825.pub2.

  PMID: 34473343 DERIVED

MeSH Terms

Conditions

COVID-19

Interventions

nafamostat; Standard of Care

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Study Officials

• Kev Dhaliwal

  University of Edinburgh

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: The biomarker analysis team will be masked to the trial treatment.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Randomised clinical trial - currently two treatment arms and one standard of care arm. More assets will be added to the protocol as evidence emerges.

Study Record Dates

• First Submitted: July 9, 2020
• First Posted: July 16, 2020
• Study Start: July 3, 2020
• Primary Completion: April 30, 2025
• Study Completion: April 30, 2025
• Last Updated: August 7, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: 90 days after data analysis has been completed for each arm. This data will be available on request and a time frame can be discussed further when required.

Locations

GB (1)