DEFINE - Evaluating Therapies for COVID-19

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.

Timeline

Start

2020-07-03

Primary completion

2025-04-30

Completion

2025-04-30

Publications

• Background 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.
• 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.
• Results 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.
• Results 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.
• 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.

Drugs

Indications