key: cord-0781374-qr4690wo authors: Lyngbakken, Magnus Nakrem; Berdal, Jan-Erik; Eskesen, Arne; Kvale, Dag; Olsen, Inge Christoffer; Rangberg, Anbjørg; Jonassen, Christine Monceyron; Omland, Torbjørn; Røsjø, Helge; Dalgard, Olav title: Norwegian Coronavirus Disease 2019 (NO COVID-19) Pragmatic Open label Study to assess early use of hydroxychloroquine sulphate in moderately severe hospitalised patients with coronavirus disease 2019: A structured summary of a study protocol for a randomised controlled trial date: 2020-06-05 journal: Trials DOI: 10.1186/s13063-020-04420-0 sha: c04a056a34719e6098398968e54604b71c1e7ac8 doc_id: 781374 cord_uid: qr4690wo OBJECTIVES: The hypothesis of the study is that treatment with hydroxychloroquine sulphate in hospitalised patients with coronavirus disease 2019 (Covid-19) is safe and will accelerate the virological clearance rate for patients with moderately severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) when compared to standard care. Furthermore, we hypothesize that early treatment with hydroxychloroquine sulphate is associated with more rapid resolve of clinical symptoms as assessed by the National Early Warning Score 2 (NEWS2), decreased admission rate to intensive care units and mortality, and improvement in protein biomarker profiles (C-reactive protein, markers of renal and hepatic injury, and established cardiac biomarkers like cardiac troponin and B-type natriuretic peptide). TRIAL DESIGN: The study is a two-arm, open label, pragmatic randomised controlled group sequential adaptive trial designed to assess the effect on viral loads and clinical outcome of hydroxychloroquine sulphate therapy in addition to standard care compared to standard care alone in patients with established Covid-19. By utilizing resources already paid for by the hospitals (physicians and nurses in daily clinical practice), this pragmatic trial can include a larger number of patients over a short period of time and at a lower cost than studies utilizing traditional randomized controlled trial designs with an external study organization. The pragmatic approach will enable swift initiation of randomisation and allocation to treatment. PARTICIPANTS: Patients will be recruited from all inpatients at Akershus University Hospital, Lørenskog, Norway. Electronic real-time surveillance of laboratory reports from the Department of Microbiology will be examined regularly for SARS-CoV-2 positive subjects. All of the following conditions must apply to the prospective patient at screening prior to inclusion: (1) Hospitalisation; (2) Adults 18 years or older; (3) Moderately severe Covid-19 disease (NEWS2 of 6 or less); (4) SARS-CoV-2 positive nasopharyngeal swab; (5) Expected time of hospitalisation > 48 hours; and (6) Signed informed consent must be obtained and documented according to Good Clinical Practice guidelines of the International Conference on Harmonization, and national/local regulations. Patients will be excluded from participation in the study if they meet any of the following criteria: (1) Requiring intensive care unit admission at screening; (2) History of psoriasis; (3) Known adverse reaction to hydroxychloroquine sulphate; (4) Pregnancy; or (5) Prolonged corrected QT interval (>450 ms). Clinical data, including standard hospital biochemistry, medical therapy, vital signs, NEWS2, and microbiology results (including blood culture results and reverse transcriptase polymerase chain reaction [RT-PCR] for other upper airway viruses), will be automatically extracted from the hospital electronic records and merged with the study specific database. INTERVENTION AND COMPARATOR: Included patients will be randomised in a 1:1 ratio to (1) standard care with the addition of 400 mg hydroxychloroquine sulphate (Plaquenil(TM)) twice daily for seven days or (2) standard care alone. MAIN OUTCOMES: The primary endpoint of the study is the rate of decline in SARS-CoV-2 viral load in oropharyngeal samples as assessed by RT-PCR in samples collected at baseline, 48 and 96 hours after randomization and administration of drug for the intervention arm. Secondary endpoints include change in NEWS2 at 96 hours after randomisation, admission to intensive care unit, mortality (in-hospital, and at 30 and 90 days), duration of hospital admission, clinical status on a 7-point ordinal scale 14 days after randomization ([1] Death [2] Hospitalised, on invasive mechanical ventilation or extracorporeal membrane oxygenation [3] Hospitalised, on non-invasive ventilation or high flow oxygen devices [4] Hospitalized, requiring supplemental oxygen [5] Hospitalised, not requiring supplemental oxygen [6] Not hospitalized, but unable to resume normal activities [7] Not hospitalised, with resumption of normal activities), and improvement in protein biomarker profiles (C-reactive protein, markers of renal and hepatic injury, and established cardiac biomarkers like cardiac troponin and B-type natriuretic peptide) at 96 hours after randomization. RANDOMISATION: Eligible patients will be allocated in a 1:1 ratio, using a computer randomisation procedure. The allocation sequence has been prepared by an independent statistician. BLINDING (MASKING): Open label randomised controlled pragmatic trial without blinding, no active or placebo control. The virologist assessing viral load in the oropharyngeal samples and the statistician responsible for analysis of the data will be blinded to the treatment allocation for the statistical analyses. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): This is a group sequential adaptive trial where analyses are planned after 51, 101, 151 and 202 completed patients, with a maximum sample size of 202 patients (101 patients allocated to intervention and standard care and 101 patients allocated to standard care alone). TRIAL STATUS: Protocol version 1.3 (March 26, 2020). Recruitment of first patient on March 26, 2020, and 51 patients were included as per April 28, 2020. Study recruitment is anticipated to be completed by July 2020. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT04316377. Trial registered March 20, 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. To date, there is no specific therapy for COVID-19. However, supportive treatment including oxygen supplementation and mechanical intervention is believed to strongly effect the course of the disease. The effect of several antivirals are currently being investigated in clinical including remdesivir, lopinavir/ritonavir (HIV protease inhibitor), rintatolimod (immune modulator), danoprevir+ritonavir (HIV protease inhibitor), Galidesivir (broad spectrum antiviral drug) and remdesivir (a nucleoside inhibitor of coronavirus polymerase) (3). In addition, chloroquine has been suggested as a treatment against COVID-19. Chloroquine is an important anti-malaria drug that has been used since 1947. Furthermore, since the late seventies it has been used as treatment against rheumatoid arthritis and other rheumatic disorders. In short term use, chloroquine has a good safety profile. Its most important side effect being reversible accommodation disturbances and swelling of the cornea. In long term use (months) it may cause chronically reduced vision. The effect of chloroquine on SARS-CoV-2 is supported by in vitro data showing a strong antiviral effect in non-toxic doses in cell culture (4) and by efficacy in treatment of COVID-19 associated pneumonia in clinical studies (5) . The antiviral mechanism of chloroquine is associated with increased endosomal pH needed for fusion-mediated viral entry into host cells, and with alteration of glycosylation of SARS-CoV-2 cellular receptors. Accordingly, the Chinese Expert Consensus on Chloroquine Phosphate for the Treatment of Novel Coronavirus Pneumonia recently recommended short term treatment with chloroquine in patients with mild, moderate and severe cases of novel coronavirus pneumonia and without contraindications to chloroquine use (6). We hypothesize that early treatment with chloroquine in patients with established COVID-19 is safe and will significantly increase the virological clearance rate of SARS-CoV-2. Furthermore, we hypothesize that early treatment with chloroquine is associated with more rapid resolve of clinical symptoms and a decreased admission rate to intensive care units and in-hospital mortality. Considering the immediate and worldwide health emergency associated with the SARS-CoV-2 outbreak and the current lack of evidence based medical interventions for this patient group, studies investigating possible treatment modalities in COVID-19 are direly needed. Specific patient groups, especially elderly patients with comorbidities, are at higher risk of contracting viral respiratory disease and hospitalization than the general population. Relevant clinical end points depend on the patient populations studied, local standards of care, and physician judgment. Studies that focus solely on ICU admission or mortality as primary outcomes are likely to require prolonged time frames for accrual of sufficient numbers of patients and also need to consider many confounding variables that affect clinical outcomes in a possibly heterogeneous patient group. Measures of rate of decline of virus replication as primary end points to evaluate and compare drug efficacy of antivirals is logical and necessary, especially in heterogeneous populations such as hospitalized and immunocompromised patients. Rapid reductions in active viral replication may be essential to prevent tissue damage and to further clinical recovery, as well as reduce risk of viral complications and mortality (7) . The recent years National Early Warning Score (NEWS) has been implemented in Norwegian hospitals as a tool to assess the degree of illness in a patient and to guide level of surveillance and intensity of treatment. This method is based on the degree of abnormality of the vital signs respiratory rate, oxygen saturation, body temperature, systolic blood pressure and heart rate, in addition to the need for supplemental oxygen and mental alertness (8) . Scores range from 0-20, with a higher score representing further removal from normal physiology and a higher risk of morbidity and mortality. We expect that approximately 75% of patients will be discharged by day 14 (9) and will therefore analyse clinical status at this day. Accordingly, the primary aim of this study is to assess whether treatment with chloroquine in patients with COVID-19 will increase the decline rate of SARS-CoV-2 in the oropharynx from baseline to 48 and 96 hours. As described above, the use of primary virological end points is strongly supported by the current literature on novel antiviral therapy. The secondary aims are to assess whether treatment with chloroquine in patients with COVID-19 (1) will improve clinical status as assessed by the NEWS score, improve clinical outcomes, including (2) admission rate to intensive care units and (3) in-hospital mortality, and (4) improve protein biomarker profile (inflammation, cardiac, renal, hepatic).  Assess the impact of early treatment with chloroquine in patients with established COVID-19 on SARS-CoV-2 presence in oropharyngeal specimens at 48 and 96 hours after inclusion in the trial  Assess the impact of early treatment with chloroquine in patients with established COVID-19 on changes in NEWS score  Assess the impact of early treatment with chloroquine in patients with established COVID-19 on admission rate to ICU  Assess the impact of early treatment with chloroquine in patients with established COVID-19 on in-hospital mortality and mortality after 30 and 90 days  Assess the impact of early treatment with chloroquine in patients with established COVID-19 on clinical outcomes after 14 days  Assess the impact of early treatment with chloroquine in patients with established COVID-19 on markers of inflammation, and cardiac, renal and hepatic injury at 96 hours after inclusion in the trial The study is a two-arm, open label, pragmatic randomized controlled trial (RCT) designed to assess the virological and clinical effect of chloroquine therapy in addition to standard of care versus standard of care in patients with established COVID-19. Pragmatic clinical trials (PCT) are characterized by 3 attributes: (1) focus on informing decision-makers (e.g. patients, politicians, administrators) on optimal clinical medicine practice, as opposed to elucidating a biological or social process; (2) intent to enrol a population representative to the decision in practice and for whom the decision is relevant; and (3) either an intent to streamline procedures and data collection in the trial or to measure a broad range of outcomes. By utilizing resources already paid for by the hospitals (physicians and nurses in daily clinical practice), pragmatic clinical trials can include a larger number of patients at a short time duration and at a lower cost than studies utilizing traditional RCT designs with an external study organization (e.g. study nurses, study physicians). Due to the immediate need for study commencement and the time frame of the current proposal, a pragmatic approach will enable swift initiation of randomization and treatment. We will especially use data from the data warehouse at Akershus University Hospital for eligible patient identification (i.e. electronic surveillance) and for automatic data extraction to the study specific database. The study will not be able to procure an acceptable placebo treatment and the study will accordingly not be placebo-controlled. In the initial phase of the study, patients will be included from a single center (Akershus University Hospital). The study is designed as a sequential adaptive trial where interim efficacy analyses are planned after the inclusion of 51 patients, with subsequent analyses after 101, 151 and 202 completed patients. This approach will enable frequent assessment of all outcome measures. After inclusion of the initial 51 patients, analyses will be performed for the predefined outcome measures. Pending these results, the study will possibly be extended to other Norwegian centres, pending separate submission to ethics committee and other regulatory bodies from new centers. See Section 10 Statistical methods and data analysis for further details. All patients at Akershus University Hospital with suspicion of acute respiratory tract infections are examined with a nasopharyngeal swab, with subsequent microbiological examination, including SARS-CoV-2 specific polymerase chain reaction (PCR). Laboratory reports from the Department of Microbiology are surveilled real-time for SARS-CoV-2 positive samples in the local data warehouse, which will allow for immediate screening and randomization in all eligible subjects. Figure 1 gives a schematic overview of the study. Participants will be recruited from the entirety of the inpatients at the participating hospitals. Electronic real-time surveillance of laboratory reports from the Department of Microbiology will be examined regularly, with maximum interval 24 hours, for SARS-CoV-2 positive subjects. We aim to include patients by a sequential adaptive approach, where analyses are planned after the inclusion of 51 patients, with subsequent interim efficacy analyses after 101, 151 and 202 completed patients. All patients included in each sequence will be used for the final analyses of the entire study. See Section 10 Statistical methods and data analysis for further details. All of the following conditions must apply to the prospective patient at screening prior to inclusion: Patients will be excluded from participation in the study if they meet any of the following criteria: Recent reports document inhibition of SARS-CoV-2 by chloroquine in vitro, as well as in experimental clinical trials conducted in China. No apparent adverse effects of chloroquine treatment has been observed in these trials on human subjects. Hydroxychloroquine has a more favourable side effect profile compared to chloroquine and is more potent than chloroquine to inhibit SARS-CoV-2 in vitro (10) . Accordingly, in the current proposal, and in accordance with the Chinese Expert Consensus on Chloroquine Phosphate for the Treatment of Novel Coronavirus Pneumonia (6), we will utilize a short term treatment with 400 mg hydroxychloroquine sulphate (equalling 310 mg base) twice daily for seven days. Standard of care will apply to both treatment arms at the discretion of the treating physician. Due to the lack of randomized evidence based therapy in COVID-19 and possibly a large proportion of patients who will present with serious to life-threatening disease, treatment by compassion will be allowed at any time at the discretion of the treating physician. For this study, hydroxychloroquine sulphate is defined as the Investigational Medicinal Product (IMP). The IMP has marketing authorization as a medicinal product, is produced by Sanofi Aventis under the trade name "Plaquenil", and is distributed through licensed pharmacists. The drug will be provided by the trial sponsor (Akershus University Hospital) to patients included in the treatment arm free of charge. At enrolment, all patients randomized to treatment will be allocated a per oral dosage of 400 mg hydroxychloroquine sulphate (equalling 310 mg base) twice daily for seven days. This is in agreement with the SPC of the IMP. The drug will be dispensed at the regular drug administration rounds of the clinical wards. Duration of therapy is per protocol seven days, equalling 14 doses of 400 mg hydroxychloroquine sulphate (equalling 310 mg base). The duration of treatment is based on a Chinese Expert Consensus that 5-10 days of chloroquine should be administered to patients with coronavirus pneumonia (6). All concomitant medication used by the patient will be recorded at admission and retrieved from the hospital electronic prescribing system. Care should be taken when patients are on antiepileptic or antidiabetic medication, as well as on therapy associated with risk of QT time prolongation. Compliance to the protocol will be monitored by the hospital electronic prescribing system, where administration status of every dose prescribed is registered. The IMP has a marketing authorization in Norway, is routinely ordered by the pharmacy and will be dispensed from the pharmacy's own stock. Dosage, batch number and shelf life will be noted from all packages of the dispensed IMPs. The IMP is labeled according to the standard production by the commercial manufacturer (Sanofi Aventis). Each subject is identified in the study by a unique subject number that is assigned when subject signs the Informed Consent Form. Once assigned the subject number cannot be reused for any other subject. The reason for discontinuation will be recorded, if the patient chooses to disclose it. Management of patients who withdraw or are withdrawn from the study will have to be individualized and should in all cases be discussed with the Principal Investigator. All patients randomized will be included in the study population. The following may trigger individual patient discontinuation from the trial:  When chloroquine is used in combination with drug therapy known to prolong QT interval, an increase in QTc above 470ms for males or 480ms for females, or the QTc interval increases 60 ms or more from pre-treatment values (11). The whole trial may be discontinued at the discretion of the sponsor in the event of any of the following:  Occurrence of AEs unknown to date in respect of their nature, severity and duration that may negatively affect the benefit/risk of the trial.  Medical or ethical reasons affecting the continued performance of the trial  Difficulties in the recruitment of patients The sponsor and principal investigator(s) will inform all investigators, the relevant Competent Authorities and Ethics Committees of the termination of the trial along with the reasons for such action. If the study is terminated early on grounds of safety, the Competent Authorities and Ethics Committees will be informed within 15 days. As described in Section 3, the current study will utilize a pragmatic approach. In this regard, we will utilize resources already paid for by the hospitals, among others laboratory tests, except for quantitative virological investigations and a pregnancy test of women of childbearing age. All laboratory sampling will be done at the discretion of the treating physician. Glucose concentrations are routinely measured in all admitted patient with diabetes mellitus and/or on antidiabetic therapy. On admission, a standard panel of laboratory test will be performed on all patients (covering haematology, electrolytes, liver-and renal function, standard serology, inflammatory markers), and these will be performed locally in accordance with hospital/laboratory standard procedures. The samples will be labelled with study specific ID only (i.e. the samples will be handled de-identified). A specific research biobank will be established in accordance with national regulations. Oropharyngeal swabs will be collected in a uniform fashion at randomization if > 12 hours have passed since the screening sample, as well as at 48 hours and 96 hours after randomization. Nasopharyngeal swab at screening from the clinical laboratories will additionally be transferred to the research biobank upon study inclusion, and stored in an ultra-freezer at Akershus University Hospital. Collection of clinical variables will start at admission and for the entirety of the hospital stay. Data will be collected from the hospital electronic record system, including electronic patient records, laboratory and medical imaging systems, and prescribing systems. The data warehouse at Akershus University Hospital will be utilized for automatic data extraction to the study specific database. All clinical variables will be registered in the study eCRF system, including clinical endpoints and quantitative virological results from serial oropharyngeal specimens. Data retrieved from hospital electronic record system Viral kinetics at 96 hours after randomization is the primary efficacy measure. We will assess the kinetics of SARS-CoV-2 by serial oropharyngeal samples with quantification of viral load, measured by RT-PCR (log10 copies/mL) (12). Safety will be monitored by the assessments described below as well as the collection of AEs, SAEs and SUSARs. For details on collection and reporting, refer to Section 8. The investigator is responsible for the detection and documentation of events meeting the criteria and definition of an adverse event (AE) or serious adverse event (SAE). The methods for collection of safety data are described below. An adverse event (AE) is any untoward medical occurrence in a patient in relation to administration of a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. The term AE is used to include both serious and non-serious AEs. If an abnormal laboratory value/vital sign are associated with clinical signs and symptoms, the sign/symptom should be reported as an AE. AESIs for this protocol is defines as gastrointestinal discomfort, visual disturbances, diarrhoea, headache, nausea and dizziness. Any untoward medical occurrence that at any dose:  Results in death  Is immediately life-threatening  Requires in-patient hospitalization or prolongation of existing hospitalization  Results in persistent or significant disability or incapacity  Is a congenital abnormality or birth defect  Is an important medical event that may jeopardize the subject or may require medical intervention to prevent one of the outcomes listed above, Medical and scientific judgment is to be exercised in deciding on the seriousness of a case. Important medical events may not be immediately life-threatening or result in death or hospitalization, but may jeopardize the subject or may require intervention to prevent one of the listed outcomes in the definitions above. In such situations, or in doubtful cases, the case should be considered as serious. Suspected Unexpected Serious Adverse Reaction: SAE (see section 8.1.2) that is unexpected as defined in section 8.2 and possibly related to the IMP. Any event other than those mentioned in the SPC of the IMP may be classified as SUSAR. The most common SAE in short-term therapy with the IMP is gastrointestinal discomfort. In addition, the following symptoms will be registered in the CRF: visual disturbances, diarrhoea, headache, nausea and dizziness. These AE and gastrointestinal discomfort is considered adverse events of special interest (AESI) and will be reported according to standard adverse event criteria. On day 1, 3 and 6 during the treatment patients will be asked specifically about AESI. Further adverse events listed in the SPC for the IMP will also be registered as AE/SAE if they occur (see Appendix Summary of Product Characteristics "PLAQUENIL"). For each patient the standard time period for collecting and recording SAEs will begin at the day of IMP treatment start and will continue for the entirety of the duration of treatment. In the case of patient discharge before the end of treatment, patients will be followed up by phone for assessment of AEs. During the course of the study all SAEs will be proactively followed up for each patient; events should be followed up to resolution, unless the event is considered by the investigator to be unlikely to resolve due to the underlying disease. Every effort should be made to obtain a resolution for all events. Except AESI, AEs will not be reported, unless they meet the definition of an SAE. Events recognized by the treating physician as a consequence of the natural clinical course of the disease will not be treated as an SAE (e.g. respiratory deterioration, hypotension, myalgia). If the patient has experienced serious adverse event(s), the investigator will record the following information in the CRF:  The nature of the event(s) will be described by the investigator in precise standard medical terminology and assigned an ICD-10 diagnosis (i.e. not necessarily the exact words used by the patient).  The duration of the event will be described in terms of event onset date and event ended data.  The intensity of the adverse event will be graded as follows (18):  Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.  Moderate: minimal, local or non-invasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL)  Severe or medically significant but not immediately life-threatening: hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL.  The causal relationship of the event to treatment will be assessed as one of the following: There is not a temporal relationship to treatment, or there is a reasonable causal relationship between noninvestigational product, concurrent disease or circumstance and the AE. There is a temporal relationship to treatment, but there is not a reasonable causal relationship between treatment and the AE. There is reasonable causal relationship between treatment and the AE. There is a reasonable causal relationship between treatment and the AE. There is a reasonable causal relationship between treatment and the AE.  Action taken.  The outcome of the adverse event -whether the event is resolved or still ongoing. It is important to distinguish between serious and severe AEs. Severity is a measure of intensity whereas seriousness is defined by the criteria in Section 8.1. An AE of severe intensity need not necessarily be considered serious. For example, nausea that persists for several hours may be considered severe nausea, but is not an SAE. On the other hand, a stroke that results in only a limited degree of disability may be considered a mild stroke, but would be an SAE. AEs with a reasonable causal relationship to the treatment will be reported in a separate AE form. All adverse events of special interest and serious adverse events that should be reported as defined in section 8.1.1 and 8.1.2 will be recorded in the patient's CRF. SAEs must be reported within 24 hours after the site has gained knowledge of the SAE. Every SAE must be documented by the investigator on the AE forms in Viedoc and signed electronically. The initial report shall promptly be followed by detailed, written reports if necessary. The initial and follow-up reports shall identify the trial subjects by unique code numbers assigned to the latter. The coordinating investigator keeps detailed records of all SAEs reported by the investigators and performs an evaluation with respect to causality and expectedness. Based on, among other, SAE reports the sponsor will evaluate whether the risk/benefit ratio associated with study is changed. SUSARs will be reported to the Norwegian Medicines Agency and REK Sør-Øst according to national regulation. The sponsor will ensure that all relevant information about SUSARs that are fatal or life-threatening is recorded and reported as soon as possible and in no case later than seven (7) days after knowledge by the sponsor of such a case, and that relevant follow-up information is subsequently communicated within an additional eight (8) days. SUSARs will be reported to The Norwegian Medicines Agency (post@legemiddelverket.no) using the CIOMS form no later than 7 days after the incident. As described previously, the inherent risk associated with IMP is low, and expected adverse events are mild and self-limiting especially in short-term use. The risk of mortality from COVID-19 is yet undetermined, but preliminary reports document significant mortality risk, especially in elderly with pre-existing chronic disease. WHO has declared COVID-19 a global pandemic, and novel measures aimed at decreasing morbidity and mortality are imminently needed. Accordingly, the possible benefit of the IMP on individual, national and international scale greatly outweighs individual risk. A data monitoring committee (DMC) will be established to monitor the safety and efficacy of the study treatment and will consist of one statistician and two physicians with experience from virology/infectious disease and clinical studies. All members will be independent from the sponsor and will not be investigators or collaborators in the current study. The DMC will review all SAEs. The study investigators may call on the DMC to review specific SAEs. The DMC will conduct its tasks according to the EMA guideline (http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003635.pdf). A DMC charter based on the NORCRIN (http://www.norcrin.no/dokumentoversikt/) template will be signed and included in the Trial Master File. DATA MANAGEMENT AND MONITORING The Clinical Data Management System (CDMS) used for the eCRF in this study is Viedoc. The eCRF system will be FDA Code of Federal Regulations 21 Part 11 compliant. The designated investigator staff will enter the data required by the protocol into the eCase report forms (eCRF). The Investigator is responsible for assuring that data entered into the eCRF is complete, accurate, and that entry is performed in a timely manner. The signature of the investigator will attest the accuracy of the data on each eCRF. If any assessments are omitted, the reason for such omissions will be noted on the eCRFs. Corrections, with the reason for the corrections will also be recorded. After database lock, the investigator will receive a digital copy of the subject data for archiving at the investigational site. Source data are all information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents (original records or certified copies). The medical records for each patient should contain information which is important for the patient's safety and continued care, and to fulfil the requirement that critical study data should be verifiable. To achieve this, the medical records of each patient should clearly describe at least:  That the patient is participating in the study, e.g. by including the enrolment number and the study code or other study identification;  Date when Informed Consent was obtained from the patient and statement that patient received a copy of the signed and dated Informed Consent;  Results of all assessments confirming a patient's eligibility for the study;  Diseases (past and current; both the disease studied and others, as relevant);  Results of assessments performed during the study;  Treatments given, changes in treatments during the study and the time points for the changes;  Serious Adverse Events (if any) including causality assessments;  Date of, and reason for, withdrawal from study; Ethnicity will be recorded directly into the Case Report Form (meaning that CRF is source data and not the hospital records). A source data list will be agreed upon for each site specifying the source at a module or a variable level. The investigator will be visited on a regular basis by the Clinical Study Monitor, who will check the following: The monitor will review the relevant CRFs for accuracy and completeness and will ask the site staff to adjust any discrepancies as required. Sponsor's representatives (e.g. monitors, auditors) and/or competent authorities will be allowed access to source data for source data verification in which case a review of those parts of the hospital records relevant to the study will be required. The investigator shall arrange for the secure retention of the patient identification and the code list. Patient files shall be kept for the maximum period of time permitted by each hospital. The study documentation (CRFs, Site File etc) shall be retained and stored during the study and for 15 years after study closure. All information concerning the study will be stored in a safe place inaccessible to unauthorized personnel. Data management will be performed by the data management unit at the Clinical Trials Unit, Oslo University Hospital. The Data management procedures will be performed in accordance with the department's SOPs and ICH guidelines. The data management process will be described in the study specific Data Handling Plan and the study specific Data Handling Report after database closure. Data entered into the eCRF will be validated as defined in the Data Validation Plan. Validation includes, but is not limited to, validity checks (e.g. range checks), consistency checks and customised checks (logical checks between variables to ensure that study data are accurately reported) for eCRF data and external data (e.g. laboratory data). A majority of edit checks will be triggered during data entry and will therefore facilitate efficient 'point of entry' data cleaning. Data management personnel will perform both manual eCRF review and review of additional electronic edit checks to ensure that the data are complete, consistent and reasonable. The electronic edit checks will run continually throughout the course of the study and the issues will be reviewed manually online to determine what action needs to be taken. Manual queries may be added to the system by clinical data management or study monitor. Clinical data managers and study monitors are able to remotely and proactively monitor the patient eCRFs to improve data quality. All updates to queried data will be made by authorised study centre personnel only and all modifications to the database will be recorded in an audit trail. Once the queries have been resolved, eCRFs will be signed by electronic signature. Any changes to signed eCRFs will be approved and resigned by the Investigator. Adverse events and medical history will be coded from the verbatim description (Investigator term) using the Medical Dictionary for Regulatory Activities (MedDRA). Once the full set of eCRFs have been completed and locked, the Sponsor will authorise database lock and all electronic data will be sent to the designated statistician for analysis. Subsequent changes to the database will then be made only by written agreement. The data will be stored in a dedicated and secured area at Oslo University Hospital. Data will be stored in a de-identified manner, where each study participant is recognisable by his/her unique trial subject number. The data will be stored until 15 years following the last patient's final study visit. The rate of decline in SARS-CoV-2 viral load from baseline to 96 hours will be used as the basis for determination of sample size. Little is known about the variance of the viral load decline rate under standard of care and the possible efficacy of the intervention. Thus, we are planning this trial as an adaptive group sequential trial assuming a rate reduction from baseline of 6 log10 copies/mL/24 hours for the control group and 8 for the active group with a standard deviation of 4 within the first 96 hours after inclusion. Under these assumptions and with a Pocock type uniform alpha spending function (see Figure 2 ) with 4 looks the maximum sample size will be 202 using a 2.5% one-sided significance level to reach 90% power to detect a difference between the treatments. The interim analyses will be at 51, 101, 151 and 202 completed trial subjects. The assumptions underlying the sample size calculation will be re-evaluated at each interim analysis possibly warranting changes in the sample size without affecting the Type 1 error rate. Eligible patients will be allocated in a 1:1 ratio, using a computer randomization procedure. The allocation sequence will be prepared by an independent statistician. The computer-generated randomized allocation sequence will be imported into the eCRF system and made available to site personnel responsible for the participant enrolment. Randomization allocation will automatically be visible when enrolling a new eligible patient. This is an open-label study and no steps to conceal allocation are necessary. The study statistician will be blinded to the randomization allocation for the writing of the statistical analysis plan (SAP). The authorisations bound to role of the study statistician in the eCRF when reading or downloading data will ensure that the statistician won't see the treatment allocation until database lock. This is an open-label study. However, the staff at the central laboratory at OUS as well as the statistician responsible for analysis of the data will be blinded to the treatment allocation for the writing of the SAP. The following populations will be considered for the analyses: -Intention to treat (ITT) population: All randomized participants will be included in the main ITT analyses, regardless of protocol adherence. -Per-protocol population (PP): Includes all patients in the ITT population having completed the study treatment without major protocol violations. Criteria for inclusion in the PP population will be specified in the SAP and the final criteria will be defined prior to database lock -Safety population: Includes all subjects with any safety information after baseline. Patients randomised to hydroxychloroquine without receiving any amount of the treatment will be excluded from the safety population. -Total population: All enrolled participants independent of study arm will be used for additional analyses in the total population. The primary population is the ITT population. This is a group sequential adaptive trial where analyses are planned after 51, 101, 151 and 202 completed patients. Each statistical analysis is planned when  The planned number of patients have been included  All included patients have either finalized their last assessment discharge or has/is withdrawn/lost to follow-up according to protocol procedures  All data have been entered, verified and validated according to the data management plan Prior to each statistical analysis, the data in the data base will be exported and the exported data will be locked for further altering of data. A SAP will provide details on the planned statistical analyses. The SAP will be finalized, signed and dated prior to first interim analysis. The statistical interim analysis will be performed by an unblinded Data Monitoring Committee (DMC) statistician based on program code from the trial statistician. The trial statistician will remain blinded to treatment when finalising the SAP prior to first interim analysis and throughout the trial until final database lock. The unblinded statistician performing the analysis will only provide the study group with information on whether the trial should be stopped or continued. Details of the DMC and their procedures will be given in a separate DMC charter.  The primary outcome is rate of decline in SARS-CoV-2 viral load in oropharyngeal samples as assessed by RT-PCR in samples collected at baseline, 48 and 96 hours after randomization. The primary outcome will be analysed using a generalized linear mixed model, with subject-specific random intercept and slope, adjusted for stratification factors in the randomization. Between group comparisons will be performed for the primary variable on the per-protocol population in addition to secondary efficacy endpoints on both efficacy populations (ITT and PP populations). The between-group comparisons for secondary variables will be tested as for the primary variable where applicable and additional analyses will be performed based on the following methods (but not limited to):  Continuous secondary variables will be subject to repeated measures mixed models or appropriate nonparametric alternatives  Binary response variables will be analysed using logistic regression (possibly adjusting for within-subject dependencies by generalized estimating equations or mixed models) or chi-square/Mantel-Haenszel tests  Time-to-event variables will be analysed using the Kaplan-Meier method and comparisons between the two groups will be performed using the log rank test, Cox regression analyses or appropriate parametric models such as the gamma or Weibull model. Unless otherwise specified, all statistical hypotheses will be tested as the primary variable, i.e. with an assessment of superiority of the estimated difference between the groups. All efficacy analyses will be presented with the results from the hypothesis testing (by p-value) in addition to estimates and 95% confidence limits of the treatment effect. The safety analyses population will include all patients. Safety analyses will be descriptive and presented as summary tables by treatment group. Descriptive statistics will be presented with number and percentages for categorical variables, and means, standard deviation, and range for continuous variables. In case of clearly skewed continuous variables, they will be presented with median, interquartile range (25 th and 75 th percentiles) and range. Demographics and baseline characteristics will be presented with descriptive statistics without any hypothesis testing. If missing data is regarded as having a significant effect on the conclusions of the trial, sensitivity analyses with different methods for handling missing data will be included. Such methods may include complete case analyses, last observation carried forward, worst case/best case imputation and multiple imputation techniques. The principal investigator is responsible for making and updating a "delegation of tasks" document listing all the involved co-workers and their role in the project. He will ensure that appropriate training relevant to the study is given to all of these staff, and that any new information of relevance to the performance of this study is forwarded to the staff involved. Investigators ascertain that they will apply due diligence to avoid protocol deviations. All significant protocol deviations will be recorded and reported in the Clinical Study Report (CSR). If it is necessary for the study protocol to be amended, the amendment and/or a new version of the study protocol (Amended Protocol) must be notified to and approved by the Competent Authority and the Ethics Committee according to EU and national regulations. Authorized representatives of a Competent Authority and Ethics Committee will visit the centre to perform inspections, including source data verification. Likewise the representatives from sponsor may visit the center to perform an audit. The purpose of an audit or inspection is to systematically and independently examine all study-related activities and documents to determine whether these activities were conducted, and data were recorded, analysed, and accurately reported according to the protocol, Good Clinical Practice (ICH GCP), and any applicable regulatory requirements. The principal investigator will ensure that the inspectors and auditors will be provided with access to source data/documents. The study will be conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with ICH/Good Clinical Practice and applicable regulatory requirements. Registration of patient data will be carried out in accordance with national personal data laws. The study protocol, including the patient information and informed consent form to be used, must be approved by the regional ethics committee before enrolment of any patients into the study. The protocol will be submitted and approved by the applicable competent authorities before commencement of the study. Amendments to the protocol will be submitted to the competent authorities according to local regulations. The protocol will be registered in www.clinicaltrials.gov before inclusion of the first patient. Application to the Norwegian Medicines Agency will be approved before inclusion of the first patient. Collection, storage and analyses of all data and sensitive information will be conducted according to current General Data Protection Regulation (GDPR) and in accordance with approval from the local Data Protection Official. The investigator is responsible for giving the patients full and adequate verbal and written information about the nature, purpose, possible risk and benefit of the study. They will be informed as to the strict confidentiality of their patient data, but that their medical records may be reviewed for trial purposes by authorized individuals other than their treating physician. It will be emphasized that the participation is voluntary and that the patient is allowed to refuse further participation in the protocol whenever she/he wants. This will not prejudice the patient's subsequent care. Documented informed consent must be obtained for all patients included in the study before they are registered in the study. This will be done in accordance with the national and local regulatory requirements. The investigator is responsible for obtaining signed informed consent. A copy of the patient information and consent will be given to the patients. The signed and dated patient consent forms will be filed in the Investigator Site File binder. In cases where the patient does not speak Norwegian, a professional translator will be used. The investigator is responsible for keeping a list of all patients (who have stopped treatment or undergone any study specific procedure) including patient's date of birth and personal number, full names and last known addresses. The patients will be identified in the CRFs by patient number. The study is sponsored by Akershus University Hospital. The Principal investigator has insurance coverage for this study through membership of the Drug Liability Association (see http://www.laf.no for more details). Upon study completion and finalization of the study report the results of this study will either be submitted for publication and/or posted in a publicly assessable database of clinical study results. The results of this study will also be submitted to the Competent Authority and the Ethics Committee according to EU and national regulations. All personnel who have contributed significantly with the planning and performance of the study (Vancouver convention 1988) may be included in the list of authors. 22 8.1.1 Adverse Event (AE) and Adverse Events of Special Intrest (AESI) Data Monitoring Committee 2.2 Allocation-procedure to randomize a patient Identification of a novel coronavirus causing severe pneumonia in human: A descriptive study Publish Ahead of Print Coronavirus disease (covid-19) outbreak Informal consultation on prioritization of candidate therapeutic agents for use in novel coronavirus 2019 infection Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-ncov) in vitro Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of covid-19 associated pneumonia in clinical studies Multicenter Collaboration Group of Department of Science Technology of Guangdong Province Health Commission of Guangdong Province for Chloroquine in the Treatment of Novel Coronavirus Pneumonia Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases 2020 End points for testing influenza antiviral treatments for patients at high risk of severe and life-threatening disease A national early warning score for acutely ill patients Clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: A retrospective cohort study In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (sars-cov-2) Qt interval prolongation and the risk of torsades de pointes: Essentials for clinicians Sars-cov-2 viral load in upper respiratory specimens of infected patients As described in Section 3, the current study will utilize a pragmatic approach. In this regard, we will utilize resources already paid for by the hospitals, and all study procedures will be performed at the discretion of the treating physician, including laboratory testing, medical imaging and other procedures deemed clinically necessary. Flow Chart X X X X X X ECG X 9 X 9 X 9 X 9 X 9 X 9 X 9 X 9 X 9 X Record of medication 10 X 11 X Clinical status 12 X 1 If > 12 hours since screening nasopharyngeal swab 2 Study specific biobanking 3 Clinical examination at the discretion of the admitting physician (full clinical examination including heart, lungs, abdomen, extremities), as well as medical history, substance use, allergies, current medication, etc. 4 At the discretion of the treating physician 5 Women of child bearing age will be tested by serum hCG for possible pregnancy 6 Every day whilst under treatment 7 AESIs for this protocol is defined as gastrointestinal discomfort, visual disturbances, diarrhoea, headache, nausea and dizziness 8 If discharged before end of treatment, assessment of AESI and SAE will be perfomed by phone directly to the patient 9 Daily ECG as long as a drug known to prolong QT interval is taken in combination with chloroquine 10 Current medication at admission and antimicrobial therapy initiated at admission 11 If discharged before 96 hours 12 Death, hospitalized (on invasive mechanical ventilation or extracorporeal membrane oxygenation), hospitalized (on non-invasive ventilation or high flow oxygen devices), hospitalized (requiring supplemental oxygen), hospitalized (not requiring supplemental oxygen), not hospitalized Patients may be discontinued from the study any time. Specific reasons for discontinuing a patient for this study are: Voluntary discontinuation by the patient who is at any time free to discontinue his/her participation in the study, without prejudice to further treatment. Incorrect enrolment i.e. the patient does not meet the required inclusion/exclusion criteria for the study  In the occurrence of severe adverse events, possibly or probably associated to the IMP, the IMP should be stopped unless a clinical risk/benefit assessment at the treating physician's discretion warrants continuation. LIST OF APPENDICES Summary of Product Characteristics "PLAQUENIL"