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1/12WHO COVID-19 core protocolPublic health emergencySOLIDARITY TRIALWorld Health OrganizationCOVID-19 core protocolAn international randomised trial of additionaltreatments for COVID-19 in hospitalised patientswho are all receiving the local standard of care This draft protocol is confidential to potential investigators. It should not be disclosed to otherswithout permission from the WHO, except to seek the consent of collaborators or participants. Version 10.0March 22, 20202/12WHO COVID-19 core protocolProtocol signature pageReviewed and approved by the following representatives of the Co-Sponsors :Signature……………………………………………………………………….Representative of the National Ministry of HealthPrint name and position __________________________________________________________________________________________________________Date_________________Signature……………………………………………………………………….Representative of the World Health Organization (WHO)Print name and position __________________________________________________________________________________________________________Date_________________3/12WHO COVID-19 core protocolSUMMARY………………………………………………………………………………………………………………………………………………………… 4OVERVIEW OF STUDY PROCEDURES WITHIN HOSPITALS ………………………………………………………………………………. 6OBJECTIVES ………………………………………………………………………………………………………………………………………………………. 7STUDY POPULATION: INCLUSION, EXCLUSION, AND RECRUITMENT ………………………………………………………………………. 7STUDY PRODUCTS AND STUDY DRUG REGIMENS …………………………………………………………………………………………………. 7PREPARATION, HANDLING, STORAGE AND, ACCOUNTABILITY………………………………………………………………………………………….. 7FORMULATION, STABILITY, LABELLING, STORAGE AND PREPARATION OF STUDY PRODUCTS……………………………………………….. 7DRUG DISCONTINUATION AND PATIENT WITHDRAWAL ………………………………………………………………………………………………… 7RANDOMISATION …………………………………………………………………………………………………………………………………………….. 8ADVERSE REACTION REPORTING …………………………………………………………………………………………………………………… 8STATISTICAL CONSIDERATIONS ……………………………………………………………………………………………………………………… 8SAMPLE SIZE……………………………………………………………………………………………………………………………………………………. 9STUDY ASSESSMENTS AND PROCEDURES …………………………………………………………………………………………………………….. 9SCHEDULE OF ASSESSMENTS………………………………………………………………………………………………………………………………. 9REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS …………………………………………………………………….. 9INFORMED CONSENT PROCESS…………………………………………………………………………………………………………………………..10CONFIDENTIALITY AND PRIVACY ………………………………………………………………………………………………………………………….10KEY ROLES AND STUDY GOVERNANCE ……………………………………………………………………………………………………………………10MONITORING PROTOCOL COMPLIANCE………………………………………………………………………………………………………………….10SOURCE RECORDS AND STUDY RECORD RETENTION………………………………………………………………………………………………..11PROTOCOL DEVIATIONS…………………………………………………………………………………………………………………………………….11SPONSORSHIP, AND MANAGEMENT OF CONFLICTS OF INTEREST………………………………………………………………..11DATA SHARING……………………………………………………………………………………………………………………………………………….11PUBLICATIONS ……………………………………………………………………………………………………………………………………………….11INSURANCE…………………………………………………………………………………………………………………………………………………….124/12WHO COVID-19 core protocolSummaryTerminology: The novel coronavirus-induced disease first described in 2019 in China is designatedCOVID-19 (or COVID), and the pathogen itself (an RNA virus) is SARS-coronavirus-2 (SARS-CoV-2).Background: In early 2020 there were no approved anti-viral treatments for COVID, and WHO expertgroups advised that four re-purposed drugs, Remdesivir, Lopinavir (given with Ritonavir, to slowhepatic degradation), Interferon (β1a), and chloroquine or hydroxychloroquine should be evaluatedin an international randomised trial. WHO has provided guidelines that local physicians may considerwhen COVID-19 is suspected on clinical management of severe acute respiratory infection.Simplicity of procedures: To facilitate collaboration even in hospitals that have become overloaded,patient enrolment and randomisation (via the internet) and all other trial procedures are greatlysimplified, and no paperwork at all is required. Once a hospital has obtained approval, electronicentry of patients who have given informed consent takes only a few minutes. At the end of it, therandomly allocated treatment is displayed on the screen and confirmed by electronic messaging.Randomisation: Adults (age ≥18 years) recently hospitalised, or already in hospital, with definiteCOVID and, in the view of the responsible doctor, no contra-indication to any of the study drugs willbe randomly allocated between• Local standard of care alone,OR local standard of care plus one of• Remdesivir (daily infusion for 10 days)• Chloroquine or hydroxychloroquine (two oral loading doses, then orally twice daily for 10 days)• Lopinavir with Ritonavir (orally twice daily for 14 days)• Lopinavir with Ritonavir (ditto) plus Interferon (daily injection for 6 days).Data reported before randomisation: Information is entered electronically on• Country, hospital (from a list of approved hospitals) and randomising doctor• Confirmation that informed consent has been obtained• Patient identifiers, age and sex• Patient characteristics (yes/no): current smoking, diabetes, heart disease, chronic lungdisease, chronic liver disease, asthma, HIV infection, active tuberculosis.• COVID-19 severity at entry (yes/no): shortness of breath, being given oxygen, already on aventilator, and, if lungs imaged, major bilateral abnormality (infiltrations/patchy shadowing)• Whether any of the study drugs are currently NOT AVAILABLE at the hospital.Exclusion from study entry: Patients will not be randomised if, in the view of the randomising doctor,ANY of the AVAILABLE study drugs are contra-indicated (eg, because of patient characteristics,chronic liver or heart disease, or some concurrent medication).Changing management of study patients: At all times the patient’s medical team remains solelyresponsible for decisions about that patient’s care and safety. Hence, if the team decide thatdeviation from the randomly allocated treatment arm is definitely necessary, this should be done.Follow-up: When patients die or are discharged, follow-up ceases and it is reported:• Which study drugs were given (and for how many days)• Whether ventilation or intensive care was received (and, if so, when it began)• Date of discharge, or date and cause of death while still in hospital.If no report is received within 6 weeks of study entry, an electronic reminder is sent.5/12WHO COVID-19 core protocolDrug safety: Suspected unexpected serious adverse reactions that are life-threatening (eg, StevensJohnson syndrome, anaphylaxis, aplastic anaemia, or anything comparably uncommon and serious)must be reported within 24 hours of being diagnosed, without waiting for death or discharge.Major outcomes: The primary outcome is all-cause mortality, subdivided by severity of disease at thetime of randomisation. The major secondary outcomes are duration of hospital stay and time to firstreceiving ventilation (or intensive care).Data monitoring: A global Data and Safety Monitoring Committee will keep the accumulating drugsafety results and major outcome results under regular review.Numbers entered: The larger the number entered the more accurate the results will be, but numbersentered will depend on how the epidemic develops. If substantial numbers get hospitalised in theparticipating centres, it may be possible to enter several thousand hospitalised patients with relativelymild disease and a few thousand with severe disease, but realistic, appropriate sample sizes couldnot be estimated at the start of the trial and will depend on the evolution of the epidemic.Heterogeneity between populations: If a study treatment does affect outcome, then this effect couldwell differ between patients who had severe disease when randomised and those who had lesssevere disease. It could also differ between younger and older patients, or between patients in oneor another country. If sufficient numbers are randomised, it may be possible to obtain statisticallyreliable treatment comparisons within each of several different countries or types of patient.Adaptive design: The WHO may decide to add novel treatment arms while the trial is in progress.Conversely, the WHO may decide to discontinue some treatment arms, especially if the Global Dataand Safety Monitoring Committee reports, based on interim analyses, that one of the trial treatmentsdefinitely affects mortality.Add-on studies: Particular countries, or particular groups of hospitals, may want to collaborate inmaking further measurements or observations, such as serial virology, serial blood gases or chemistry,serial lung imaging, or serial documentation of other aspects of disease status (eg, through linkage toelectronic healthcare records and routine medical databases). While well-organised additionalresearch studies of the natural history of the disease or of the effects of the trial treatments could wellbe valuable, they are not core requirements.Data security: Patient information will be encrypted and held securely by the WHO. Those analysing itwill use only anonymised data, and no identifiable patient details will appear in publications.Publication: This international collaboration is co-ordinated through the World Health Organisation.Any wholly reliable interim findings on mortality will be disseminated rapidly by the WHO and will bepublished in the names of the collaborators.6/12WHO COVID-19 core protocolOverview of study procedures within hospitalsTo facilitate collaboration, even in hospitals with many patients, all trial procedures are simplified, andno paperwork is required. Within each country, the national co-ordinator invites selected hospitals tojoin and helps them get ethical approval and supplies of the study drugs (SOP-1). Once an invitedhospital has ethical approval and its pharmacy has some or all of the study drugs, patient entry can begin. Procedures within collaborating hospitalsSOP1Provisional eligibility Eligible patients are adults (age ≥18 years) recently admitted asinpatients, or already in hospital, with definite COVID-19 for whom the responsible doctorwould be willing to initiate any of the study treatment arms that might be allocated.2Consent The study website www.who.int/COVIDcore has printable patient information inlocal languages, inviting consent to join the study. If laboratory confirmation is not yetavailable, the information required for consent can be provided to the patient inpreparation for when laboratory results do emerge.Once the information has been explained, obtaining consent takes only a few minutes, asthe signature process is easy. An electronic image of the signature page is kept, andprinted information and original consent stays with the patient, isolated from study staff.SOP-23Patient details Enter the following information onto www.who/COVIDcore– Country, hospital (from an electronic list), and email of randomising doctor– Confirmation that informed consent has been obtained– Patient identifiers, including admission date, age and sex– Patient characteristics (each yes/no): Smoking? Diabetes? Heart disease? Chronic liverdisease? Chronic lung disease? Asthma? HIV infection? Active TB?– COVID-19 severity (each yes/no): Shortness of breath? On oxygen? Already ventilated?and, if lungs imaged, major bilateral abnormality? (infiltrations/patchy shadowing)5Drug availability, and random allocation– List which of the 5 study drugs are currently available in this hospital (5 yes/no answers,although chloroquine is asked about only if hydroxychloroquine is not available)– Confirm this patient has no contra-indications to any of these available drugs (1 answer)A study ID for the patient is then generated and displayed, and the random allocation(to something available) is displayed and confirmed by electronic messaging.This patient is now in the study, and their in-hospital outcome will be sought.6Trial treatment If the random allocation includes study medication, then that medicationshould begin promptly, and continue daily until completed, or until the responsiblephysician decides it should stop.Any suspected serious adverse reaction is reported within 24 hours, using patient’s study ID.SOP-4 to 77Follow-up At discharge or death, log into www.who/COVIDcore and enter– The patient’s study ID– Which study drugs were given (and for how many days)– Whether ventilation or intensive care was received (and, if so, when)– Date of discharge, or date and cause of death.If follow-up information is not received within 6 weeks of patient entry, a reminder is sent.SOP-8 7/12WHO COVID-19 core protocolObjectivesThe aim of this core protocol is to compare the effects on major outcomes in hospital of the localstandard of care alone versus the local standard of care plus one of four alternative anti-viral agents.The primary objective of this large international randomised trial is to provide reliable estimates onany effects of these anti-viral treatments on in-hospital mortality in moderate and in severe COVID.The secondary objectives are to assess any effects of these anti-viral treatments on hospital durationand receipt of ventilation or intensive care, and to identify any serious adverse reactions.It is not expected that any of the treatments currently being tested will have a large effect on the riskof death, but if any had just a moderate effect and was widely practicable then this could avoidlarge numbers of deaths. Conversely, reliable demonstration that certain agents have no materialeffect on major outcomes would be of value. Moderate effects can, however, be reliablydemonstrated or refuted only by large-scale randomized evidence.Study population: inclusion, exclusion, and recruitmentEligibility: consenting adults (age ≥18) hospitalised with definite COVID-19, not already receiving anyof the study drugs, without known allergy or contra-indications to any of them (in the view of thephysician responsible for their care), and without anticipated transfer within 72 hours to a non-studyhospital. Patients invited to join the study will be those who are admitted to a collaborating hospital;no wider recruitment efforts are expected.A patient is not eligible for the trial if believed by their physician to have a significant contraindication to any one of the study drugs (eg, serious chronic liver or heart disease or pregnancy)Study products and study drug regimensFour potential anti-viral agents, Remdesivir, Chloroquine/Hydroxychloroquine, Lopinavir (given withRitonavir, to slow hepatic degradation) and Interferon (β1a) are to be evaluated (see SOPs-4 to 7b).Preparation, handling, storage and, accountabilityStudy drugs will be shipped to the site either directly from participating companies, or from otherregional or local drug repositories. All other supplies will be provided by the site. The site principalinvestigator is responsible for study drug disposition and product accountability (see SOPs-4 to 7b).Formulation, stability, labelling, storage and preparation of study productsSee SOP-4 to SOP-7 for details of each of the study products.Drug discontinuation and patient withdrawal8/12WHO COVID-19 core protocolAt all times the patient’s medical team remains solely responsible for decisions about that patient’scare and safety. Hence, if the medical team decide that deviation from the randomly allocatedtreatment arm is definitely necessary then this should be done.The study drug administration must be stopped if the team suspects any serious unexpected drugrelated reaction that is life-threatening.Patients are free to withdraw from study treatment at any time, but could still remain in the study, within-hospital outcome reported to the study at death or discharge.Patients are also free to withdraw from the whole study at any time without any consequence andwould continue to be offered the local standard of care (but not be reported on).RandomisationPatients will be randomised through the study website equally between all the locally availabletreatment regimens (5 possibilities if all study drugs are locally available, fewer if not – see SOP 2):• Local standard of care alone,OR local standard of care plus one of• Remdesivir (daily infusion for 10 days)• Chloroquine or Hydroxychloroquine (two oral loading doses, then orally twice daily for 10 days)[NB Some collaborating hospitals will study chloroquine, others hydroxychloroquine]• Lopinavir with Ritonavir (orally twice daily for 14 days)• Lopinavir with Ritonavir (ditto) plus Interferon (daily injection for 6 days).Adverse reaction reportingAny serious unexpected adverse reaction that is life-threatening (e.g. anaphylaxis, Stevens-Johnsonsyndrome, aplastic anaemia, or anything comparably strange) must be reported through the studywebsite within 24 hours. Such complications should be extremely rare, and there is no good reason toexpect the trial treatments will cause them, so many hospitals will never make such a report (SOP 9).Statistical considerationsAnalyses relate outcome to the randomly allocated treatment (ie, intent-to-treat). The primaryanalyses assess any effects of treatment allocation on all-cause in-hospital mortality, analysingseparately people who already had severe disease at entry and those who did not.The main secondary analyses assess any effects of treatment allocation on the duration ofhospitalization (time from randomisation to discharge) and need for ventilation or intensive care.9/12WHO COVID-19 core protocolSample sizeNo specific sample size is specified in this public health emergency core protocol. Interim results willbe kept under review by an independent Global Data and Safety Monitoring Committee, and thisCommittee will decide how often to conduct interim analyses. It is anticipated that at least severalthousand patients will be recruited into the trial.The larger the numbers entered the more accurate the results will be, but the numbers that can beentered will depend critically on how large the epidemic becomes. If substantial numbers of patientsare hospitalised in the participating centres then it may be possible to enter several thousandhospitalised patients with relatively mild disease when admitted and a few thousand admitted withsevere disease, but realistic, appropriate sample sizes could not be estimated at the start of the trial.Another reason for entering large numbers is that the response to certain treatments may differsubstantially between different populations or sub-populations (eg, patients with particular priorconditions, older adults, patients in one or another large country). If sufficient numbers arerandomised, it may be possible to obtain statistically reliable treatment comparisons within each ofseveral different countries or types of patient.Study assessments and proceduresSchedule of assessments AtrecruitmentDuringhospitalizationAt death or hospitaldischargeELIGIBILTYDefinite confirmation of COVID-19XInformed consentXRANDOMIZATIONEnter into www.who.int/COVIDcore patient identity,concomitant conditions, and severity of diseaseXThe study issues a patient study number, and arandom treatment allocationXSTUDY INTERVENTIONAdminister any anti-viral agents specified by therandom allocation, unless the local doctors decidefor any reason to stopDaily for 6-14 days,unless discontinuedReport any serious and unexpected adversereactions to study websiteReport promptlywithin

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