Ananworanich 2021.

Study characteristics
Methods	Prospective, multicentre, 2‐armed, parallel‐assignment RCT
Participants	Number of participants: 497 Age: ≥ 18 years Gender: female (267 participants) and male (177 participants) Inclusion criteria Participants must be at high risk for COVID‐19 disease progression by fulfilling at least 1 of the following criteria at screening: Presence of chronic pulmonary disease, COPD, pulmonary hypertension DM (type 1 or type 2), requiring oral medication or insulin for treatment Hypertension, requiring at least 1 oral medication for treatment Immunocompromised status due to disease (e.g. those living with HIV with a CD4 T‐cell count of < 200/mm3) Immunocompromised status due to medication (e.g. taking 20 mg or more of prednisone equivalents a day, anti‐inflammatory monoclonal antibody therapies, cancer therapies) Any chronic disease that is associated with high risk for severe COVID in the opinion of the site investigator BMI ≥ 35 kg/m2 (based on self‐reported weight and height) Documented SARS‐CoV‐2 positive diagnostic test of ≤ 7 days at the time of screening Symptomatic for COVID‐19 for ≤ 72 hours at the time of screening (defined as having at least 2 of the following symptoms of COVID‐19 that is of new onset or has worsened from baseline: fever, chills, myalgia, arthralgia, headache, fatigue, cough, sore throat, nasal congestion, anosmia, ageusia, nausea, vomiting, or diarrhoea. If only 2 symptoms are present, they cannot both be anosmia and ageusia.) Capable of giving informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form and in the protocol Agree to participate in all remote, in‐person, or home visits as required in the protocol and provide updated contact information as necessary Female of childbearing potential must agree to practise adequate contraception during the study Exclusion criteria Currently hospitalised or under immediate consideration for hospitalisations at screening and Day 1 Have new‐onset shortness of breath or increased shortness of breath from pre‐COVID‐19 (for people with known COPD) at screening and Day 1 Hypoxaemia (oxygen saturation < 94% in ambient air or oxygen saturation below pre‐COVID‐19 level for people with known COPD) at Day 1 Require supplemental oxygen (new requirement or increase in requirement from pre‐COVID‐19 condition) at screening and Day 1 Have a history of (in the past 3 months) or current active pathological bleeding Have a history of haemorrhagic stroke or intracranial haemorrhage Have a recent severe head trauma within 30 days which includes concussion, skull fracture, or hospitalisation for head injury Have known intracranial neoplasm, cerebral metastases, arteriovenous malformation, or aneurysm Have history of pregnancy‐related haemorrhage Have active gastroduodenal ulcer or other GI bleeding diagnosed in the past 3 months Currently are in a haemodynamically unstable state Currently require thrombolysis or pulmonary embolectomy Have history of severe hypersensitivity reaction to rivaroxaban (Xarelto) Currently have a prosthetic heart valve Have known diagnosis of triple positive antiphospholipid syndrome Have known diagnosis of chronic kidney disease (stage IV or receiving dialysis) Have a history of thrombocytopenia or known platelet count < 100,000 cells/mm3 Have history of bronchiectasis and pulmonary cavitation Have active cancer (e.g. receiving chemotherapy or treatment for complication of the active cancer) Had epidural or neuraxial anaesthesia or spinal puncture in the past 2 weeks and plan to undergo these procedures during the study Had surgery in the past 4 weeks or plan to undergo surgery during the study Currently is pregnant or plans to become pregnant Currently is breastfeeding Share household with an enrolled participant in this study Co‐enrolment in any clinical trial that includes prohibited procedures (spinal puncture or surgery) or that includes treatments within the same drug class as rivaroxaban or treatments for which co‐administration with rivaroxaban are prohibited. Note that any co‐enrolment other than this requires approval by the Sponsor. For any co‐enrolled study, the total volume of blood samples collected across the studies should not exceed 275 mL in 4 weeks. Currently using and plan to use the following medications during the study: Rivaroxaban or drugs in the same class Dual antiplatelets therapy Other anticoagulants Combined P‐gp and CYP3A inhibitors and inducers
Interventions	Intervention: rivaroxaban (one 10 mg tablet), orally daily for 21 consecutive days Control: placebo‐equivalent (multivitamin, 1 tablet), orally daily for 21 consecutive days
Outcomes	Primary outcomes Frequency of AE including Grades 3 and 4, resulting in discontinuation through day 35 Number of participants with AE resulting in study intervention discontinuation through day 35 Number of participants with serious AE through day 35 Hypersensitivity and major bleeding events through Day 35 Proportion of participants who progressed to moderate or severe disease category Secondary outcomes Time to disease resolution Incidence of hospitalisation Proportion of participants with disease progression Proportion of participants with disease resolution
Funding	Bill & Melinda Gates Medical Research Institute
Declaration of interest	EG reports support from AstraZeneca, Genentech, Regeneron, TEVA, and DBV; consulting fees from P&T AscellaHealth; payment/honoraria from TEVA (Digihaler) and Genentech (omalizumab); and serving on Regeneron Pediatric Asthma Advisory Board and ACAAI Patient Advocacy Board. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Sequence generation is not specified
Allocation concealment (selection bias)	Low risk	Quote: 'Participants were randomised 1:1, stratified by site and symptom duration (< 6 days vs ≥ 6 days), to receive either rivaroxaban (one 10‐mg tablet) or placebo equivalent (multivitamin, 1 tablet) orally daily for 21 consecutive days.' Quote: 'Participants received a box delivered to their home that contained the study drug (e.g., either rivaroxaban or placebo), thermometer, pulse oximeter, nasal swab test kit and labels, and personal protective equipment. There were 12 telemedicine visits (days 1, 4, 6, 8, 10, 12, 14, 18, 21, 24, 28, and 35)' Comment: information from study article
Blinding of participants and personnel (performance bias)	Low risk	Quote: 'The bottle of medication the participants receive will not identify the treatment allocation. The active or placebo bottles will be labeled for investigational use with a randomized number to maintain blinding.' Quote: 'This randomization strategy can easily be generalized beyond 3 contemporaneously available interventions and will ensure approximately equal randomization of each intervention to control, while helping to maintain blinding and minimize possible bias.' Comment: from supplementary data of the study report.
Blinding of outcome assessment (detection bias)	Low risk	Quote: 'Independent data monitoring committee will be convened for this study with expertise in COVID‐19 or respiratory viruses and emerging epidemics as well as biostatistics'. Comment: data from supplementary data of the study report.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: 'Between 16 August 2020 and 3 February 2021, 538 adults were screened and 497 were enrolled (246 in rivaroxaban and 251 in placebo). The numbers of participants in each analysis population were similar between treatment groups. Sixty‐four participants discontinued the study and 89 discontinued the study drug (similar between groups).' Comment: information from study article
Selective reporting (reporting bias)	Low risk	The study protocol is available and all of the study's prespecified (primary and secondary) outcomes that are of interest in the review have been reported as prespecified
Other bias	Low risk	We did not find other bias in the study.