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Other than as permitted in any relevant BMJ Author's Self Archiving Policies, I confirm this Work has not been accepted for publication elsewhere, is not being considered for publication elsewhere and does not duplicate material already published. I confirm all authors consent to publication of this Work and authorise the granting of this licence. 19) is caused by the newly discovered SARS-CoV-2 coronavirus. Data on the severity of confirmed cases have varied over time. Subjects with severe acute respiratory syndrome (SARS) and high levels of pro-inflammatory cytokines and chemokine are associated with T-cell depletion, pulmonary inflammation and extensive lung damage. The levels of these cytokines negatively correlate with absolute lymphocyte counts, thus inducing T-cell exhaustion and apoptosis and causing acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). [1] A similar phenomenon is observed in the case of cytokine release syndrome (CRS) associated with chimeric antigen receptor T-cell (CAR-T) therapy. One of the key mediators of autoimmunity, inflammation, viral cytokine storms and CRS-induced damage is interleukin-6 (IL-6). Patients with SARS-CoV-2 infection have high plasma IL-6 levels, especially those with a more severe presentation and high C-reactive protein (CRP) levels. [2] It has been suggested that IL-6 blockade may constitute a novel therapeutic strategy for cytokine storm and systemic inflammatory response syndrome in sepsis, macrophage activation syndrome and haemophagocytic lymphohistiocytosis. [3] Remarkable beneficial effects of IL-6 blockade therapy using an IL-6 receptor inhibitor have been described in patients with severe SARS-CoV-2 pneumonia in a retrospective case series from China. [4] Sarilumab is a human monoclonal antibody against the IL-6 receptor that is currently licensed for rheumatoid arthritis. It is safe and well tolerated. [5] The most common side effects are upper respiratory tract infections, headache, hypertension and abnormal liver function tests. The most serious side effects are infections, such as diverticulitis, and hypersensitivity reactions. [6] It is hypothesised that IL-6 might play a key role in the cytokine storm in SARS-CoV-2 patients with pneumonia, and that blockade of IL-6 would be a suitable therapeutic target for these patients. This study investigates the efficacy and safety of early treatment with sarilumab compared to standard of care in patients with severe SARS-CoV-2 pneumonia.
This is a phase II, open-label, randomised, multicentre, controlled clinical trial. The patients will be assigned to three treatment groups ( Figure 1 ):
1. Control group: 40 patients will receive the best available therapy (BAT) for a maximum of 14 days.
2. Treatment group 1 (T1): 40 patients will receive BAT for a maximum of 14 days + 200 mg of sarilumab subcutaneously (single dose) 3 . Treatment group 2 (T2): 40 patients will receive BAT for a maximum of 14 days + 400 mg of sarilumab subcutaneously (single dose)
Ten university hospitals located in Andalusia, Spain, will participate in the trial. The trial will include hospitalised patients with confirmed SARS-CoV-2 infection causing respiratory disease and presenting high serum levels of IL-6 or D-Dimer (DD). Patients who meet all the inclusion criteria and have no exclusion criteria will be prospectively included in the study. The inclusion and exclusion criteria for the trial are described in Box 1. 
Patients may withdraw from the study at any time, for any reason and without prejudice to future medical treatment. Patients who do not comply with the study procedure or have not been followed up will be considered a study "withdrawal". The reasons for withdrawal will be examined in full accordance with bioethical principles regarding the guarantee of patients' rights. The criteria for withdrawal from the study are described below.
1. Patient request 2. Violation or deviation from the protocol (e.g. breach of administration of treatment, need for prohibited treatment). 3 . Researchers decision, based on clinical reasons 4. Administrative decision of the investigators, promoter or regulatory authorities 5. Loss to follow-up 6. Suspected unexpected serious adverse reaction (SUSAR) 7. Serious adverse event (SAE) that at the discretion of the promoter or investigator is not acceptable. 8. Any adverse event considered intolerable by either the patient or the investigator 9. Pregnancy
The primary outcome variable is the development of adult respiratory distress syndrome requiring high-flow nasal oxygenation (HFNO) or mechanical ventilation, both non-invasive and invasive.
The secondary outcome variables are: all-cause (crude) mortality at day 28, time (in days) to clinical improvement, time (in days) until oxygenation improvement for at least 48 Clinical improvement will be assessed on a seven-category ordinal scale consisting of the following categories: 1, not hospitalised with resumption of normal activities; 2, not hospitalised, but unable to resume normal activities; 3, hospitalised, not requiring supplemental oxygen; 4, hospitalised, requiring supplemental oxygen; 5, hospitalised, requiring high-flow oxygen therapy; 6, hospitalised requiring ECMO, invasive mechanical ventilation or both; and 7, death.
The following demographics and clinical information will be collected from all patients: age, sex, weight, height, body mass index (BMI), comorbidities, previous treatment, history of the current disease, respiratory rate (bpm), basal oxygen saturation (%), arterial pO2 (mm Hg), pO2/FiO2 rate, oxygen saturation/FiO2 rate, blood pressure (mmHg), heart rate (bpm), consciousness level, temperature (°C), clinical improvement, organ failure assessment score (SOFA), microbiological test, analytical parameters (haematimetry, glucose, creatinine, AST, ALT, C-reactive protein, albumin, LDH, ferritin, troponin I, protein kinase, procalcitonin, lipid profile, IL-6, D-dimer, prothrombin time, INR). All concomitant medication and adverse events will be recorded and monitored in accordance with regulatory procedures. SARS-CoV-2019 in nasopharyngeal swab and a panel of cytokines (IL1-,IL1-β, IL6, IL8, IL10, IL12, IL18, IL38, INFɣ, TNF , CCL2, CCL3, CCL4, MIF y PAI-1) will be determined before randomisation and on days 5, 10, 14, 21 and 28.
A total of 120 patients will be recruited (40 in each group). Patients who meet the selection criteria will be randomised to be included in the control group or the two experimental groups. Randomisation will be carried out by means of electronic case report forms (eCRFs). The ratio will be 1:1:1 for each group (balanced randomisation). The study design is open, but the investigator will not know the treatment assignment until the patient signs the informed consent form and randomisation is performed, thus minimising selection bias. Patients will be identified by a code that includes the centre code followed by the patient number (XX-YY).
The investigational medication (IM) is sarilumab (ATC code: L04AC14), a human monoclonal antibody (IgG1 subtype) that specifically binds to both soluble and membranebound IL-6 (IL-6Rα) receptors and inhibits the transmission of IL-6 mediated signals involving signal transducer glycoprotein 130 (gp130) and activator of transcription 3 (STAT-3).
The commercial subcutaneous medication available in Spain (SANOFI-AVENTIS) will be used. Administration of the IM will be carried out according to the technical sheet and the local practice of each centre. The BAT will include any combination of drugs included in the current protocol of the Spanish Ministry of Health (https://www.mscbs.gob.es/profesionales/saludPublica/ccayes/alertasActual/nCov-China/documentos.htm ) and complementary notes issued by the Spanish Agency of Medicines and Medical Products (www.aemps.gob.es)
The duration of follow-up for each patient will be 28 days and will start from the moment the patient is randomised. A total of 6 visits will be scheduled during the trial: baseline, day 5, day 10, day 14, day 21 and day 28. The scheduled follow-up is shown in Table 1 . The visit following the end of treatment will be considered as the end-of-treatment visit. Visit 5 (day 28 after randomisation) will be considered the final study visit. The final study visit can be moved forward to the day of hospital discharge. Additionally, data on clinical improvement (on a 7point ordinal scale), axillary temperature, oxygen saturation (or PO 2 ) and oxygen therapy will be collected daily.
Nasopharyngeal swabs will be performed on days 0, 5, 10, 14, 21 and 28. Plasma will also be obtained on days 0, 5, 10, 14, 21 and 28. The samples will be locally preserved (frozen at -80 °C) until dispatched to the Biobank of the Reina Sofía University Hospital of Córdoba, Spain.
The principal investigator will be responsible for the detection and documentation of adverse events (AE) throughout the study. All AEs must be notified during all phases of the study and followed up until resolution or until an adequate explanation is found, although the patient has completed study treatment. Periodic reports will also be submitted on AEs that occurred during the study, including causality assessment, severity and intensity.
Since this is a phase II study, a sufficient number of patients are included to perform an initial analysis of efficacy and safety. We have calculated an overall sample size of 120 patients, 40 patients for each arm, to detect a 30% reduction in the primary outcome with an alpha error of 0.05, a beta risk of 0.2 and assuming that the modified intention-to-treat population will be 90% of the randomised patients.
Clinical data will be collected in an electronic case report form (eCRF). All analyses will be performed using PASW Statistics software V. 15 .0 (IBM Corporation) and R software (V.3.5.0). Frequencies will be calculated for the qualitative variables and compared using the X 2 test or Fisher's test. For quantitative variables, the mean and standard deviation will be calculated. Normality will be analysed using the Kolmogorov-Smirnov test and comparisons will be made using the Student's t-test or the Mann-Whitney test depending on whether or not they follow a normal distribution, respectively. For the comparison of three or more groups, the analysis of variance (ANOVA) or Kruskal-Wallis tests will be used. The analyses will be based on the intention-to treat population (randomised patients receiving treatment). The time until the primary outcome variable is reached will be plotted on a Kaplan-Meier curve and compared using a log-rank test. A Cox regression analysis will be performed for the primary efficacy variable and the results reported in terms of the hazard ratio (HR) with 95% confidence intervals. 
The number of people diagnosed with coronavirus disease 2019 (COVID-19) worldwide crossed the two million mark on April 25, 2020. The vast majority of patients with the COVID- 19 have had a good prognosis, but there were critical individuals and deaths. ARDS is the leading cause of death in patients infected with SARS-CoV-2. [7] ARDS is a life-threatening lung condition that prevents enough oxygen from getting to the lungs and into circulation. Despite the efforts to characterise the clinical picture of COVID-19, very little is known about the pathologic manifestations, in particular lung inflammation. The first report of pathological findings from a severe COVID-19 patient showed pulmonary bilateral diffuse alveolar damage with cellular fibromyxoid exudates. Interstitial mononuclear inflammatory infiltrates, dominated by lymphocytes, were observed in both lungs. The authors suggested an over-activation of T cells manifested by an increase of Th17 and high cytotoxicity of CD8 T cells leading to severe immune injury and inflammation. [8] The clinical presentation of patients with severe forms of COVID-19 resembles cytokine release syndrome observed in some oncology patients treated with CAR-T cell therapies.
Cytokine dysregulation is of particular interest in patients with COVID-19, who have higher levels of inflammatory cytokines. Some cytokines seem to be up-regulated, especially in patients with more severe disease. The overwhelming release of proinflammatory cytokines and chemokines may be involved in the pulmonary injury characterised by diffuse alveolar damage with epithelial and endothelial apoptosis, dysregulated coagulation and pulmonary fibrinolysis. Among the cytokines produced by activated macrophages, IL-6 is one of the key cytokines. The role of IL-6 has been consistently reported in several studies of COVID-19. [9, 10, 11] A large retrospective cohort study found that IL-6 levels were correlated with mortality in 158 patients with COVID-19. [12] Interestingly, Chen et al. showed that levels of IL-6 are 10 times higher in critical patients compared with other patients. IL-6 levels were closely correlated with mortality. [13] Therefore, antiviral therapy alone may be inadequate for patients with uncontrolled inflammatory response. For this reason, numerous protocols have recommended tocilizumab, a humanised monoclonal antibody against the IL-6 receptor, in critical patients with ARDS and elevated IL-6. [14] F o r p e e r r e v i e w o n l y Another point of interest is the rapid increase in the number of cases of COVID-19 across the world, which has shown how quickly health systems can be challenged to provide adequate care. Mortality was 7-fold higher for patients in Hubei compared with other non-affected Chinese provinces, emphasising the importance of ICU capacity in the care of patients with COVID-19. [15] Access to ICU beds and ventilators can be rapidly saturated if the overwhelming inflammation is not stopped at early stages. Xie et al. highlighted the importance of the limited capacity of ICUs as only 25% of patients who died had received invasive mechanical ventilation. [16] Therefore, it seems plausible to speculate that the anti-IL6R plays a protective role if given at the time of overwhelming elevated immune response, preventing the cytokine storm. We propose that the early use of sarilumab, in addition to antiviral therapy, can attenuate the detrimental host immune response in patients with elevated markers of inflammation and reduce the development of severe respiratory failure and other organ damage. In conclusion, the SARICOR study aims to reduce the severity and mortality associated with COVID-19. 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59 is caused by the newly discovered SARS-CoV-2 coronavirus. Data on the severity of confirmed cases have varied over time. Subjects with severe acute respiratory syndrome (SARS) and high levels of pro-inflammatory cytokines and chemokine are associated with T-cell depletion, pulmonary inflammation and extensive lung damage. The levels of these cytokines negatively correlate with absolute lymphocyte counts, thus inducing T-cell exhaustion and apoptosis and causing acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). [1] A similar phenomenon is observed in the case of cytokine release syndrome (CRS) associated with chimeric antigen receptor T-cell (CAR-T) therapy. One of the key mediators of autoimmunity, inflammation, viral cytokine release syndromes and CRS-induced damage is interleukin-6 (IL-6). Patients with SARS-CoV-2 infection have high plasma IL-6 levels, especially those with a more severe presentation and high C-reactive protein (CRP) levels. [2] F o r p e e r r e v i e w o n l y 3 It has been suggested that IL-6 blockade may constitute a novel therapeutic strategy for cytokine release syndrome and systemic inflammatory response syndrome in sepsis, macrophage activation syndrome and haemophagocytic lymphohistiocytosis. [3] Remarkable beneficial effects of IL-6 blockade therapy using an IL-6 receptor inhibitor have been described in patients with severe SARS-CoV-2 pneumonia in a retrospective case series from China. [4] Sarilumab is a human monoclonal antibody against the IL-6 receptor that is currently licensed for rheumatoid arthritis. It is safe and well tolerated. [5] The most common side effects are upper respiratory tract infections, headache, hypertension and abnormal liver function tests. The most serious side effects are infections, such as diverticulitis, and hypersensitivity reactions. [6] It is hypothesised that IL-6 might play a key role in the cytokine release syndrome in SARS-CoV-2 patients with pneumonia, and that blockade of IL-6 would be a suitable therapeutic target for these patients. The research question of this trial is: does early treatment with sarilumab reduce the evolution to respiratory distress syndrome that requires ventilatory support in hospitalized patients with COVID-19?
This is a phase II, open-label, randomised, multicentre, controlled clinical trial. The patients will be assigned to three treatment groups ( Figure 1 ):
1. Control group: 40 patients will receive the best available therapy (BAT) for a maximum of 14 days.
2. Treatment group 1 (T1): 40 patients will receive BAT for a maximum of 14 days + 200 mg of sarilumab subcutaneously (single dose).
3. Treatment group 2 (T2): 40 patients will receive BAT for a maximum of 14 days + 400 mg of sarilumab subcutaneously (single dose).
At the time the protocol has been written, and in the absence of scientific evidence, BAT is considered any combination of drugs authorized in Spain for this indication. This variable will be taken into account in the efficacy analysis.
Ten university hospitals located in Andalusia, Spain, will participate in the trial. The trial will include hospitalised patients with confirmed SARS-CoV-2 infection causing respiratory disease and presenting high serum levels of IL-6 or D-Dimer (DD). Patients who meet all the inclusion criteria and have no exclusion criteria will be prospectively included in the study. Following hospital admission, patients may be randomized as soon as they meet the inclusion criteria, even in the emergency department. The inclusion and exclusion criteria for the trial are described in Box 1. 
Patients may withdraw from the study at any time, for any reason and without prejudice to future medical treatment. Patients who do not comply with the study procedure or have not been followed up will be considered a study "withdrawal". The reasons for withdrawal will be examined in full accordance with bioethical principles regarding the guarantee of patients' rights. The criteria for withdrawal from the study are described below.
1. Patient request 2. Violation or deviation from the protocol (e.g. breach of administration of treatment, need for prohibited treatment). 3. Researchers decision, based on clinical reasons 4. Administrative decision of the investigators, promoter or regulatory authorities 5. Loss to follow-up 6. Suspected unexpected serious adverse reaction (SUSAR) 7. Serious adverse event (SAE) that at the discretion of the promoter or investigator is not acceptable. 8. Any adverse event considered intolerable by either the patient or the investigator 9. Pregnancy
The inclusion and exclusion criteria can be modified in consecutive versions of the protocol, based on the scientific evidence that is published during the development of the trial, after justification and approval by the reference ethics committee. 
The primary outcome variable is the development of adult respiratory distress syndrome requiring high-flow nasal oxygenation (HFNO) or mechanical ventilation, both non-invasive and invasive.
The secondary outcome variables are: all-cause (crude) mortality at day 28, time (in days) to clinical improvement, time (in days) until oxygenation improvement for at least 48 hours, proportion of patients who require invasive mechanical ventilation, negativisation of PCR to SARS-CoV-2, cytokine kinetics and side effects.
Time to clinical improvement is defined as number of days until 2 points rise in the seven category ordinal scale.
Clinical improvement will be assessed on a seven-category ordinal scale consisting of the following categories: 1, not hospitalised with resumption of normal activities; 2, not hospitalised, but unable to resume normal activities; 3, hospitalised, not requiring supplemental oxygen; 4, hospitalised, requiring supplemental oxygen; 5, hospitalised, requiring high-flow oxygen therapy; 6, hospitalised requiring ECMO, invasive mechanical ventilation or both; and 7, death.
Time (in days) until improvement in oxygenation for at least 48 hours: (i) Time to verify an increase in the SpO2 / FiO2 ratio with respect to the worst SpO2 / FiO2 prior to treatment with Sarilumab and stratified according to levels of IL-6 or DD; (ii) Time until the absence of oxygen need to maintain a saturation in ambient air of ≥ 93%; (iii) Number of days in need of supplemental oxygen.
The following demographics and clinical information will be collected from all patients: age, sex, weight, height, body mass index (BMI), comorbidities, previous treatment, history of the current disease, respiratory rate (bpm), basal oxygen saturation (%), arterial pO2 (mm Hg), pO2/FiO2 rate, oxygen saturation/FiO2 rate, blood pressure (mmHg), heart rate (bpm), consciousness level, temperature (°C), clinical improvement, organ failure assessment score (SOFA), microbiological test, analytical parameters (haematimetry, glucose, creatinine, AST, ALT, C-reactive protein, albumin, LDH, ferritin, troponin I, protein kinase, procalcitonin, lipid profile, IL-6, D-dimer, prothrombin time, INR). All concomitant medication and adverse events will be recorded and monitored in accordance with regulatory procedures. SARS-CoV-2019 in nasopharyngeal swab and a panel of cytokines (IL1-,IL1-β, IL6, IL8, IL10, IL12, IL18, IL38, INFɣ,  TNF , CCL2 , CCL3, CCL4, MIF y PAI-1) RAGE, Ang-2 and Protein C will be determined before randomisation and on days 5, 10, 14, 21 and 28.
A total of 120 patients will be recruited (40 in each group). Patients who meet the selection criteria will be randomised to be included in the control group or the two experimental groups. Randomisation will be carried out by means of electronic case report forms (eCRFs). The ratio will be 1:1:1 for each group (balanced randomisation). The study design is open, but the 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y   7 investigator will not know the treatment assignment until the patient signs the informed consent form and randomisation is performed, thus minimising selection bias. Patients will be identified by a code that includes the centre code followed by the patient number (XX-YY).
The investigational medication (IM) is sarilumab (ATC code: L04AC14), a human monoclonal antibody (IgG1 subtype) that specifically binds to both soluble and membranebound IL-6 (IL-6Rα) receptors and inhibits the transmission of IL-6 mediated signals involving signal transducer glycoprotein 130 (gp130) and activator of transcription 3 (STAT-3).
The commercial subcutaneous medication available in Spain (SANOFI-AVENTIS) will be used. Administration of the IM will be carried out according to the technical sheet and the local practice of each centre.
The BAT will include any combination of drugs included in the current protocol of the 
The duration of follow-up for each patient will be 28 days and will start from the moment the patient is randomised. A total of 6 visits will be scheduled during the trial: baseline, day 5, day 10, day 14, day 21 and day 28. The scheduled follow-up is shown in Table 1 . The visit following the end of treatment will be considered as the end-of-treatment visit. Visit 5 (day 28 after randomisation) will be considered the final study visit. The final study visit can be moved forward to the day of hospital discharge. Additionally, data on clinical improvement (on a 7point ordinal scale), axillary temperature, oxygen saturation (or PO2) and oxygen therapy will be collected daily. Nasopharyngeal swabs will be performed on days 0, 5, 10, 14, 21 and 28. Plasma will also be obtained on days 0, 5, 10, 14, 21 and 28. The samples will be locally preserved (frozen at -80 °C) until dispatched to the Biobank of the Reina Sofía University Hospital of Córdoba, Spain.
The principal investigator will be responsible for the detection and documentation of adverse events (AE) throughout the study. All AEs must be notified during all phases of the study and followed up until resolution or until an adequate explanation is found, although the patient has completed study treatment. Periodic reports will also be submitted on AEs that occurred during the study, including causality assessment, severity and intensity. 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59 
Since this is a phase II study, a sufficient number of patients are included to perform an initial analysis of efficacy and safety. We have calculated an overall sample size of 120 patients, 40 patients for each arm, to detect a 30% reduction in the primary outcome with an alpha error of 0.05, a beta risk of 0.2 and assuming that the modified intention-to-treat population will be 90% of the randomised patients.
Clinical data will be collected in an electronic case report form (eCRF). All analyses will be performed using PASW Statistics software V.15.0 (IBM Corporation) and R software (V.3.5.0). Frequencies will be calculated for the qualitative variables and compared using the X 2 test or Fisher's test. For quantitative variables, the mean and standard deviation will be calculated. 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y   9 Normality will be analysed using the Kolmogorov-Smirnov test and comparisons will be made using the Student's t-test or the Mann-Whitney test depending on whether or not they follow a normal distribution, respectively. For the comparison of three or more groups, the analysis of variance (ANOVA) or Kruskal-Wallis tests will be used. The analyses will be based on the intention-to treat population (randomised patients receiving treatment). The time until the primary outcome variable is reached will be plotted on a Kaplan-Meier curve and compared using a log-rank test. A Cox regression analysis will be performed for the primary efficacy variable and the results reported in terms of the hazard ratio (HR) with 95% confidence intervals.
No patient involved.
This clinical trial will be conducted in accordance with the protocol and the ethics principles of the Declaration of Helsinki (Fortaleza, 2013) and in accordance with the applicable regulatory requirements, in particular the ICH Tripartite Guideline "Standards of Good Clinical Practice", Royal Decree 1090/2015 regulating clinical trials with medications in Spain and Regulation (EU) No. 536/2014 of 16 April 2014 on clinical trials on medicinal products for human use. The protocol, the informed consent form, the patient information form and any documents applicable to the study have required approval by the appropriate regulatory agencies. The Committee for Biomedical Research Ethics of the Reina Sofia University Hospital approved the trial. Authorisation has also been obtained from the Spanish Agency of Medicines and Medical Products (AEMPS, 20-0262). The trial is registered in accessible public databases such as the Spanish Clinical Studies Registry (REec), EUDRACT (2020-001531-27) and ClinicalTrials. gov (NCT04357860).
The number of people diagnosed with coronavirus disease 2019 (COVID-19) worldwide crossed the two million mark on April 25, 2020. The vast majority of patients with the COVID-19 have had a good prognosis, but there were critical individuals and deaths. ARDS is the leading cause of death in patients infected with SARS-CoV-2. [7] ARDS is a life-threatening lung condition that prevents enough oxygen from getting to the lungs and into circulation. Despite the efforts to characterise the clinical picture of COVID-19, very little is known about the pathologic manifestations, in particular lung inflammation. The first report of pathological findings from a severe COVID-19 patient showed pulmonary bilateral diffuse alveolar damage with cellular fibromyxoid exudates. Interstitial mononuclear inflammatory infiltrates, dominated by lymphocytes, were observed in both lungs. The authors suggested an over-activation of T cells manifested by an increase of Th17 and high cytotoxicity of CD8 T cells leading to severe immune injury and inflammation. [8] The clinical presentation of patients with severe forms of COVID-19 resembles cytokine release syndrome observed in some oncology patients treated with CAR-T cell therapies.
Cytokine dysregulation is of particular interest in patients with COVID-19, who have higher levels of inflammatory cytokines. Some cytokines seem to be up-regulated, especially in patients with more severe disease. The overwhelming release of proinflammatory cytokines and chemokines may be involved in the pulmonary injury characterised by diffuse alveolar damage with epithelial and endothelial apoptosis, dysregulated coagulation and pulmonary fibrinolysis. Among the cytokines produced by activated macrophages, IL-6 is one of the key cytokines. The 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y 10 role of IL-6 has been consistently reported in several studies of COVID-19. [9, 10, 11] A large retrospective cohort study found that IL-6 levels were correlated with mortality in 158 patients with COVID-19. [12] Interestingly, Chen et al. showed that levels of IL-6 are 10 times higher in critical patients compared with other patients. IL-6 levels were closely correlated with mortality. [13] Therefore, antiviral therapy alone may be inadequate for patients with uncontrolled inflammatory response. For this reason, numerous protocols have recommended tocilizumab, a humanised monoclonal antibody against the IL-6 receptor, in critical patients with ARDS and elevated IL-6. [14] Another point of interest is the rapid increase in the number of cases of COVID-19 across the world, which has shown how quickly health systems can be challenged to provide adequate care. Mortality was 7-fold higher for patients in Hubei compared with other non-affected Chinese provinces, emphasising the importance of ICU capacity in the care of patients with COVID-19. [15] Access to ICU beds and ventilators can be rapidly saturated if the overwhelming inflammation is not stopped at early stages. Xie et al. highlighted the importance of the limited capacity of ICUs as only 25% of patients who died had received invasive mechanical ventilation. [16] Therefore, it seems plausible to speculate that the anti-IL6R plays a protective role if given at the time of overwhelming elevated immune response, preventing the cytokine release syndrome. We propose that the early use of sarilumab, in addition to antiviral therapy, can attenuate the detrimental host immune response in patients with elevated markers of inflammation and reduce the development of severe respiratory failure and other organ damage. In conclusion, the SARICOR study aims to reduce the severity and mortality associated with COVID-19.
Dr. Julián Torre-Cisneros, Dr. Rafael León López and Antonio Miguel Luque Pineda collaborate in the design of the protocol and the informed consent form. 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y   11 the approval of a single medicinal research ethics committee (reference MREC) and of the Spanish Agency of Medicines and Medical Products (AEMPS). This clinical trial has been approved by the reference MREC of the province of Córdoba and the AEMPS (Code: 20-0262; EudraCT Number: 020-001531-27).
This is an open access article distributed in accordance with the Creative Commons Attribution-NonCommercial license (CC BY-NC 4.0), which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, providing the original work is properly cited, appropriate credit is given, any changes made indicated and the use is non-commercial. See: http:// creativecommons.org/licenses/bync/4.0/. 12 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59 The funder Ministry of Health and Families, Regional Government of Andalusia had no role in the design of this study and will not have any role during its execution, analyses, interpretation of the data or decision to submit results. 
Independent physicians will monitor the available data concerning safety and effectiveness of the treatment and they will meet on a regular basis to discuss about the risk/benefit balance and the conduction of the trial.
 Maintenance of trial IT system 
In each participating centre a principal investigator is identified, to be responsible for identification, recruitment, data collection and completion of CRFs, along with follow up of study patients and adherence to study protocol and SmPC.
Background and rationale 6a
It has been suggested that IL-6 blockade may constitute a novel therapeutic strategy for cytokine release syndrome and systemic inflammatory response syndrome in sepsis, macrophage activation syndrome and haemophagocytic lymphohistiocytosis.
Although currently approved for the treatment of rheumatoid arthritis, sarilumab, an interleukin-6 (IL-6) receptor antibody, is being investigated for its ability to reduce the overactive inflammatory immune response associated with COVID-19. This is based on evidence of markedly elevated levels of IL-6 in patients who develop severely acute respiratory distress syndrome.
The research question of this trial is: Does early treatment with sarilumab reduce the evolution to respiratory distress syndrome that requires ventilatory support in hospitalized patients with COVID-19?
6b
At the time the protocol has been written, and in the absence of scientific evidence, best available therapy (BAT) is considered any combination of drugs authorized in Spain for this indication. This variable will be taken into account in the efficacy analysis.
The BAT will include any combination of drugs included in the current protocol of the Research hypothesis It is hypothesised that IL-6 might play a key role in the cytokine release syndrome in SARS-CoV-2 patients with pneumonia, and that blockade of IL-6 would be a suitable therapeutic target for these patients.
Decrease cases of ARDS in adults requiring HFNO or either non-invasive or invasive mechanical ventilation.
 To reduce crude mortality at 28 days  To reduce the time (in days) to clinical improvement  To reduce the time (in days) until improvement in oxygenation for at least 48 hours  To reduce the proportion of patients who require invasive mechanical ventilation  To study the effect of the drug on the negativization of the PCR to COVID-19  To study the effect of the drug on the profile of cytokines  To study the safety of the experimental drug Trial design 8
Phase II, open-label, randomised, multicentre, controlled, three parallel groups clinical trial. The primary endpoint is crude mortality at 28 days. Randomization will be performed as block randomization with a 1:1:1 allocation.
Study setting 9 Ten university hospitals located in Andalusia (South of Spain) will participate in the trial, with sufficient incidence at the community level.
The site selected are sufficiently distant from each other so that almost all Andalusia Community population is covered (8.460.000 inhabitants). Following hospital admission and before performing any study activity, the participating subjects must sign the informed consent form. To participate in the study, patients must meet all of the inclusion criteria and none of the exclusion criteria.
Once the selection criteria are confirmed the patient will be randomized and allocated to one of the following treatment groups:
1. Control group: 40 patients will receive the best available therapy (BAT) for a maximum of 14 days.
At the time the protocol has been written, and in the absence of scientific evidence, BAT is considered any combination of drugs authorized in Spain for this indication. This variable will be taken into account in the efficacy analysis.
2. Treatment group 1 (T1): 40 patients will receive BAT for a maximum of 14 days + 200 mg of sarilumab subcutaneously (single dose).
3. Treatment group 2 (T2): 40 patients will receive BAT for a maximum of 14 days + 400 mg of sarilumab subcutaneously (single dose).
The total expected duration of each patient in the study is up to 28 days (or until the last day they are hospitalized, if less than 28 days).
Every patient will be visited on days 5, 10, 14, 21 and 28 after randomization. These visits may be made at home if the patient has been discharged. An evaluation of the clinical improvement will be made daily according to the ordinal scale of 7 points of gravity, the measurement of axillary temperature, oxygen saturation (or blood gas with PpO2) and oxygen therapy or respiratory support. These values will be collected in the CRD on planned visits. Patients may withdraw from the study at any time, for any reason and without prejudice to future medical treatment. Patients who do not comply with the study procedure or have not been followed up will be considered a study "withdrawal". The reasons for withdrawal will be examined in full accordance with bioethical principles regarding the guarantee of patients' rights. The criteria for withdrawal from the study are described below. The toxicity will come given by the adverse effects: -Very common (may affect more than 1 in 10 people): low white blood cell count based on blood tests. -Frequent (may affect up to 1 in 10 people):
 Sinus or throat infections, congestion, runny nose, and sore throat (upper respiratory tract infection).  Infection in the urinary tract.  Fevers (oral herpes).  Low platelet count based on blood tests.  High cholesterol, high triglycerides according to blood tests.  Abnormal liver function tests.  Injection site reactions (including redness and itching).
11c
The participating subjects will hospitalized and the site investigators will be responsible of the administration of the study treatment.
11d
During the study, concomitant treatments used in clinical practice are allowed, as well as BAT. The BAT will include any combination of drugs included in the current protocol of the Spanish Ministry of Health (https://www.mscbs.gob.es/profesionales/saludPublica/ccayes/alertasActu al/nCov-China/documentos.htm). The following demographics and clinical information will be collected from all patients: age, sex, weight, height, body mass index (BMI), comorbidities, previous treatment, history of the current disease, respiratory rate (bpm), basal oxygen saturation (%), arterial pO2 (mm Hg), pO2/FiO2 rate, oxygen saturation/FiO2 rate, blood pressure (mmHg), heart rate (bpm), consciousness level, temperature (°C), clinical improvement, organ failure assessment score (SOFA), microbiological test, analytical parameters (haematimetry, glucose, creatinine, AST, ALT, C-reactive protein, albumin, LDH, ferritin, troponin I, protein kinase, procalcitonin, lipid profile, IL-6, D-dimer, prothrombin time, INR).
All concomitant medication and adverse events will be recorded and monitored in accordance with regulatory procedures.
SARS-CoV-2019 in nasopharyngeal swab and a panel of cytokines (IL1-,IL1-β, IL6, IL8, IL10, IL12, IL18, IL38, INFɣ, TNF , CCL2, CCL3, CCL4, MIF y PAI-1) RAGE, Ang-2 and Protein C will be determined before randomisation and on days 5, 10, 14, 21 and 28. The total expected duration of each patient in the study is up to 28 days (or until the last day they are hospitalized, if less than 28 days):
Each patient will visit on days 5, 10, 14, 21 and 28 after randomization. These visits may be made at home if the patient has been discharged.
An assessment of clinical improvement will be made daily according to the ordinal scale of 7 points of gravity, axillary temperature measurement, oxygen saturation (or blood gas with PpO2) and oxygen therapy or respiratory support. These values will be collected in the CRF on planned visits.
See the table below.
Sample size 14 We have calculated an overall sample size of 120 patients, 40 patients for each arm, to detect a 30% reduction in the primary outcome with an alpha error of 0.05, a beta risk of 0.2 and assuming that the modified intentionto-treat population will be 90% of the randomised patients.
The enrolment will depended on the evolution of the pandemic in Spain. All COVID-19 teams in the participating sites are informed and involved. 
Allocation:
Sequence generation 16a
Patients will be randomly assigned to one of the three treatment groups in a 1: 1: 1 ratio, using a random allocation list generated by a specific computer system embedded in the eCRF.
For randomization, patients will be stratified using basal oxygen saturation by breathing room air or pO2 on arterial blood gas.  According to pulse oximetry in ambient air <90% or pO2 <60 mmHg.  In case of not having the previous data to ambient air, the relation pO2 / FiO2 <250 will be used.
The participating subjects will be randomized by a computerized system embedded in the electronic data capture and they will be allocated to one of the three treatment groups.
Participants will be randomised using REDCAP, which is an online eCRF which allows central randomisation.
Allocation concealment will be ensured, as the service will not release the randomisation code until the patient has been recruited into the trial, which takes place after all baseline measurements have been completed.
All patients who give consent for participation and who fulfil the inclusion criteria will be randomized. Randomisation will be performed by the principal investigator or delegated staff.
In return, the allocation will be shown in the eCRF. The investigator will provide the randomization information to the pharmacist. The main variable is a variable related to the efficacy of the study drug to avoid progression to SARD and avoid the need for ICU admission.
Secondary variables are designed to measure efficiency and safety objectives.
All the participating sites will be trained centrally in the study methods and requirements. The data to be collected and the procedures to be conducted at each visit will be reviewed in detail. Each of the data collection forms and the nature of the required information will be discussed in detail on an item by item basis.
Study coordinators and investigators will learn how to enter the information in the eCRF and how to communicate any Adverse Event or Reaction. Entering data forms, responding to data discrepancy queries and general information about obtaining research quality data will also be covered during the training session.
Data entered in the eCRF will be reviewed and monitored by Clinical Research Associates from the IMIBIC Clinical Research Unit and the corresponding queries will be raised in case inconsistencies are found. The subjects will be recruited once they are hospitalized and they will remain in the site until discharge.
The total expected duration of each patient in the study is up to 28 days (or until the last day they are hospitalized, if less than 28 days).
A subject will be considered to have completed the trial when they make the last scheduled visit.
Patients can withdraw at any time throughout the study, for whatever reason and without prejudice to future medical treatment.
The reasons for the withdrawal will be analysed with full compliance with the principles of Bioethics, in terms of guaranteeing the rights of patients and autonomous and informed decision.
Although patients can withdraw without having to explain why, as soon as a patient has decided to do so, the researchers will try to establish contact with the subjects and establish that the patient's decision is an informed choice, as well as to check to what extent the patient may be willing to continue participating in the study on a limited basis, eg if they would be willing to continue to contact or be seen in order to obtain follow-up information. The collected data will be electronically entered by the investigator at every participating site via the eCRF platform. Original study forms will be entered and kept on file at the participating site.
Participant files are to be stored in numerical order and stored in a secure and accessible place and manner. Participant files will be maintained in storage for a period of 25 years after completion of the study.
Data integrity will be enforced through a variety of mechanisms. Referential data rules, valid values, range checks, and consistency checks against data already stored in the database will be supported.
Modifications to data written to the database will be documented through either the data change system or an inquiry system.
Data entered into the database will be retrievable for viewing through the data entry applications. The type of activity that an individual user may undertake is regulated by the privileges associated with his/her user identification code and password.
Additional errors will be detected by programs designed to detect missing data or specific errors in the data. These errors will be summarized along with detailed descriptions for each specific problem in Data Query Reports, which will be sent to the sites.
The Study Coordinator who receives the queries will respond by checking the original forms for inconsistency, checking other sources to determine the correction, modifying the original (paper) form entering a response to the query.
The Coordinating Center (IMIBIC Clinical Research Unit) and participating site personnel will be responsible for making appropriate corrections to the original paper forms whenever any data item is changed. Written documentation of changes will be available via electronic logs and audit trails. 
Types of analysis The analyses will be performed on the population by modified intention to treat. This includes all randomized patients to whom the drug or control is administered. Patients who die before administering the drug or those who are not administered for any other reason are excluded.
It will be performed based on the intention of treatment and will be measured by the proportion of patients requiring high-flow nasal oxygen / mechanical ventilation in the first 14 days. For this analysis, patients will be measured on day 14. The time in days until the end point is reached will be plotted on a Kaplan-Meier curve and compared using a Long Rank test. A univariate Cox regression analysis will be performed for the primary efficacy variable and They will represent the results in terms of Hazard Ratio with 95% confidence intervals.
Secondary efficiency analysis CRUDE MORTALITY. Following the criteria of the primary efficacy analysis, mortality from any cause at 14 and 28 days will be analysed. For this 28-day analysis, the sample will be measured at 28 days, which will be the end point of the study. CLINICAL IMPROVEMENT. Following the criteria of the primary analysis, an analysis of the time in days to clinical improvement or mean change according to the 7-point ordinal scale will be performed. IMPROVEMENT OF OXYGENATION. Following the criteria of the primary analysis, an analysis of the time in days until oxygenation will be performed. NEED FOR INVASIVE MECHANICAL VENTILATION. The proportion of patients requiring invasive mechanical ventilation in each arm will be compared. NEGATIVIZATION OF THE PCR TO COVID-19. The proportion of patients who have negative PCR in each arm of the trial will be compared. CYTOKIN LEVELS. The mean levels of each cytokine in each arm of the study will be compared. SECURITY. A description of the adverse events will be made for each arm of the study and the proportion of the same in each arm of the trial will be compared.
20b
Interim analysis The sponsor will perform an Interim analysis of the data collected when it has been reached half the sample size (60 recruited subjects) in order to assess safety and efficacy of research treatment. 
The safety dataset covers all patients included in the study who have received at least one dose of any study medication.
The modified intention-to-treat population is defined as all randomized patients to whom the drug or control is administered. Patients who die before administering the drug or those who are not administered for any other reason are excluded.
Data monitoring 21a A Data Safety Monitoring Committee has been established and it is independent of the sponsor. During the period of recruitment to the trial, monthly analyses will be provided to the Data Safety Monitoring Committee, together with any other analyses that the committee may request. The Data Safety Monitoring Committee will advise the sponsor about the study conduction, protocol modifications and/or trial halt if needed.
21b
Interim analysis The sponsor will perform an Interim analysis of the data collected when it has been reached half the sample size (60 recruited subjects) in order to assess safety and efficacy of research treatment.
The results of this analysis will be communicated to the participating researchers. In the event of detection of a significant lack of efficacy or an unacceptable risk-benefit balance, the sponsor will communicate this circumstance to the health authorities, Ethics Committee and local authorities and proceed to the premature termination of the study, according to what is indicated in the Royal Decree 1090/2015. The principal investigator will be responsible for the detection and documentation, throughout the study, of adverse events.
It is the responsibility of the principal investigator to report all events in the eCRF, both observed by him/her and spontaneously reported by the participants, regardless of the relationship with the investigational medication.
All the events should be reported during all phases of the study and followed up until resolution or until an adequate explanation is found, even if the patient has completed study treatment. In addition, reports will be made periodically on the events that occurred during the study, including evaluation of causality, severity and intensity.
Patients will be informed of possible adverse reactions of the investigational medication through the Patient Information Sheet, as well as their commitment to report any adverse event they experience. They will be given a way to contact the study researchers for this purpose. At all study visits, patients will be questioned about the presence of new events or about the evolution of pre-existing ones.
All events that are severe and manifest during the course of the study, regardless of the treatment group in which they occur, the sponsor must be notified in the course one working day (24 hours) from the time the investigator is aware of the event.
The safety information will be recorded in the eCRF and it will be provided to the Data Safety Monitoring Committee for it analysis. The clinical trial will be monitored by the IMIBIC Clinical Research Unit staff. According to the agreed Trial Monitoring Plan, the participating sites will be regularly monitored on-site and online by the CRA.
The primary objectives of the CRA during the on-site visits are to educate, support and solve problems. The monitors will discuss the protocol in detail and identify and clarify any areas of weakness. At the initiation of the trial, the monitor will conduct a tutorial on the eCRF. The investigators will practice entering data so that the monitors can confirm that they are proficient in all aspects of data entry, query response, and communication with the CRA. They will audit the overall quality and completeness of the data, examine source documents, interview investigators and coordinators, and confirm that the clinical site has complied with the requirements of the protocol. The monitors will verify that all adverse events were documented in the correct format, and are consistent with protocol definition.
The monitors will review the source documents as needed, to determine whether the data reported in the electronic data capture system are complete and accurate. Source documents are defined as medical charts, associated reports and records including initial hospital admission report.
The monitors will confirm that the regulatory binder is complete and that all associated documents are up to date. The regulatory binder should include the protocol and informed consent (all revisions), Ethics Committee/Health Authorities approvals for all of the above documents, Ethics Committee/Health Authorities correspondence, case report form hardcopy templates, investigator's agreements, etc.
Scheduling monitoring visits will be a function of patient enrolment, site status and other commitments. The CRA will notify the site in writing at least two weeks prior to a scheduled visit. The investigators must be available to meet with the monitors. Although notification of the visits will include the list of patients scheduled to be reviewed, the monitors reserve the right to review additional patients if possible.
If a problem is identified during the visit, the monitor will assist the site in resolving the issues. Some issues may require input from the Data Safety Monitoring Committee, Sponsor or the coordinating investigator.
The focus of the visit/electronic monitoring will be on source document review and confirmation of adverse events. The monitor will verify the following all the variables for all patients, eg. signed informed consent, 
Research ethics approval 24 The protocol and the informed consent form, as well as other required documents will be reviewed and approved by the sponsor and the applicable Ethics Committee/Health Authority with respect to scientific content and compliance with applicable research and human subjects regulations.
The protocol, informed consent form, participant education and recruitment materials, and other requested documents-and any subsequent modificationsalso will be reviewed and approved by the Ethics Committee/Health Authority.
Subsequent to initial review and approval, the Ethics Committee/ Health Authority will review the protocol annually. The Investigator will make safety and progress reports to the Ethics Committee/ Health Authority at least annually and within twelve months of study termination or completion at his/her site. These reports will include the total number of participants enrolled y their status within the trial, as well as a review of safety and/or efficacy.
Any modifications to the protocol which may impact on the conduct of the study, potential benefit of the patient or may affect patient safety, including changes of study objectives, study design, patient population, sample sizes, study procedures, or significant administrative aspects will require a formal amendment to the protocol.
Such amendment will be agreed upon by the sponsor and must be submitted for approval to the Ethics Committee/Health Authority prior to implementation in accordance with local regulations.
Administrative changes of the protocol that are minor corrections and/or clarifications that have no effect on the way the study is to be conducted. These administrative changes will be agreed by the sponsor and will be documented in a memorandum. The Ethics Committee/Health Authority may be notified of administrative changes in the next protocol substantial amendment. The site principal investigator or delegated subinvestigator will introduce the trial to patients. The site principal investigator or delegated subinvestigator will discuss the trial with patients in light of the information provided in the information sheets. Patients will then be able to have an informed discussion with the participating investigator. The site principal investigator or delegated subinvestigator will obtain written consent from patients willing to participate in the trial and file it in the site binder.
26b
As biological samples would be collected, an additional informed consent form will be provided by the site principal investigator or delegated subinvestigator to the trial to patients. The consent procedure will be similar to the one explained in point 26a. All study-related information will be stored securely at the study site. All participant information will be stored in locked file cabinets in areas with limited access. All laboratory specimens, reports, data collection, process, and administrative forms will be identified by a coded ID [XX-YY coding] number only to maintain participant confidentiality. All records that contain names or other personal identifiers, such as locator forms and informed consent forms, will be stored separately from study records identified by code number. All local databases will be secured with password-protected access systems. Forms, lists, logbooks, appointment books, and any other listings that link participant ID numbers to other identifying information will be stored in a separate, locked file in an area with limited access.
All test results will be kept strictly confidential, all counselling and blood draws will be conducted in private rooms, and study staff will be required to preserve the confidentiality of all participants.
Participants' study information will not be released outside of the study without the written permission of the participant, except as necessary for monitoring, audit and or inspections by regulatory authorities or for safety reasons.
The sponsor guarantees that the data will be processed with security 
The authors declare no conflicts of interest. Access to data 29 All Principal Investigators will be given access to the cleaned data sets. Project data sets will be housed on IMIBIC servers they will be accessible by password. Project Principal Investigators will have direct access to their own site's data sets, and will have access to other sites data by request.
To ensure confidentiality, data dispersed to project team members will be blinded of any identifying participant information.
Once the trial has ended and the data has been collected, analysed and published, the anonymized database will be available to other researchers upon request.
Ancillary and posttrial care 30
Patients that are enrolled into the study are covered by indemnity for nonnegligent harm through a specific insurance contracted by the sponsor.
Should this study provide evidence of the effectiveness of Sarilumab, it will be critical to provide access to the effective product(s) to study participants in a timely manner.
Dissemination policy 31a
Once the study has been completed and the statistical report has been carried out, the investigating team shall prepare the final report of the study to be submitted to Ethics Committee/Health Authority. This final report will be the basis for the preparation of the manuscripts to be published in medical journals. 31c
Once the trial has ended and the data has been collected, analysed and published, the anonymized database, the full protocol, statistical code and other materials will be available to other researchers upon request to IMIBIC Clinical Research Unit (uicec@imibic.org).
See attached forms (General informed consent and Biological Samples informed consent). The samples will be stored locally (frozen at -80oC) until they are sent to the Biobank of the Reina Sofía University Hospital in Córdoba.
The cytokines will be quantified centrally using the CUSTOM KITS MILIPLEX® MAP (Merk-Millipore) following the protocol provided by the manufacturer. Samples will be purchased on a Luminex LABScan 200 platform, using xPONENT vs. 2.1 as acquisition and analysis software.
The cytokine panel to be quantified will be the following: IL1-A, IL1-A, IL6, IL8, IL10, IL12, IL18, IL38, INFɣ, TNF, CCL2, CCL3, CCL4, MIF and PAI-1.
*It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 Explanation & Elaboration for important clarification on the items. Amendments to the protocol should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT Group under the Creative Commons "Attribution-NonCommercial-NoDerivs 3.0 Unported" license. Nuestra intención es que usted reciba la información correcta y suficiente para que pueda decidir si acepta o no participar en este estudio. Para ello lea esta hoja informativa con atención y nosotros le aclararemos las dudas que le puedan surgir. Además, puede consultar con las personas que considere oportuno.
Le invitamos a participar en el estudio porque presenta un proceso infeccioso respiratorio por SARS-CoV-2 (COVID19). Debe saber que su participación en este estudio es voluntaria y que puede decidir NO participar. Si decide participar, puede cambiar su decisión y retirar el consentimiento en cualquier momento, sin que por ello se altere la relación con su médico ni se produzca perjuicio alguno en su atención sanitaria.
El objetivo principal del estudio es saber la eficacia y la seguridad de la administración precoz de Sarilumab en pacientes con infección respiratoria por SARS-CoV-2 (COVID19) para evitar el deterioro de la función pulmonar y la necesidad de requerir soporte respiratorio mediante diferentes métodos habitualmente utilizados en esta situación.
Este estudio pretende incluir un total de 120 participantes con alto riesgo de que su función pulmonar se deteriore y precisen de dispositivos para ayudar a su respiración.
La literatura actual recoge un grupo de pacientes que por sus características clínicas y/o analíticas presentan mayor probabilidad de empeorar desde el punto de vista respiratorio y pueden necesitar mayor soporte respiratorio, incluso requerir ingreso en las El procedimiento de asignación a uno de los tres grupos del estudio se realizará al azar. La probabilidad de que usted sea asignado a cualquiera de los tres grupos será de una entre tres o del 33%.
En ningún caso usted dejará de estar tratado con los medicamentos habitualmente utilizados. Si usted decide no participar en este estudio es posible que usted reciba un fármaco similar pero más tarde, cuando el deterioro respiratorio ya ha sido establecido.
Participando en este estudio usted tiene la posibilidad de recibirlo antes para estudiar si evita ese deterioro.
Si decide participar en este estudio le haremos un seguimiento diario desde el día que firme el consentimiento informado hasta el día 28 de su inclusión en el estudio o hasta el último día que esté hospitalizado, lo que ocurra antes.
Evaluaremos diariamente su evolución clínica. En los días 0, 5, 10, 14, 21 y 28 (o hasta el último día que esté hospitalizado) le realizaremos un frotis nasofaríngeo para 
Sarilumab es un medicamento ya aprobado y comercializado para el tratamiento de la artritis reumatoide avanzada.
Las reacciones adversas más frecuentemente notificadas con el tratamiento con Sarilumab son: disminución anormal de los neutrófilos y las plaquetas, aumento de las enzimas hepáticas, enrojecimiento en el lugar de la inyección, infecciones del tracto respiratorio superior e infecciones del tracto urinario. Como riesgo derivado de la extracción de sangre puede producirse un pequeño hematoma, puede haber dolor local, hemorragia y muy excepcionalmente, puede producirse infección en el punto donde se extrae la sangre.
Como participante en el estudio tiene la responsabilidad de cumplir todas las visitas y actividades del estudio. También deberá notificar cualquier evento que le suceda o cambios en la medicación en caso de urgencia, ya que no podrá modificarla por su cuenta ni tomarla junto a "plantas medicinales" sin consultar antes con el médico del estudio.
Si demostramos la hipótesis de este estudio, usted habrá contribuido a evitar el deterioro de la función pulmonar por COVID-19 en otros pacientes que, como usted, padecen una infección respiratoria con factores de riesgo para mala evolución y necesidad de oxigenación a alto flujo o ventilación mecánica tanto de forma invasiva como no invasiva.
Esto evitará medidas más agresivas de manejo de su función respiratoria, el ingreso en la Unidad de Cuidados Intensivos y la prolongación de la estancia hospitalaria. 
Las mujeres en edad fértil deben evitar un embarazo mediante el uso de métodos anticonceptivos eficaces durante y hasta tres meses después del tratamiento.
No hay datos disponibles del efecto de Sarilumab sobre la fertilidad humana. Los estudios en animales mostraron que no se producía deterioro de la fertilidad ni en los machos ni en las hembras.
No hay datos o estos son limitados relativos al uso de Sarilumab en mujeres embarazadas. Los estudios en animales no sugieren efectos perjudiciales directos ni indirectos en términos de toxicidad para la reproducción.
Se desconoce si Sarilumab se excreta en la leche materna o si se absorbe de forma sistemática después de la ingestión. No se ha estudiado la excreción de Sarilumab en la leche en animales.
Dado que las inmunoglobulinas G1 se excretan en la leche humana, se debe decidir si es necesario interrumpir la lactancia o interrumpir el tratamiento con Sarilumab teniendo en cuenta el beneficio de la lactancia para el niño y el beneficio del tratamiento para la madre.
En caso de producirse un embarazo durante su participación en el estudio debe informar a su médico de inmediato para recibir la asistencia médica adecuada. En caso de producirse un embarazo, se solicitará mediante un consentimiento específico la recogida de datos del mismo y de datos de salud del bebé hasta 3 meses después del parto.
Los datos recopilados sobre usted y su bebé serán tratados por el promotor del estudio de acuerdo a la normativa de protección de datos personales vigente (consulte el apartado "Protección de datos personales" para más información). El investigador principal del estudio le proporcionará toda la información que precise sobre los posibles tratamientos alternativos.
El Promotor del estudio dispone de una póliza de seguros que se ajusta a la legislación vigente (Real decreto 1090/2015) y que le proporcionará la compensación e indemnización en caso de menoscabo de su salud o de lesiones que pudieran producirse en relación con su participación en el estudio, siempre que no sean consecuencia de la propia enfermedad que se estudia o de la evolución propia de su enfermedad como consecuencia de la ineficacia del tratamiento. Si desea más información relativa a este apartado, consulte con el investigador principal del estudio en su centro.
Le recomendamos consultar las condiciones generales y particulares (cobertura) de sus pólizas de seguros privadas (vida, salud, accidente...) por si se ven afectadas por la participación en un ensayo clínico. El promotor no es responsable de estas potenciales modificaciones de cobertura debida a su participación y por tanto, le recomendamos que lo consulte con su aseguradora antes de dar su consentimiento.
En este estudio se cumplirá la normativa de protección de datos en vigor; la Ley Los datos recogidos para el estudio estarán identificados mediante un código, de manera que no se incluya información que pueda identificarle, y sólo su médico del estudio/colaboradores podrá relacionar dichos datos con usted y con su historia clínica. Por lo tanto, su identidad no será revelada a ninguna otra persona salvo a las autoridades sanitarias, cuando así lo requieran, o en casos de urgencia médica.
Los Comités de Ética de la Investigación, los representantes de la Autoridad Sanitaria en materia de inspección y el personal autorizado por el Promotor, podrán acceder para comprobar los datos personales, los procedimientos del estudio clínico y el cumplimiento de las normas de buena práctica clínica (siempre manteniendo la confidencialidad de la información).
Los datos se recogerán en un fichero de investigación responsabilidad de la institución y se tratarán en el marco de su participación en este estudio. El promotor adoptará las medidas pertinentes para garantizar la protección de su privacidad y no permitirá que sus datos se crucen con otras bases de datos que pudieran permitir su identificación. Si usted decide retirar el consentimiento para participar en este estudio, ningún dato nuevo será añadido a la base de datos, pero sí se utilizarán los que ya se hayan recogido.
El Investigador y el Promotor están obligados a conservar los datos recogidos para el estudio al menos hasta 25 años tras su finalización. Posteriormente, su información personal sólo se conservará por el centro para el cuidado de su salud y por el promotor para otros fines de investigación científica si usted hubiera otorgado su consentimiento y si así lo permite la ley y requisitos éticos aplicables.
Si realizáramos transferencia de sus datos codificados fuera de la UE a las entidades de nuestro grupo, a prestadores de servicios o a investigadores científicos que colaboren con nosotros, los datos del participante quedarán protegidos con salvaguardas tales como contratos u otros mecanismos establecidos por las autoridades de protección de datos. Si el participante quiere saber más al respecto, puede contactar al Delegado de Protección de Datos del promotor en dpd@imibic.org. 
Una descripción de este ensayo clínico estará disponible en https://reec.aemps.es, según exige la legislación española, así como en https://clinicaltrials.gov.
Cualquier nueva información referente al fármaco utilizado en el estudio y que pueda afectar a su disposición para participar en el estudio, que se descubra durante su participación, le será comunicada por su médico lo antes posible.
Debe saber que puede ser excluido del estudio si el promotor o los investigadores del estudio lo consideran oportuno, ya sea por motivos de seguridad, por cualquier acontecimiento adverso que se produzca por la medicación en estudio o porque consideren que no está cumpliendo con los procedimientos establecidos. En cualquiera de los casos, usted recibirá una explicación adecuada del motivo que ha ocasionado su retirada del estudio.
Al firmar la hoja de consentimiento adjunta, se compromete a cumplir con los procedimientos del estudio que se le han expuesto. En aquellos casos en que un participante dejara de acudir a las visitas sin retirar el consentimiento, el promotor podrá realizar un seguimiento de dicho participante.
Debe usted saber que es posible que su médico de Atención Primaria tenga conocimiento de su participación en este estudio.
Cuando acabe su participación recibirá el mejor tratamiento disponible y que su médico considere el más adecuado para su enfermedad.
En caso de que el estudio se suspenda o finalice mientras usted está en tratamiento con la medicación en investigación, su enfermedad permanezca controlada, los datos del estudio indiquen que la medicación en investigación muestra un beneficio en el manejo de su enfermedad, y se disponga de existencias adecuadas del fármaco, el promotor le 
Si durante su participación tiene alguna duda o necesita obtener más información, póngase en contacto con Dr./Dra.:______________________________ Del servicio de____________________________en el teléfono_________________.
A cada participante se le extraerán en las visitas 0, 5, 10, 14, 21 y 28 (o hasta el último día que esté hospitalizado):
 Un frotis nasofaríngeo para la determinación del ARN del virus.
 Un tubo con 9 ml de sangre para el estudio de la inmunidad frente a este virus.
Dependiendo de cómo monitorice la replicación de dicho virus su centro, es posible que se le precise extraer también un tubo con 6 ml de sangre más, para saber si el virus está replicando.
En el caso de almacenamiento de estas muestras una vez terminado el ensayo, para su uso posterior en investigación se cumplirá con los requisitos éticos y legales dispuestos en el Real Decreto 1716/2011. Para ello, se le pedirá su consentimiento para que dichas muestras puedan ser almacenadas, una vez que acabe el ensayo clínico, en el Biobanco del Sistema Sanitario Público de Andalucía/Nodo de Córdoba.
Las muestras biológicas donadas, así como sus datos clínicos e información asociados se utilizarán de conformidad con lo establecido en la Ley 14/2007, de 3 de julio, de Investigación biomédica. La donación es voluntaria y altruista, por lo que usted no tendrá derecho alguno sobre los resultados que pudieran derivarse de las investigaciones que se lleven a cabo con dichas muestras biológicas y su información asociada, de conformidad con la normativa vigente. Yo (nombre y apellidos del participante):__________________________________ He leído la hoja de información que se me ha entregado sobre el estudio.
He podido hacer preguntas sobre el estudio.
He recibido suficiente información sobre el estudio.
He hablado con (nombre del investigador):_______________________________________ Comprendo que mi participación es voluntaria.
Comprendo que puedo retirarme del estudio:
-Cuando quiera.
-Sin tener que dar explicaciones.
-Sin que esto repercuta en mis cuidados médicos.
Deseo que me comuniquen la información derivada de la investigación que pueda ser relevante para mi salud:
Recibiré una copia firmada y fechada de este documento de consentimiento informado.
Presto libremente mi conformidad para participar en el estudio. He podido hacer preguntas sobre el estudio.
He recibido suficiente información sobre el estudio.
He hablado con (nombre del investigador):_______________________________________ Comprendo que la participación es voluntaria.
Comprendo que puedo retirarlo del estudio:
-Cuando quiera.
-Sin tener que dar explicaciones.
-Sin que esto repercuta en sus cuidados médicos.
Deseo que me comuniquen la información derivada de la investigación que pueda ser relevante para su salud: Existe un apartado en el consentimiento en el que podrá decidir si quiere que sus muestras biológicas e información asociada se conserven de forma codificada (en cuyo caso se identifican con un código que protege su identidad) o anonimizada (eliminándose de forma irreversible toda vinculación con su identidad).
Sus muestras y los datos asociados a las mismas sólo se cederán a terceros de manera anónima o disociada. Sus muestras biológicas e información asociada a las mismas sólo se podrán ceder a terceros como uso exclusivo para la investigación biomédica que ayuden a la obtención de nuevos conocimientos científicos, confirmación de hipótesis, adecuación tecnológica, controles de calidad, docencia, u otros usos de interés sanitario, pudiendo usted en cualquier momento establecer las restricciones de utilización que considere oportunas.
Si la naturaleza del proyecto en el que vaya a utilizarse la muestra biológica requiriese información asociada a la misma, y para la que fuese necesario la consulta de su historia clínica, el Biobanco establecerá un sistema de control y trazabilidad del acceso mediante una autorización previa y registros de acceso, que será responsabilidad del Director del nodo donde se lleve a cabo la consulta siempre que la muestra no hubiera sido anonimizada.
Las muestras serán obtenidas durante el procedimiento médico-quirúrgico al que va a someterse o se ha sometido durante su proceso asistencial, o a través de un procedimiento expreso para obtenerla, según lo indicado en el apartado del consentimiento referente a la obtención de muestras.
Se podrán obtener diferentes tipos de muestras biológicas como sangre, tejidos, saliva, líquidos biológicos, uñas o pelo. En la hoja de consentimiento se indicarán los tipos de muestras a recoger de forma expresa en este acto de donación.
En el caso de que usted done las muestras obtenidas durante un procedimiento médico-quirúrgico asistencial, no existe ningún inconveniente adicional derivado de la donación de las mismas.
Si, por el contrario, las muestras biológicas fueran extraídas expresamente para la donación al Biobanco, podrían existir inconvenientes vinculados con la obtención de las mismas, de las que será convenientemente informado en la hoja de información del procedimiento correspondiente. 
Usted autoriza, con la firma del consentimiento informado, a que las muestras donadas puedan ser sean utilizadas en:
Investigación: las muestras e información asociada podrán ser utilizados en cualquier investigación biomédica, en los términos que indica la ley. En el caso de que la obtención de la muestra se lleve a cabo a petición de un proyecto concreto, éste y su investigador principal quedarán reflejados en la hoja de consentimiento. El excedente de la muestra e información asociada, quedarán disponibles para su uso en otros proyectos de investigación biomédica si usted así lo indica. Sólo se cederán muestras a proyectos de investigación dentro de una misma línea y científicamente avalados, que cumplan las exigencias legales y los principios éticos que rigen la investigación en salud y que sean autorizados por los órganos competentes, de conformidad con lo establecido en la normativa vigente.
-Docencia: actividades de formación en el ámbito sanitario o biomédico.
-Evaluación / Control de Calidad: muchas de las actividades relacionadas con la investigación o el diagnóstico requieren la puesta a punto de equipos, validación de nuevas tecnologías y procedimientos, encaminados a mejorar el impacto en salud de la tecnología empleada. Para ello es necesario la utilización de muestras biológicas.
Para el caso de que las muestras se utilicen exclusivamente con fines docentes o de control de calidad, y no sea necesaria la información asociada, la conservación, cesión, y uso, se realizará siempre de forma anonimizada.
Las muestras sólo podrán ser utilizadas en proyectos de investigación científicamente avalados, que cumplan las exigencias legales y los principios éticos que rigen la investigación en salud y que sean autorizados por los órganos competentes, de conformidad con lo establecido en la normativa vigente.
Cuando, por razones de salud, usted o su familia lo necesiten, podrán hacer uso de las muestras, siempre que no se hayan agotado o eliminado y no se encuentren anonimizadas.
Si lo solicita, el Biobanco le facilitará la información sobre los proyectos de investigación en los que se utilicen las muestras donadas, si éstas no hubieran sido anonimizadas. 
Puede que sea necesario ponerse en contacto nuevamente con usted, con el fin de recabar datos o muestras adicionales, o proporcionarle la información relevante para su salud, salvo que haya solicitado que las muestras sean anonimizadas.
La información proporcionada en este apartado será aplicable siempre que sus muestras no se encuentren anonimizadas.
Los datos personales recabados serán confidenciales y tratados de acuerdo con el Reglamento (UE) -Los datos personales que nos proporcione serán utilizados con la finalidad de poder gestionar las muestras biológicas, quedando almacenados durante el tiempo necesario para cumplir con las obligaciones legales estipuladas.
-La base jurídica de este tratamiento es el consentimiento que nos presta al cumplimentar y firmar el documento de consentimiento informado, sin el cual no podríamos cumplir con la finalidad descrita -Sus datos no serán cedidos a terceros, salvo que se disponga en una obligación legal.
-Puede usted ejercer sus derechos de acceso, rectificación, supresión, portabilidad de sus datos, y la limitación u oposición a su tratamiento, solicitándolo por escrito, con copia del 
Salvo que usted manifieste lo contrario en el apartado dedicado al consentimiento, se podrán realizar análisis genéticos. Excepto si sus muestras son anonimizadas, tiene derecho a conocer los datos genéticos que se obtengan a partir del análisis de las muestras donadas, así como de la información relativa a su salud derivada de dichos análisis.
Si no desea recibir dicha información y ésta fuera necesaria para evitar un grave perjuicio para su salud o la de sus familiares biológicos, se informará a un familiar o a un representante. La comunicación se limitará exclusivamente a los datos necesarios para evitar tal perjuicio.
Una vez informado/a de los aspectos relacionados anteriormente en este documento, si decide donar dichas muestras deberá firmar el consentimiento informado para la donación. 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59 Las muestras biológicas e información asociada serán recogidas para: PROYECTO (actividades de investigación biomédica que ayuden a la obtención de nuevos conocimientos científicos): Codificada (serán identificadas con un código que protege mi identidad, siendo posible volver a ligarlas conmigo) o Anonimizada (no se podrán asociar las muestras conmigo, por haberse eliminado de forma irreversible la vinculación entre las mismas y mi identidad).
Deseo establecer restricciones respecto al uso de la muestra, para que no sea utilizada en 
Revocación total: las muestras biológicas e información asociada serán destruidas excepto aquellas que ya hayan sido utilizadas en proyectos.
Revocación parcial: solicito que mis muestras NO sean utilizadas para para la/s siguiente/s finalidad/es:
Anonimización de las muestras biológicas e información asociada: la anonimización no permitirá recibir ningún tipo de información relevante para la salud derivada de los proyectos en los que sea utilizada. 
Introduction About 25% of patients with COVID-19 develop acute respiratory distress syndrome (ARDS) associated with a high release of pro-inflammatory cytokines such as interleukin-6 (IL-6). The aim of the SARICOR study is to demonstrate that early administration of sarilumab (an IL-6 receptor inhibitor) in hospitalised patients with COVID-19, pulmonary infiltrates and a high IL-6 or D-Dimer (DD) serum level could reduce the progression of ARDS requiring high-flow nasal oxygen or mechanical ventilation (non-invasive or invasive).
Phase II, open-label, randomised, multicentre, controlled clinical trial to study the efficacy and safety of the administration of two doses of sarilumab (200 and 400 mg) plus best available therapy (BAT) in hospitalised adults with COVID-19 presenting cytokine release syndrome. This strategy will be compared with a BAT control group. The efficacy and safety will be monitored up to 28 days post-administration. A total of 120 patients will be recruited (40 patients in each arm).
The clinical trial has been approved by the Research Ethics Committee of the coordinating centre and authorised by the Spanish Agency of Medicines and Medical Products (AEMPS). If the hypothesis is verified, the dissemination of the results could change clinical practice by increasing early administration of sarilumab in adult patients with COVID-19 presenting cytokine release syndrome, thus reducing ICU admissions.
 Early use of sarilumab can reduce the progression of respiratory failure and prevent the saturation of ICUs.  The trial will study two doses of the drug. One could be selected for phase III trials with a larger sample.  Limitations include not being a blind trial and having a limited sample size.  The stock of sarilumab is limited in Spain. The government distributes the drug to ensure treatment of patients with rheumatoid arthritis. Pharmacies must request authorisation for dispensation of the drug on a case-by-case basis.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for coronavirus disease 2019 (COVID-19). Scientific evidence on the pathogenesis of severe COVID-19, which occurs with respiratory distress, indicates that there is a disordered inflammatory response, an imbalance in the renin-angiotensin system (RAS) and a characteristic coagulopathy [1, 2, 3] . Typically, patients present lymphopenia at the expense of CD4+ and CD8+ T cells. The deregulated and aberrant immune response affects innate immunity, T-cell activation and cytokine production [1, 4] . The end point of this deregulation is diffuse alveolar damage (DAD) characterised by generalised inflammation of the lung with endothelial injury, thrombosis and angiogenesis [5] .
At serum level, this deregulation translates into elevated levels of numerous cytokines and chemokines, such as interleukin-6 (IL-6), interleukin-8 (IL-8) and tumour necrosis factor alpha (TNFα) [4] . A recent meta-analysis has shown a strong correlation between IL-6 levels and the most severe forms of the disease [6] . Furthermore, there is an inverse relationship between IL-6 levels and absolute lymphocyte counts related to DAD [7] . For this reason, IL-6 blockade is considered a therapeutic target to control cytokine release syndrome (CRS) related to COVID-19 [8] . Sarilumab is a human anti-IL-6 receptor monoclonal antibody licensed for the treatment of rheumatoid arthritis. It is a safe and well-tolerated drug [8] . The most common side effects are respiratory tract infections, neutropenia, hypercholesterolemia and mild hepatotoxicity. The most serious side effects are gastrointestinal infections and perforations [9] .
This clinical trial tests the hypothesis that early blockade of IL-6 could halt the progression to severe respiratory failure in hospitalised patients infected with SARS-CoV-2. For this purpose, we investigated the efficacy and safety of early treatment with sarilumab added to standard treatment to prevent progression to severe pulmonary forms of COVID-19.
This is a phase II, open-label, randomised, multicentre, controlled clinical trial. The patients will be assigned to three treatment groups ( Figure 1 ):
1. Control group: 40 patients will receive the best available therapy (BAT) for a maximum of 14 days.
2. Treatment group 1 (T1): 40 patients will receive BAT for a maximum of 14 days + 200 mg of sarilumab subcutaneously (single dose).
3. Treatment group 2 (T2): 40 patients will receive BAT for a maximum of 14 days + 400 mg of sarilumab subcutaneously (single dose).
At the time the protocol has been written, and in the absence of scientific evidence, BAT is considered any combination of drugs authorized in Spain for this indication. This variable will be taken into account in the efficacy analysis.
Ten university hospitals located in Andalusia, Spain, will participate in the trial. The trial will include hospitalised patients with confirmed SARS-CoV-2 infection causing respiratory disease and presenting high serum levels of IL-6 or D-Dimer (DD). Patients who meet all the inclusion criteria and have no exclusion criteria will be prospectively included in the study. Following hospital admission, patients may be randomized as soon as they meet the inclusion criteria, even in the emergency department. The inclusion and exclusion criteria for the trial are described in Box 1. 14. Concomitant treatment with immunomodulators, including dexamethaxone, vitamin D or statins. Macrolides such as azithromycin are acceptable. 
Patients may withdraw from the study at any time, for any reason and without prejudice to future medical treatment. Patients who do not comply with the study procedure or have not been followed up will be considered a study "withdrawal". The reasons for withdrawal will be examined in full accordance with bioethical principles regarding the guarantee of patients' rights. The criteria for withdrawal from the study are described below.
1. Patient request 2. Violation or deviation from the protocol (e.g. breach of administration of treatment, need for prohibited treatment). 3. Researchers decision, based on clinical reasons 4. Administrative decision of the investigators, promoter or regulatory authorities 5. Loss to follow-up 6. Suspected unexpected serious adverse reaction (SUSAR) 7. Serious adverse event (SAE) that at the discretion of the promoter or investigator is not acceptable. 8. Any adverse event considered intolerable by either the patient or the investigator 9. Pregnancy
The inclusion and exclusion criteria can be modified in consecutive versions of the protocol, based on the scientific evidence that is published during the development of the trial, after justification and approval by the reference ethics committee. 
The primary outcome variable is the development of adult respiratory distress syndrome requiring high-flow nasal oxygenation (HFNO) or mechanical ventilation, both non-invasive and invasive.
The secondary outcome variables are: all-cause (crude) mortality at day 28, time (in days) to clinical improvement, time (in days) until oxygenation improvement for at least 48 hours, proportion of patients who require invasive mechanical ventilation, negativisation of PCR to SARS-CoV-2, cytokine kinetics and side effects.
Time to clinical improvement is defined as number of days until 2 points rise in the seven category ordinal scale.
Clinical improvement will be assessed on a seven-category ordinal scale consisting of the following categories: 1, not hospitalised with resumption of normal activities; 2, not hospitalised, but unable to resume normal activities; 3, hospitalised, not requiring supplemental oxygen; 4, hospitalised, requiring supplemental oxygen; 5, hospitalised, requiring high-flow oxygen therapy; 6, hospitalised requiring ECMO, invasive mechanical ventilation or both; and 7, death.
Time (in days) until improvement in oxygenation for at least 48 hours: (i) Time to verify an increase in the SpO2 / FiO2 ratio with respect to the worst SpO2 / FiO2 prior to treatment with Sarilumab and stratified according to levels of IL-6 or DD; (ii) Time until the absence of oxygen need to maintain a saturation in ambient air of ≥ 93%; (iii) Number of days in need of supplemental oxygen.
The following demographics and clinical information will be collected from all patients: age, sex, weight, height, body mass index (BMI), comorbidities, previous treatment, history of the current disease, respiratory rate (bpm), basal oxygen saturation (%), arterial pO2 (mm Hg), pO2/FiO2 rate, oxygen saturation/FiO2 rate, blood pressure (mmHg), heart rate (bpm), consciousness level, temperature (°C), clinical improvement, organ failure assessment score (SOFA), microbiological test, analytical parameters (haematimetry, glucose, creatinine, AST, ALT, C-reactive protein, albumin, LDH, ferritin, troponin I, protein kinase, procalcitonin, lipid profile, IL-6, D-dimer, prothrombin time, INR). All concomitant medication and adverse events will be recorded and monitored in accordance with regulatory procedures. SARS-CoV-2019 in nasopharyngeal swab and a panel of cytokines (IL1-,IL1-β, IL6, IL8, IL10, IL12, IL18, IL38, INFɣ, TNF , CCL2, CCL3, CCL4, MIF y PAI-1) RAGE, Ang-2 and Protein C will be determined before randomisation and on days 5, 10, 14, 21 and 28.
A total of 120 patients will be recruited (40 in each group). Patients who meet the selection criteria will be randomised to be included in the control group or the two experimental groups. Randomisation will be carried out by means of electronic case report forms (eCRFs). The ratio will be 1:1:1 for each group (balanced randomisation). The study design is open, but the investigator will not know the treatment assignment until the patient signs the informed consent form and randomisation is performed, thus minimising selection bias. Patients will be identified by a code that includes the centre code followed by the patient number (XX-YY).
The investigational medication (IM) is sarilumab (ATC code: L04AC14), a human monoclonal antibody (IgG1 subtype) that specifically binds to both soluble and membranebound IL-6 (IL-6Rα) receptors and inhibits the transmission of IL-6 mediated signals involving signal transducer glycoprotein 130 (gp130) and activator of transcription 3 (STAT-3).
The commercial subcutaneous medication available in Spain (SANOFI-AVENTIS) will be used. Administration of the IM will be carried out according to the technical sheet and the local practice of each centre.
The BAT will include any combination of drugs included in the current protocol of the 
The duration of follow-up for each patient will be 28 days and will start from the moment the patient is randomised. A total of 6 visits will be scheduled during the trial: baseline, day 5, day 10, day 14, day 21 and day 28. The scheduled follow-up is shown in Table 1 . The visit following the end of treatment will be considered as the end-of-treatment visit. Visit 5 (day 28 after randomisation) will be considered the final study visit. The final study visit can be moved forward to the day of hospital discharge. Additionally, data on clinical improvement (on a 7point ordinal scale), axillary temperature, oxygen saturation (or PO2) and oxygen therapy will be collected daily. Nasopharyngeal swabs will be performed on days 0, 5, 10, 14, 21 and 28. Plasma will also be obtained on days 0, 5, 10, 14, 21 and 28. The samples will be locally preserved (frozen at -80 °C) until dispatched to the Biobank of the Reina Sofía University Hospital of Córdoba, Spain.
The principal investigator will be responsible for the detection and documentation of adverse events (AE) throughout the study. All AEs must be notified during all phases of the study and followed up until resolution or until an adequate explanation is found, although the patient has completed study treatment. Periodic reports will also be submitted on AEs that occurred during the study, including causality assessment, severity and intensity. 
Since this is a phase II study, a sufficient number of patients are included to perform an initial analysis of efficacy and safety. We have calculated an overall sample size of 120 patients, 40 patients for each arm, to detect a 30% reduction in the primary outcome with an alpha error of 0.05, a beta risk of 0.2 and assuming that the modified intention-to-treat population will be 90% of the randomised patients.
Clinical data will be collected in an electronic case report form (eCRF). All analyses will be performed using PASW Statistics software V.15.0 (IBM Corporation) and R software (V.3.5.0). Frequencies will be calculated for the qualitative variables and compared using the X 2 test or Fisher's test. For quantitative variables, the mean and standard deviation will be calculated. Normality will be analysed using the Kolmogorov-Smirnov test and comparisons will be made using the Student's t-test or the Mann-Whitney test depending on whether or not they follow a normal distribution, respectively. For the comparison of three or more groups, the analysis of variance (ANOVA) or Kruskal-Wallis tests will be used. The analyses will be based on the intention-to treat population (randomised patients receiving treatment). The time until the primary outcome variable is reached will be plotted on a Kaplan-Meier curve and compared using a log-rank test. A Cox regression analysis will be performed for the primary efficacy variable and the results reported in terms of the hazard ratio (HR) with 95% confidence intervals.
No patient involved. 
Worldwide, the number of people infected with SARS-CoV-2 has continued to increase steadily to the millions. Although the vast majority of patients are asymptomatic or develop mild forms, a proportion develop severe forms of adult respiratory distress syndrome (ARDS) with high mortality [9] . The interaction between the virus and the immune system plays an essential role in the pathogenesis of this severe clinical presentation [10] .
To enter respiratory epithelial cells, SARS-CoV-2 spike protein (S-protein) binds to the cellular angiotensin-converting enzyme 2 (ACE2) for which the collaboration of transmembrane serine protease 2 (TMPRSS2) and cathepsin B/L are required. ACE2, a carboxypeptidase widely expressed in the respiratory tract, is the cornerstone of RAS and modulates the effect of angiotensin 2 on respiratory tissue. Excess angiotensin 2 is related to immune system activity and lung thrombogenesis [11, 12, 13] . The expression of ACE2 in the respiratory epithelium differs among patients depending on their genetic factors, sex, age and lifestyle. These variables may explain the variability of the clinical expression of COVID-19 [11, 14] .
However, prior to the evidence on the relationship between RAS and COVID-19, it had already been observed that ARDS produced by SARS-CoV-2 was clinically similar to the cytokine release syndrome (CRS) caused by chimeric antigen receptor (CAR) T-cell therapy [15] . The overproduction of pro-inflammatory cytokines, such as IL-6, IL-2, IL-17, TNF, IL-10, IFN--protein 10 (IP-10) or macrophage inflammatory protein 1 (MCP-1), is a clinical marker of severity with intense pulmonary inflammation and thrombus formation [1] . IL-6 plays an essential role in this pathogenesis and has attracted therapeutic interest because it can be therapeutically blocked [14, 15, 16] . There is evidence that IL-6 levels are related to mortality [17, 18] . It is logical to think that antiviral treatment is insufficient to control immune deregulation in severe cases. The use of humanised monoclonal antibody against the IL-6 receptor (IL-6R) has been proposed in patients with COVID-19 requiring invasive ventilation who present elevated levels of IL-6 [19] . As is usual in science, there is no lack of dissenting opinions regarding this hypothesis [20, 21, 22] .
At the healthcare level, improving the management of critical patients is not sufficient. It is necessary to detect patients at risk of progression to ARDS early on and to investigate therapeutic strategies that prevent the progression of the disease. This is the only way we will be able to reduce the need for mechanical ventilation, avoid collapsing intensive care units and reduce mortality [23, 24] .
Therefore, it seems rational to speculate that, if done early, blocking IL-6 could play a protective role in mitigating the elevated immune response to the virus and preventing the cytokine storm. We propose that the early use of sarilumab, in addition to standard therapy, can attenuate the detrimental host immune response in patients with elevated markers of inflammation by reducing the development of severe respiratory failure and other organ damage.
In conclusion, the SARICOR study aims to reduce the severity and mortality associated with COVID-19. 
Attribution-NonCommercial license (CC BY-NC 4.0), which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, providing the original work is properly cited, appropriate credit is given, any changes made indicated and the use is non-commercial. See: http:// creativecommons.org/licenses/bync/4.0/. 5c The funder Ministry of Health and Families, Regional Government of Andalusia had no role in the design of this study and will not have any role during its execution, analyses, interpretation of the data or decision to submit results.
n/a 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y Data Safety Monitoring Committee Independent physicians will monitor the available data concerning safety and effectiveness of the treatment and they will meet on a regular basis to discuss about the risk/benefit balance and the conduction of the trial.
• Maintenance of trial IT system • Data verification
In each participating centre a principal investigator is identified, to be responsible for identification, recruitment, data collection and completion of CRFs, along with follow up of study patients and adherence to study protocol and SmPC.
Background and rationale 6a It has been suggested that IL-6 blockade may constitute a novel therapeutic strategy for cytokine release syndrome and systemic inflammatory response syndrome in sepsis, macrophage activation syndrome and haemophagocytic lymphohistiocytosis.
Although currently approved for the treatment of rheumatoid arthritis, sarilumab, an interleukin-6 (IL-6) receptor antibody, is being investigated for its ability to reduce the overactive inflammatory immune response associated with COVID-19. This is based on evidence of markedly elevated levels of IL-6 in patients who develop severely acute respiratory distress syndrome.
The research question of this trial is: Does early treatment with sarilumab reduce the evolution to respiratory distress syndrome that requires ventilatory support in hospitalized patients with COVID-19?
6b At the time the protocol has been written, and in the absence of scientific evidence, best available therapy (BAT) is considered any combination of drugs authorized in Spain for this indication. This variable will be taken into account in the efficacy analysis.
The BAT will include any combination of drugs included in the current protocol of the 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y   Objectives  7 Research hypothesis It is hypothesised that IL-6 might play a key role in the cytokine release syndrome in SARS-CoV-2 patients with pneumonia, and that blockade of IL-6 would be a suitable therapeutic target for these patients.
Decrease cases of ARDS in adults requiring HFNO or either noninvasive or invasive mechanical ventilation. Trial design 8
Phase II, open-label, randomised, multicentre, controlled, three parallel groups clinical trial. The primary endpoint is crude mortality at 28 days. Randomization will be performed as block randomization with a 1:1:1 allocation.
Study setting 9 Ten university hospitals located in Andalusia (South of Spain) will participate in the trial, with sufficient incidence at the community level.
The site selected are sufficiently distant from each other so that almost all Andalusia Community population is covered (8.460.000 inhabitants). 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y Interventions 11a Following hospital admission and before performing any study activity, the participating subjects must sign the informed consent form. To participate in the study, patients must meet all of the inclusion criteria and none of the exclusion criteria.
Once the selection criteria are confirmed the patient will be randomized and allocated to one of the following treatment groups:
1. Control group: 40 patients will receive the best available therapy (BAT) for a maximum of 14 days.
At the time the protocol has been written, and in the absence of scientific evidence, BAT is considered any combination of drugs authorized in Spain for this indication. This variable will be taken into account in the efficacy analysis.
2. Treatment group 1 (T1): 40 patients will receive BAT for a maximum of 14 days + 200 mg of sarilumab subcutaneously (single dose).
3. Treatment group 2 (T2): 40 patients will receive BAT for a maximum of 14 days + 400 mg of sarilumab subcutaneously (single dose).
The total expected duration of each patient in the study is up to 28 days (or until the last day they are hospitalized, if less than 28 days).
Every patient will be visited on days 5, 10, 14, 21 and 28 after randomization. These visits may be made at home if the patient has been discharged. An evaluation of the clinical improvement will be made daily according to the ordinal scale of 7 points of gravity, the measurement of axillary temperature, oxygen saturation (or blood gas with PpO2) and oxygen therapy or respiratory support. These values will be collected in the CRD on planned visits. 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y 11b Patients may withdraw from the study at any time, for any reason and without prejudice to future medical treatment. Patients who do not comply with the study procedure or have not been followed up will be considered a study "withdrawal". The reasons for withdrawal will be examined in full accordance with bioethical principles regarding the guarantee of patients' rights. The criteria for withdrawal from the study are described below.
1. Patient request 2. Violation or deviation from the protocol (e.g. breach of administration of treatment, need for prohibited treatment). 3. Researchers decision, based on clinical reasons 4. Administrative decision of the investigators, promoter or regulatory authorities 5. Loss to follow-up 6. Suspected unexpected serious adverse reaction (SUSAR) 7. Serious adverse event (SAE) that at the discretion of the promoter or investigator is not acceptable. 8. Any adverse event considered intolerable by either the patient or the investigator 9. Pregnancy
The toxicity will come given by the adverse effects: -Very common (may affect more than 1 in 10 people): low white blood cell count based on blood tests.
-Frequent (may affect up to 1 in 10 people):
• Sinus or throat infections, congestion, runny nose, and sore throat (upper respiratory tract infection).
• Infection in the urinary tract.
• Fevers (oral herpes).
• Low platelet count based on blood tests. • High cholesterol, high triglycerides according to blood tests.
• Abnormal liver function tests.
• Injection site reactions (including redness and itching).
The participating subjects will hospitalized and the site investigators will be responsible of the administration of the study treatment.
n/a 11d During the study, concomitant treatments used in clinical practice are allowed, as well as BAT. The BAT will include any combination of drugs included in the current protocol of the Spanish Ministry of Health (https://www.mscbs.gob.es/profesionales/saludPublica/ccayes/alertasA ctu al/nCov-China/documentos.htm).
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For peer review only -http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59 The following demographics and clinical information will be collected from all patients: age, sex, weight, height, body mass index (BMI), comorbidities, previous treatment, history of the current disease, respiratory rate (bpm), basal oxygen saturation (%), arterial pO2 (mm Hg), pO2/FiO2 rate, oxygen saturation/FiO2 rate, blood pressure (mmHg), heart rate (bpm), consciousness level, temperature (°C), clinical improvement, organ failure assessment score (SOFA), microbiological test, analytical parameters (haematimetry, glucose, creatinine, AST, ALT, C-reactive protein, albumin, LDH, ferritin, troponin I, protein kinase, procalcitonin, lipid profile, IL-6, D-dimer, prothrombin time, INR).
All concomitant medication and adverse events will be recorded and monitored in accordance with regulatory procedures. (IL1-,IL1-β, IL6, IL8, IL10, IL12, IL18, IL38, INFɣ, TNF , CCL2 , CCL3, CCL4, MIF y PAI-1) RAGE, Ang-2 and Protein C will be determined before randomisation and on days 5, 10, 14, 21 and 28.
The total expected duration of each patient in the study is up to 28 days (or until the last day they are hospitalized, if less than 28 days):
Each patient will visit on days 5, 10, 14, 21 and 28 after randomization. These visits may be made at home if the patient has been discharged.
An assessment of clinical improvement will be made daily according to the ordinal scale of 7 points of gravity, axillary temperature measurement, oxygen saturation (or blood gas with PpO2) and oxygen therapy or respiratory support. These values will be collected in the CRF on planned visits. 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y   Sample size 14 We have calculated an overall sample size of 120 patients, 40 patients for each arm, to detect a 30% reduction in the primary outcome with an alpha error of 0.05, a beta risk of 0.2 and assuming that the modified intention-to-treat population will be 90% of the randomised patients.
Estimated number of participants needed to achieve study objectives and how it was determined, including clinical and statistical assumptions supporting any sample size calculations Page 8
The enrolment will depended on the evolution of the pandemic in Spain. All COVID-19 teams in the participating sites are informed and involved.
n/a
Allocation:
Sequence generation 16a Patients will be randomly assigned to one of the three treatment groups in a 1: 1: 1 ratio, using a random allocation list generated by a specific computer system embedded in the eCRF.
For randomization, patients will be stratified using basal oxygen saturation by breathing room air or pO2 on arterial blood gas.
• According to pulse oximetry in ambient air <90% or pO2 <60 mmHg.
• In case of not having the previous data to ambient air, the relation pO2 / FiO2 <250 will be used. 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y   Allocation  concealm  ent  mechanis  m   16b The participating subjects will be randomized by a computerized system embedded in the electronic data capture and they will be allocated to one of the three treatment groups.
Participants will be randomised using REDCAP, which is an online eCRF which allows central randomisation.
Allocation concealment will be ensured, as the service will not release the randomisation code until the patient has been recruited into the trial, which takes place after all baseline measurements have been completed.
Implement ation 16c All patients who give consent for participation and who fulfil the inclusion criteria will be randomized. Randomisation will be performed by the principal investigator or delegated staff.
In return, the allocation will be shown in the eCRF. The investigator will provide the randomization information to the pharmacist. The main variable is a variable related to the efficacy of the study drug to avoid progression to SARD and avoid the need for ICU admission.
Secondary variables are designed to measure efficiency and safety objectives.
All the participating sites will be trained centrally in the study methods and requirements. The data to be collected and the procedures to be conducted at each visit will be reviewed in detail. Each of the data collection forms and the nature of the required information will be discussed in detail on an item by item basis.
Study coordinators and investigators will learn how to enter the information in the eCRF and how to communicate any Adverse Event or Reaction. Entering data forms, responding to data discrepancy queries and general information about obtaining research quality data will also be covered during the training session.
Data entered in the eCRF will be reviewed and monitored by Clinical Research Associates from the IMIBIC Clinical Research Unit and the corresponding queries will be raised in case inconsistencies are found.
n/a 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y 18b The subjects will be recruited once they are hospitalized and they will remain in the site until discharge.
The total expected duration of each patient in the study is up to 28 days (or until the last day they are hospitalized, if less than 28 days).
A subject will be considered to have completed the trial when they make the last scheduled visit.
Patients can withdraw at any time throughout the study, for whatever reason and without prejudice to future medical treatment.
The reasons for the withdrawal will be analysed with full compliance with the principles of Bioethics, in terms of guaranteeing the rights of patients and autonomous and informed decision.
Although patients can withdraw without having to explain why, as soon as a patient has decided to do so, the researchers will try to establish contact with the subjects and establish that the patient's decision is an informed choice, as well as to check to what extent the patient may be willing to continue participating in the study on a limited basis, eg if they would be willing to continue to contact or be seen in order to obtain follow-up information.
n/a 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y   Data  management 19 Data collection The collected data will be electronically entered by the investigator at every participating site via the eCRF platform. Original study forms will be entered and kept on file at the participating site.
Participant files are to be stored in numerical order and stored in a secure and accessible place and manner. Participant files will be maintained in storage for a period of 25 years after completion of the study.
Data integrity will be enforced through a variety of mechanisms. Referential data rules, valid values, range checks, and consistency checks against data already stored in the database will be supported.
Modifications to data written to the database will be documented through either the data change system or an inquiry system.
Data entered into the database will be retrievable for viewing through the data entry applications. The type of activity that an individual user may undertake is regulated by the privileges associated with his/her user identification code and password.
Additional errors will be detected by programs designed to detect missing data or specific errors in the data. These errors will be summarized along with detailed descriptions for each specific problem in Data Query Reports, which will be sent to the sites.
The Study Coordinator who receives the queries will respond by checking the original forms for inconsistency, checking other sources to determine the correction, modifying the original (paper) form entering a response to the query.
The Coordinating Center (IMIBIC Clinical Research Unit) and participating site personnel will be responsible for making appropriate corrections to the original paper forms whenever any data item is changed. Written documentation of changes will be available via electronic logs and audit trails.
n/a 20a Types of analysis The analyses will be performed on the population by modified intention to treat. This includes all randomized patients to whom the drug or control is administered. Patients who die before administering the drug or those who are not administered for any other reason are excluded.
It will be performed based on the intention of treatment and will be measured by the proportion of patients requiring high-flow nasal oxygen / mechanical ventilation in the first 14 days. For this analysis, patients will be measured on day 14. The time in days until the end point is reached will be plotted on a Kaplan-Meier curve and compared using a Long Rank test. A univariate Cox regression analysis will be performed for the primary efficacy variable and They will represent the results in terms of Hazard Ratio with 95% confidence intervals.
Secondary efficiency analysis CRUDE MORTALITY. Following the criteria of the primary efficacy analysis, mortality from any cause at 14 and 28 days will be analysed. For this 28-day analysis, the sample will be measured at 28 days, which will be the end point of the study. CLINICAL IMPROVEMENT. Following the criteria of the primary analysis, an analysis of the time in days to clinical improvement or mean change according to the 7-point ordinal scale will be performed. IMPROVEMENT OF OXYGENATION. Following the criteria of the primary analysis, an analysis of the time in days until oxygenation will be performed. NEED FOR INVASIVE MECHANICAL VENTILATION. The proportion of patients requiring invasive mechanical ventilation in each arm will be compared. NEGATIVIZATION OF THE PCR TO COVID-19. The proportion of patients who have negative PCR in each arm of the trial will be compared. CYTOKIN LEVELS. The mean levels of each cytokine in each arm of the study will be compared. SECURITY. A description of the adverse events will be made for each arm of the study and the proportion of the same in each arm of the trial will be compared.
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20b The sponsor will perform an Interim analysis of the data collected when it has been reached half the sample size (60 recruited subjects) in order to assess safety and efficacy of research treatment.
n/a 
The modified intention-to-treat population is defined as all randomized patients to whom the drug or control is administered. Patients who die before administering the drug or those who are not administered for any other reason are excluded.
n/a
Data monitoring 21a A Data Safety Monitoring Committee has been established and it is independent of the sponsor. During the period of recruitment to the trial, monthly analyses will be provided to the Data Safety Monitoring Committee, together with any other analyses that the committee may request. The Data Safety Monitoring Committee will advise the sponsor about the study conduction, protocol modifications and/or trial halt if needed.
n/a 21b Interim analysis The sponsor will perform an Interim analysis of the data collected when it has been reached half the sample size (60 recruited subjects) in order to assess safety and efficacy of research treatment.
The results of this analysis will be communicated to the participating researchers. In the event of detection of a significant lack of efficacy or an unacceptable risk-benefit balance, the sponsor will communicate this circumstance to the health authorities, Ethics Committee and local authorities and proceed to the premature termination of the study, according to what is indicated in the Royal Decree 1090/2015.
n/a The principal investigator will be responsible for the detection and documentation, throughout the study, of adverse events.
It is the responsibility of the principal investigator to report all events in the eCRF, both observed by him/her and spontaneously reported by the participants, regardless of the relationship with the investigational medication.
All the events should be reported during all phases of the study and followed up until resolution or until an adequate explanation is found, even if the patient has completed study treatment. In addition, reports will be made periodically on the events that occurred during the study, including evaluation of causality, severity and intensity.
Patients will be informed of possible adverse reactions of the investigational medication through the Patient Information Sheet, as well as their commitment to report any adverse event they experience. They will be given a way to contact the study researchers for this purpose. At all study visits, patients will be questioned about the presence of new events or about the evolution of pre-existing ones.
All events that are severe and manifest during the course of the study, regardless of the treatment group in which they occur, the sponsor must be notified in the course one working day (24 hours) from the time the investigator is aware of the event.
The safety information will be recorded in the eCRF and it will be provided to the Data Safety Monitoring Committee for it analysis. The primary objectives of the CRA during the on-site visits are to educate, support and solve problems. The monitors will discuss the protocol in detail and identify and clarify any areas of weakness. At the initiation of the trial, the monitor will conduct a tutorial on the eCRF. The investigators will practice entering data so that the monitors can confirm that they are proficient in all aspects of data entry, query response, and communication with the CRA. They will audit the overall quality and completeness of the data, examine source documents, interview investigators and coordinators, and confirm that the clinical site has complied with the requirements of the protocol. The monitors will verify that all adverse events were documented in the correct format, and are consistent with protocol definition.
The monitors will review the source documents as needed, to determine whether the data reported in the electronic data capture system are complete and accurate. Source documents are defined as medical charts, associated reports and records including initial hospital admission report.
The monitors will confirm that the regulatory binder is complete and that all associated documents are up to date. The regulatory binder should include the protocol and informed consent (all revisions), Ethics Committee/Health Authorities approvals for all of the above documents, Ethics Committee/Health Authorities correspondence, case report form hardcopy templates, investigator's agreements, etc.
Scheduling monitoring visits will be a function of patient enrolment, site status and other commitments. The CRA will notify the site in writing at least two weeks prior to a scheduled visit. The investigators must be available to meet with the monitors. Although notification of the visits will include the list of patients scheduled to be reviewed, the monitors reserve the right to review additional patients if possible.
If a problem is identified during the visit, the monitor will assist the site in resolving the issues. Some issues may require input from the Data Safety Monitoring Committee, Sponsor or the coordinating investigator.
The focus of the visit/electronic monitoring will be on source document review and confirmation of adverse events. The monitor will verify the following all the variables for all patients, eg. signed informed consent, eligibility criteria, date of randomization, treatment assignment, adverse events and endpoints. 
Research ethics approval 24 The protocol and the informed consent form, as well as other required documents will be reviewed and approved by the sponsor and the applicable Ethics Committee/Health Authority with respect to scientific content and compliance with applicable research and human subjects regulations.
The protocol, informed consent form, participant education and recruitment materials, and other requested documents-and any subsequent modificationsalso will be reviewed and approved by the Ethics Committee/Health Authority.
Subsequent to initial review and approval, the Ethics Committee/ Health Authority will review the protocol annually. The Investigator will make safety and progress reports to the Ethics Committee/ Health Authority at least annually and within twelve months of study termination or completion at his/her site. These reports will include the total number of participants enrolled y their status within the trial, as well as a review of safety and/or efficacy.
Protocol amendments 25 Any modifications to the protocol which may impact on the conduct of the study, potential benefit of the patient or may affect patient safety, including changes of study objectives, study design, patient population, sample sizes, study procedures, or significant administrative aspects will require a formal amendment to the protocol.
Such amendment will be agreed upon by the sponsor and must be submitted for approval to the Ethics Committee/Health Authority prior to implementation in accordance with local regulations.
Administrative changes of the protocol that are minor corrections and/or clarifications that have no effect on the way the study is to be conducted. These administrative changes will be agreed by the sponsor and will be documented in a memorandum. The Ethics Committee/Health Authority may be notified of administrative changes in the next protocol substantial amendment.
Consent or assent 26a The site principal investigator or delegated subinvestigator will introduce the trial to patients. The site principal investigator or delegated subinvestigator will discuss the trial with patients in light of the information provided in the information sheets. Patients will then be able to have an informed discussion with the participating investigator. The site principal investigator or delegated subinvestigator will obtain written consent from patients willing to participate in the trial and file it in the site binder.
Page 38 of 66 26b As biological samples would be collected, an additional informed consent form will be provided by the site principal investigator or delegated subinvestigator to the trial to patients. The consent procedure will be similar to the one explained in point 26a.
Confidentialit y 27 All study-related information will be stored securely at the study site. All participant information will be stored in locked file cabinets in areas with limited access. All laboratory specimens, reports, data collection, process, and administrative forms will be identified by a coded ID [XX-YY coding] number only to maintain participant confidentiality. All records that contain names or other personal identifiers, such as locator forms and informed consent forms, will be stored separately from study records identified by code number. All local databases will be secured with password-protected access systems. Forms, lists, logbooks, appointment books, and any other listings that link participant ID numbers to other identifying information will be stored in a separate, locked file in an area with limited access.
All test results will be kept strictly confidential, all counselling and blood draws will be conducted in private rooms, and study staff will be required to preserve the confidentiality of all participants.
Participants' study information will not be released outside of the study without the written permission of the participant, except as necessary for monitoring, audit and or inspections by regulatory authorities or for safety reasons.
The sponsor guarantees that the data will be processed with security Access to data 29 All Principal Investigators will be given access to the cleaned data sets. Project data sets will be housed on IMIBIC servers they will be accessible by password. Project Principal Investigators will have direct access to their own site's data sets, and will have access to other sites data by request.
To ensure confidentiality, data dispersed to project team members will be blinded of any identifying participant information.
Once the trial has ended and the data has been collected, analysed and published, the anonymized database will be available to other researchers upon request.
Ancillary and post-trial care 30 Patients that are enrolled into the study are covered by indemnity for non-negligent harm through a specific insurance contracted by the sponsor.
Should this study provide evidence of the effectiveness of Sarilumab, it will be critical to provide access to the effective product(s) to study participants in a timely manner.
n/a Disseminatio n policy 31a Once the study has been completed and the statistical report has been carried out, the investigating team shall prepare the final report of the study to be submitted to Ethics Committee/Health Authority. This final report will be the basis for the preparation of the manuscripts to be published in medical journals. 31c Once the trial has ended and the data has been collected, analysed and published, the anonymized database, the full protocol, statistical code and other materials will be available to other researchers upon request to IMIBIC Clinical Research Unit (uicec@imibic.org). Nuestra intención es que usted reciba la información correcta y suficiente para que pueda decidir si acepta o no participar en este estudio. Para ello lea esta hoja informativa con atención y nosotros le aclararemos las dudas que le puedan surgir. Además, puede consultar con las personas que considere oportuno.
Le invitamos a participar en el estudio porque presenta un proceso infeccioso respiratorio por SARS-CoV-2 (COVID19). Debe saber que su participación en este estudio es voluntaria y que puede decidir NO participar. Si decide participar, puede cambiar su decisión y retirar el consentimiento en cualquier momento, sin que por ello se altere la relación con su médico ni se produzca perjuicio alguno en su atención sanitaria.
El objetivo principal del estudio es saber la eficacia y la seguridad de la administración precoz de Sarilumab en pacientes con infección respiratoria por SARS-CoV-2 (COVID19) para evitar el 
Este estudio pretende incluir un total de 120 participantes con alto riesgo de que su función pulmonar se deteriore y precisen de dispositivos para ayudar a su respiración.
La literatura actual recoge un grupo de pacientes que por sus características clínicas y/o analíticas presentan mayor probabilidad de empeorar desde el punto de vista respiratorio y pueden necesitar mayor soporte respiratorio, incluso requerir ingreso en las Unidades de Cuidados
Intensivos para ser intubados. En ningún caso usted dejará de estar tratado con los medicamentos habitualmente utilizados.
Si usted decide no participar en este estudio es posible que usted reciba un fármaco similar pero más tarde, cuando el deterioro respiratorio ya ha sido establecido. Participando en este estudio usted tiene la posibilidad de recibirlo antes para estudiar si evita ese deterioro.
Si decide participar en este estudio le haremos un seguimiento diario desde el día que firme el consentimiento informado hasta el día 28 de su inclusión en el estudio o hasta el último día que esté hospitalizado, lo que ocurra antes.
Evaluaremos diariamente su evolución clínica. En los días 0, 5, 10, 14, 21 y 28 (o hasta el último día que esté hospitalizado) le realizaremos un frotis nasofaríngeo para estudiar si continúa teniendo el virus. Estas muestras se seguirán tomando aunque alguna de ellas fuera negativa.
También en los días 0, 5, 10, 14, 21 y 28 (o hasta el último día que esté hospitalizado) se le extraerá un tubo con 9 ml de sangre que será almacenada para posteriores estudios inmunológicos.
Dependiendo de cómo monitorice la replicación de dicho virus su centro, es posible que se le precise extraer también un tubo con 6 ml de sangre más, para saber si el virus está replicando. 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n l y
Sarilumab es un medicamento ya aprobado y comercializado para el tratamiento de la artritis reumatoide avanzada.
Las reacciones adversas más frecuentemente notificadas con el tratamiento con Sarilumab son: disminución anormal de los neutrófilos y las plaquetas, aumento de las enzimas hepáticas, enrojecimiento en el lugar de la inyección, infecciones del tracto respiratorio superior e infecciones del tracto urinario.
Los riesgos de sufrir algún efecto no deseado con el uso de Sarilumab son: 1 de cada 10 pacientes sufren neutropenia (disminución de los neutrófilos en la sangre), 1 de cada 100 pacientes sufren trombocitopenia (disminución de las plaquetas en la sangre), infección del tracto respiratorio superior, infección del tracto urinario, nasofaringitis (resfriado), herpes oral, hipercolesterolemia (colesterol alto), hipertrigliceridemia (triglicéridos altos), enzimas hepáticas elevadas, enrojecimiento en el lugar de la inyección y picor en el lugar de la inyección.
Los resultados de los estudios disponibles no permiten establecer diferencias entre Sarilumab y otros fármacos biológicos, incluido Tocilizumab. Si usted no participa en el estudio usted podría recibir Tocilizumab por práctica clínica una vez que su función respiratoria se haya deteriorado.
Para conocer más sobre los posibles efectos no deseados de estos medicamentos, consulte al médico de este estudio.
Como riesgo derivado de la extracción de sangre puede producirse un pequeño hematoma, puede haber dolor local, hemorragia y muy excepcionalmente, puede producirse infección en el punto donde se extrae la sangre.
Como participante en el estudio tiene la responsabilidad de cumplir todas las visitas y actividades del estudio. También deberá notificar cualquier evento que le suceda o cambios en la medicación en caso de urgencia, ya que no podrá modificarla por su cuenta ni tomarla junto a "plantas medicinales" sin consultar antes con el médico del estudio.
Si demostramos la hipótesis de este estudio, usted habrá contribuido a evitar el deterioro de la función pulmonar por COVID-19 en otros pacientes que, como usted, padecen una infección respiratoria con factores de riesgo para mala evolución y necesidad de oxigenación a alto flujo o ventilación mecánica tanto de forma invasiva como no invasiva. Esto evitará medidas más agresivas de manejo de su función respiratoria, el ingreso en la Unidad de Cuidados Intensivos y la prolongación de la estancia hospitalaria. 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y Es posible que usted no obtenga ningún beneficio adicional para su salud por participar en este estudio. Sin embargo, los datos obtenidos pueden resultar de utilidad para futuros pacientes que se encuentren en su misma situación.
Las mujeres en edad fértil deben evitar un embarazo mediante el uso de métodos anticonceptivos eficaces durante y hasta tres meses después del tratamiento.
No hay datos disponibles del efecto de Sarilumab sobre la fertilidad humana. Los estudios en animales mostraron que no se producía deterioro de la fertilidad ni en los machos ni en las hembras.
No hay datos o estos son limitados relativos al uso de Sarilumab en mujeres embarazadas.
Los estudios en animales no sugieren efectos perjudiciales directos ni indirectos en términos de toxicidad para la reproducción.
Se desconoce si Sarilumab se excreta en la leche materna o si se absorbe de forma sistemática después de la ingestión. No se ha estudiado la excreción de Sarilumab en la leche en animales.
Dado que las inmunoglobulinas G1 se excretan en la leche humana, se debe decidir si es necesario interrumpir la lactancia o interrumpir el tratamiento con Sarilumab teniendo en cuenta el beneficio de la lactancia para el niño y el beneficio del tratamiento para la madre.
En caso de producirse un embarazo durante su participación en el estudio debe informar a su médico de inmediato para recibir la asistencia médica adecuada. En caso de producirse un embarazo, se solicitará mediante un consentimiento específico la recogida de datos del mismo y de datos de salud del bebé hasta 3 meses después del parto.
Los datos recopilados sobre usted y su bebé serán tratados por el promotor del estudio de acuerdo a la normativa de protección de datos personales vigente (consulte el apartado "Protección de datos personales" para más información). 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59 El investigador principal del estudio le proporcionará toda la información que precise sobre los posibles tratamientos alternativos.
El Promotor del estudio dispone de una póliza de seguros que se ajusta a la legislación vigente (Real decreto 1090/2015) y que le proporcionará la compensación e indemnización en caso de menoscabo de su salud o de lesiones que pudieran producirse en relación con su participación en el estudio, siempre que no sean consecuencia de la propia enfermedad que se estudia o de la evolución propia de su enfermedad como consecuencia de la ineficacia del tratamiento. Si desea más información relativa a este apartado, consulte con el investigador principal del estudio en su centro.
Le recomendamos consultar las condiciones generales y particulares (cobertura) de sus pólizas de seguros privadas (vida, salud, accidente...) por si se ven afectadas por la participación en un ensayo clínico. El promotor no es responsable de estas potenciales modificaciones de cobertura debida a su participación y por tanto, le recomendamos que lo consulte con su aseguradora antes de dar su consentimiento. 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59 Los datos recogidos para el estudio estarán identificados mediante un código, de manera que no se incluya información que pueda identificarle, y sólo su médico del estudio/colaboradores podrá relacionar dichos datos con usted y con su historia clínica. Por lo tanto, su identidad no será revelada a ninguna otra persona salvo a las autoridades sanitarias, cuando así lo requieran, o en casos de urgencia médica.
Los Comités de Ética de la Investigación, los representantes de la Autoridad Sanitaria en materia de inspección y el personal autorizado por el Promotor, podrán acceder para comprobar los datos personales, los procedimientos del estudio clínico y el cumplimiento de las normas de buena práctica clínica (siempre manteniendo la confidencialidad de la información).
Los datos se recogerán en un fichero de investigación responsabilidad de la institución y se tratarán en el marco de su participación en este estudio. El promotor adoptará las medidas pertinentes para garantizar la protección de su privacidad y no permitirá que sus datos se crucen con otras bases de datos que pudieran permitir su identificación.
De acuerdo a lo que establece la legislación de protección de datos, usted puede ejercer los derechos de acceso, modificación, oposición y cancelación de datos. Además de los derechos que ya conoce, ahora también puede limitar el tratamiento de datos que sean incorrectos, solicitar una copia o que se trasladen a un tercero (portabilidad) los datos que usted ha facilitado para el estudio.
Para ejercitar sus derechos, diríjase al investigador principal del estudio o al Delegado de
Protección de Datos del promotor en dpd@imibic.org. Le recordamos que los datos no se pueden eliminar aunque deje de participar en el ensayo para garantizar la validez de la investigación y cumplir con los deberes legales y los requisitos de autorización de medicamentos. Así mismo tiene derecho a dirigirse a la Agencia de Protección de Datos si no queda satisfecho.
Si usted decide retirar el consentimiento para participar en este estudio, ningún dato nuevo será añadido a la base de datos, pero sí se utilizarán los que ya se hayan recogido.
El Investigador y el Promotor están obligados a conservar los datos recogidos para el estudio al menos hasta 25 años tras su finalización. Posteriormente, su información personal sólo se conservará por el centro para el cuidado de su salud y por el promotor para otros fines de investigación científica si usted hubiera otorgado su consentimiento y si así lo permite la ley y requisitos éticos aplicables. 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59 
Usted no tendrá que pagar por los medicamentos ni por pruebas específicas del estudio. Su participación en el estudio no le supondrá ningún gasto adicional a la práctica clínica habitual.
Una descripción de este ensayo clínico estará disponible en https://reec.aemps.es, según exige la legislación española, así como en https://clinicaltrials.gov.
Cualquier nueva información referente al fármaco utilizado en el estudio y que pueda afectar a su disposición para participar en el estudio, que se descubra durante su participación, le será comunicada por su médico lo antes posible.
Debe saber que puede ser excluido del estudio si el promotor o los investigadores del estudio lo consideran oportuno, ya sea por motivos de seguridad, por cualquier acontecimiento adverso que se produzca por la medicación en estudio o porque consideren que no está cumpliendo con los procedimientos establecidos. En cualquiera de los casos, usted recibirá una explicación adecuada del motivo que ha ocasionado su retirada del estudio.
Al firmar la hoja de consentimiento adjunta, se compromete a cumplir con los procedimientos del estudio que se le han expuesto. En aquellos casos en que un participante dejara de acudir a las visitas sin retirar el consentimiento, el promotor podrá realizar un seguimiento de dicho participante.
Debe usted saber que es posible que su médico de Atención Primaria tenga conocimiento de su participación en este estudio.
Cuando acabe su participación recibirá el mejor tratamiento disponible y que su médico considere el más adecuado para su enfermedad.
En caso de que el estudio se suspenda o finalice mientras usted está en tratamiento con la medicación en investigación, su enfermedad permanezca controlada, los datos del estudio indiquen que la medicación en investigación muestra un beneficio en el manejo de su enfermedad, y se disponga de existencias adecuadas del fármaco, el promotor le asegurará el suministro adecuado y gratuito de dicha medicación, hasta que esté disponible, de manera que usted continuará su tratamiento mientras su enfermedad permanezca controlada. 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  Un tubo con 9 ml de sangre para el estudio de la inmunidad frente a este virus.
Dependiendo de cómo monitorice la replicación de dicho virus su centro, es posible que se le precise extraer también un tubo con 6 ml de sangre más, para saber si el virus está replicando.
En el caso de almacenamiento de estas muestras una vez terminado el ensayo, para su uso posterior en investigación se cumplirá con los requisitos éticos y legales dispuestos en el Real
Decreto 1716/2011. Para ello, se le pedirá su consentimiento para que dichas muestras puedan ser almacenadas, una vez que acabe el ensayo clínico, en el Biobanco del Sistema Sanitario Público de Andalucía/Nodo de Córdoba.
Las muestras biológicas donadas, así como sus datos clínicos e información asociados se utilizarán de conformidad con lo establecido en la Ley 14/2007, de 3 de julio, de Investigación biomédica. La donación es voluntaria y altruista, por lo que usted no tendrá derecho alguno sobre los resultados que pudieran derivarse de las investigaciones que se lleven a cabo con dichas muestras biológicas y su información asociada, de conformidad con la normativa vigente. 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59 Yo (nombre y apellidos del participante):
He leído la hoja de información que se me ha entregado sobre el estudio.
He podido hacer preguntas sobre el estudio.
He recibido suficiente información sobre el estudio.
He hablado con (nombre del investigador):
Comprendo que mi participación es voluntaria.
Comprendo que puedo retirarme del estudio:
-Cuando quiera.
-Sin tener que dar explicaciones.
-Sin que esto repercuta en mis cuidados médicos.
Deseo que me comuniquen la información derivada de la investigación que pueda ser relevante para mi salud:
Recibiré una copia firmada y fechada de este documento de consentimiento informado.
Presto libremente mi conformidad para participar en el estudio. 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59 Nombre del representante:
Relación con el paciente:
Se me ha solicitado mi consentimiento en nombre de la siguiente persona, para que él/ella pueda participar en este estudio de investigación médica:
Nombre y apellidos del paciente:
He leído la hoja de información que se me ha entregado sobre el estudio.
He podido hacer preguntas sobre el estudio.
He recibido suficiente información sobre el estudio.
He hablado con (nombre del investigador):
Comprendo que la participación es voluntaria.
Comprendo que puedo retirarlo del estudio:
-Cuando quiera.
-Sin tener que dar explicaciones.
-Sin que esto repercuta en sus cuidados médicos.
Deseo que me comuniquen la información derivada de la investigación que pueda ser relevante para su salud:
Recibiré una copia firmada y fechada de este documento de consentimiento informado.
Presto libremente mi conformidad para que participe en el estudio. 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59 Ha podido hacer preguntas sobre el estudio.
Ha recibido suficiente información sobre el estudio.
Ha hablado con (nombre del investigador):
Comprende que su participación es voluntaria.
Comprende que puede retirarse del estudio:
-Cuando quiera.
-Sin tener que dar explicaciones.
-Sin que esto repercuta en sus cuidados médicos.
El participante desea que se le comunique la información derivada de la investigación que pueda ser relevante para su salud:
Recibirá una copia firmada y fechada de este documento de consentimiento informado.
Presta libremente su conformidad para participar en el estudio. 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59 Es posible que la información obtenida de las investigaciones en las que se utilicen sus muestras biológicas e información asociada no le genere un beneficio directo, pero habrá contribuido al avance de la medicina y del conocimiento de diversas enfermedades, lo que supondrá, sin duda, un beneficio para la sociedad.
La donación es voluntaria y altruista, por lo que usted no tendrá derecho alguno sobre los resultados que pudieran derivarse de las investigaciones que se lleven a cabo con dichas muestras biológicas y Existe un apartado en el consentimiento en el que podrá decidir si quiere que sus muestras biológicas e información asociada se conserven de forma codificada (en cuyo caso se identifican con un código que protege su identidad) o anonimizada (eliminándose de forma irreversible toda vinculación con su identidad).
Sus muestras y los datos asociados a las mismas sólo se cederán a terceros de manera anónima o disociada.
Sus muestras biológicas e información asociada a las mismas sólo se podrán ceder a terceros como uso exclusivo para la investigación biomédica que ayuden a la obtención de nuevos conocimientos científicos, confirmación de hipótesis, adecuación tecnológica, controles de calidad, docencia, u otros usos de interés sanitario, pudiendo usted en cualquier momento establecer las restricciones de utilización que considere oportunas.
Si la naturaleza del proyecto en el que vaya a utilizarse la muestra biológica requiriese información asociada a la misma, y para la que fuese necesario la consulta de su historia clínica, el Biobanco establecerá un sistema de control y trazabilidad del acceso mediante una autorización previa y registros de acceso, que será responsabilidad del Director del nodo donde se lleve a cabo la consulta siempre que la muestra no hubiera sido anonimizada.
Las muestras serán obtenidas durante el procedimiento médico-quirúrgico al que va a someterse o se ha sometido durante su proceso asistencial, o a través de un procedimiento expreso para obtenerla, según lo indicado en el apartado del consentimiento referente a la obtención de muestras. Se podrán obtener diferentes tipos de muestras biológicas como sangre, tejidos, saliva, líquidos biológicos, uñas o pelo. En la hoja de consentimiento se indicarán los tipos de muestras a recoger de forma expresa en este acto de donación.
En el caso de que usted done las muestras obtenidas durante un procedimiento médico-quirúrgico asistencial, no existe ningún inconveniente adicional derivado de la donación de las mismas.
Si, por el contrario, las muestras biológicas fueran extraídas expresamente para la donación al Biobanco, podrían existir inconvenientes vinculados con la obtención de las mismas, de las que será convenientemente informado en la hoja de información del procedimiento correspondiente. 
Usted autoriza, con la firma del consentimiento informado, a que las muestras donadas puedan ser sean utilizadas en:
Investigación: las muestras e información asociada podrán ser utilizados en cualquier investigación biomédica, en los términos que indica la ley. En el caso de que la obtención de la muestra se lleve a cabo a petición de un proyecto concreto, éste y su investigador principal quedarán reflejados en la hoja de consentimiento. El excedente de la muestra e información asociada, quedarán disponibles para su uso en otros proyectos de investigación biomédica si usted así lo indica. Sólo se cederán muestras a proyectos de investigación dentro de una misma línea y científicamente avalados, que cumplan las exigencias legales y los principios éticos que rigen la investigación en salud y que sean autorizados por los órganos competentes, de conformidad con lo establecido en la normativa vigente.
-Docencia: actividades de formación en el ámbito sanitario o biomédico.
-Evaluación / Control de Calidad: muchas de las actividades relacionadas con la investigación o el diagnóstico requieren la puesta a punto de equipos, validación de nuevas tecnologías y procedimientos, encaminados a mejorar el impacto en salud de la tecnología empleada. Para ello es necesario la utilización de muestras biológicas.
Para el caso de que las muestras se utilicen exclusivamente con fines docentes o de control de calidad, y no sea necesaria la información asociada, la conservación, cesión, y uso, se realizará siempre de forma anonimizada.
Las muestras sólo podrán ser utilizadas en proyectos de investigación científicamente avalados, que cumplan las exigencias legales y los principios éticos que rigen la investigación en salud y que sean autorizados por los órganos competentes, de conformidad con lo establecido en la normativa vigente.
Cuando, por razones de salud, usted o su familia lo necesiten, podrán hacer uso de las muestras, siempre que no se hayan agotado o eliminado y no se encuentren anonimizadas.
Si lo solicita, el Biobanco le facilitará la información sobre los proyectos de investigación en los que se utilicen las muestras donadas, si éstas no hubieran sido anonimizadas. El Biobanco mantiene un registro detallado del lugar de realización de los análisis realizados.
La información que se obtenga puede tener implicaciones para sus familiares, por lo que debe transmitirles dicha información.
Puede que sea necesario ponerse en contacto nuevamente con usted, con el fin de recabar datos o muestras adicionales, o proporcionarle la información relevante para su salud, salvo que haya solicitado que las muestras sean anonimizadas.
La información proporcionada en este apartado será aplicable siempre que sus muestras no se encuentren anonimizadas.
Los datos personales recabados serán confidenciales y tratados de acuerdo con el Reglamento (UE) -Los datos personales que nos proporcione serán utilizados con la finalidad de poder gestionar las muestras biológicas, quedando almacenados durante el tiempo necesario para cumplir con las obligaciones legales estipuladas.
-La base jurídica de este tratamiento es el consentimiento que nos presta al cumplimentar y firmar el documento de consentimiento informado, sin el cual no podríamos cumplir con la finalidad descrita -Sus datos no serán cedidos a terceros, salvo que se disponga en una obligación legal.
-Puede usted ejercer sus derechos de acceso, rectificación, supresión, portabilidad de sus datos, y la limitación u oposición a su tratamiento, solicitándolo por escrito, con copia del Los efectos de la revocación no se extenderán a los resultados de las investigaciones llevadas a cabo con anterioridad.
Información relativa a análisis genéticos Salvo que usted manifieste lo contrario en el apartado dedicado al consentimiento, se podrán realizar análisis genéticos. Excepto si sus muestras son anonimizadas, tiene derecho a conocer los datos genéticos que se obtengan a partir del análisis de las muestras donadas, así como de la información relativa a su salud derivada de dichos análisis.
Si no desea recibir dicha información y ésta fuera necesaria para evitar un grave perjuicio para su salud o la de sus familiares biológicos, se informará a un familiar o a un representante. La comunicación se limitará exclusivamente a los datos necesarios para evitar tal perjuicio.
Una vez informado/a de los aspectos relacionados anteriormente en este documento, si decide donar dichas muestras deberá firmar el consentimiento informado para la donación. 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59 He podido hacer preguntas sobre la información recibida y hablar con el profesional indicado, quien me ha resuelto todas las dudas que le he planteado.
Excedentes del procedimiento médico-quirúrgico asistencia al que va a someterse o se ha sometido ………………………………………………………………………………………………………… 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59 Codificada (serán identificadas con un código que protege mi identidad, siendo posible volver a ligarlas conmigo) o Anonimizada (no se podrán asociar las muestras conmigo, por haberse eliminado de forma irreversible la vinculación entre las mismas y mi identidad).
Deseo establecer restricciones respecto al uso de la muestra, para que no sea utilizada en…………………… Autorizo que se pueda contactar conmigo posteriormente:
En caso afirmativo, por favor, indique el medio de hacerlo: 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59 Revocación total: las muestras biológicas e información asociada serán destruidas excepto aquellas que ya hayan sido utilizadas en proyectos.
Revocación parcial: solicito que mis muestras NO sean utilizadas para para la/s siguiente/s finalidad/es: Investigación Docencia
Anonimización de las muestras biológicas e información asociada: la anonimización no permitirá recibir ningún tipo de información relevante para la salud derivada de los proyectos en los que sea utilizada. 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60 