DEFINE: A Phase IIa Randomised Controlled Trial to Evaluate Repurposed Treatments for COVID-19 (2021)

Abstract Introduction COVID-19 (Coronavirus Disease 2019) is a new viral-induced pneumonia caused by infection with a novel coronavirus, SARS CoV2 (Severe Acute Respiratory Syndrome Coronavirus 2). At present there are few proven effective treatments. This early phase experimental medicine 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. Methods and analysis DEFINE is an ongoing exploratory multicentre platform, open label, randomised study. COVID-19 positive patients will be recruited from the following cohorts; a) community cases 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 patients 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 primary statistical analyses are concerned with the safety of candidate agents as add-on therapy to standard of care in patients with COVID-19. Safety will be assessed using Haematological and biochemical safety laboratory investigations. Physical examination Vital signs (blood pressure/heart rate/temperature and respiratory rate) Daily electrocardiogram (ECG) readings Adverse events The analysis population will consist of (i) all patients randomised to a treatment arm who receive any dose of the study drug and (ii) all patients randomised to the control arm who would also have been eligible to receive a study drug. Secondary analysis will assess the following variables during treatment period 1) the response of key exploratory biomarkers 2) change in WHO ordinal scale and NEWS2 score 3) oxygen requirements 4) viral load 5) duration of hospital stay 6) PK/PD and 7) changes in key coagulation pathways. Ethics and dissemination The DEFINE trial platform and its initial two treatment and standard of care arms have received full ethical approval from Scotland A REC (20/SS/0066), the MHRA (EudraCT 2020-002230-32) and NHS Lothian and NHS Greater Glasgow and Clyde. The results of each study arm will be published as soon as the treatment arm has finished recruitment, data input is complete and any outstanding patient safety follow-ups have been completed. Depending on the results of these or future arms, data will be shared with larger clinical trial networks, including RECOVERY, and to other partners for rapid roll out in larger patient cohorts. Registration details The DEFINE protocol has been registered on ISRCTN ( https://www.isrctn.com/ ) and Clinicaltrials.gov ( https://www.clinicaltrials.gov/ ). ClinicalTrials.gov Identifier: NCT04473053 ISRCTN Identifier: ISRCTN14212905 Strengths and limitations of this study The trial is as flexible as possible to ensure a broad range of patients can be recruited and candidate therapies can be added or removed as evidence emerges. The team are collecting real world data of medications at an early stage of their use in COVID-19 across the full spectrum of disease; allowing the administration of different treatment formulations (inhaled vs oral vs intravenous). The simultaneous collection of clinical outcomes as well as exploratory endpoints including clinical biomarkers, flow cytometry, PK/PD and thromboelastography allows further characterisation and elucidation of the temporal immuno-inflammatory cascade in COVID-19 to inform on future therapy selection. This is a Phase 1b/IIa platform study and thus the primary end point is clinical safety therefore our anticipated numbers will be too small to allow for definitive data on efficacy. DEFINE is an experimental medicine platform, currently restricted to three clinical sites and so the generation of data will be slower than that of larger platforms with access to a greater number of patients.