Phase II randomized controlled trial to evaluate the ecacy and safety of HeberFERON versus Heberon alpha R in symptomatic or asymptomatic patients infected with the SARS-CoV-2 (Study ESPERANZA/HOPE).

Background: As the outbreak of COVID-19 has accelerated, an urgent need for nding strategies to combat the virus is growing. Results from in vitro studies suggest that a combination of IFN type I and Type II may be effective against SARS-CoV. The aim of this study is to investigate the ecacy of treatment with a recombinant IFN alpha 2b and gamma, provided with standard protocol (Kaletra (lopinavir-ritonavir 200/50 mg; 200/100 mg every 12 hour for 30 days; Chloroquine (250 mg) every 12 hours for 10 days) for COVID-19 patients, compared to standard protocol (IFN alpha 2b/Kaletra/Chloroquine) for COVID-19 hospitalized patients, positive diagnosed for SARS-Cov-2. Methods: Hospitalized adult patients with qPCR conrmed SARS-Cov-2 will be enrolled in this open-labeled, single center, prospective, randomized and controlled clinical trial. One hundred and twenty eligible patients with conrmed SARS-CoV-2 positivity by qPCR amplication in oropharyngeal/nasopharyngeal swab samples will be enrolled at “Luis Diaz Soto” Hospital, Havana, Cuba. The primary outcomes are the time to 2019-nCoV RNA negativity in patients and the time until progression to severe COVID-19. Discussion: This will be the rst randomized controlled trial of a potential treatment for SARC-Cov-2 using the combinations of IFNs.


Background and rationale {6a}
As the SARS-Cov-2 infection has spread to more than 180 countries of the world and generated a signi cant number of deaths, more than 5% of lethality, with great social and economic consequences, it is very urgent to nd and develop strategies to combat this new virus.
There are guides issued by expert committees of WHO, Singapore, South Korea and US institutions, that recommend the clinical use of interferon (IFN) for the treatment and prevention of COVID-19 1,2,3 . Countries like China and Spain have incorporated this medicine in their protocols and national clinical guidelines for the care of this type of patient 4,5 .
There are three types of Interferons (IFNs): type I (IFN-a and IFN-b), type II (IFN-g) and type III (IFN-l) 6 . IFNs are proteins created by nature for the rst line defense against pathogens (viruses, bacteria, parasites), a function demonstrated in a group of species at different levels of the evolution chain, con rming their protective role.
Infection with mammalian cell viruses incites the innate immune system to establish a rst line of defense. IFNs play a key role in these events, as they activate the innate immune system and help shape adaptive immunity 7 . IFN-g is the main modulator in establishing the relationship between these two types of immune responses 8 .
IFNs possess pleiotropic effects that overlap on various cellular functions. IFNs-a and b have a greater antiproliferative and antiviral effect and IFN-g a superior immunoregulatory activity 9,10 .
IFNs-a and -g exercise their functions through different but related signaling pathways. Studies in animal models have shown that IFNs-a and -g are essential for antiviral defense and are functionally nonredundant 11 .
Viruses have developed mechanisms to evade the functions of the IFN system by simulating proteins that intervene in the synthesis mechanisms of IFNs, and intracellular signaling to establish the protection mechanisms by these (IFN receptor and other signaling cascade proteins) 12,13 .
Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 is a positive-sense, enveloped, singlestranded RNA β coronavirus similar to Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) virus. This type of virus is susceptible to the antiviral action of IFNs, but variations have been developed to interfere with this activity 14 .
Viruses have developed mechanisms to evade the functions of the IFN system by simulating proteins that intervene in the synthesis mechanisms of IFNs, and intracellular signaling to establish the protection mechanisms (IFN receptor and other proteins of signaling cascades) 15,13 . SARS-Co, which emerged in 2003 and caused widespread human mortality, encodes at least ve proteins that function as IFN antagonists 16,17,18,19 , suppressing signaling and production components. These proteins are believed to be responsible for the pathogenesis of SARS-CoV.
The induction of IFNs plays a fundamental role in defending the body against CoV infections. Numerous studies have presented the effectiveness of direct administration of IFN to eliminate these viruses 20 .
IFN-g has been reported to have an antiviral effect in coronavirus infection. This effect is described mediated by the recruitment of monocytes and T lymphocytes to the area of the infected cells and the production of IFN-g by them. In the absence of IFN-mediated signaling, infection leads to the death of infected animals 21 .
The IFN-α e IFN-g combination in the infection of coronavirus The combination of IFN-g and -λ has been described to synergistically inhibit the replication of SARS-CoV in vitro 22,23 . Larkin et al. 24 indicate that the combination of IFN-α and IFN-g generates strong synergistic antiviral activity. Another study demonstrates that co-administration of IFN-α and IFN-g causes hyperactivation of IRF-1 and STAT1, ultimately leading to a more robust antiviral response against viral replication 25 . The combination of type I IFN (IFN-α, β) with IFN-γ synergistically inhibits virus replication in vitro 22 .
The effects of IFNs on the replication of SARS-CoV, showed that treatment of Vero E6 cells with 100 U / mL of IFN-β or IFN-g marginally reduced viral replication. However, treatment with IFN-β and IFN-g inhibited SARS-CoV plaque formation 30 times and replication 3000 times at 24 h, and> 1 x 10 5 times at 48 and 72 h after the infection. This result demonstrates the synergistic inhibition of SARS-CoV replication by IFN type I and IFN-g22.
The higher mortality rate from COVID-19 in elderly patients has been associated with a greater delay between the time of infection and the response of the immune system, caused mainly by the inhibitory effects of the virus on it. Early administration of IFNs could reduce this window of antiviral inactivity and decrease SARS mortality. Combining IFN-g and IFN-α synergistically could maximize this bene t.

Heberon alpha R®
Heberon Alfa R® (IFN alfa-2b) is a drug produced in Cuba by the Center for Genetic Engineering and Biotechnology (CIGB), which has remained a product with proven antiviral e cacy and an adequate safety pro le for 34 years 26 .
The evidences are different for preventive use and the treatment at early stage of the disease, so Heberon Alpha R is one of the interventions included in the Cuban protocol for the management of COVID-19 and about 76,900 doses have been supplied to the National Health System by the CIGB since March 2020.
The current Cuban recommendation for patients is to use recombinant interferon alfa 2b (Heberon alfa 2b) 3 million of units intramuscular routs thrice a week at early stage.
Today there are several clinical studies with IFN alpha-2b in COVID-19 registered at clinicaltrials.gov and guideline issued by Expert Committees of WHO, Singapore, South Korea and US Institutions recommend the clinical use of IFN alpha for the treatment and prevention of COVID-19. However, the use of IFN in advance stages of the disease has been inconsistent.
HeberFERON®HeberFERON® (IFN-α2b+ IFN-γ) is a drug produced in Cuba by CIGB, which was approved in Cuba by CECMED in 2016 for the treatment of basal cell carcinomas (BCC), and since then it has been routinely administered to more than 3,000 patients with advanced, high-risk or multiple BBC in the country.
HeberFERON® has been extensively studied through physicochemical studies, biological activity in vitro 27 and in vivo 28 , in studies of pharmacokinetics, pharmacodynamics in humans 29,30 , animals 31 and toxicology ,32 .
The proteins, enzymes and metabolites mediating the antiviral effect (2-5 OAS, β-2 microglobulin, Neopterin) of IFNs are synergistically stimulated by HeberFERON 29,30 . The main intracellular signaling factor common to both IFNs, STAT-1 7 has also been synergistically stimulated and has been shown to be a target of SARS-CoV antagonism on the IFN system 12 .
These evidences support the use of this therapeutic candidate for the control of COVID-19 in the early stages of the disease and in patients positive for the virus.
We have decided to compare these two formulations of IFNs to de ne the antiviral of IFN formulations activity against SARS-CoV-2 in a controlled randommized clinical trial.

Objectives {7}
Primary objective: To assess the e cacy and safety of subcutaneous administration of HeberFERON (combination of IFN-α2b and -γ) and Heberon (IFN-α2b) in patients con rmed to be infected by SARS-CoV-2. Secondary objectives: To determine the effect of treatment in terms of the time until SARS-CoV-2 RNA negativization  6. Pregnancy or lactation, 7. Obvious mental inability to issue consent and act accordingly on study.
Who will take informed consent? {26a} a. Patients will be asked for written consent to participate after having been duly informed about the characteristics of the trial, objectives, bene ts and possible risks. They will have the necessary time to decide (minimum 24 hours). Likewise, they will be informed of the right to participate or not and to withdraw their consent at any time, without exposing themselves to limitations for their medical care or other retaliation.
b. The investigator should obtain the patient's written consent only after making sure they understood all the information offered. The procedure will be provided by means of a standard writing; in language easily understood by the patient (it should not be technical, but practical). Neither the investigator nor the trial staff can in uence the patient's decision to participate or continue in the trial. All patients who provide informed consent will be randomly allocated into one of two study groups.

Additional consent provisions for collection and use of participant data and biological specimens {26b}
The consent for collection and use of participant data and biological specimens is included in the informed consent

Interventions
Explanation for the choice of comparators {6b} The CUBAN NATIONAL ACTION PROTOCOL FOR COVID-19 Error! Bookmark not de ned. , taking in account the e xperience and results from Chine with the use of Kaletra and chloroquine plus IFN alpha in the treatment of COVID-19 patients, established the obligatory use of this combination for the treatment of SARS-CoV-2 patients. It was not possible to introduce a 3-arm with the sole use of kaletra and chloroquine, because the Cuban health authority prohibited the exclusion of Heberon Alpha R (IFN alpha2b) from the treatment schedule. Then, the combination of Kaletra, chloroquine and IFN alpha 2b was used as comparator.

Intervention description {11a}
Are all medications are administered by hospital staff so the patient has no responsibility for intake

Intervention group
The intervention group will receive Kaletra (200/50 mg orally twice daily) and chloroquine (250 mg orally twice daily), as described Error! Bookmark not de ned. , and HeberFERON. HeberFERON will be administered two times per week at 3.5 MIU for 3 weeks. The use of HeberFERON does not contradict the obligatory use of Kaletra and chloroquine, and Heberon Alpha R, because it self-contains IFN alpha2b at the same concentration as used in the comparator.

Control group
The control group will use Kaletra and chloroquine, plus Heberon Alpha R administered three times per week at 3.0 MIU for 3 weeks, as described in the CUBAN NATIONAL ACTION PROTOCOL FOR COVID-19 Version 1.4.Error! Bookmark not de ned..

Criteria for discontinuing or modifying allocated interventions {11b}
The allocated intervention may be discontinued by the medical staff or by the patient himself, decision.
The patients may withdraw their consent at any time, without exposing themselves to limitations for their medical care or other retaliation.
In the event of serious adverse events (with proven causality) the administration of the product will be interrupted and the required measures will be taken depending on the event and the possible expedited report of the same will be considered. The occurrence of the event will be noti ed to the monitor within a period not exceeding 24 hours.
The person responsible for the investigation, the monitors and the team of investigators, will carry out the corresponding investigations in order to determine the component causing the undesired effect.
After recovery from the adverse event, the patient may restart treatment according to the treatment scheme has been received. If severe toxicity occurs again, treatment is permanently discontinued.

Strategies to improve adherence to interventions {11c}
Prior to the preparation of this protocol, a criteria uni cation workshop was held with the participation of clinical specialists and opinion leaders involved in the project, where the experimental evidence in animals and humans, as well as the elements of rationality, were presented and discussed. The analysis, discussion and mastery of the protocol will favor adherence and compliance with GCP by all researchers.
The trial monitors will make quality monitoring visits at all stages of its execution, ensuring strict compliance with the provisions of the protocol.
In the case report form (CRF) there is a table to control the use of the in study drugs that signs the doctor.

Relevant concomitant care permitted or prohibited during the trial {11d}
Rules for the use of concomitant treatments.
Medicines may be used concomitantly to prevent or mitigate adverse events of probable causation with the use of Heberon Alfa R and HeberFERON.
Indications for treatment with antihistamines and / or steroids Dipirone or acetaminophen will be indicated to relieve fever, headache, and pain if necessary, depending on the doses listed below, taken from the AHCPR "Guidelines for the Management of Acute Pain" 33 . In case of need for other concomitant medication, this will be administered at the discretion of the investigator in charge of the patient. The conduct before any adverse event will be the decision of the responsible investigator and will depend on the type, magnitude and severity of the clinical manifestations in each case. The sample size was estimated for the difference in the proportion of negative patients at different time (secondary outcomes), early in the disease, when the effect of external agent can exerts the highest effect, using the PASS software .Taking in account that the 100% of patients will be positive to SARS-CoV-2 and that only 15% will have the probability to became severe ill, we hope to enroll a sample size of one hundred and twenty patients for this study, based on a power of 80%, and a level of con dence set at 95%, while also considering a dropout rate of 5%.

Recruitment {15}
The source of patients is all the positive patients that are hospitalized at the study hospital positive by RT-qPCR ampli cation in oropharyngeal swab to SARS-CoV-2.

Assignment of interventions: allocation
Sequence generation {16a} There will be a centralized randomization at CIGB. The randomization procedure will be carried out by the Supply Group of the Direction of Clinical Investigations at CIGB. Patients will be block randomized individually to one of two treatment arms by means of random computer-generated lists, with an allocation ratio of 1:1, with block sizes of six patients

Concealment mechanism {16b}
The allocation of treatment will be done after the patients have been included following the inclusion and exclusion criteria, and will be mediated by an email with attached allocation form that must include the following information: name and family name initials, clinical history number, age, sex, previous or current concurrent diseases, doctor name, health intuition name and province. It should be send also an electronic copy of writing consent of the patient, signed by the patient and the medial doctor responsible for the study. The allocated vials of the drug will contain etiquette with the inclusion code, the short name of the trial (ESPERANZA), and the lot, and its spired data.

Implementation {16c}
The information of the treatment group (A or B) will only be known after the patient is included. At the time of inclusion (after the selection criteria have been veri ed and written informed consent has been obtained), the clinical investigator will give the information to the CIGB monitors (who will visit the hospital daily and remain at their posts command). After collecting the general patient information to include (initials, date and time), will assign the inclusion number and the corresponding treatment (consecutive, according to a random list in their possession).

Assignment of interventions: Blinding
Who will be blinded {17a} This is an open label RCT so patients, doctors are aware of treatment allocation and outcome assessment is not blinded. The virological data analysis will be conducted blind by external laboratory personal and the clinical data analysis by external statistic committee.

Procedure for unblinding if needed {17b}
The design is open label with only data analysts being blinded, so unblinding will not occur Data collection and management

Plans for assessment and collection of outcomes {18a}
For the conduction of the trial following the Good Clinical Practice, the Steering Committee and any other personal related to the trail execution (laboratory technician, nurses, and pharmacist) will participate in a workshop to receive speci c technical information about the products for clinical interventions during the investigation and information and training in procedures for assessment and collection of outcomes, ensuring compliance with the study procedures, The design, execution of the trial, the clinical and analytical determinations, as well as the analysis of the data will be carried by suitably quali ed personnel.
Doctors and nurses were aware of the possible adverse effects of IFNs and their management, both those expected immediately after applying the product (local to the injection site) and hours later ( ulike symptoms).
Routine blood examinations will be performed included whole blood counts, coagulation pro les, serum biochemical tests (including renal and liver function, electrolytes, and coagulation), C-reactive protein (CRP) and ferritin levels.
These determinations will be done using reagents of the required quality and validated techniques. In the case of hematological determinations, several equipment will be used (BC 3200 Hematological Complex, BC 5800 Hematological Complex, as well as a Coagulograph). For blood chemistry determinations, the Midray BS -400 equipment will be used. The reagents to be used for each determination are the following: Throat swab specimens will be transported to a BSL2 certi ed laboratory at the CIGB for SARS-CoV-2 viral nucleic acid detection by RT-qPCR, using the QIAamp Viral RNA Mini kit (Qiagen,USA), as per the manufacturer's instructions.
Demographic, clinical, laboratory, treatments and outcome characteristics of patients will be extracted from medical record, registered in the case report forms (CRFs) and then entered in duplicate (independently by two operators) for the subsequent process of automatic comparison and cleaning of the database.
The blood determinations data will be kept in the GALEN LAB software, which is an information system for diagnostic means, aimed at managing them, facilitating the request for examinations, recording and evaluation of the results obtained, as well as the generation of statistical information. This software is designed to be used by diagnostic technicians, physicians, and administrative personnel who need to optimize their work and increase their e ciency. It guarantees a strict control of the information, differentiating for each one, the available options according to their responsibility. It is a useful tool, for a possible evaluation by a committee of experts outside the investigation if it is considered necessary

Plans to promote participant retention and complete follow-up {18b}
There is no any patient retention plan due to the complex pandemic situation. Patients that discontinued the treatment will be asked to nish the planned laboratory and clinical evaluations up to day 14 at home.
The medical staff from the trial will design a technician and specialist in internal medicine to obtain blood samples for routine haematological and biochemical determinations from the patient as planed in the procedures at home, and will ask for any adverse events.

Data management {19}
For the purposes of this study, a data entry system will be generated at OpenClinica, which is a free software platform for protocol con guration and CRF design, which allows the electronic capture, storage and management of data.
The data entry will be carried out in duplicate (independently by two operators) for the subsequent process of automatic comparison and correction of the bases, necessary for statistical analysis with accurate information from the trial. For debugging errors, the data that does not match the one registered in the original CRF will be corroborated to avoid confusion. The comparison will be repeated until no differences are found between the databases. This process will guarantee the cleanliness of the data included in the databases that will later be used in the statistical analysis. This activity will be recorded, so that it can be traced to national and foreign inspections and / or audits.

Con dentiality {27}
The protocol's medical specialists, the promoter, the monitors and auditors appointed by the promoter will guarantee that the personal data of the subjects included in the protocol are treated in accordance with the provisions established in Law 15/1999 on data protection personal nature and the regulations that develop it. Likewise, the anonymity of the subjects included and the protection of their identity will be maintained; no personal data of the subjects of the protocol will be transferred, except in those circumstances allowed by law.
Monitors and auditors appointed by the promoter may access clinical information and documentation on the subjects included, in order to verify the accuracy and reliability of the data, but must not collect the personal identi cation data of the subjects. Access to this data should also be provided to the inspectors of the competent health authorities.
The results of the clinical trial, as well as all the work and reports carried out and all the industrial property rights derived from it, are the exclusive property of the promoter. The latter is committed to disseminating them, once the protocol is nished and whether they are negative or positive, in public access media.
The publication of the results, by the medical specialists of the hospital institutions, in scienti c magazines or books and the oral presentations or posters at scienti c events, workshops or meetings, must be carried out in agreement with the promoting center.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33} The promoter center will be in charge of transmitting, operationally, the procedure for the extraction, identi cation and conservation of the biological samples that will be transferred to the CIGB according to

Statistical methods for primary and secondary outcomes {20a}
The statistical analysis will be done as intention to treat (patients that will receive at least one doses of the in study drugs) and per protocol (patients that will receive at least four doses of HeberFERON or six doses of Heberon Alpha R). We will compare the study endpoints between the two arms using time-toevent methods with the Cox proportional-hazards model. The different categorical variables will be analyzed using the one-way analysis of variance. To describe the e cacy and safety of the IFN regimens, Kaplan-Meier estimates and a multivariate Cox proportional hazards model will be used to compare severity of patients and adverse events among the two arms during the study period at week four. A p-value of <0.05 will be deemed to confer statistical signi cance.

Interim analyses {21b}
The promotor did not considered to undertake interim analyses for this RCT because of the expected high rate of inclusion and the necessity to rapid ending of the trial to have results to de ne clinical decision for the best treatment of patient in the pandemic situation that permit to have a high rate of discharges in the lowest time as possible.
The promotor did not expect any harm that will justi es the anticipated stop of the trial based in the safety of IFNs in this short time and low does intervention schedules.
Methods for additional analyses (e.g. subgroup analyses) {20b} No additional analyses were planed Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c} All the patients that receive at least one doses of the in study interventions will be evaluated by intention treat independent of the non-adherence to the protocol. The missing data will be considered as part of the statistically analysis for demographic data. In the case of virological evaluations, the analyses will be take in account only the evaluated samples, the missing data will be non-considered In the case of virological determination when two rst consecutive samples (24 hour and 72 hours) will be negative by RT-qPCR, the thirst sample (96 hours) will be no evaluated, and the patient will be declared negative.
Plans to give access to the full protocol, participant level-data and statistical code {31c} The datasets analysed during the current study are available from the corresponding author on reasonable request.

Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d} Steering Committee The Steering Committee, led by the principal investigator, will be responsible for overseeing the conduction of the trial, providing training for new sites, ensuring compliance with the study procedures, addressing challenges that occur at all sites, reviewing serious adverse events and formulating the statistical analysis plan.
For clinical trials at CIGB, the function of coordinating centre is playing by the Direction of Clinical Research that is the responsible for design, endpoint adjudication, data management, statistical analysis and nal report for the clinical trial.
Monitors The trial monitors will carry out quality monitoring visits at all stages of its execution, ensuring strict compliance with the provisions of the protocol.
The ow of primary protocol information to and from health institution will be guaranteed by the CIGB.
The research product (HeberFERON), CRF and other models will be delivered / collected by the CIGB, directly by the study monitors. The monitors, in the quality monitoring visits, will collect the CRFs of those patients who concluded their participation in the trial. The Supply Group at CIGB is responsible for the adequate supply of medicines and medical supplies, as well as the collection of the product under investigation (dispensed and not dispensed).
The investigator should have a report of the number of patients included, the detected adverse events, the study departures and the causes of these, as well as any other relevant information during the course of the trial, for when they are requested during the quality monitoring visits.

Adverse event reporting and harms {22}
All the information related to the occurrence of adverse events presented in the patients included in the clinical trial will be recorded and described, as explicitly as possible, by the investigators in the Adverse Event Form of the CRF. The type, duration, intensity, severity, causality and the behavior followed will be described, specifying the frequency and dose of the treatment necessary to alleviate them.
The occurrence of the event will be noti ed to the sponsor monitor within a period not exceeding 24 hours. This must within the rst 24 hours of occurrence. The information may be communicated by phone, fax, email or in person. The person responsible for the investigation, the monitors and the team of investigators, will carry out the corresponding investigations in order to determine the component causing the undesired effect.
Noti cation of adverse events It will consist of two stages: the immediate noti cation of all serious adverse events and the reporting of serious and unexpected adverse events in relation to causation, which will be independent of each other.
The Responsible Investigator will notify the CER and the Sponsor will inform CECMED in the following terms.
In the event of a Serious and Unexpected adverse event that causes death or endangers the life of the patient, it will be reported to the CER, CECMED as soon as possible and never after 7 calendar days from the rst moment in which the occurrence of the reaction is known.
Immediate noti cation will be made to the national regulatory agency in Cuba, Center for State Control of the Quality of Medicines (CECMED), within the rst 72 hours after the Promoter becomes aware of the serious (serious) and unexpected adverse event and will be mandatory. This model will be lled in duplicated..

Frequency and plans for auditing trial conduct {23}
Project Management Group will meet to review trial conduct weekly during the rst month and every 15 day in the second or thirst month. Quality monitoring and control will be carried out by the monitors, quality control managers, consultants and specialists responsible for the trial. These visits will also serve to discuss any aspect of the protocol that the researcher suggests.
Execution check visits will be made daily from the beginning of the study. The rst Quality Control visit will be made immediately after the rst patient is included.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25} Protocol amendments during the study will be noti ed to the sponsor, to the promotor and to the clinical sites, to trail participants and ethic committee. A copy of the revised protocol will be sent to the promotor and to the Investigator Site File. Any deviations from the Protocol will be fully documented using a breach report form. The protocol will be updated in the clinical trial registry.
As responsibility of the clinician's investigators they must to have an archive with the documents coming from the trail execution, as any communication with the promotor, monitor, quality assurance personal, ethic committee, a copy of the protocol and all the amendments to it during the study.

Dissemination plans {31a}
The nal results of the study will be presented in a nal report workshop with the participation of all the clinician's investigators and other technical personal involved in the trial executions and supervisors, as well as monitor and other specialist involved from the promotor. The personal eel involved direct achievements of the results (clinical, virological, clinical laboratory, and others) will have the right to communicate the respective results in conferences, national and international meeting, always with the consent of the promotor Discussion For many emerging infectious diseases patients are often treated with therapeutics minimal evidences. Due to the urgency of COVID-19 pandemic, not only IFN alpha, but various drugs are being used as therapeutic tools, even though their e cacy has not been completely demonstrated for the treatment of SARS-CoV-2. If these patients had been included in a properly designed study, conclusive evidence might have been generated. Performing such a trial meets a critical need.
Some limitations to our study design should be noted. The blinding was not feasible, it will maintained for laboratory SARS-CoV-2 RNA detection by PCR, that is one of the endpoint of the study.