Canadian Adaptive Platform Trial of Treatments for COVID in Community Settings (CanTreatCOVID): protocol for a randomized controlled adaptive platform trial of treatments for acute SARS-CoV-2 infection in community settings

Canadian Adaptive Platform Trial of Treatments for COVID in Community Settings (CanTreatCOVID): protocol for a randomized controlled adaptive platform trial of treatments for acute SARS-CoV-2 infection in community settings | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Canadian Adaptive Platform Trial of Treatments for COVID in Community Settings (CanTreatCOVID): protocol for a randomized controlled adaptive platform trial of treatments for acute SARS-CoV-2 infection in community settings Benita Hosseini , Amanda Condon , Bruno R. da Costa , Peter Daley , Michelle Greiver , Peter Jüni , View ORCID Profile Todd C. Lee , Kerry McBrien , Emily G. McDonald , Srinivas Murthy , View ORCID Profile Peter Selby , Melissa Andrew , View ORCID Profile Kris Aubrey-Bassler , David Barber , Brendan Barrett , View ORCID Profile Chris Butler , Noah Crampton , Simone Dahrouge , Ali Damji , Robert Fowler , Stephanie Garies , View ORCID Profile Catherine Hudon , Jennifer Hulme , Jennifer Isenor , View ORCID Profile David Jenkins , Rosemarie Lall , View ORCID Profile Annie LeBlanc , View ORCID Profile Christine Leong , View ORCID Profile Paul Little , View ORCID Profile Aisha Lofters , Sarvesh Logsetty , Sylvain Lother , Marie-Thérèse Lussier , Laura MacLaren , Derelie Mangin , View ORCID Profile Emily Marshall , John Marshall , View ORCID Profile Rita McCracken , View ORCID Profile Rahim Moineddin , Briana Orava , View ORCID Profile Jean-Sebastien Paquette , Jay Jae Hee Park , View ORCID Profile Navindra Persaud , Valeria Rac , View ORCID Profile Vivian Ramsden , Jennifer Rayner , View ORCID Profile Diana Sanchez Ramirez , View ORCID Profile Lynora Saxinger , Haolun Shi , Alexander Singer , View ORCID Profile Rae Spiwak , Anita Srivastava , View ORCID Profile Abhimanyu Sud , Jean-Éric Tarride , Deanna Telner , Ross Upshur , Sakina Walji , Rachel Walsh , Machelle Wilchesky , View ORCID Profile Sabrina Wong , Brianne Wood , Ryan Zarychanski , Barbara Zelek , Yoav Keynan , Jolanta Pisczek , Daniel Warshafsky , View ORCID Profile Andrew D. Pinto doi: https://doi.org/10.1101/2024.11.25.24317904 Benita Hosseini 1 Unity Health Toronto, Upstream Lab, MAP Centre for Urban Health Solution, Li Ka Shing Knowledge Institute , Toronto, ON, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Amanda Condon 2 University of Manitoba Max Rady College of Medicine, Department of Family Medicine , Winnipeg, MB, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Bruno R. da Costa 3 University of Oxford , Oxford, Oxfordshire, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Peter Daley 4 Memorial University of Newfoundland Faculty of MedicineSt. John’s, NL , CA2. Eastern Regional Health AuthoritySt John’s, NL, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Michelle Greiver 5 North York General Hospital, Department of Family and Community Medicine , Toronto, ON, CA M2K 1E1 2. University of Toronto, Department of Family and Community Medicine, Toronto, CA M5S 1A1 Find this author on Google Scholar Find this author on PubMed Search for this author on this site Peter Jüni 6 University of Oxford, Nuffield Department of Population Health , Oxford, UK OX3 7LF Find this author on Google Scholar Find this author on PubMed Search for this author on this site Todd C. Lee 7 McGill University Health Centre , Montreal, QC, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Todd C. Lee Kerry McBrien 8 University of Calgary Cumming School of Medicine, Family Medicine , 3280 Hospital Dr NW, Calgary, AB, CA T2N 4Z6 Find this author on Google Scholar Find this author on PubMed Search for this author on this site Emily G. McDonald 9 McGill University , Medicine, 1001 Decarie boulevard, Montreal, QC, CA H4A3J1 Find this author on Google Scholar Find this author on PubMed Search for this author on this site Srinivas Murthy 10 University of British Columbia , Paediatrics, 4500 Oak Street, Vancouver, BC, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Peter Selby 11 Centre for Addiction and Mental Health, Addiction Programs , Toronto, ON, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Peter Selby Melissa Andrew 12 Dalhousie University, Division of Geriatric Medicine , Halifax, NS, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Kris Aubrey-Bassler 13 Memorial University, Primary Healthcare Research Unit , c/o Discipline of Family Medicine, MUN, 300 Prince Phillip Dr., St. John’s, NL, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Kris Aubrey-Bassler David Barber 14 Queen’s University , Kingston, ON, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Brendan Barrett 15 Memorial University, Medicine Nephrology , St. John’s, NL, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Chris Butler 16 University of Oxford, Nuffield Department of Primary Health Care Sciences, Radcliffe Observatory Quarter , Woodstock Road, Oxford, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Chris Butler Noah Crampton 17 University of Toronto Department of Family & Community Medicine , Toronto, ON, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Simone Dahrouge 18 Elisabeth Bruyere Research Institute, C.T. Lamont Primary Health Care Research Centre , 43 Bruyere Street, Annex E, Room 103, 43 Bruyere Street, Room 341Y, Ottawa, ON, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ali Damji 19 University of Toronto Department of Family and Community Medicine , Toronto, ON, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Robert Fowler 20 University of Toronto, Institute of Health Policy, Management and Evaluation , Toronto, ON, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Stephanie Garies 21 UCalgary Cumming School of Medicine, Department of Family Medicine , Calgary, AB, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Catherine Hudon 22 Université de Sherbrooke 3001 , 12e Avenue N, Sherbrooke, QC, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Catherine Hudon Jennifer Hulme 23 University of Toronto, Department of Family and Community Medicine Toronto , ON, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jennifer Isenor 24 Dalhousie University, College of PharmacyHalifax , NS, CA2. Dalhousie University, Canadian Center for VaccinologyHalifax, NS, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site David Jenkins 25 University of Toronto, Department of Nutritional Sciences , 1 King’s College Circle Toronto, ON, Toronto, ON, CA M5S 1A82. St. Michael’s Hospital, Risk Factor Modification Centre, 61 Queen Street East, 6th floor; Room 6133Q, Toronto, ON, CA M5C 2T2 Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for David Jenkins Rosemarie Lall 26 University of Toronto, Department of Family and Community Medicine , Toronto, ON, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Annie LeBlanc 27 VITAM Research Center on Sustainable Health , 2601, Chemin de la Canardière, Quebec, QC, CA G1J0A4 Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Annie LeBlanc Christine Leong 28 University of Manitoba , 750 McDermot Avenue Winnipeg, MB, CA R3E0T Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Christine Leong Paul Little 29 University of Southampton, Primary Care and Population Science, Aldermoor Health Centre , Southampton, UK SO16 5ST Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Paul Little Aisha Lofters 30 Women’s College Hospital, Department of Family and Community Medicine , Toronto, CA2. St. Michael’s Hospital, Department of Family and Community Medicine, Toronto, CA3. Women’s College Hospital, Department of Family and Community Medicine, Toronto, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Aisha Lofters Sarvesh Logsetty 31 University of Manitoba, Departments of Surgery and Psychiatry , 820 Sherbrook Street, Winnipeg, CA R3A1R9 Find this author on Google Scholar Find this author on PubMed Search for this author on this site Sylvain Lother 32 University of Manitoba Max Rady College of Medicine, Department of Internal Medicine , Winnipeg, MB, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Marie-Thérèse Lussier 33 Research Center of the Centre Hospitalier de l'Université de Montreal , Montreal, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Laura MacLaren 34 McGill University Faculty of Medicine and Health Sciences, Department of Family Medicine , Montreal, QC, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Derelie Mangin 35 Christchurch School of Medicine and Health Sciences, Public Health and General Practice , Christchurch, NZ 8001 Find this author on Google Scholar Find this author on PubMed Search for this author on this site Emily Marshall 36 Dalhousie University, Family Medicine , 5909 Veterans' Memorial Lane, Abbie J. Lane Building, Halifax, NS, CA B3H 2E2 Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Emily Marshall John Marshall 37 University of Toronto, Department of Surgery , Toronto, ON, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Rita McCracken 38 Providence Health Care, Family Medicine , 1081 Burrard Street, Vancouver, BC, CA V6Z 1Y62. University of British Columbia Faculty of Medicine, Family Practice, Vancouver, BC, CA V6T 1Z3 Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Rita McCracken Rahim Moineddin 39 University of Toronto, Family and Community Medicine , 500 University Ave, Toronto, ON, CA M5G 1V7 Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Rahim Moineddin Briana Orava 40 University of Toronto Lawrence S Bloomberg Faculty of Nursing , Toronto, ON, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jean-Sebastien Paquette 41 VITAM, Research Centre on Sustainable Health , 2480 chemin de la canardière, Quebec City, QC, CA G1J2G12. Université Laval, Département de médecine familiale et de médecine durgence, Quebec, CA G1V 0A63. Laboratoire Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Jean-Sebastien Paquette Jay Jae Hee Park 42 McMaster University Faculty of Health Sciences, Department of Health Research Methods , Evidence and Impact, Hamilton, ON, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Navindra Persaud 43 St. Michael’s Hospital, Li Ka Shing Knowledge Institute , 80 Bond Street, Toronto, ON, CA M5B 1X2 Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Navindra Persaud Valeria Rac 44 Toronto General Hospital, Research Institute , Toronto, ON, CA2. University of Toronto Dalla Lana School of Public Health, Toronto, ON, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Vivian Ramsden 45 University of Saskatchewan, Department of Academic Family Medicine , Saskatoon, SK, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Vivian Ramsden Jennifer Rayner 46 Alliance for Healthier Communities , 970 Lawrence Ave, Suite 500, Toronto, ON, CA M6A 3B62. Alliance for Healthier Communities Find this author on Google Scholar Find this author on PubMed Search for this author on this site Diana Sanchez Ramirez 47 University of Manitoba , Room 334 -771 McDermot Ave, Winnipeg, MB, CA R3E 0T62. University of Manitoba Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Diana Sanchez Ramirez Lynora Saxinger 48 University of Alberta Faculty of Medicine and Dentistry, Department of Medicine, Division of Infectious Diseases , Edmonton, AB, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Lynora Saxinger Haolun Shi 49 Simon Fraser University, Department of Statistics and Actuarial Science , Burnaby, BC, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Alexander Singer 50 University of Manitoba College of Medicine, Department of Family Medicine , Winnipeg, MB, CA2. Manitoba Primary Care Research Network, Winnipeg, MB, CA 204-789-3314 Find this author on Google Scholar Find this author on PubMed Search for this author on this site Rae Spiwak 51 University of Manitoba, Department of Surgery , Winnipeg, CA R3T 2N2 Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Rae Spiwak Anita Srivastava 26 University of Toronto, Department of Family and Community Medicine , Toronto, ON, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Abhimanyu Sud 52 University of Toronto Faculty of Medicine , 500 University Avenue, 5th Floor, Toronto, ON, CA M5G 1V7 Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Abhimanyu Sud Jean-Éric Tarride 53 McMaster University, Department of Clinical Epidemiology & Biostatistics , 1280 Main St W, Hamilton, ON, CA L8S 4L8, Find this author on Google Scholar Find this author on PubMed Search for this author on this site Deanna Telner 26 University of Toronto, Department of Family and Community Medicine , Toronto, ON, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ross Upshur 54 University of Toronto Dalla Lana School of Public Health , Toronto, ON, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Sakina Walji 26 University of Toronto, Department of Family and Community Medicine , Toronto, ON, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Rachel Walsh 55 Sunnybrook Research Institute, Evaluative Clinical Sciences Platform, Integrated Community Program , Toronto, ON, CA2. Sunnybrook Academic Family Health Team, Toronto, CA3. University of Toronto, Department of Family and Community Medicine, Toronto, O Find this author on Google Scholar Find this author on PubMed Search for this author on this site Machelle Wilchesky 56 McGill University, Departments of Medicine and of Family Medicine , 5858 rue Cote des Neiges, Suite 300, Montreal, QC, CA H3S 1Z12. Jewish General Hospital, Lady Davis Institute for Medical Research, Montreal, QC, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Sabrina Wong 57 University of British Columbia, Centre for Health Services and Policy Research , 2211 Wesbrook Mall, Vancouver, BC, CA V6T2B5 Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Sabrina Wong Brianne Wood 58 Thunder Bay Regional Health Research Institute , 980 Oliver Road, Thunder Bay, ON, CA P7B 6V4, 6474590022 Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ryan Zarychanski 59 University of Manitoba, Sections of Critical Care and Hematology/Medical Oncology , ON2051, 675 McDermot Ave, Winnipeg, MB, CA R3E0V9, 2048994288 Find this author on Google Scholar Find this author on PubMed Search for this author on this site Barbara Zelek 60 Northern Ontario School of Medicine, Clinical Sciences , Sudbury, ON, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Yoav Keynan 61 University of Manitoba, Medical Microbiology and Infectious Diseases , Winnipeg, MB, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jolanta Pisczek 62 The University of British Columbia, Faculty of Pharmacy,Vancouver , BC, CA2. British Columbia Ministry of Health, Victoria, BC, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Daniel Warshafsky 63 University of Ottawa, School of Epidemiology and Public Health , Ottawa, ON, CA2. Ontario Ministry of Health, Toronto, ON, CA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Andrew D. Pinto 64 Unity Health Toronto, Upstream Lab, MAP Centre for Urban Health Solutions , Li Ka Shing Knowledge Institute, Toronto, ON, CA2. St. Michael’s Hospital, Department of Family and Community Medicine, Toronto, ON, CA3. University of Toronto, Department of Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Andrew D. Pinto For correspondence: andrew.pinto{at}utoronto.ca Abstract Full Text Info/History Metrics Supplementary material Data/Code Preview PDF ABSTRACT Introduction While effective vaccines and natural immunity have significantly reduced hospitalizations and the need for critical care, SARS-CoV-2 is now endemic and is expected to continue to pose a threat to health. New variants are expected to continue to emerge, and vaccines may become less effective. Effective and affordable therapeutics for SARS-CoV-2 that can be easily used in community settings are needed to accelerate recovery, reduce hospitalizations and mortality, and mitigate the development of post-acute sequelae of SARS-CoV-2, also known as “long COVID.” In this paper we present the design of the Canadian Adaptive Platform Trial of Treatments for COVID in Community Settings (CanTreatCOVID). Methods and analysis CanTreatCOVID is an open-label, individually randomized, multi-centre, national adaptive platform trial designed to evaluate the clinical and cost-effectiveness of therapeutics for non-hospitalized SARS-CoV-2 patients across Canada. Eligible participants must present with symptomatic SARS-CoV-2 infection, confirmed by PCR or rapid antigen testing (RAT), within 5 days of symptom onset. The trial targets two groups that are expected to be at higher risk of more severe disease: (1) individuals aged 50 years and older, and (2) those aged 18-49 years with one or more comorbidities. CanTreatCOVID uses numerous approaches to recruit participants to the study, including a multi-faceted public communication strategy and outreach through primary care, out-patient clinics, and emergency departments. Participants are randomized to receive either usual care, including supportive and symptom-based management, or an investigational therapeutic selected by the Canadian COVID-19 Outpatient Therapeutics Committee. The first therapeutic arm evaluates nirmatrelvir/ritonavir (Paxlovid™), administered twice daily for 5 days. The second therapeutic arm investigates a combination antioxidant therapy (selenium 300 µg, zinc 40 mg, lycopene 45 mg, and vitamin C 1.5 g), administered for 10 days. The primary outcome is all-cause hospitalization or death within 28 days of randomization. Ethics and dissemination The CanTreatCOVID master protocol and sub-protocols have been approved by Health Canada and local research ethics boards in the participating provinces across Canada. The results of the study will be disseminated to policymakers, presented at conferences, and published in peer-reviewed journals to ensure that findings are accessible to the broader scientific and medical communities. Trial registration number: NCT05614349 Strengths and Limitations Box The CanTreatCOVID community-focused design allows enrollment without in-person visits. The adaptive platform trial structure provides flexibility to add promising therapies and remove ineffective ones, which is critical in a rapidly changing pandemic environment CanTreatCOVID gathers real-world data on outpatient COVID-19 care The open-label design avoids logistical challenges associated with placebo controls in large-scale trials, though it may introduce bias related to subjective outcomes The reliance on self-reported adherence to study medications could lead to variability INTRODUCTION While the acute phase of the COVID-19 pandemic has ended, SARS-CoV-2 continues to circulate globally, with over seven million deaths annually attributed to the virus. 1 Vaccines and natural immunity have now substantially reduced hospitalizations and the need for critical care; however, SARS-CoV-2 is endemic and remains a threat to health. 2 New variants of SARS-CoV-2 continue to emerge with the risk that vaccine effectiveness and acquired immunity may decline. 3 Therefore, there will remain an ongoing need for therapeutics that are effective, safe, affordable, and suitable for use in community settings. 4 While several agents have been evaluated for mild to moderate infections in outpatient settings, current guidelines from Canada, 5 , 6 the United states, 7 and international bodies 8 , 9 primarily have recommended nirmatrelvir/ritonavir (Paxlovid™). 9 Other therapeutics, such as fluvoxamine or metformin 10 have moderate (and mixed) supporting evidence, 11 and inhaled therapeutics have weak evidence to support their use but may be considered. 9 , 12 Nirmatrelvir/ritonavir is a promising treatment; however, the key randomized controlled trial (RCT) that assessed its efficacy, the Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients (EPIC-HR) study, was conducted in unvaccinated patients before the emergence of more recent variants of SARS-CoV-2. 13 Data from the EPIC-SR study showed no significant difference in time to recovery (12 days for nirmatrelvir/ritonavir vs. 13 days for placebo) or hospitalization/death rates (0.8% vs. 1.6%) in vaccinated or unvaccinated non-hospitalized patients with SARS-CoV-2. 14 A recent systematic review and network meta-analysis of antivirals for non-severe SARS-CoV-2 infection highlighted the need for further studies to evaluate nirmatrelvir/ritonavir and other therapeutics in vaccinated populations and against newer variants of SARS-CoV-2. 15 In addition, current antiviral therapies for SARS-CoV-2 infection have limitations, including potential adverse effects ranging from mild symptoms to severe reactions, and eligibility restrictions that limit their use in certain populations. In a systematic review we completed, antioxidant treatments hold promise, but further evidence from randomized controlled trials are needed. 16 Adaptive platform trials (APTs) are an ideal design to assess multiple therapies simultaneously, with the flexibility to introduce new treatments as they emerge. 17 APTs have played a crucial role in identifying effective treatments for hospitalized COVID-19 patients. 18 RECOVERY identified dexamethasone as significantly reducing mortality in patients requiring oxygen, 19 and tocilizumab in severe disease. 20 REMAP-CAP highlighted the efficacy of intravenous steroids in intensive care unit (ICU) patients. 21 Collaborative efforts across APTs, such as ATTACC, REMAP-CAP, and ACTIV-IV, demonstrated that therapeutic-dose heparin reduces progression to ICU-level care and mortality in non-critically ill hospitalized patients. 22 , 23 In the outpatient setting, the PRINCIPLE trial in the UK demonstrated the efficacy of inhaled budesonide. 24 Given the evolving nature of the virus and the limitations of current therapeutic options, ongoing evaluation of treatments in community settings remains essential to ensure optimal care for patients. The Canadian Adaptive Platform Trial of Treatments for COVID in Community Settings (CanTreatCOVID) is a multi-arm adaptive platform trial that aims to evaluate the clinical and cost-effectiveness of multiple therapeutic interventions compared to usual care for non-hospitalized patients with SARS-COV-2 at high risk of severe complications. The trial uses a flexible design that allows for the assessment of various treatments simultaneously, ensuring that new and promising therapies can be quickly tested and incorporated to improve patient outcomes in community-based settings. METHODS AND ANALYSIS Trial Design CanTreatCOVID is an open label, individually randomized, adaptive platform trial conducted across Canada. The trial currently involves six provinces: Ontario, Québec, Alberta, Manitoba, British Columbia, and Newfoundland and Labrador. Each province has a dedicated research hub with a team of research staff, and recruitment occurs through “spokes” in primary care centers and other community settings, as well as other recruitment methods. The primary objective is to evaluate the clinical and cost-effectiveness of multiple therapeutics for non-hospitalized SARS-CoV-2 patients at high risk of severe complications. The trial also aims to address practical challenges related to the implementation of these therapies in diverse healthcare settings. By using an APT design, CanTreatCOVID allows for the continuous evaluation and comparison of treatments, incorporating new interventions as evidence emerges. Recruitment strategy We recruit participants through several channels to ensure broad outreach across Canada. Public communications and community partnerships has played a key role, with recruitment materials available in English and French in each province. The trial website ( www.CanTreatCOVID.org ) provides clear information and supports public engagement, transparency, and knowledge sharing, based on insights from previous Canadian trials and the PANORAMIC study in the UK 25 . Additionally, a toll-free hotline, available from 8 AM to 6 PM ET, Monday to Friday, provides direct support for potential participants, with trained research assistants available to intake participants and answer questions. We have also developed recruitment materials for public advertising (e.g., transit, print/online media, traditional media) and digital channels (e.g. Google ads, Facebook, Twitter, Instagram). Primary care practice-based research networks are another source of recruitment. We have engaged primary care practices and physicians, and with their permission, we use existing electronic medical record data to identify patients who meet key eligibility criteria (age and underlying health condition). This has enabled proactive communication with potentially eligible participants should they contract SARS-CoV-2. In outpatient settings, including primary care clinics, urgent care centers, specialty clinics, emergency departments, and pharmacies, we disseminate recruitment materials and encourage referrals, particularly for high-risk populations. We have leveraged institutional and provincial databases to maximize outreach. Our interdisciplinary team is affiliated with institutions that maintain databases of participants from past studies who have consented to be contacted for future research. This has allowed us to connect directly with individuals who have already expressed a willingness to contribute to scientific studies. Additionally, we collaborate with provincial organizations, such as provincial Ministries of Health, to access databases of individuals who have received the COVID-19 vaccine and consented to be contacted for research purposes. Eligibility criteria Eligible participants include individuals aged 50 years and older, or those aged 18-49 with pre-existing comorbidities that increase their risk of severe illness. Participants must also have a positive SARS-CoV-2 test (PCR or RAT) with proof of a positive test provided via a picture of the result. Patients must be enrolled within 5 days of onset of symptoms associated with SARS-CoV-2 infection 9 , 26 because some therapeutics must be taken early in an infection to be effective. Eligible symptoms include at least one of the following: fever or chills, cough, shortness of breath, decreased or loss of taste or smell, runny nose or nasal congestion, headache, fatigue, sore throat, muscle aches or joint pain, or gastrointestinal symptoms. Exclusion criteria include participants who have been hospitalized or remained in an emergency department for more than 24 hours, prior enrollment in CanTreatCOVID, current participation in another SARS-CoV-2 therapeutic trial, use of or contraindications to a trial therapeutic, or inability of the participant or caregiver to provide informed consent. Patients with contraindications to specific trial drugs are excluded from that particular intervention arm but remain eligible for randomization into other treatment arms. To participate, patients must be eligible for both the usual care arm and at least one intervention arm of the trial. Screening Regardless of how the potential participant learned about the trial, potential participants must speak to a research assistant via telephone call to undergo initial screening. The initial screening process includes reviewing the eligibility criteria and conducting a preliminary assessment of the compatibility of the potential participant’s medications based on a list provided by the participant. The initial screen also serves the potential participant by clarifying questions about trial involvement, and if English is not the first language, research assistants have access to translation services to ensure potential participants can be served without a language barrier. If eligible, the research assistant proceeds to engage the potential participant in the process of obtaining written informed consent. The participant also provides consent to having a team member contact their usual community pharmacy and primary care provider, as needed, to clarify any discrepancies in their health status, including their medications. Once these consents are obtained, the study pharmacist conducts a detailed review of the participant’s medications using a medication list from the patient’s usual pharmacy or provincial repository. If additional information is required to determine eligibility, this is obtained using electronic clinical resources and, if further necessary, the study team contacts the participant’s primary care provider for further clarification. Once the detailed medication and eligibility review has been satisfactorily completed, the study pharmacist makes a recommendation (which may include strategies to mitigate potential drug-interactions) to the provincial principal investigator (PI) who approves and signs off on the participant’s eligibility. Randomization and allocation Following confirmation of eligibility, participants are immediately randomized through an interactive, secure, web-based system maintained by the data management group. Randomization is conducted using fixed, equal allocation ratios corresponding to the number of active treatment arms for which the participant is eligible. If a participant is eligible for two arms (e.g., usual care and one therapeutic), they will be randomized in a 1:1 ratio between these two options. If a participant qualifies for more than two arms, the randomization ratio will adjust accordingly (e.g., 1:1:1 if there are three eligible arms). Initially, participants were randomized in a 1:1 ratio between usual care and the first therapeutic arm (nirmatrelvir/ritonavir). As additional therapeutics are introduced (antioxidant therapy as the second arm), the randomization ratio adjusts accordingly (e.g., 1:1:1). To ensure balance and minimize bias, randomization is stratified by age group (<65 years vs. ≥65 years) and employs permuted blocks of varying sizes. Blinding In this open-label adaptive platform trial, both participants and recruiting clinicians are aware of the assigned intervention. Therefore, no unblinding or code breaking is required. However, trial investigators who are not involved in participant recruitment, as well as the lead statisticians, remain blinded to treatment allocations. Unblinded statisticians, along with independent members of the DSMC, have access to unblinded data. These individuals are responsible for monitoring interim outcomes and will only disclose unblinded information once a decision is reached to stop recruitment for any specific intervention arm. Intervention As the trial progresses, the selection of therapeutics to be evaluated for SARS-CoV-2 treatment in outpatient settings is guided by the Canadian COVID-19 Out-Patient Therapeutics Committee. This committee continuously reviews the latest evidence and provides recommendations to the Steering Committee. The decision to include a new therapy is based on several key criteria: Strong scientific and biological rationale, supported by compelling evidence or successful independent studies (e.g., phase I/II trials) demonstrating efficacy for treating SARS-CoV-2 in outpatient settings. Sufficient availability of the therapeutic to ensure consistent supply throughout the trial. Scalability of the therapeutic, allowing widespread use if found to be effective. The addition of a new arm must not interfere with the completion of ongoing research arms. The therapeutic must remain clinically relevant by the time the trial arm is completed. The adaptive platform design and master protocol structure enable the seamless incorporation of new interventions, ensuring flexibility and responsiveness to emerging evidence. Detailed information for each therapeutic, including dosage, known side effects, adverse reactions, duration of treatment, and existing data, is provided to participants along with a patient handout in lay language to ensure clear understanding. The first intervention arm is nirmatrelvir/ritonavir (Paxlovid™), consisting of 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet), with all three tablets taken together orally twice daily for 5 days. Upon randomization to this arm, participants are urgently provided with a participant pack containing nirmatrelvir/ritonavir, along with dosing instructions and safety information. Participants are advised to complete the full 5-day treatment course, which should be initiated as soon as possible after a diagnosis of SARS-CoV-2 has been made, and ideally within 5 days of symptom onset. Adherence to the study therapeutic is monitored through participant self-reporting. Participants are eligible for the nirmatrelvir/ritonavir arm if they meet all platform-level inclusion criteria and none of the platform-level exclusion criteria. Additional nirmatrelvir/ritonavir specific exclusion criteria include: a history of clinically significant hypersensitivity to nirmatrelvir /ritonavir or its excipients; known hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption; severe liver impairment (characterized by severe ascites, encephalopathy, jaundice, or prolonged INR (patients with liver disease without any of these features are eligible); being a solid organ transplant recipient on immunosuppressants; having moderate or severe renal disease (defined as CKD stage 3, 4 or 5 or current acute kidney injury or most recent eGFR in the past 6 months <60 ml/min); currently taking nirmatrelvir/ritonavir; clinical requirement to continue taking a drug contraindicated or not recommended for administration with nirmatrelvir/ritonavir; known or suspected pregnancy; breastfeeding; or being of childbearing potential without using highly effective contraception. The second intervention arm is antioxidant therapy (selenium 300 µg, zinc 40 mg, lycopene 45 mg, and vitamin C 1.5 g) administered as three capsules taken once per day for 10 days. Participants are advised to complete the full 10-day treatment course. Upon randomization to this arm, participants are promptly provided with a participant pack containing the antioxidant therapy, along with dosing instructions and safety information. Eligibility for the antioxidant therapy arm also requires meeting all platform-level inclusion criteria and none of the platform-level exclusion criteria. Additional exclusion criteria specific to antioxidant therapy include: known or suspected pregnancy, breastfeeding, childbearing potential without highly effective contraception, allergy or intolerance to any of the ingredients (selenium, zinc, lycopene, vitamin C, ascorbyl palmitate, hypromellose, microcrystalline cellulose, or sodium stearyl fumarate), use of warfarin as a preventive measure, advanced chronic kidney disease (CKD stage 3-5, eGFR <60 mL/min), liver disease awaiting transplantation, a history of calcium oxalate kidney stones, head and neck cancer within the past five years, history of non-melanoma skin cancer, current use of supplements with selenium (≥300 µg/day), zinc (≥40 mg/day), lycopene (≥45 mg/day), and vitamin C (≥1500 mg/day), and consumption of omega-3 fatty acids at baseline without willingness to stop during the intervention period. Primary and secondary outcomes Our primary outcome is all-cause hospitalization or death within 28 days from randomization. This is captured through daily diaries (completed from day 1-day 14) as well as during participant follow-up at 21 and 28 days. It will also be cross-checked with administrative data. Based on a robust understanding of SARS-CoV-2 infection, it is likely that severe outcomes would occur within 28 days of symptom onset, 38 and this outcome has been used in several key studies of SARS-CoV-2 treatments in community settings. 39–41 This timeframe also corresponds to when hospitalizations due to adverse drug events from therapy (or drug-interactions) would be expected to occur. The secondary outcomes include: (1) time to recovery, defined as the first instance that a participant report feeling fully recovered. This will be captured through daily diaries (day 1-day 14) using the questions: “Do you feel recovered today? i.e., symptoms associated with illness are no longer a problem”, which has been used in PRINCIPLE 39 and PANORAMIC 36 , and the Flu Pro Plus relevant questions about returning to usual health and activities 42 ; (2) time to sustained resolution, defined as the number of days from randomization to the first of 3 consecutive days of resolution or alleviation (without subsequent relapse by day 28); (3) time to progression of signs or symptoms, defined as the number of days from randomization to the first of 2 consecutive days of worsening); (4) symptom severity, will be captured through daily diaries using the questions: “How well are you feeling today? Please rate how you are feeling now using a scale of 1 – 4, where 1 is no symptoms, and 4 is very severe symptoms” and by rating symptoms, if present, as “No problem, mild problem, moderate problem, or major problem”; (5) post-acute sequelae of SARS-CoV-2, collected at 90 days and 36 weeks, using the World Health Organization clinical case definition 43,44 and the validated Symptom Burden Questionnaire for Long COVID 45 ; (6) Quality of life, using EQ-5D-5L, collected at baseline, 21 days, 28 days, 90 days, and 36 weeks and analyzed using Canadian reference values; health service use, treatment costs, cost/QALY, analyzed using standard trial-based economic evaluation methods 46 ; and (7) early discontinuation and severe adverse events (SAEs). Data collection and participants follow up procedures At baseline, we collect data on sociodemographic including date of birth, sex assigned at birth, gender identity, education level, household income, income source, ethnicity, rurality. We also collect health care numbers, all phone numbers, an emergency contact, an email address, and seek permission to use text messaging, as well as alternative contacts and caregivers (for obtaining follow-up data should the need arise). All participants receive a call from the trial team 1 day after randomization to confirm the receipt of study materials and medication (if randomized to a study drug) and to address any questions. For participants randomized to nirmatrelvir/ritonavir, an additional safety call is made on day 4 to monitor for any early side effects and to ensure that no new medications have been taken that may be contraindicated with nirmatrelvir/ritonavir. Similarly, participants randomized to the antioxidant therapy arm receive an additional safety call on day 6 to check for potential adverse drug reactions or any contraindicated medications. These safety calls ensure that participants remain safe while adhering to the study protocol. Participants in all arms will complete an online daily diary each day for 14 days ( Supplementary file 1 ), a validated approach from similar trials. 24 , 25 , 27 Participants self-report symptoms and severity, as well as contact with health services (e.g., hospital admissions, ED visits, visits to specialists and primary care), which will be corroborated with administrative data when the data become available. Moreover, 10% of participants are randomized to complete additional Flu Pro Plus questions in the daily diary, which collect detailed information on severity of symptoms ( Supplementary file 2). Our primary study outcome is reported by the patient or their alternative contact and does not rely on administrative data for publication and timely dissemination of results. Participants are prompted to complete online follow-up surveys using REDCap Cloud© electronically through automated emails sent through the survey software. Research staff call participants with no internet access, as well as those who prefer to complete surveys over the phone. Participants who have not completed their diary for at least two consecutive days before day 7 or again before day 14 will be contacted by staff by email, phone, or text. Staff make 3 attempts over 3 days before considering it missing data. Research staff contact patients at 21 days and 28 days, focusing on the primary outcome, and at 90 days and 36 weeks from randomization, with a focus on post-acute sequelae of SARS-CoV-2. The EQ-5D-5L 28 will be administered at baseline, 21 days, 28 days, 90 days, and 36 weeks. Adverse events will be assessed throughout the study period; data on serious adverse events considered by the investigator to be related to the assigned regimen will be collected through the end of study participation. Statistical Analysis Primary analysis population The primary intention-to-treat (ITT) analysis population is defined as all randomised participants according to the group they were randomly allocated to, regardless of deviation from protocol. The ITT Population is typically the primary population for the analysis of efficacy parameters. A subset of efficacy parameters will be evaluated for the per protocol (PP) population, defined as randomized patients who adhered to more than 80% of the assigned therapy. For patients who have an early outcome, 80% applies to the expected number of doses by that time and not the total number. For the usual care group, per protocol will be defined as not receiving an investigational product for the duration corresponding to the PP duration needed for the investigational product. The Safety Population, defined as randomized patients who received at least 1 dose of study drug, is the primary population for the analysis of safety endpoints, compared to the usual care group. Primary and Secondary outcome(s) analysis For our primary outcome analysis, we use a Bayesian logistic regression model which includes the randomized treatment group, age, and vaccination status as covariates. We will calculate and report model-based estimates of the difference in hospitalization/deaths rates between each treatment arm and the Usual Care, along with 95% Bayesian credible intervals. For the secondary endpoints, logistic regression, ordinal logistic regression, and linear regression will be used, depending on the data types of endpoints. Randomized group, age and vaccination status will be included covariates. Where logistic regression and ordinal logistic regression are used, the odds ratios will be reported for each pairwise treatment arm comparison with the usual care group, along with their respective p-value and 95% confidence interval. Where linear regression is used, the mean and standard deviation will be reported in each treatment arm. The adjusted difference in means, along with the 95% confidence interval for each pairwise treatment arm comparison with the usual care group, will be reported. The interim analysis plan will be determined by using a series of clinical trial simulations to ensure that satisfactory operating characteristics in terms of controlling the type I error rate in cases where all treatment arms are the same, while attempting to maximize the statistical power in cases where one or more treatment arms yield meaningful treatment benefits. Before any unblinded analyses are performed by an independent statistician, the simulations will be performed by the Methods and Statistical Analysis Committee who will be blinded to the knowledge of group assignments. The interim analysis will determine a) the superiority of the treatment arm in comparison with the Standard of Care (SOC); b) switching the SOC arm to another treatment arm with significant superiority; c) futility and suspension of a treatment arm; and d) adding additional treatment arms. Interim futility determines whether a treatment arm should be suspended, i.e., halted from receiving new patients for the next cohort. We compute the model-based hospitalization/death rate for each treatment arm, denoted as p j , with the stratification covariates being set to the respective populational averages. Using Markov chain Monte Carlo (MCMC) sampling, we compute the Bayesian posterior probability that hospitalization/death rate of treatment arm j is smaller than that of the SOC by at least a margin of 1%, Pr(p SOC - p j > 0.01), and if it is smaller than a precalibrated stopping boundary, e.g., 0.001, the interim futility rule for hospitalization/death endpoint is satisfied. If interim futility rules are satisfied for a treatment, then it will be suspended over the next cohort. If the two interim futility rules are no longer satisfied in the next interim analysis in the light of new data in other treatment arms, the suspension might be canceled. Subgroup analyses will be performed on several populations, including age, sex, gender, body mass index (BMI), income, race and ethnicity, rurality, medical conditions (multimorbidity and immunocompromised), number of vaccine doses received (< 2 vs ≥2), and place of recruitment (emergency departments vs other settings). We will also examine the moderating effects of concomitant medications, such as corticosteroids. For each subgroup, we will calculate model-based estimates of the difference in rates of emergency visits, death, and hospitalization between the treatment arms and the usual care, accompanied by 95% Bayesian credible intervals computed using the primary analysis model. Sample size Given the open, ‘perpetual’ trial structure, the trial does not have a finite ending based on sample size. We have determined our estimated sample size per arm based on Bayesian logistic regression to estimate the adjusted odds ratio for hospitalization or death at 28 days for a pairwise comparison of treatment arm (initially nirmatrelvir/ritonavir) vs. comparator (initially usual care). Assuming a conservative 5% comparator event rate of hospitalization or death 29 , 30 , we deemed that a reduction from 5% to 3.35% would be clinically meaningful, based on the current published evidence. 13 , 24 , 31 We estimate that approximately 2,413 participants per arm will be required to provide 90% power for detecting a 25% reduction in the relative risk of hospitalization/death. Ethical considerations and governance The CanTreatCOVID master protocol and sub-protocols have been approved by Health Canada and local research ethics boards in the participating provinces across Canada. All participants provide informed consent, which can be completed online, via email, or verbally via telephone. An independent Data Monitoring and Safety Committee (DMSC) oversees safety data, review interim analyses provided by the Statistical Analysis Committee (SAC), and communicate recommendations to the Trial Steering Committee (TSC). The TSC provides guidance and oversight to the Trial Management Group (TMG). The results of the study will be disseminated to policymakers, presented at conferences, and published in peer-reviewed journals to ensure that findings are accessible to the broader scientific and medical communities. DISCUSSION CanTreatCOVID is an open-label, individually randomized, adaptive platform trial designed to evaluate therapeutics for SARS-CoV-2 infection in high-risk outpatient populations. Eligible participants include those aged 50 years or older, or those aged 18-49 with at least one chronic medical condition or immunosuppression. Patients must be enrolled within 5 days of symptom onset. The trial evaluates therapeutics against usual care and may compare treatments directly as new interventions are added. The Canadian COVID-19 Out-Patient Therapeutics Committee oversees the selection of investigational therapies based on emerging evidence, ensuring that relevant and promising treatments are assessed in real-time. CanTreatCOVID’s adaptive design allows modifications based on interim analyses of primary outcome data, enabling the removal of interventions deemed futile or successful. This structure also facilitates the integration of findings from international trials and the addition of new treatment arms as they become available. This flexible approach ensures the trial remains responsive to the evolving nature of the COVID-19 pandemic and the therapeutic landscape, while contributing to the broader knowledge base on outpatient management of SARS-CoV-2. Comparison with other studies Several other adaptive platform trials (APTs) share similar objectives and methodologies. The multi-center, adaptive, randomized platform trial to evaluate the effect of repurposed medicines in outpatients with early COVID-19 and high-risk for complications (TOGETHER) trial 32 is multi-center APT assesses repurposed medicines for treating high-risk COVID-19 outpatients in early stages of infection. The study was conducted in Brazil and recruited over 10,000 participants. The trial has concluded investigations on six medications including hydroxychloroquine, lopinavir / ritonavir, ivermectin, fluvoxamine maleate, metformin, and doxazosin; and currently have four treatments (Peginterferon Lambda, fluvoxamine, fluvoxamine plus molnupiravir and fluvoxamine plus inhaled corticosteroid) under investigation. The trial ability to test a range of inexpensive, repurposed drugs has offered valuable data on treatments that are scalable, especially in low-and middle-income countries. While TOGETHER shares CanTreatCOVID’s focus on early treatment in outpatients, it differs in its geographic scope and focus on repurposed drugs. The Platform Adaptive trial of NOvel antiviRals for eArly treatment of COVID-19 in the Community (PANORAMIC) 31 conducted in the UK, is one of the largest APTs for outpatient COVID-19 therapeutics. It is an open-label APT that assessed the safety and efficacy of antiviral treatments versus usual care in patients at increased risk of COVID-19 related morbidity and mortality. PANORAMIC has enrolled over 29,000 participants across 65 sites. The trial evaluated both molnupiravir 25 and nirmatrelvir/ritonavir. Recruitment for both treatments has now concluded, with the trial playing a significant role in confirming the real-world effectiveness of these antiviral agents in highly vaccinated populations. PANORAMIC shares CanTreatCOVID’s community-based approach, but it is primary focused on antiviral treatments, while CanTreatCOVID aims to evaluate a broader range of therapies. The Accelerating COVID-19 Treatment Interventions and Vaccines (ACTIV-2 and ACTIV-6) were launched by the U.S. National Institutes of Health to assess outpatient treatments for mild-to-moderate COVID-19 cases in individuals at risk of severe disease progression. 33 ACTIV-2, a Phase II/III trial, evaluates monoclonal antibodies, oral antivirals, and inhaled interferons and has enrolled 4,044 participants across 172 sites worldwide, including locations in Argentina, Brazil, and the United States. 33 , 34 ACTIV-6, a Phase III platform trial, examines the effectiveness of widely available prescription and over-the-counter medications in managing COVID-19 symptoms in outpatients. 33 With a focus on repurposed medications, such as ivermectin and fluvoxamine, ACTIV-6 has enrolled over 10,000 participants across 110 sites within the United States. 33 Similar to TOGETHER, ACTIV-6 aims to provide data on accessible, affordable treatments, but focuses on medications readily available to the public. Both ACTIV-2 and ACTIV-6 provide valuable insights into outpatient management of SARS-CoV-2, though they differ from CanTreatCOVID by targeting specific therapeutic classes rather than a broad spectrum of treatments. Strengths and limitations One of CanTreatCOVID’s major strengths is its community-focused approach, which prioritizes early intervention for patients in outpatient settings. By allowing enrollment without the need for in-person visits, the trial maximizes accessibility and reduces barriers to participation. This approach captures a broader, more diverse patient population, and also ensures that therapeutics are tested during the early, milder stages of COVID-19, where timely intervention may yield the greatest benefits. This emphasis on community care reflects the growing recognition that managing SARS-CoV-2 in outpatient settings is critical to reducing the burden on healthcare systems and preventing severe outcomes. Another key strength is the trial’s adaptive design, which allows for real-time flexibility. As new data become available, treatments that show promise can be added, while ineffective ones can be removed. This adaptability is essential in a rapidly evolving pandemic, where new variants and therapies continue to emerge. A key limitation of the trial is its open-label design. Without blinding, both participants and study clinicians are aware of the intervention being administered, which introduces the potential for bias. However, the decision to forgo placebo control was made deliberately, as usual care in the community does not typically include placebo administration. Additionally, creating placebo equivalents for multiple investigational drugs in a large-scale platform trial would be logistically challenging and may delay the rapid evaluation of potentially life-saving treatments. While the open-label design could impact subjective outcomes, it remains the most feasible and practical option given the trial’s scale and the urgency of the pandemic. Furthermore, previous open-label trials have shown no difference in subjective outcomes, specifically, time to recovery between different intervention arms and usual care 35 , indicating that the absence of a placebo did not impact participants’ perception of being fully recovered. Another potential limitation is the reliance on self-reported data for adherence to the study medications, which may introduce variability in how accurately participants follow the therapeutic regimen. To address this, the trial uses online questionnaires and regular check-ins with study staff to support accurate reporting and help participants stick to the regimen. CanTreatCOVID represents a robust, adaptive platform trial designed to address the urgent need for effective therapeutics in the outpatient management of SARS-CoV-2. By focusing on high-risk populations and leveraging real-world healthcare settings, the trial offers the potential to identify treatments that can significantly improve outcomes in the community. The adaptive design enables the trial to evolve in response to emerging evidence. While challenges such as the open-label design and self-reported adherence exist, these are outweighed by the trial’s strengths in accessibility, scalability, and responsiveness to the changing pandemic landscape. Data Availability All data produced in the present study are available upon reasonable request to the authors. Competing interests None declared. Contributors ADP, BH, PD, MG, PJ, TL, EM, SM, PS conceived of the work. BH and ADP drafted the work. All authors contributed to revising the manuscript for important intellectual content, gave final approval of the version to be published and agreed to be accountable for all aspects of the work. Funding CanTreatCOVID trial is funded by the Canadian Institutes of Health Research (CIHR) and Health Canada (Grant # FRN 183092 and PPE 190332), with the first trial therapeutic, nirmatrelvir/ritonavir (Paxlovid™), provided by the Public Health Agency of Canada. Andrew Pinto is supported as a Clinician-Scientist by the Department of Family and Community Medicine, Faculty of Medicine at the University of Toronto and at St. Michael’s Hospital, the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, and a CIHR Applied Public Health Chair in Upstream Prevention. The opinions, results and conclusions reported in this article are those of the authors and are independent from any funding sources. View this table: View inline View popup Download powerpoint Table 1- Study outcomes in CanTreatCOVID Trial Supplementary File 1: Participant daily dairy Date Today’s date: _ _/ _ _ _ / (DD/MMM/YYYY) Symptoms 1. Do you feel you have recovered today? (i.e., Symptoms associated with the illness are no longer a problem). ___ YES ___ NO 2. How are you feeling today? 0 no symptoms/ 1 Mild / 2 Moderate/ 3 Severe/ 4 Very severe 3. Please rate interference in daily activities due to illness: 1 Not at all/ 2 A little bit/ 3 Somewhat/ 4 Quite a bit/ 5 Very much 4. How is your general health? 1 Poor/ 2 Fair/ 3 Good / 4 Very good/ 5 Excellent 5. Have you returned to your usual health today? ____ YES ____ No 6. Have you returned to your usual activities today? ____ YES ____ No 6a) For those taking study medication, have you taken the prescribed dose? ____ YES ____ No 6b) If no, why not? _________________________ If you feel recovered and returned to your usual activities, you do not need to answer any further questions today. Thank you for your time. ______________________________ As you do not feel recovered, please rate the following symptoms: 7. Fever: No problem / Mild problem / Moderate problem / Major problem 8. Cough: No problem / Mild problem / Moderate problem / Major problem 9. Shortness of breath: No problem / Mild problem / Moderate problem / Major problem 10. Loss of taste/ smell: No problem / Mild problem / Moderate problem / Major problem 11. Muscle ache: No problem / Mild problem / Moderate problem / Major problem 12. Nausea / vomiting: No problem / Mild problem / Moderate problem / Major problem 13. Fatigue: No problem / Mild problem / Moderate problem / Major problem 14. Difficult concentrating: No problem / Mild problem / Moderate problem / Major problem 15. Anxious mood: No problem / Mild problem / Moderate problem / Major problem 16. Please describe any other symptoms with your current illness: _______________________________________________________________________________ _______________________________________________________________________________ _______________________________________________________________________________ 17. Please tell us whether or not you have taken any of these following today. Please answer Yes or No. View this table: View inline View popup Download powerpoint Healthcare services 18. Have you contacted or visited the following healthcare services in the last 24 hours? Please answer Yes or No. View this table: View inline View popup Supplementary File 2: Participant daily dairy (Flu Pro Plus) Date Today’s date: _ _/ _ _ _ / (DD/MMM/YYYY) Symptoms 7. Do you feel you have recovered today? (i.e., Symptoms associated with the illness are no longer a problem). ____ YES ____ No 8. How are you feeling today? 0 no symptoms/ 1 Mild / 2 Moderate/ 3 Severe/ 4 Very severe 9. Please rate interference in daily activities due to illness: 1 Not at all/ 2 A little bit/ 3 Somewhat/ 4 Quite a bit/ 5 Very much 10. How is your general health? 1 Poor/ 2 Fair/ 3 Good / 4 Very good/ 5 Excellent 11. Have you returned to your usual health today? ____ YES ____ No 12. Have you returned to your usual activities today? ____ YES ____ No 6a) For those taking study medication, have you taken the prescribed dose? ____ YES ____ No 6b) If no, why not? ____________________________ If you feel recovered and returned to your usual activities, you do not need to answer any further questions today. Thank you for your time. ________________________________________________________ As you do not feel recovered, please rate the following symptoms: 7. Fever: No problem / Mild problem / Moderate problem / Major problem 8. Cough: No problem / Mild problem / Moderate problem / Major problem 9. Shortness of breath: No problem / Mild problem / Moderate problem / Major problem 10. Loss of taste/ smell: No problem / Mild problem / Moderate problem / Major problem 11. Muscle ache: No problem / Mild problem / Moderate problem / Major problem 12. Nausea / vomiting: No problem / Mild problem / Moderate problem / Major problem 13. Fatigue: No problem / Mild problem / Moderate problem / Major problem 14. Difficult concentrating: No problem / Mild problem / Moderate problem / Major problem 15. Anxious mood: No problem / Mild problem / Moderate problem / Major problem Flu-Pro Plus Nose 16. Runny or dripping Not at all/ A little bit/ Somewhat/ Quite a bit/ Very much 17. Congestion or stuffy Not at all/ A little bit/ Somewhat/ Quite a bit/ Very much 18. Sneezing Not at all/ A little bit/ Somewhat/ Quite a bit/ Very much 19. Sinus pressure Not at all/ A little bit/ Somewhat/ Quite a bit/ Very much Throat 20. Sore throat Not at all/ A little bit/ Somewhat/ Quite a bit/ Very much 21. Scratchy or itchy throat Not at all/ A little bit/ Somewhat/ Quite a bit/ Very much 22. Difficulty swallowing Not at all/ A little bit/ Somewhat/ Quite a bit/ Very much Eyes 23. Teary or watery eyes Not at all/ A little bit/ Somewhat/ Quite a bit/ Very much 24. Sore or painful eyes Not at all/ A little bit/ Somewhat/ Quite a bit/ Very much 25. Eyes sensitive to light Not at all/ A little bit/ Somewhat/ Quite a bit/ Very much Chest/Respiratory 26. Trouble breathing Not at all/ A little bit/ Somewhat/ Quite a bit/ Very much 27. Chest congestion Not at all/ A little bit/ Somewhat/ Quite a bit/ Very much 28. Chest tightness Not at all/ A little bit/ Somewhat/ Quite a bit/ Very much 29. Dry or hacking cough Not at all/ A little bit/ Somewhat/ Quite a bit/ Very much 30. Wet or loose cough Not at all/ A little bit/ Somewhat/ Quite a bit/ Very/much 42. Body aches or pains Not at all/ A little bit/ Somewhat/ Quite a bit/ Very much 43. Weak or tired Not at all/ A little bit/ Somewhat/ Quite a bit/ Very much 44. Chills of shivering much 45. Felt cold much 46. Felt hot much 47. Sweating much Sense 48. Lack of taste much 49. Lack of smell much 50. Please describe any other symptoms with your current illness: _______________________________________________________________________________ _______________________________________________________________________________ _______________________________________________________________________________ 51. Please tell us whether or not you have taken any of these following today. Please answer Yes or No. View this table: View inline View popup Download powerpoint Healthcare services 52. Have you contacted or visited the following healthcare services in the last 24 hours? Please answer Yes or No. View this table: View inline View popup Acknowledgements The authors thank our incredible patient and community partners: Brenda Andreas, Cris Carter, Jane Cooney, Gabriela Covaci, Letlotlo Gariba, Jennifer Hulme, Veronika Kiryanova, Kathy Kobow, Mike Lapenna, Mary Liu, Chris Maddison, Dorothy Nelson, Moon Ja Park, Lyric Paul, Donna Rubenstein, Dorothy Senior, Allard Schipper, Kimberly Strain, Margo Twohig, Mike Warren, John Zhan, and Alexander Zsager. REFERENCES 1. ↵ World Health Organization . WHO Coronovirus Disease (COVID-19) Dashboard [Internet] . 2024 [cited 2024 September 18];Available from: https://data.who.int/dashboards/covid19/deaths?n=c . 2. ↵ Ashton J . COVID-19 and herd immunity . J R Soc Med 2022 ; 115 ( 2 ): 76 – 7 . OpenUrl PubMed 3. ↵ Telenti A , Arvin A , Corey L , et al. After the pandemic: perspectives on the future trajectory of COVID-19 . Nature 2021 ; 596 ( 7873 ): 495 – 504 . OpenUrl CrossRef PubMed 4. ↵ McCullough PA , Kelly RJ , Ruocco G , et al. Pathophysiological Basis and Rationale for Early Outpatient Treatment of SARS-CoV-2 (COVID-19) Infection . Am J Med 2021 ; 134 ( 1 ): 16 – 22 . OpenUrl PubMed 5. ↵ Public Health Agency of Canada . COVID-19 treatments . 2022 ; 6. ↵ Ontario COVID-19 Science Advisory Table . Ontario COVID-19 Drugs and Biologics Clinical Practice Guidelines Working Group. Clinical practice guideline summary: recommended drugs and biologics in adult patients with COVID-19 (Version 9.0) . 2022 . 7. ↵ COVID-19 Treatment Guidelines Panel - National Institutes of Health . Coronovirus Disease 2019 (COVID-19) Treatment Guidelines . 2022 . 8. ↵ Siemieniuk RA , Bartoszko JJ , Ge L , et al. Drug treatments for covid-19: living systematic review and network meta-analysis . BMJ 2020 ; m2980 . 9. ↵ World Health Organization . Therapeutics and COVID-19: Living Guideline (March 3, 2022) . 2022 . 10. ↵ Lee TC , Boulware DR . Is There Room for Metformin at COVID-19’s Dinner Table? Updated Analysis of Clinical Trials . Clinical Infectious Diseases [Internet] 2024 ;Available from: https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciae284/7675654 11. ↵ Lee TC , Vigod S , Bortolussi-Courval É , et al. Fluvoxamine for Outpatient Management of COVID-19 to Prevent Hospitalization . JAMA Netw Open 2022 ; 5 ( 4 ): e226269 . OpenUrl 12. ↵ Lee TC , Bortolussi-Courval É , Belga S , et al. Inhaled corticosteroids for outpatients with COVID-19: a meta-analysis . European Respiratory Journal 2022 ; 59 ( 5 ): 2102921 . OpenUrl Abstract / FREE Full Text 13. ↵ Hammond J , Leister-Tebbe H , Gardner A , et al. Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19 . New England Journal of Medicine 2022 ; 14. ↵ Hammond J , Fountaine RJ , Yunis C , et al. Nirmatrelvir for Vaccinated or Unvaccinated Adult Outpatients with Covid-19 . New England Journal of Medicine 2024 ; 390 ( 13 ): 1186 – 95 . OpenUrl PubMed 15. ↵ Pitre T , Van Alstine R , Chick G , et al. Antiviral drug treatment for nonsevere COVID-19: a systematic review and network meta-analysis . Can Med Assoc J 2022 ; 194 ( 28 ): E969 – 80 . OpenUrl Abstract / FREE Full Text 16. ↵ Sharma R , Patel A , Ojha T , et al. Role of Antioxidant Therapy in the Treatment and Prognosis of COVID-19: A Systematic Review and Meta-analysis of Randomized Controlled Trials . Curr Dev Nutr [Internet ] 2024 ; 8 ( 5 ): 102145 . Available from: https://linkinghub.elsevier.com/retrieve/pii/S2475299124000799 OpenUrl 17. . Adaptive platform trials: definition, design, conduct and reporting considerations . Nat Rev Drug Discov 2019 ; 18 ( 10 ): 797 – 807 . OpenUrl CrossRef PubMed 18. ↵ Vanderbeek AM , Bliss JM , Yin Z , Yap C . Implementation of platform trials in the COVID-19 pandemic: A rapid review . Contemp Clin Trials 2022 ; 112 : 106625 . OpenUrl PubMed 19. ↵ RECOVERY Collaborative Group . Dexamethasone in Hospitalized Patients with Covid-19 . New England Journal of Medicine 2021 ; 384 ( 8 ): 693 – 704 . OpenUrl CrossRef PubMed 20. ↵ RECOVERY Collaborative Group . Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial . Lancet [Internet ] 2021 ; 397 ( 10285 ): 1637 – 45 . Available from: http://www.ncbi.nlm.nih.gov/pubmed/33933206 OpenUrl 21. ↵ Angus DC , Derde L , Al-Beidh F , et al. Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19 . JAMA 2020 ; 324 ( 13 ): 1317 . OpenUrl CrossRef PubMed 22. ↵ REMAP-CAP, ACTIV-4a and AI . Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19 . New England Journal of Medicine 2021 ; 385 ( 9 ): 777 – 89 . OpenUrl CrossRef PubMed 23. ↵ ATTACC, ACTIV-4a and R-CI . Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19 . New England Journal of Medicine 2021 ; 385 ( 9 ): 790 – 802 . OpenUrl CrossRef PubMed 24. ↵ Yu L-M , Bafadhel M , Dorward J , et al. Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial . The Lancet 2021 ; 398 ( 10303 ): 843 – 55 . OpenUrl 25. ↵ Butler CC , Hobbs FDR , Gbinigie OA , et al. Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial . Lancet 2023 ; 401 ( 10373 ): 281 – 93 . OpenUrl CrossRef PubMed 26. ↵ Public Health Agency of Canada . COVID-19 treatments . 2022 ; 27. ↵ Lee TC , Morris AM , Grover SA , Murthy S , McDonald EG . Outpatient Therapies for COVID-19: How Do We Choose? Open Forum Infect Dis 2022 ; 9 ( 3 ). 28. ↵ van Reenen M , Oppe M . EQ-5D-3L user guide: basic information on how to use the EQ-5D-3L instrument . EuroQol Research Foundation 2015 ;(April): 22 . 29. ↵ Richardson S , Hirsch JS , Narasimhan M , et al. Presenting Characteristics, Comorbidities, and Outcomes among 5700 Patients Hospitalized with COVID-19 in the New York City Area . JAMA - Journal of the American Medical Association 2020 ; 323 ( 20 ): E1 – 8 . OpenUrl 30. ↵ Gold JAW , Wong KK , Szablewski CM , et al. Characteristics and Clinical Outcomes of Adult Patients Hospitalized with COVID-19 - Georgia, March 2020 . MMWR Morbidity and mortality weekly report 2020 ; 69 ( 18 ). 31. ↵ Reis G , dos Santos Moreira-Silva EA , Silva DCM , et al. Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial . Lancet Glob Health 2022 ; 10 ( 1 ): e42 – 51 . OpenUrl 32. ↵ Butler C , PANORAMIC Investigators . Platform Adaptive trial of Novel antivirals for early treatment of COVID-19 in the Community (PANORAMIC): Study protocol - April 1, 2022, Version 3.0 . 2022 . 33. ↵ Keshtkar-Jahromi M , Adam SJ , Brar I , et al. ACTIV trials: cross-trial lessons learned for master protocol implementation . J Clin Transl Sci 2024 ; 8 ( 1 ): e152 . OpenUrl 34. ↵ Currier JS , Moser C , Eron JJ , et al. ACTIV-2: A Platform Trial for the Evaluation of Novel Therapeutics for the Treatment of Early COVID-19 in Outpatients . J Infect Dis 2023 ; 228 ( Supplement_2 ): S77 – 82 . OpenUrl PubMed 35. ↵ Hayward G , Butler CC , Yu L-M , et al. Platform Randomised trial of INterventions against COVID-19 In older peoPLE (PRINCIPLE): protocol for a randomised, controlled, open-label, adaptive platform, trial of community treatment of COVID-19 syndromic illness in people at higher risk . BMJ Open 2021 ; 11 ( 6 ): e046799 . OpenUrl Abstract / FREE Full Text 36. ↵ Munblit D , O’Hara ME , Akrami A , Perego E , Olliaro P , Needham DM . Long COVID: aiming for a consensus . Lancet Respir Med 2022 ; 37. World Health Organization . A clinical case definition of post COVID-19 condition by a Delphi consensus . Geneva : 2021 . 38. ↵ Hughes SE , Haroon S , Subramanian A , et al. Development and validation of the Symptom Burden Questionnaire TM for Long COVID: a Rasch analysis . BMJ 2022 ;2022.01.16.22269146. View the discussion thread. Back to top Previous Next Posted November 27, 2024. Download PDF Supplementary Material Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. 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Pinto medRxiv 2024.11.25.24317904; doi: https://doi.org/10.1101/2024.11.25.24317904 Share This Article: Copy Citation Tools Canadian Adaptive Platform Trial of Treatments for COVID in Community Settings (CanTreatCOVID): protocol for a randomized controlled adaptive platform trial of treatments for acute SARS-CoV-2 infection in community settings Benita Hosseini , Amanda Condon , Bruno R. da Costa , Peter Daley , Michelle Greiver , Peter Jüni , Todd C. Lee , Kerry McBrien , Emily G. McDonald , Srinivas Murthy , Peter Selby , Melissa Andrew , Kris Aubrey-Bassler , David Barber , Brendan Barrett , Chris Butler , Noah Crampton , Simone Dahrouge , Ali Damji , Robert Fowler , Stephanie Garies , Catherine Hudon , Jennifer Hulme , Jennifer Isenor , David Jenkins , Rosemarie Lall , Annie LeBlanc , Christine Leong , Paul Little , Aisha Lofters , Sarvesh Logsetty , Sylvain Lother , Marie-Thérèse Lussier , Laura MacLaren , Derelie Mangin , Emily Marshall , John Marshall , Rita McCracken , Rahim Moineddin , Briana Orava , Jean-Sebastien Paquette , Jay Jae Hee Park , Navindra Persaud , Valeria Rac , Vivian Ramsden , Jennifer Rayner , Diana Sanchez Ramirez , Lynora Saxinger , Haolun Shi , Alexander Singer , Rae Spiwak , Anita Srivastava , Abhimanyu Sud , Jean-Éric Tarride , Deanna Telner , Ross Upshur , Sakina Walji , Rachel Walsh , Machelle Wilchesky , Sabrina Wong , Brianne Wood , Ryan Zarychanski , Barbara Zelek , Yoav Keynan , Jolanta Pisczek , Daniel Warshafsky , Andrew D. 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