Wilkinson 2020.

Study name	A platform to investigate the safety and effectiveness of several new medicines for the treatment of COVID‐19 in hospitalised patients
Starting date	08 May 2020
Contact information	Tom Wilkinson Southampton University Faculty of Medicine Mailpoint 810, Level F, South Block Southampton General Hospital SO16 6YD Southampton UK +44 (0)2381 205341 | accord@uhs.nhs.uk
Methods	Multicentre, open‐label RCT
Participants	1800 participants, ≥ 18 years, female and male Inclusion criteria: Adults (= 18 years) with SARS‐CoV‐2 infection confirmed by laboratory tests and/or point‐of‐care tests A score of Grade 3‐5 on the 9‐point ordinal scale Is a woman who is not of childbearing potential or the patient, and their partner(s), agree to use medically‐accepted double‐barrier methods of contraception (e.g. barrier methods, including male condom, female condom or diaphragm with spermicidal gel) during the study and for at least 6 weeks after termination of study therapy Ability to provide informed consent signed by the study patient or legally authorised representative Exclusion criteria: Patients who have previously had a score of 6 or 7 on the 9‐point ordinal scale Any patient whose interests are not best served by study participation, as determined by a senior attending clinician ALT/AST > 5 × the ULN Known active infection with HIV or hepatitis B or C Stage 4 severe chronic kidney disease or requiring dialysis (i.e. estimated GFR < 30 mL/min/1.73 m²) History of the following cardiac conditions: myocardial infarction within 3 months prior to the first dose unstable angina history of clinically significant dysrhythmias (long QT features on ECG, sustained bradycardia (= 55 beats/min)), left bundle branch block, cardiac pacemaker or ventricular arrhythmia) or history of familial long QT Screening 12‐lead ECG with a measurable QTc interval according to Fridericia correction (QTcF) > 500 ms Anticipated transfer to another hospital that is not a study centre within 72 h Allergy to any study medication Experimental off‐label usage of medicinal products as treatments for COVID‐19 Patients participating in another clinical study of an investigational medicinal product
Interventions	The study consists of 2 stages: Stage 1 of the study (evaluation/pilot) will evaluate the candidate agents as an add‐on to the standard care to assess preliminary safety and efficacy. A patient will be considered to be a responder if they show an improvement of at least 2 points (from randomisation) on a 9‐point category ordinal scale, are discharged from hospital, or are considered fit for discharge (a score of 0, 1, or 2 on the ordinal scale), whichever comes first, by day 29. The time to response will be analysed on day 29 and used to evaluate if an agent should proceed to Stage 2 of the study. Stage 1 data will additionally be used to determine optimal study endpoints, and the number of patients to enrol into Stage 2 of the study. Stage 2 of the study (confirmation) is intended to provide confirmatory data of the identified candidate agents from Stage 1, to fully evaluate disease outcomes, including severe AEs, overall AEs, sdverse event of special interest, disease‐related co‐infection complications (e.g. pneumonia, septic shock), and overall mortality in an expansion stage. Patients and outcomes from Stage 1 will not form part of Stage 2 Some candidate agents will still be in Stage 1 of the study at the point where other candidate agents have progressed to Stage 2 First dose of candidate agent must take place within 72 h of investigator receipt of laboratory or validated point‐of‐care test confirmation of SARS‐CoV‐2 infection. This may include results from a test that was performed prior to hospital admission if, in the opinion of the Investigator, it is relevant to ongoing COVID‐19 infection. Any exceptions to this must be authorised by the Chief Investigator or delegate
Outcomes	Primary Time to clinical improvement of at least 2 points (from randomisation) on a 9‐point category ordinal scale, live discharge from the hospital, or considered fit for discharge (a score of 0, 1, or 2 on the ordinal scale), whichever comes first, by day 29 (this will also define the 'responder' for the response rate analyses) Secondary Measured from patient records unless otherwise noted: The proportion of patients not deteriorating according to the ordinal scale by 1, 2, or 3 points on days 2, 8, 15, 22, and 29 Duration (days) of oxygen use and oxygen‐free days Duration (days) of ventilation and ventilation‐free days Incidence of any form of new ventilation use and duration (days) of new ventilation use Qualitative and quantitative PCR determination of SARS CoV 2 in oropharyngeal/nasal swab while hospitalised on days 1, 3, 5, 8, 11, 15, and (optional) day 29 Response rate (number and %) by treatment arm at days 2, 8, 15, 22, and 29 Time to live discharge from the hospital Mortality at days 15, 29, and 60 Time from treatment start date to death Change in SpO2/FiO2 ratio, measured daily from randomisation to day 15, hospital discharge, or death Safety of candidate agents measured using: physical examination clinical laboratory examinations vital signs (blood pressure/heart rate/temperature/respiratory rate) AEs duration (days) of ICU and hospitalisation NEWS2 assessed daily while hospitalised and on days 15 and 29 Time to a NEWS2 of = 2, maintained for at least 24 h
Notes	ISRCTN57085639 | No data provided

aPTT: activated partial thromboplastin time; ACS: acute coronary syndrome; ACCT: Adaptive COVID‐19 Treatment Trial; AE: adverse event; AKI: acute kidney injury; AKIN: Acute Kidney Injury Network; ALT: alanine aminotransferase; ANC: absolute neutrophil count; ARDS: acute respiratory distress syndrome; ARs: adverse reactions; AST: aspartate aminotransferase; BARC: Bleeding Academic Research Consortium; BiPAP: bilevel positive airway pressure; BMI: body mass index; BP: blood pressure; CKI‐EPI: Chronic Kidney Disease Epidemiology Collaboration; CNS: central nervous system; COPD: chronic obstructive pulmonary disease; CPAP: continuous positive airway pressure; CPR: cardiopulmonary resuscitation; CrCl: creatinine clearance; CUS: serial compression ultrasonography; CT: computed tomography; CVVHD: continuous veno‐venous haemodialysis; DBP: diastolic blood pressure; DIC: disseminated intravascular coagulation; DMARDs: disease‐modifying antirheumatic drugs; DOAC: direct oral anticoagulant; DVT: deep vein thrombosis; ECG: electrocardiogram; ECMO: extracorporeal membrane oxygenation; ELISA: enzyme‐linked immunosorbent assay; ESKD: end‐stage kidney disease; FiO2: fraction of inspired oxygen concentration; FSH: follicle‐stimulating hormone; GFR: glomerular filtration rate; GI: gastrointestinal; GGT: glutamyltransferases; HCG: human chorionic gonadotropin; HFOV: high‐frequency oscillatory ventilation; HIT: heparin‐induced thrombocytopenia ICU: intensive care unit; INR: international normalised ratio; ISTH: International Society on Thrombosis and Haemostasis; IV: intravenous(ly); JAKi: Janus kinase inhibitors; LMWH: low molecular weight heparin; MOHFW: Ministry of Health and Family Welfare; MVTE: Major vascular thrombotic events; NEWS: National Early Warning Score; NIV: non‐invasive ventilation; NOACS: novel oral anticoagulants; NSAIDs: non‐steroidal antiflammatory drugs; NYHA: New York Heart Association; PaO2: partial pressure of oxygen; PCR: polymerase chain reaction; PD: Pharmacodynamic; PE: pulmonary embolism; PK: Pharmacokinetic; PRCB: packed red blood cell; PT(T): partial thromboplastin (time); RAS: Renin‐Angiotensin System; RCT: randomised controlled trial; RT‐PCR: reverse transcription polymerase chain reaction;  SAE: serious adverse event; SARS: severe acute respiratory syndrome; SBP: systolic blood pressure; SC: subcutaneous(ly);SIC: sepsis‐induced coagulopathy;SOFA: sequential organ failure assessment; SpO2: ratio of oxygen saturation in the blood; TB: tuberculosis; TIA: transient ischaemic attack; UFH: unfractionated heparin; ULN: upper limit of normal; VKA: vitamin K antagonists; VTE: venous thromboembolism; WBC: white blood cells; WHO: World Health Organization