key: cord-0985122-las80vpw
authors: Bosaeed, Mohammad; Mahmoud, Ebrahim; Hussein, Mohammad; Alharbi, Ahmad; Alsaedy, Abdulrahman; Alothman, Adel; Aljeraisy, Majed; Alqahtani, Hajar; Nashabat, Marwan; Almutairi, Badriah; Almaghaslah, Manar; Aldibasi, Omar; AlJohani, Sameera; Bouchama, Abderrezak; Arabi, Yaseen; Alaskar, Ahmad
title: A Trial of Favipiravir and Hydroxychloroquine combination in Adults Hospitalized with moderate and severe Covid-19: A structured summary of a study protocol for a randomised controlled trial
date: 2020-10-31
journal: Trials
DOI: 10.1186/s13063-020-04825-x
sha: c7d9e27720f4baabffbc43cc386a6dd02c21e0c2
doc_id: 985122
cord_uid: las80vpw

OBJECTIVES: The selected combination was based on limited evidence clinically and in vitro on the efficacy of the Favipiravir and Hydroxychloroquine in SARS-CoV-2. The two medications were listed in many guidelines as treatment options and ongoing trials assessing their efficacy and safety. Thus, we want to prove the clinical effectiveness of the combination as therapy. TRIAL DESIGN: This is an Open label, multicenter, randomized controlled clinical trial to evaluate the safety and efficacy of novel therapeutic agents in hospitalized adults diagnosed with COVID-19. It is a multicenter trial that will compare Favipiravir plus Hydroxychloroquine combination (experimental arm) to a control arm. PARTICIPANTS: All study procedures will be conducted in eight centres in Saudia Arabia: King Abdulaziz Medical City National Guard Health Affairs in Riyadh. King Abdulaziz Hospital - Al Ahsa, Saudi Arabia AlMadina General Hospital, Madnia, Saudi Arabia Al-Qatif Central Hospital, Saudi Arabia Imam Abdulrahman Al Faisal Hospital, Dammam, Saudi Arabia King Abdulaziz Medical City, Jeddah, Saudi Arabia King Abdulaziz Hospital, Makkah, Saudi Arabia Imam Abdulrahman Alfaisal Hospital, Riyadh, Saudi Arabia Inclusion Criteria • Should be at least 18 years of age, • Male or nonpregnant female, • Diagnosed with COVID-19 by PCR confirmed SARS-coV-2 viral infection. • Able to sign the consent form and agree to clinical samples collection (or their legal surrogates if subjects are or become unable to make informed decisions).. • Moderate or Severe COVID-19, defined as oxygen saturation (Sao2) of 94% or less while they were breathing ambient air or significant clinical symptoms that require hospital admission. • patients had to be enrolled within 10 days of disease onset. Exclusion Criteria • Patients who are pregnant or breastfeeding. • Will be transferred to a non-study site hospital or discharged from hospital within 72 hours. • Known sensitivity/allergy to hydroxychloroquine or Favipiravir • Current use of hydroxychloroquine for another indication • Prior diagnosis of retinopathy • Prior diagnosis of glucose-6-phosphate dehydrogenase (G6PD) deficiency • Major comorbidities increasing the risk of study drug including: i. Hematologic malignancy, ii. Advanced (stage 4-5) chronic kidney disease or dialysis therapy, iii. Known history of ventricular arrhythmias, iv. Current use of drugs that prolong the QT interval, Severe liver damage (Child-Pugh score ≥ C, AST> 5 times the upper limit), HIV. • The investigator believes that participating in the trial is not in the best interests of the patient, or the investigator considers unsuitable for enrollment (such as unpredictable risks or subject compliance issues). • Clinical prognostic non-survival, palliative care, or in deep coma and no have response to supportive treatment within three hours of admission • Patient with irregular rhythm • Patient with a history of heart attack (myocardial infarction) • Patient with a family history of sudden death from heart attack before the age of 50 • Take other drugs that can cause prolonged QT interval • Patient who is receiving immunosuppressive therapy (cyclosporin) which cannot be switched to another agent or adjusted while using the investigational drug • Gout/history of Gout or hyperuricemia (above the ULN), hereditary xanthinuria or xanthine calculi of the urinary tract. INTERVENTION AND COMPARATOR: The treatment intervention would be for a maximum of 10 days from randomization and it would be as follows: Favipiravir for 10 days: Administer 1800 mg (9 tablets) by mouth twice daily for one day, followed by 800mg (4 tablets) twice daily (total days of therapy is 10 days) Hydroxychloroquine for 5 days: (400mg) twice daily on day 1; for days 2-5 (200mg) twice daily. Reference Comparator Therapy: Standard of care is defined as: Treatment that is accepted by medical experts as a proper treatment for Covid-19 disease. Standard care comprised of, as necessary, supplemental oxygen, noninvasive and invasive ventilation, antibiotic agents, vasopressor support, renal-replacement therapy, extracorporeal membrane oxygenation (ECMO), and antiviral therapy except Favipiravir. Also, it may include intravenous fluids and medications for symptoms relief . MAIN OUTCOMES: The primary endpoint is the time to clinical improvement, defined as the time from randomization to an improvement of two points (from the status at randomization) on a seven-category ordinal scale or live discharge from the hospital, whichever came first (14 days from Randomization). RANDOMISATION: Eligible participants will be randomized in a 1:1 ratio to either the combination group (Favipiravir and Hydroxychloroquine) or a control group. The patients will be randomized utilizing Web based data entry System with a stratification based on the centre and the ICU admission. BLINDING (MASKING): This is an Open label study and only the analyst will be blinded during the study conduct. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Under the classical two arm parallel design the total effective sample sizes needed is 472 subjects (236 subjects per group). TRIAL STATUS: Protocol version 3.1 (dated 11 Aug 2020), and currently recruitment is ongoing. The date recruitment started was May 21, 2020 and the investigators anticipate the trial will finish recruiting by the end of December 2020. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04392973, 19 May 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. SUPPLEMENTARY INFORMATION: Supplementary information accompanies this paper at 10.1186/s13063-020-04825-x.

of 94% or less while they were breathing ambient air or significant clinical symptoms with Chest X ray changes that require hospital admission. 6 . Patients had to be enrolled within 10 days of disease onset.

7. Not part of any other clinical trial and agrees not to participate in any. Furthermore, it was superior to Arbidol in having a higher 7-day clinical recovery rate in patients with Covid-19 and a more effective in reducing the incidence of fever and cough 1 .

While Chloroquine is a widely used antimalarial that was found to be a potential broadspectrum antiviral in 2006 6 . Chloroquine was found to block SARS-CoV-2 infection at low-micromolar concentration 7 . Hydroxychloroquine, an analogue of chloroquine, has a clinical safety profile that is better than that of chloroquine and allows higher daily dose 8 HCQ antiviral activity is believed to be related to it's ability to inhibit SARS-CoV entry through changing the glycosylation of ACE2 (Angiotensin Converting Enzyme-2) receptor and spike protein and also inhibits post-entry stages of SARS-CoV-2 by blocking the transport of SARS-CoV-2 from early endosomes to endolysosomes, which appears to be a requirement to release the viral genome. 12 1.3. Dose Adjustment 13, 14  Antiepileptics drugs effect might be compromised with HCQ due to lower seizure threshold  Cyclosporin serum level may increase when administered with HCQ. Cyclosporin serum level monitoring is recommended.

There is an urgent need to explore therapeutic options for SARS-CoV-2 in order to face the pandemic. In the current guidelines, HCQ has been recommended for treatment of COVID- Theoretically, combining both agents would result into synergistic effect due to different target sites. However, no previous studies have explored this theory yet. In vitro data demonstrate antiviral effect of both agents against COVID-19.

Well conducted/established clinical trials are yet to be developed to evaluate the safety and efficacy of both agents among other agents that believed to have antiviral effect against COVID-19. We believed that both agents have reasonable safety profile if used appropriately. Therefore, combining two potential therapeutic options seems to be an attractive approach, taking into consideration that we are targeting patients with moderate to severe COVID-19

were mortality rate reaches up to 20% in severe cases.

Ongoing clinical trials applying a combination of various potential therapies for COVID-19 is a common approach in these situations, such as lopinavir/ritonavir NCT04303299; tocilizumab NCT04310228; chloroquine NCT04319900; and HCQ NCT04303299, among others, which all have not been completed yet.

The selected combination was based on limited evidence clinically and in vitro on the efficacy of the Favipiravir and Hydroxychloroquine in SARS-CoV-2. The two medications were listed in many guidelines as treatment options and ongoing trials assessing their efficacy and safety.

Thus, we want to prove the effectiveness of the combination as therapy.

We assume superiority of combination therapy compared to standard of care.

Time to discharge or clinical improvement by 2 points in the standard of care arm is expected to be (median: 11 days) 5 . The exact treatment effect from Favipiravir tables + Hydroxychloroquine is not exactly known but can be approximated using prior clinical studies. A study comparing the effect of Favipiravir to lopinavir/ritonavir on virus clearance has shown a 64% reduction in time to viral clearance in the Favipiravir arm. This was equivalent to a median of 11 days. We assume that clinical improvement might take place a little later to viral clearance and therefore we assume that the treatment arm might result in a minimum clinically meaningful expected reduction of 30% (form a median of 11 days to a median of 7.7 days). This is equivalent to a Hazard ratio of 0.7.

We further assume, that 50% of the patients in the control group will have clinical improvement/ discharged and 70% will have clinical improvement/discharged in the treatment arm.

This study is a randomized, controlled, open-label trial to evaluate the safety and efficacy of novel therapeutic agents in hospitalized adults diagnosed with COVID-19. It is a multicenter trial that will compare Favipiravir plus Hydroxychloroquine combination (experimental arm) to a control arm. Suggested dose for COVID-19 by the manufacturer FFTC and the Japanese guideline: 1800 mg BID on day 1 followed by 800 mg BID on day 2-10

Evidence demonstrating safety and efficacy of higher doses for influenza infection: 1. Higher concentrations of favipiravir were required to inhibit EBOV than H1N1 based on preclinical studies (150 mg/kg/day vs 100 mg/kg/day in infected mice) 2. In JIKI Trial (prove of concept trial), participants infected with EBOV received oral favipiravir (day0:6,000 mg; day1 to day9:2,400mg/d)

Although RNA viral load values and mortality were not significantly different between adults starting favipiravir within <72h of symptoms compared to others.

Favipiravir was well tolerated.

Administer 1800 mg (9 tablets) by mouth twice daily for one day, followed by 800mg (4 tablets) twice daily (total days of therapy is 10days)

For patients with Nasogastric tube:

Prepare the drug suspension by adding 5 ml of warm water to each tablet (simple suspension method; concentration 40 mg/mL).

Slowly inject the suspension into NG tube using a piston.

Wash nasogastric tube with 5 mL of water.

 Follow all precaution during preparing suspension due to teratogenic effect observed in animal studies.

No dosage regimen has been approved for HCQ as antiviral agent, however, a robust data derived from pharmacokinetic study confirmed that the dosing regimen below has demonstrated maximum viral killing activity with lowest toxicity treatment of SARS-CoV-2. 12 Oral Tablet:

Administer 400 mg (2 tablets) by mouth twice daily for one day, followed by 200mg

(1 tablet) twice daily on day 2-5 (total days of therapy is 5 days)

For patients with Nasogastric tube, prepare suspension at bedside as follows:

 Prepare the drug suspension by adding 5 mLs of water to each tablet (simple suspension method; concentration 40 mg/mL).

 Slowly inject the suspension into NG tube using a piston.

 Wash nasogastric tube with 5 mL of water.

There are limited data on hydroxychloroquine teratogenicity. We advice to follow all precaution during preparing suspension Duration: In one study, 10 days course of favipiravir was compared to Arbidol and found to be superior in having a higher 7-day clinical recovery rate in patients with COVID-19 and more effective in reducing the incidence of fever and cough.

In JIKI Trial, 10 days course of favipiravir was administered Based on the proposed/hypothetical pathogenesis of COVID-19, the clinical phase is divided into three phases: the viremia phase, the acute phase (pneumonia phase) and the recovery phase. Based on the proposed duration of viremia phase, 10 days treatment is recommended.

The selection of those endpoints based on the objectivity and to present the most reliable to assess moderate to severe infection. It is expected that the majority of the cases would be mild. Therefore, the markers used (seven-category ordinal scale), which capture the requirement of hospitalization and Oxygen requirement, reflect the best assessment for such a spectrum. 

Page 25 of 56 

In the participating centers, daily notification from the microbiology laboratory for the new positive cases to the research coordinators. Then assessment of the eligibility would be done.

Premature discontinuation of the trial would be based on the decision of DSMB or the investigator initiated based on the following: -Adverse event: clinical or laboratory event that in the medical judgment of the investigator, for the best interest of the patient are grounds for discontinuation -Major deviation from the protocol: the patient's findings or conduct failed to adhere to the protocol requirements.

-Other reason: e.g., administrative problem such as termination of study by the sponsor. Although it would not be preferred to use medication that has antiviral activity, the treating physician would have the authority/ autonomy to start the patient on antiviral but not Favipiravir,

i.e., Lopinavir-Ritonavir, interferon, ribavirin, Hydroxychloroquine or Remdesivir). Anyone of those medications with possible antiviral activity against SARS-CoV-2 would be accepted to be used in the case that treating physicians thought it would be the best of interest for the patient. 

Eligible participants will be randomized in a 1:1 ratio to either the combination group (Favipiravir and Hydroxychloroquine) or a control group. Randomization will be stratified by clinical site.

The patients will be randomized utilizing Web based data entry System. The sequence of treatment assignment will be determined prior to the start of the study. Compliance with the study drug will be assessed by the study coordinator at each study visit and he / she will be required to record in the CRF any missed dose, the reason for missing doses, any adverse effect, and any associated issues, beginning from visit 1.

In compliance with the International Conference on Harmonization (ICH) guidelines, Title E6-Good Clinical Practices section 4.6, and CFR 21 Part 312.61, the Investigator is responsible for maintaining records reflecting the receipt and dispensation of the investigational product.

Additionally, the Investigator must comply with any local regulations regarding the proper documentation of study drug accountability.

The study drug must be stored and handled in accordance with the Sponsor's instructions.

At the end of the study, remaining therapeutic unit will be destroyed locally and a certificate of destruction will be issued by King Abdulaziz Medical City.

B. Patient will remain on medications he/she is taking prior to the study. However Use Favipiravir must be with caution while using acetaminophen aution while usingns he/she is taking prior than 3000mg/day (or less in patients with hepatic insufficiency)

The Study comprises of three major parts Screening, Treatment and Follow-up period. Each

Part consists of specified procedures to be done and assessments to be carried. All study procedures will be conducted in King Abdul-Aziz Medical City National Guard Health Affairs in Riyadh. The investigator and supporting study team will be responsible to document all the procedures and assessments done in the appropriate source document and the patient e CRFs. All procedures and assessments will support the safety and validity of conclusions drawn from the study protocol. Procedures and assessments such as vital signs, laboratory tests…etc will follow in-house policies and guidelines. When multiple assessments are taken at the same time point, the most out-of-range value shall be considered

In the participating site, the research coordinator/ delegated study personnel for the site will Daily assessment and data reporting will be done by the research coordinator/ delegated study personnel including the side effect using the included CRF.

While the management will be done by the treating physician and even stopping the medication in case of concerns. Stopping the interventional medication need to be justified; where a form would be filled.

The treatment intervention would be for a maximum of 10 days from randomization and it would be as follow:

Favipiravir for 10 days as follow:

Page 32 of 56

Administer 1800 mg (9 tablets) by mouth twice daily for one day, followed by 800mg (4 tablets) twice daily (total days of therapy is 10 days)

Hydroxychloroquine for 5 days:

(400mg) twice daily on day 1; for days 2-5 (200mg) twice daily.

Site PI should follow on a daily basis all the possible AEs while using the investigational medications and up to day-14. This includes regular monitoring of hematology and blood chemistry. Daily ECG and QT interval monitoring. And LFT every other day. In case of any concerns that might require holding/stopping medication, causality assessment should be done by PI and with a consultation to an independent clinician.

Details of cardiac toxicity monitoring as follow:

1. A baseline ECG before starting then daily ECG after.

2. Daily ECG to be done through day 1-10 or twice daily if the corrected QT interval more than 480ms.

2. Maintain serum level of Mg>1.0 meq, and K>4.5 meq throughout the 10 days of therapy.

If the QTc prolonged more than 500ms after starting, stop the medication.

4. Avoid any other QT prolong medication during the regimen.

If the patient develops torsades de-pointes, stop the medication immediately, follow ACLS protocol and call the cardiologist on-call.

If you have any query or help, please call for cardiology team in you center.

The follow up period would be till discharge from the hospital or day 28 from randomization.

Where serial oropharyngeal swab or lower respiratory samples will be obtained on day 1 (-3 days) (before therapy was administered) and on days 5±1 day, 10±2 days, 14±2 days, 21±2 days, and 28±3 days or until 2 consecutive testing are negative which comes first. Any extra Respiratory PCR COVID19 samples requested by the treating team will be recorded. Other laboratory investigations will be recorded as per flow chart.

The laboratory tests that intended to be used for upper ( HR is the hazard ratio of treatment compared to control arm.

Under the classical two arms parallel design the total effective sample sizes needed is 472 subjects (236 subjects per group). The Estimated sample size achieve 85 % power to detect a minimum of 30% reduction in the median time, to clinical improvement by at least two points or hospital discharge, in the treatment group compared to the control group. The median time in the treatment arm is 11 days under the null hypothesis and 7.7 days under the alternative hypothesis.

The median time in control group under the null hypothesis is 11 days. The two survival curves will be analyzed using one sided cox proportional hazard regression. The significance level of the test is 0.025. Assuming 10% drop out rate, the overall sample size for the trial is estimated to be 520 (260 per group). Sample size adjustment will be considered after interim analysis of 60% of the subjects' recruitment and based on DSMB recommendation.

We have performed several sensitivity analyses to determine the effect of different assumptions on the sample size. Figure 

The current study will have a single interim analysis which will take place at the completion of the recruitment and follow-up of 60% of the total number of subjects (i.e. 312). The interim analysis is designed to test for early stopping for futility or efficacy as well as for sample size re-estimation. The The sample size Re-estimation will be based on the ratio of the planned effect size to the observed effect size from the interim analysis according to the following formula:

Where a is a constant which will be set to 2 and 0 is a number chosen to be slightly larger than the classical sample size per group, 0 is the planned effect size of .7 and E is the observed effect size from the interim analysis.

A detailed statistical analysis plan will be developed before undertaking any comparative analyses of outcomes. The following provides a brief summary of approach to analysis for the primary endpoint.

Analysis of the primary endpoint:

The primary endpoint of the current study is Median time to clinical improvement by at least 2 points or discharge from the hospital. The number and percent of subjects who met the endpoint by day 28 of follow up will be calculated and tabulated. Kaplan-Meier plot of time from randomization to endpoint will be generated (censoring at 28 days if completed follow-up, or at date of last contact if lost to follow-up prior to 28 days), with associated table showing: number censored and number (%) meeting the endpoint, median time to endpoint and associated HR with 95% confidence interval; p-value from cox proportional hazard regression.

For secondary endpoints:

 Quantitative variables such as duration of ICU stay and change from baseline in clinical scores, etc., are expected to have reasonably skewed distributions and may be subject to censoring (e.g., for subjects in hospital on Day 28; these will be compared between randomized arms using non-parametric tests (e.g., Wilcoxon's Test adapted, if necessary, to handle censoring).

 Analysis of the ordinal scale endpoints will use a proportional odds model with an indicator variable for randomized treatment. The Wald test will be used to generate a pvalue comparing treatments, as well as the estimated proportional odds ratio comparing treatments with associated 95% CI.

 Analysis of AE data will primarily be descriptive based on MedDRA coding of events.

The proportion of subjects experiencing an SAE and the proportion experiencing a Grade 3 or higher AE will be compared between randomized arms using Fisher's Exact Test.

For enrolled subjects who were not randomized (i.e. screen failures) or who were randomized but did not receive the treatment, the final analysis will detail safety (deaths and SAEs), and reasons they were not randomized or did not received treatment respectively. Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in other situations, such as important medical events that may not be immediately life threatening or result in death or hospitalization but may jeopardize the subject or may require medical or surgical intervention to prevent one of other outcomes listed in the above definition. These should also be considered serious.

Examples of such events are invasive or malignant cancers, intensive treatment in emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or development of drug dependency or drug abuse.

For the purpose of this trial, the information related to the emergency visits due to hyperammonemia will be collected specifically on the CRF, and should not be consider an AE or SAE.

Favipiravir Adverse Drug Reactions  Major adverse drug reactions include increase of uric acid serum level (~4.8%), diarrhea (~4.8%), decrease neutrophil count (1.8%), and increase in AST and ALT (1.8%, 1.6%) respectively.

 Other clinically significant ADRs include skin rash, neurological and psychiatric symptoms (e.g. suddenly running away, wandering around), anaphylactic shock, pneumonia, hepatic dysfunction, acute renal failure, decrease in white blood cell count and platelet count, and hemorrhagic colitis.

 Adverse drug reactions have been reported after administering hydroxychloroquine include: 

All AEs encountered during the clinical study will be reported on the CRF. Adverse events, whether or not associated with study medication administration, will be recorded on the Adverse Event form of the CRF.

The information to be entered in the CRF will include: 

All adverse drug events encountered during the clinical study will be reported on the CRF.

Serious adverse events (SAEs), whether or not associated with study medication administration, will be recorded both on the Adverse Event form of the CRF as for non-serious AE and the SAE form.

ALL SAEs occurring during this study and up to 30 days after a subject discontinued or completed the study, whether or not related to the administration of study medication, must be reported by faxing the completed SAE form, after reviewing the report for consistency and accuracy within 24 hours of awareness by the investigator, to KAIMRC / IRB.

As far as possible, investigators should follow-up participants with AEs until the event is resolved or until, in the opinion of the investigator, the event is stabilized or determined to be chronic. Details of AE resolution must be documented in the CRF. Participants should be followed-up for 30 days after receiving the last dose of study medication and any AEs, which occur during this time, should be reported according to the procedures outlined above. Any significant changes in AEs should be reported even though the subject has completed the study, including the protocol-required post-treatment follow-up.

The sponsor has a responsibility to report to the regulatory authorities and Ethics Committee safety information according to the local regulations. Therefore, prompt notification of serious adverse events by the investigator is required so that reporting timelines can be met and also to ensure ethical responsibilities towards the safety of other subjects are met.

The sponsor will also inform all participating investigators and Ethics Committee according to the local regulations.

This study must be carried out in compliance with the protocol and in accordance with the laws and regulations of Saudi Arabia, and the sponsor or their representative's standard operating procedures. These are designed to ensure adherence to Good Clinical Practice, as described in The study may not start before written approval has been obtained for the protocol and the informed consent form.

In obtaining and documenting informed consent, the investigator should comply with the applicable regulatory requirement(s), and should adhere to GCP and to the ethical principles. Prior to the beginning of the trial, the investigator should have the IRB written approval of the written informed consent form and consenting process.

The investigator, or a person designated by the investigator, should fully inform the subject, subjects family or the subject's Legally Acceptable Representative (LAR), of all pertinent aspects of the trial including the nature of the study, its purpose, the procedures involved, the expected duration, the potential risks and benefits involved and any discomfort it may entails. All questions about the trial should be answered to the satisfaction of the subject or the subject's family member or subject's LAR.

Due to the nature of the study and the risk of spreading the virus to the study team, and after waiver is granted by the IRB, special measures related to the consenting and the documentation process will be implemented. These measures are: -Prior to a subject's participation in the trial, the written informed consent form should be signed and personally dated by the subject and the PI and/or the delegated person who explained the trial to the patient, using two original copies, one to be given to the patient and one with the study team. . To reduce the risk of spreading the virus, the original consent forms will be kept in the secure place with minimal access in the hospital before filing.

-If the subject is unable to give the consent, a subject's family member or subject's LAR will give the consent. In some situations where the family or subject's LAR are not able to be present, an oral consent over the phone will be obtained in a timely manner followed by sending the consent form to be signed and collected via the email communication or mobile phone if possible at the earliest opportunity valuable or to be signed at a later time at the site when allowed.

-If a subject is unable to read or if a family member or subject's LAR is unable to read, then an impartial witness should present during the entire informed consent discussion, and signs the consent form in addition to the subject or the subject's family member or subject's LAR.

-Subjects who are unable to read and who do not speak Arabic nor English as their first language have the consent form read to them by a qualified interpreter and that the interpreter signs the consent form as well as the subject, subject's family member, subject's LAR and the PI.

-If the subject is unable to give a consent and has no family member or subject's LAR or in case the PI or the study team could not reach to a family member or subject's LAR after doing all possible efforts, the PI has to seek the consent from the subject's attending physician (most responsible physician) for the enrollment in the trial.

-Procedures to inform, at the earliest feasible opportunity, the subject (i.e., if his/her condition improves), a family member, a subject's LAR of the subject's inclusion in the trial, the details of the research, and the right to discontinue the subject's participation at any time without penalty or a loss of entitled benefits.

Any changes to the proposed consent form suggested by the investigator must be agreed to by the Sponsor before submission to the IRB/IEC and a copy of the approved version must be provided to the Sponsor after IRB/IEC approval.

As an Investigator Initiated Trial, this study will not be formally monitored. A research assistant who has expertise in data entry will enter data into a password-protected database. Data will be entered and double checked for accuracy. After resolution of any discrepancies and a combination of manual and automated data-review procedures, the final data set will be subject to a quality assurance audit.

To ensure the quality of the clinical data across all participants and sites, a clinical data management review will be performed on all subject data. During this review, subject data will be checked for consistency, omissions and any apparent discrepancies. In addition, the data will be reviewed for adherence to protocol. To resolve any questions arising from the clinical data review process, data queries will be sent to the site for completion.

It is the responsibility of the Investigators to record all observations and other data pertinent to the clinical investigation. For this study an electronic CRF (eCRF) will be used.

Data on subjects during the trial will be documented in an anonymous fashion and the subject will only be identified by the subject number, and his/her initials. The Investigator must maintain source documents for each patient in the study. All information in the study database must be traceable to these source documents, which are generally maintained in the patient's file. The source documents should contain all demographic and medical information, including laboratory data, and a copy of the signed informed consent form, which should indicate the study number and title of the trial.

Essential documents, as listed below, must be retained by the Investigators for as long as needed to comply with national and international regulations. The Investigators agree to adhere to the document retention procedures by signing the protocol.

 IRB/IEC approvals for the study protocol and all amendments;

 Source documents and laboratory records;

 Patients' informed consent forms;

 All other pertinent study documents.

A Data and Safety Management Board (DSMB) will be convened to monitor the unblinded data from the trial focusing mainly on the assuring that the study is following the protocol properly and to monitor the safety issues related to the trial. This committee will be composed of independent team members with relevant therapeutic and/or biostatistical experience to allow for the ongoing review of data from this trial. The DSMB will meet regularly throughout the course of the trial and when AEs trigger study pausing/stopping criteria are triggered. Further details will be described in an DSMB charter prior to the start of the clinical trial.

By signing the protocol, the investigator agrees to keep all information provided by the sponsor in strict confidence and to request similar confidentiality from his/her staff and the IRB/EC. Study documents provided by the sponsor will be stored appropriately to ensure their confidentiality.

The information provided by the sponsor or the partner to the investigator may not be disclosed to others without direct written authorization from the sponsor/ partner, except to the extent necessary to obtain informed consent from patients who wish to participate in the trial.

Any change or addition to this protocol requires a written amendment that must be approved by the sponsor and the investigators.

Before implementation, the investigators must transmit all major amendments to the Ethics Committees having examined the initial protocol. The investigators must transmit a copy of the Ethics Committee's opinion to the sponsor.

All minor amendments must be notified by the investigators to the Ethics Committee having examined the initial protocol.

The investigator must maintain all study records, subject files and other source data for at least 15 years.

The sponsor certifies having taken out a liability insurance policy which covers the investigators and his co-workers and which is in accordance with the local laws and requirements.

The investigator should be informed that an audit may be carried out, at the request of the sponsor during or after the end of the study.

Authorities may also carry out an inspection. The intention is to publish the results of the complete study at conclusion. All information obtained during the conduct of this study will be regarded as confidential and written permission from the Sponsor is required prior to disclosing any information relative to this study. A formal publication of data collected as a result of the study is planned and will be considered a joint publication by all Investigators and the appropriate Sponsor personnel. Authorship will be determined by mutual agreement. Submission to the Sponsor for review and comment is required prior to submission to the publisher. This requirement should not be construed as a mean of restricting publication, but is intended solely to ensure concurrence regarding data, evaluations, and conclusions, and to provide an opportunity to share with the Investigator any new or unpublished information of which he or she may be unaware.

Events (CTCAE), Version 4.0. 

Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial. medRxiv

Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention

Favipiravir as a potential countermeasure against neglected and emerging RNA viruses

Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase

Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study

New insights into the antiviral effects of chloroquine. The Lancet Infectious diseases

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy

Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies

COVID-19 Treatment: A Review of Early and Emerging Options. Open Forum Infectious Diseases

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)

Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro

Sulfate package insert

Avigan-Favipiravir package insert

Determinants of Hydroxychloroquine Blood Concentration Variations in Systemic Lupus Erythematosus

Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial

Avigan-Favipiravir package insert

Hypothesis for potential pathogenesis of SARS-CoV-2 infection-a review of immune changes in patients with viral pneumonia

Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase

targeting the upstream SARS-CoV-2 envelope protein gene. The laboratory should follow the Saudi CDC recommendations for Results interpretation of Real-Time RT-PCR and follow the manufacturer recommendations for the defined cut-off CT value for the positive results based on the CT value for each target gene.