Covid-19 Living Data

Trial NCT04505774
Publication ACTIV-4a - Berger JS, JAMA (2022) (published paper)
Dates: 2021-02-26 to 2021-06-19
Funding: Public/non profit (National Institutes of Health; National Heart, Lung, and Blood Institute )
Conflict of interest: Yes

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Brazil, Italy, Spain, USA Follow-up duration (days): 90
Inclusion criteria	≥ 18 years of age laboratory-confirmed SARS-CoV-2 infection hospitalized for COVID-19 non–critically ill (hospitalized but did not require intensive care–level support) at enrollment and met any 1 of the following criteria: had a D-dimer level that was 2-fold or greater than the upper limit of normal (determined at each hospital site) or were 60 to 84 years of age. If a patient was younger than 60 years of age, if at least 1 of the following criteria were met: had an oxygen requirement greater than 2 L per minute or had hypertension, diabetes, chronic kidney disease (estimated glomerular filtration rate <60 mL/min/1.73 m2), cardiovascular disease, or a body mass index (calculated as weight in kilograms divided by height in meters squared) of 35 or greater
Exclusion criteria	Pregnancy required at enrollment intensive care–level support: defined as use of respiratory or cardiovascular organ support (oxygen via high-flow nasal cannula ≥20 L per minute, noninvasive or invasive mechanical ventilation, vasopressors, inotropes, or extracorporeal membrane oxygenation) 72 hours or more had elapsed from the hospital admission for COVID-19 or SARSCoV-2 infection confirmation hospital discharge was expected within 72 hours had a contraindication to P2Y12 inhibitors/anticoagulation (e.g., risk of bleeding, etc.) or a clinical requirement for dual antiplatelet therapy imminent death age >85 Platelet count < 50 x 109/L Hemoglobin < 8 g/dL Indication for P2Y12 inhibitor in the case that it cannot be stopped safely Indication for aspirin in the case that aspirin cannot be exchanged for a P2Y12 inhibitor (aspirin must be able to be discontinued)
Interventions
	Treatment Therap AC+P2Y12 inh If Ticagrelor: 60 mg twice daily for 14 days or until hospital discharge, whichever was sooner. If Clopidogrel: Initial dose: 300 mg load dose -Maintenance dose: 75 mg/day, for 14 days or until hospital discharge, whichever was sooner.
	Control Therap AC
Participants
	Randomized participants : Therap AC+P2Y12 inh=293 Therap AC=269
	Characteristics of participants N= 562 Mean age : NR 329 males Severity : Mild: n=58 / Moderate: n=343 / Severe: n=99 Critical: n=0 Number of vaccinated participants: NR
Primary outcome
	In the register 1) 21 Day Organ Support (respiratory or vasopressor) Free Days [Time Frame: 21 days from study enrollment]: which is defined as the number of days that a patient is alive and free of organ support through the first 21 days after trial entry. Organ Support is defined as receipt of non-invasive mechanical ventilation, high flow nasal canula oxygen, mechanical ventilation, or vasopressor therapy, with death at any time during the index hospitalization assigned -1 days. 2) Primary Safety Endpoint of Major Bleeding [Time Frame: 28 days from study enrollment]: Major bleeding (as defined by the ISTH).
	In the report 1) Organ support–free days: evaluated on an ordinal scale that combined in-hospital death (assigned a value of −1) and, for those who survived to hospital discharge, the number of days free of respiratory or cardiovascular organ support up to day 21 of the index hospitalization (range, −1 to 21 days; higher scores indicate less organ support and better outcomes); 2) Major bleeding by 28 days (as defined by the International Society on Thrombosis and Hemostasis).
Documents available	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the registry, protocol, statistical analysis plan and supplementary appendices were used in data extraction and assessment of risk of bias. This article reports on a non–critically ill cohort, to which enrollment was discontinued when the pre-specified criterion for futility was met. The study continued in a critically ill cohort. There is no change from the trial registration in the intervention and control treatments. Ticagrelor was the preferred P2Y12 inhibitor used: 63% in intervention group received ticagrelor; 37% had clopidogrel. The primary outcome in the article reflects that in the registry. The trial (n = 562) was stopped due to futility at repeated monthly interim analyses; the trial had an adaptive sample size of 200-2000 participants.