INTRODUCTION: COVID-19 is a new viral-induced pneumonia caused by infection with a novel coronavirus, SARS-CoV-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 data in patients with COVID-19, 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 patients positive for COVID-19. METHODS AND ANALYSIS: Define is an ongoing exploratory multicentre-platform, open-label, randomised study. Patients positive for COVID-19 will be recruited from the following cohorts: (a) community cases; (b) hospitalised patients with evidence of COVID-19 pneumonitis; and (c) hospitalised patients requiring assisted ventilation. The cohort recruited from will be dependent on the experimental therapy, its route of administration and mechanism of action. Randomisation will be computer generated in a 1:1:n ratio. Twenty patients will be recruited per arm for the initial two arms. This is permitted to change as per the experimental therapy. 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. Secondary analysis will assess the following variables during treatment period: (1) the response of key exploratory biomarkers; (2) change in WHO ordinal scale and National Early Warning Score 2 (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 a favourable ethical opinion from Scotland A Research Ethics Committee (REC) (20/SS/0066), notice of acceptance from The Medicines and Healthcare Products Regulatory Agency (MHRA) (EudraCT 2020-002230-32) and approval from the relevant National Health Service (NHS) Research and Development (R&D) departments (NHS Lothian and NHS Greater Glasgow and Clyde). Appropriate processes are in place in order to be able to consent adults with and without capacity while following the necessary COVID-19 safe procedures. Patients without capacity could be recruited via a legal representative. Witnessed electronic consent of participants or their legal representatives following consent discussions was established. The results of each study arm will be submitted for publication in a peer-reviewed journal 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 the Randomised Evaluation of COVID-19 Therapy trial (RECOVERY), and to other partners for rapid roll-out in larger patient cohorts. TRIAL REGISTRATION NUMBER: ISRCTN14212905, NCT04473053