Clinical trial NCT04780581
Conditions: Corona Virus Infection
Sponsor: Fundación Instituto de Estudios de Ciencias de la Salud de Castilla y León
Start date: 2021-02-01; Completion date: 2021-11-09
Enrollment: 128 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Treatment with glucocorticoids in COVID patients. Low-intervention, phase IV, open-label, randomised, low-intervention clinical trial comparing 2 active treatments.

Detailed description:
The use of high-dose bolus glucocorticoids in the treatment of patients with COVID-19 infection will increase the anti-inflammatory effect without increasing side effects. This will allow a better patient outcome, reducing the number of deaths and the need for intubation or admission to the Intensive Care Unit.

Arms: arm 1: intermediate-dose dexamethasone (6mg/24h - 10 days) arm 2: high-dose methylprednisolone bolus (250mg/4h - 3 days)
Interventions: intervention 1: Dexamethasone intervention 2: Methylprednisolone
Intervention descriptions: intervention 1: 6 mg/24h - 10 days intervention 2: 250 mg/ 24h - 3 days

Protocol documents:
Prot_SAP_000.pdf: 
Page 1 of 54 
 
 
Study Sponsor 
Fundación Instituto de Estudios Ciencias de la Salud de Castilla y León 
(IECSCYL)-Instituto de Investigación Biomédica de Salamanca (IBSAL) 
EUDRA CT Number 
2020-005026-28 
Project Code 
MP3-pulses-COVID-19 
Date 
11/12/2020 
Version 
1.4 
 
 
MP3-pulses-COVID-19. PULSES OF 
METHYLPREDNISOLONE VERSUS 
DEXAMETHASONE RECOVERY REGIMEN IN 
PATIENTS WITH PNEUMONIA DUE TO SARS-
COV-2 CORONAVIRUS INFECTION 
 
 
 
 
 
 
 
 
Confidentiality 
The information included in this clinical trial protocol is completely confidential. It is directed and available only to 
investigators and other personnel directly associated with the trial, health authorities and members of the relevant 
Research Ethics Committee. No part thereof may be reproduced, transmitted, disclosed or used in any way without 
the written permission of the Test Promoter. These restrictions will apply to all protocol signatories. 


 
 
 
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STUDY SUMMARY 
PROMOTER 
Fundación Instituto de Estudios Ciencias de la Salud de Castilla y León (IECSCYL)-
Instituto de Investigación Biomédica de Salamanca (IBSAL 
EudraCT NUMBER 
2020-005026-28 
STUDY CODE 
MP3-pulses-COVID-19 
TITLE 
MP3-pulses 
COVID-19. 
PULSES 
OF 
METHYLPREDNISOLONE 
VERSUS 
DEXAMETHASONE RECOVERY REGIMEN IN PATIENTS WITH PNEUMONIA DUE TO 
SARS-COV-2 CORONAVIRUS INFECTION. 
PHASE OF THE CLINICAL TRIAL 
Phase IV 
COORDINATING RESEARCHER  
Luis Corral Gudino 
PARTICIPATING CENTERS 
Río Hortega University Hospital (HURH) 
University Assistance Complex of Salamanca (CAUSA) 
University Clinical Hospital of Valladolid (HCUV) 
University Assistance Complex of Burgos 
University Assistance Complex of León (CAULE) 
PRINCIPAL INVESTIGATORS 
Luis Corral Gudino (Río Hortega University Hospital) 
José Ignacio Martín González (University Assistance Complex of Salamanca) 
Iván Cusácovich Torres (University Clinical Hospital of Valladolid) 
María López Veloso (University Assistance Complex of Burgos) 
Alberto Muela Molinero (University Assistance Complex of León) 
MANAGEMENT AND 
MONITORING 
The integral management of the project will be carried out by the Biomedical 
Research Institute of Salamanca.  


 
 
 
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DRUG IN RESEARCH AND 
REFERENCE, THERAPEUTIC 
REGIMEN AND ROUTE OF 
ADMINISTRATION  
Investigational medicine: 
1)     Desamethasona (RECOVERY)  
2)     Methylprednisolone (BOLUS) 
 
Dose: 
RECOVERY branch: Dexamethasone 6 mg/24h - 10 days (alternative 
Methylprednisolone 30mg/24h) 
BOLUS: Methylprednisolone 250mg/ 24 hours - 3 days (alternative 
Dexamethasone 50mg/24h) 
Administration: Intravenous administration. In the case of the RECOVERY 
branch, the investigator may prescribe oral administration if he considers it 
necessary from the third day of treatment.  
HYPOTHESIS 
The use of high doses of bolus glucocorticoids will increase the anti-inflammatory 
effect without increasing side effects. This will allow a better evolution of 
patients, reducing the number of deaths and the need for intubation or admission 
to the Intensive Care Unit. 
OBJECTIVES  
Primary: 
To compare the effect of high-dose methylprednisolone boluses versus the 
dexamethasone intermediate dose regimen (RECOVERY trial) in COVID-19 
patients with non-critical respiratory failure. 
Side: 
 
• 
To assess the efficacy profile of the use of high-dose glucocorticoids for a 
short course on mortality in patients with COVID-19 
• 
To assess the efficacy profile of the use of high-dose glucocorticoids for a 
short course on the evolution to need respiratory support (invasive 
mechanical ventilation or not) in patients with COVID-19 
• 
To assess the efficacy profile of the use of high-dose glucocorticoids for a 
short course on the time of admission in patients with COVID-19 
• 
To assess the safety profile of the administration of high doses of 
glucocorticoids in relation to the presence of added infections, 
hyperglycemia, psychotic symptoms or other adverse events. 
DESIGN 
Clinical trial of low level of intervention, phase IV, open-label, randomized, 
comparison of 2 active treatments. 


 
 
 
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DISEASE OR DISORDER UNDER 
STUDY 
COVID (coronavirus disease) 
POPULATION AND TOTAL 
NUMBER OF PATIENTS 
Sample size: 290 (two groups of 145 patients) 
Hospitalized patients, diagnosed with certainty of SARS-CoV-2 infection in acute 
phase (RT-PCR-or antigen positive) who have respiratory failure. 
SELECTION CRITERIA 
Inclusion criteria: 
1. 
Over 18 years old. 
2. 
Hospitalized patient. 
3. 
Diagnosis of SARS-CoV-2 infection confirmed by RT-PCR or 
antigen. 
4. 
Computed tomography (CT) evidence of lung involvement 
attributed to COVID infection is presented. Patients in whom CT 
is not performed should have suspicion of pulmonary 
involvement by clinically with compatible or suggestive simple 
radiology. 
5. 
Requires supplemental oxygen by basal saturation ≤ 93% (with 
ambient O2, 21%)  
Exclusion criteria: 
1. 
The patient's situation is so serious that the doctor responsible thinks 
he could die in the next 24 hours. 
2. 
Patients require at randomization one of the following 4 ventilatory 
supports: 
• 
High Oxygen Flow Devices 
• 
Non-invasive mechanical ventilation  
• 
invasive mechanical ventilation  
• 
extracorporeal membrane oxygenation (ECMO). 
3. 
The patient is or has been treated in the 2 weeks prior to randomization 
with 
glucocorticoids 
or 
inflammation-modifying 
drugs, 
both 
conventional 
(thiopurines, 
cyclophosphamide, 
cyclosporine, 
tracolimus, leflunomide, methotrexate, mycophenolate mofetil / 
mycophenolic acid, sulfasalazine, hydroxychloroquine or chloroquine) 
and synthetic or biological directed against therapeutic targets 
(abatacept, belimumab, CD-20, IL1, IL6, Il12.23, IL-23, Il.17,  TNF, 
integrin α4β7 or JAK inhibitors). 
4. 
The patient is pregnant or breastfeeding 
5. 
The patient has stage 4 or 5 chronic kidney disease (rCC <30 ml/min) 
6. 
Moderate to severe dementia at the discretion of the investigator. 
7. 
Hypersensitivity to any of the active ingredients or to any of the 
excipients included in its formulation. 
8. 
Untreated systemic infections not caused by COVID-19. 
9. 
Active stomach ulcer or duodenal ulcer. 


 
 
 
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10. Recent vaccination with live vaccines. 
11. There is another infection or disease that explains the lung disorder 
12. Inability of the patient to understand the study or sign the informed 
consent unless a consent delegated to a legal representative is made. 
13. Active participation in another clinical trial in the past 15 days 
VISIT PROGRAMME 
Selection Visit  
Randomization 
Day 4-6 (any day between 4 and 6) 
Day 12-16 (any day between the 12th and the 16th) 
Day 28 (window allowed: d24-d30) 
3 months (window allowed: ±2weeks)  
Visit to discharge or premature withdrawal 
TRIAL SCHEDULE 
Recruitment is planned to begin in December 2020.  
The overall duration of the study is estimated at approximately 9 months, from 
the start of the recruitment period (6 months of recruitment) to the last follow-
up visit (3 months of follow-up). This study is expected to be completed in 
September 2021. 
 
 
 


 
 
 
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1. SIGNATURES APPROVINGTHE PROTOCOL 
Protocol Title : USE OF GLUCOCORTICOIDS IN PATIENTS WITH SARS-COV2 CORONAVIRUS INFECTION. 
Pragmatic essay inserted in real practice during pandemic. 
Eudragact number: 2020-005026-28 
Protocol code: MP3-pulses-COVID-19 
Promoter: Fundación Instituto de Estudios Ciencias de la Salud de Castilla y León (IECSCYL)-Instituto de 
Investigación Biomédica de Salamanca (IBSAL) 
 
 
 Signature of the Promoter: 
Representative of the promoter: 
María de Lorenzo Santiago (Director of Management - IBSAL) 
 
 
 
Signature  
 
 
    Date 
 
 
 
Signature of the Coordinating Researcher: 
Coordinating Investigator of the Study:  
Luis Corral Gudino 
 
 
 


 
 
 
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Signature  
 
 
    Date 
PRINCIPAL INVESTIGATOR'S SIGNATURE PAGE 
PROTOCOL TITLE: MP3-pulses COVID-19. PULSES OF METHYLPREDNISOLONE VERSUS DEXAMETHASONE 
RECOVERY REGIMEN IN PATIENTS WITH PNEUMONIA DUE TO SARS-COV-2 CORONAVIRUS INFECTION 
Eudragact number: 2020-005026-28 
Protocol code: MP3-pulses-COVID-19 
Promoter: Fundación Instituto de Estudios Ciencias de la Salud de Castilla y León (IECSCYL)-Instituto de 
Investigación Biomédica de Salamanca (IBSAL) 
PCOS CONFIDENTIALITY AND DECLARATION OF CONFORMITY   
I have read the protocol   of the previous clinical study  and agree  that it  contains all the  
information necessary to conduct  the study. 
 I hereby confirm that I have  thoroughly read and  understood this clinical study protocol, and I   
agree  that my staff and    I will conduct  the  study in accordance with  the protocol    and  comply 
with its  requirements, including ethical and safety considerations. 
I understand that if the  Promoter decides to  terminate or suspend the study prematurely for any 
reason, such decision will be communicated to me in writing. On the  contrary, if I decide  to withdraw 
from the  execution of the study, I will immediately  communicate  this decision to  the Promoter.  
I agree not to publish any part of the results  of the study  conducted under this clinical study 
protocol without the prior  written consent  of the Sponsor.  
Principal Investigator 
Center/Hospital 
 
 
Compan
y 
 


 
 
 
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Date 
 
 
Fundación Instituto de Estudios Ciencias de la Salud de Castilla y León (IECSCYL)-Instituto de Investigación 
Biomédica de Salamanca (IBSAL) 
University Hospital of Salamanca 
Virgen de la Vega Building, 10th floor Pº San Vicente, 55-182. 37007 Salamanca 
 


 
 
 
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2. Acronyms 
AA: Adverse Event 
AAG: Serious Adverse Events 
CCR: Creatine clearance 
CD: cluster of differentiation 
CEIm: Ethical Committee on Research with Medicines 
COVID-19: Corona Virus Disease 2019. 
CRDe: Electronic data collection notebook 
DXA: Dexamethasone 
ECG: Electrocardiogram 
ECMO: Extra-corporeal membrane oxygenation 
VF: Pharmacovigilance 
GC: Glucocorticoids 
HDC: Hydrocortisone 
IL: Interleucine 
HOW: Janus cinasa 
MP: Methylprednisolone 
NHC: Medical history number 
WHO: World Health Organization 
CRP: C-reactive protein 
RA: Adverse reaction 
RAI:Unexpected adverse reaction 
RAG: Adverse reaction grbird 
RAGI: unexpected serious adverse reactions 


 
 
 
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RT-PCR: Real Time-Polymerase Chain Reaction 
Rx: Simple X-ray 
SARS-CoV-2: Severe Acute Respiratory Syndrome Coronavirus 
CT, Computed Axial Tomography 
TNF: Factor de necrosis tumoral. 
ICU: Intensive Care Unit 
NIV: Non-invasive mechanical ventilation 
 
 


 
 
 
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Table of Contents 
STUDY 
SUMMARY ............................................................................................................... 22
 
2 
1.SIGNATURES 
APPROVING ................................................................................................................ 
 
6PROTOCOL 
6  .............................................................................................................................. 6 
PRINCIPAL INVESTIGATOR'S SIGNATURE 
PAGE ....................................................................................................................... 77
 
7 
2.Acrónimos ................................................................................................................ 
 
98 ............................................................................................................................ 
 
9 
3.Información 
General ........................................................................................................................ 
 
1713 ......................................................................................................................... 
 
17 
4.Introduction and justification of the 
study ............................................................................................................................ 
 
1814 ......................................................................................................................... 
 
18 
5.Objective and Purpose of the 
Test .............................................................................................................................. 
 
2016 ......................................................................................................................... 
 
20 
5.1.Hypothesis  ......................................................................................................... 
 
20of the study. ............................................................................................. 
 
20 16 ............................................................................................................. 
 
20 
5.2.Main  .................................................................................................................... 
 
20objective. ................................................................................................. 
 
20 16 ............................................................................................................. 
 
20 
5.3.Secondary  .......................................................................................................... 
 
20objectives: ............................................................................................... 
 
2016 .............................................................................................................. 
 
20 


 
 
 
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6.Test 
Design ......................................................................................................................... 
 
2117 ......................................................................................................................... 
 
21 
6.1.Selection and Randomization ............................................................................ 
 
2117 .............................................................................................................. 
 
21 
7.Selection and Withdrawal of 
Subjects ...................................................................................................................... 
 
2218 ......................................................................................................................... 
 
22 
7.1.Criteria for inclusion of subjects ....................................................................... 
 
2218 .............................................................................................................. 
 
22 
7.2.Exclusion criteria for subjects. ......................................................................... 
 
2218 .............................................................................................................. 
 
22 
7.3.Criteria for withdrawal of subjects.  .................................................................. 
 
2319 .............................................................................................................. 
 
23 
7.4.Premature discontinuation of the Study.  ......................................................... 
 
2420 .............................................................................................................. 
 
24 
8.Description of the treatment. 
 
 ........................................................................................................................ 2521
 
 ............................................................................................................................ 25 
8.1.Investigational Product Characteristics ........................................................... 
 
2521 .............................................................................................................. 
 
25 
8.2.Treatment groups and selected doses.  ........................................................... 
 
2622 .............................................................................................................. 
 
26 
8.3.Concomitant treatments .................................................................................... 
 
2723 .............................................................................................................. 
 
27 
8.3.1.Permissible concomitant treatment............................................................................... 
 
2723 ............................................................................................................................. 
 
27 
8.3.2.Concomitant treatments prohibited.  ............................................................................ 
 
2824 ............................................................................................................................. 
 
28 


 
 
 
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9.Development of the study. 
 
 ........................................................................................................................ 2824
 
 ............................................................................................................................ 28 
9.1.Study timetable.  ................................................................................................. 
 
2824 .............................................................................................................. 
 
28 
9.2.Schedule of visits.  ............................................................................................. 
 
2825 .............................................................................................................. 
 
28 
9.3.Description of the visits and the procedures to be carried out in each visit.  
 
2925 .............................................................................................................. 
 
29 
9.3.1.Study visits ...................................................................................................................... 
 
2925 ............................................................................................................................. 
 
29 
9.3.2.Study procedures ........................................................................................................... 
 
2925 ............................................................................................................................. 
 
29 
10. Study variables and 
parameters .......................................................................................................... 3127
 
31 
10.1.Variable Principal: ............................................................................................ 
 
3127 .............................................................................................................. 
 
31 
10.2.Secondary Variables ........................................................................................ 
 
3127 .............................................................................................................. 
 
31 
10.3.Security variables ............................................................................................. 
 
3127 .............................................................................................................. 
 
31 
11. Statistical 
considerations .................................................................................................... 3228
 
32 
11.1.Estimation of sample size.  .............................................................................. 
 
3228 .............................................................................................................. 
 
32 
11.2.Data Management ............................................................................................. 
 
3228 .............................................................................................................. 
 
32 


 
 
 
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11.2.1.Electronic data collection notebook (CRDe) ................................................................ 
 
3228 ......................................................................................................................... 
 
32 
11.2.2.Identificación ................................................................................................................ 
 
3329 ......................................................................................................................... 
 
33 
11.2.3.Recording in medical records ....................................................................................... 
 
3329 ......................................................................................................................... 
 
33 
11.3.Statistical analysis ........................................................................................... 
 
3329 .............................................................................................................. 
 
33 
11.4.Responsabilidades ........................................................................................... 
 
3430 .............................................................................................................. 
 
34 
12. Security Assessment. 
 
3531 ..................................................................................................................... 35 
12.1.Definiciones.  .................................................................................................... 
 
3531 .............................................................................................................. 
 
35 
12.2.Causality Criteria .............................................................................................. 
 
3632 .............................................................................................................. 
 
36 
12.3.Reference Security Information ....................................................................... 
 
3632 .............................................................................................................. 
 
36 
12.4.Safety variables and parameters ..................................................................... 
 
3632 .............................................................................................................. 
 
36 
12.5.Information on Adverse Events ....................................................................... 
 
3733 .............................................................................................................. 
 
37 
12.6.Assessment of the intensity of adverse events and their relationship to 
treatment ................................................................................................................... 
 
3734 .............................................................................................................. 
 
37 
12.7.Assessment of the imputability of adverse events and serious adverse 
events with study treatment: Imputability criteria.  ............................................... 
 
3834 .............................................................................................................. 
 
38 


 
 
 
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12.8.Monitoring adverse events .............................................................................. 
 
3935 .............................................................................................................. 
 
39 
12.9.AAG Notification, Expedited Notification, and Pregnancy Notification ........ 
 
3935 .............................................................................................................. 
 
39 
12.10.Reporting of Serious Adverse Events ........................................................... 
 
3936 .............................................................................................................. 
 
39 
12.10.1.Expedited notification of RAGIs ................................................................................. 
 
4137 ......................................................................................................................... 
 
41 
12.10.2.Expedited notification of other relevant safety information ..................................... 
 
4138 ......................................................................................................................... 
 
41 
12.10.3.Notification of Pregnancy ........................................................................................... 
 
4238 ......................................................................................................................... 
 
42 
12.11.Periodic safety report ..................................................................................... 
 
4238 .............................................................................................................. 
 
42 
12.12.Report to investigators .................................................................................. 
 
4239 .............................................................................................................. 
 
42 
12.13.Discontinuation of study drugs due to adverse events ............................... 
 
4239 .............................................................................................................. 
 
42 
13. Quality Control and 
Assurance ........................................................................................................... 4339
 
43 
14. Ethical and legal aspects. 
 
4440 ..................................................................................................................... 44 
14.1.Patient Patient .................................................................................................. 
 
44and  .......................................................................................................... 
 
44 Informed Patient Patient ........................................................................ 
 
44 .................................................................................................................. 
 
44 Record  (HIP-CI) ...................................................................................... 
 
4441 .............................................................................................................. 
 
44 


 
 
 
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14.2.Audit and monitoring.  ..................................................................................... 
 
4441 .............................................................................................................. 
 
44 
14.3.Breach of Protocol.  ......................................................................................... 
 
4542 .............................................................................................................. 
 
45 
15. Data Management and Archiving of 
Records ............................................................................................................... 4642
 
46 
16. Financing and 
Insurance ............................................................................................................ 4643
 
46 
17. Difficulties and limitations of the 
study .................................................................................................................... 4743
 
47 
18. Publication 
Policy ................................................................................................................... 4744
 
47 
19. Bibliographical references. 
 
4744 ..................................................................................................................... 47 
ANNEX 1: Scales of 
measure .............................................................................................................. 5046
 
50 
A.Serious situation. WHO Proposal ........................................................................ 
 
5046 .............................................................................................................. 
 
50 
B.Gravity scale R ...................................................................................................... 
 
51x Brixia Score (0 to 18 points) ................................................................ 
 
5147 .............................................................................................................. 
 
51 
 
 
 


 
 
 
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3. Overview 
1.1. Title, protocol identification number and date.  
PROTOCOL 
TITLE: 
MP3-pulses-COVID-19. 
PULSES 
OF 
METHYLPREDNISOLONE 
VERSUS 
DEXAMETHASONE 
RECOVERY 
REGIMEN IN PATIENTS WITH PNEUMONIA DUE TO SARS-COV-2 
CORONAVIRUS INFECTION. 
Eudragact number: 2020-005026-28 
Protocol code: MP3-pulses-COVID-19 
1.2. Name and address of the promoter. 
Promoter: Fundación Instituto de Estudios Ciencias de la Salud de Castilla y León 
(IECSCYL)-Instituto de Investigación Biomédica de Salamanca (IBSAL) 
University Assistance Complex of Salamanca. 
Hospital Virgen de la Vega, 10th Floor. 
Paseo de San Vicente, 58-182. 37007 Salamanca 
1.3. Reference CEIm 
Salamanca Health Area.  
1.4. Study phase. 
Phase IV clinical trial. 
1.5. Name and title of the Study Coordinator, address and contact details. 
Luis Corral Gudino, graduate specialist in Internal Medicine, Internal Medicine Service, 
Río Hortega University Hospital. Associate Professor of the degree of Medicine at the 
University of Valladolid 
Río Hortega University Hospital, Calle Dulzaina, 2, 47012 Valladolid.  
Phone 983 42 04 00, extension 85801 
Email:  
lcorral@saludcastillayleon.es 
corralgudino@yahoo.es 
1.6. Participating centers. 
1. 
Río Hortega University Hospital 
2. 
University Assistance Complex of Salamanca 
3. 
University Clinical Hospital of Valladolid  


 
 
 
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4. 
University Assistance Complex of Burgos 
5. 
University Assistance Complex of León 
 
4. Introduction and justification of the study 
At the end of December 2019, cases of viral pneumonia caused by previously unknown people 
in the city of Wuhan China began to be described. A few weeks later, severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) was isolated for the first time, and the disease was 
referred to as COVID-19. Since then the virus has been spreading and causing a global epidemic 
that has overwhelmed global health systems and for which there is still no established cure. 
 
During the first phase of the pandemic, different therapeutic approaches were used, mainly 
aimed at preventing both the viral phase (the virus entering cells or replicating) and a second 
phase of severe inflammation. This second phase is characterized by a marked elevation of acute 
phase reactants and the development of adult respiratory distress syndrome. To stop this 
second phase, different immunomodulatory treatments have been tested, including 
glucocorticoids. 
 
The RECOVERY1 study  has demonstrated the usefulness of an intermediate regimen of 
dexamethasone in critically ill patients with SARS-CoV-2 infection and less markedly in patients 
who need oxygen but are not in critical condition. Another 3 studies in critically ill patients 
(CoDEX2, CAPE-COVID3, REMAP-CAP-COVID4) have confirmed these results. In severe but non-
critical patients, GLUCOCOVID5 demonstrated improvement in a combined endpoint (death, ICU 
admission, mechanical ventilation) with an intermediate dose of glucocorticoids (GC). The 
METCOVID6 study,  however, has not refuted these data with a 5-day course of 
methylprednisolone at intermediate-high doses (see Figure 1 and Table 1). 
On the other hand, uncontrolled observational studies have shown possible improvement with 
the use of higher doses of GC during a short cycle instead of the intermediate dose 7–9. 
 
The pathophysiological explanation for this possible improved higher dose response would be 
activation of the non-genomic GC activation pathway. GCs exert their action in two ways, 
genomics and non-genomics. The mechanisms of this second way are not fully defined 10,11. The 
genomic pathway is responsible for the classic immunomodulatory and anti-inflammatory 
action of GCs and the main side effects, glycemic, lipid and bone. The non-genomic pathway is 
mediated by the interaction of GCs with a specific membrane receptor that is particularly 
expressed in inflammatory cells. This pathway begins to be activated with boluses, but not with 
intermediate doses. Activation of this pathway could justify improved bowling response. 
 
 


 
 
 
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Table 1. GC randomized clinical trials guidelines in COVID. 
I am a student 
Agenda 
Equivalent in prednisone 
day 
Days 
RECOVERY 
Dexamethasone 6 mg/24h 
DXA 6 mg = 30 mg  
10 days 
METCOVID 
Methylprednisolone 0.5 mg/kg/12h 
Patient type 70 kg 
MP 70 mg = 87,5 mg  
5 days 
GLUCOCOVID 
Methylprednisolone 40 mg/12h x 3 days 
and then 20 mg/12h x 3 days 
MP 80 mg = 100 mg  
6 days 
CoDEX 
Dexamethasone 20 mg/24h x 5 days 
Dexamethasone  10 mg/24h x 5 days 
DXA 20 mg= 125 mg 
DXA 10 mg= 62,5 mg 
10 days 
REMP-CAP C  
Hydrocortisone 50-100mg/6h x 7 days 
HDC 200 mg = 50 mg 
7 days 
CAPE COVID 
Hydrocortisone 200 mg/24h x7 days, then 
100 mg/24h x4 days, 
Then 50 mg/24hh x 3 days. 
HDC 200 mg = 50 mg 
14 days  
(8 if good 
evolution) 
 
Figure 1. Results of the different studies published with CG in covid-19 


 
 
 
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5. Objective and Purpose of the Test 
 
5.1. 
Hypothesis of the study. 
The use of high doses of bolus glucocorticoids will increase the anti-inflammatory effect 
without increasing side effects. This will allow a better evolution of patients, reducing the 
number of deaths and the need for intubation or admission to the Intensive Care Unit. 
 
5.2. 
 Main objective. 
To compare the effect of high-dose methylprednisolone boluses versus the dexamethasone 
intermediate-dose regimen (RECOVERY trial) in non-critical COVID-19 patients with 
respiratory failure. 
 
5.3. 
Secondary objectives: 
• 
To assess the efficacy profile of the use of high-dose glucocorticoids for a short course 
on mortality in patients with COVID-19. 


 
 
 
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• 
To assess the efficacy profile of the use of high doses of glucocorticoids for a short 
cycle on the evolution to need respiratory support (invasive mechanical ventilation or 
not) in patients with COVID-19. 
• 
To assess the efficacy profile of the use of high-dose glucocorticoids for a short course 
on the time of admission in patients with COVID-19. 
• 
To assess the safety profile of the administration of high doses of glucocorticoids in 
relation to the presence of added infections, hyperglycemia, psychotic symptoms or 
other adverse events. 
 
6. Trial Design 
Low-intervention  clinical trial, phase IV, open-label, randomized, comparison of 2 active 
treatments. 
[Justification for the low level of intervention: paragraph 8.3 of this Protocol and Annex 2] 
 
 
 
6.1. 
Selection and Randomization 
 
Action 
Responsible 
1. 
Inclusion of the patient in 
the study 
The doctor who attends the patient is the one who decides the need 
to prescribe corticosteroids and informs the patient to propose 
their inclusion in the study 
2. 
Patient randomization 
It will be carried out centrally through the electronic data collection 
notebook (CRDe).  
Eligible subjects will be randomly assigned 1:1 to the two treatment 
groups. 
3. 
Implementation of 
treatment. 
Once the patient is randomized, the doctor will prescribe the 
treatment as usual, which will be prepared and dispensed in each 
center according to the usual practice of the same.  


 
 
 
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Since randomization is centralized and through the CRDe, the treatment list of patients 
is not accessible to researchers, so they do not know a priori what may be the treatment 
arm assigned to each patient. 
 
7. Selection and Withdrawal of Subjects 
 
7.1. 
Criteria for inclusion of subjects 
Patients must meet ALL of the following criteria to be included in the study: 
1) Over 18 years old 
2) Inpatient 
3) Diagnosis of SARS-CoV-2 infection confirmed by RT-PCR or antigen. 
4) Computed tomography (CT) evidence of lung involvement attributed to COVID 
infection is presented. Patients in whom CT is not performed should have suspicion of 
pulmonary involvement by clinically with compatible or suggestive simple radiology. 
5) Requires supplemental oxygen by basal saturation ≤ 93% (with ambient O2, 21%)  
 
7.2. 
Criteria for excluding subjects. 
Patients who present ANY of the following criteria may not be selected to participate in this 
study: 
1) The patient's situation is so serious that the doctor responsible thinks he could die in 
the next 24 hours. 
2) Patients require at randomization one of the following 4 ventilatory supports: 
a) High oxygen flow devices. 
b) VNon-invasive mechanical entilation. 
c) Invasive mechanical ventilation. 
d) extracorporeal membrane oxygenation (ECMO). 


 
 
 
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3) The patient is or has been on  treatmentin the s 2 weeks s prior to randomization with 
glucocorticoids or inflammation-modifying drugs, both conventional (thiopurines, 
cyclophosphamide, 
cyclosporine, 
tracolimus, 
leflunomide, 
methotrexate, 
mycophenolate mofetil / mycophenolic acid, sulfasalazine, hydroxychloroquine or 
chloroquine) and synthetic or biological directed against therapeutic targets (abatacept, 
belimumab, CD-20,  IL1, IL6, Il12.23, IL-23, Il.17, TNF, integrin α4β7 or Janus kinase 
inhibitors JAK). Patients who are only on maintenance therapy with corticosteroid 
doses less than or equal to 7.5 mg of prednisone or equivalent per day will not be 
excluded. 
4) The patient is pregnant or nursing. 
5) The patient has stage 4 or 5 chronic kidney disease (rCC <30 ml/min). 
6) Moderate to severe dementia at the discretion of the investigator. 
7) Hypersensitivity to any of the active ingredients or to any of the excipients included in 
its formulation. 
8) Untreated systemic infections not caused by COVID-19. 
9) Stomach ulcer the ulcer duodenal active. 
10) Recent vaccination with live vaccines. 
11) There is another infection or disease that explains the lung disorder 
12) Inability of the patient to understand the study or sign the informed consent unless a 
consent delegated to a legal representative is made. 
13) Active participation in another clinical trial in the past 15 days. 
7.3. 
Criteria for withdrawal of subjects. 
• 
Voluntary patient abandonment: patients have the right to withdraw from the study at 
any time and for any reason, being able to express it personally or through their 
representative. 
• 
By medical criteria (safety and efficacy): 
− that it is necessary to adopt new treatments due to the presence of serious 
adverse events that may be related to the use of corticosteroids such as severe 
infection of bacterial origin, etc. 


 
 
 
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− the deterioration of this is severe and it is considered necessary to replace the 
administered corticosteroid or initiate additional immunosuppressants or 
immunodulators. 
− That there is scientific evidence that supports the administration of new 
treatments that change the prognosis of patients and force them to modify the 
standard treatment of these. 
• 
For non-compliance or violation of the rules contained in the protocol: when the patient 
no longer complies with the rules or procedures established in this protocol or there is 
loss of follow-up. 
All patients who, regardless of the cause and stage of the study in which they are, prematurely 
and permanently discontinue treatment or follow-up, should complete the premature 
withdrawal visit, which will take place within 24-48 hours of becoming aware of withdrawal. 
 
7.4. 
Premature discontinuation of the Study. 
This study may be temporarily interrupted or terminated prematurely if in the opinion of the 
sponsor there is sufficient reasonable cause. The investigator will receive written notice that 
the terminating party documents the reason for the suspension of the study.  
The circumstances justifying the suspension of the present study include, but are not limited 
to:  
(a)Identification of unforeseen, substantial or unacceptable risks to patients.  
(b)Inability to enroll an acceptable number of patients.  
(c)Insufficient compliance with the requirements of the protocol.  
d) Plans for modification, suspension or discontinuity of the development of the study drug.  
e) Administrative reasons that the promoter could not solve with the health authorities.  
f) The study is interrupted if scientific evidence appears to support the administration of 
new treatments that change the prognosis of patients and force them to modify the 
standard treatment of these. 
A safety rule to stop the trial is to find significant differences in efficacy endpoint or adverse 
event variables in interim analyses. The significance level established for stopping the test is 
p<0.01 for safety and p<0.001 for efficiency(Haybittle-Peto limit) 13. 


 
 
 
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If the trial ends early or is suspended for any reason, the investigator shall promptly inform 
the trial subjects, ensuring appropriate treatment and follow-up of the trial and, where 
required by applicable law, inform the regulatory authority. 
If the investigator terminates or suspends a trial without the prior agreement of the sponsor, 
he or she shall promptly inform the institution, and the investigator/institution shall promptly 
inform the sponsor and the CEIm and provide them with written justification for the cause of 
such termination or suspension. 
If the sponsor terminates or suspends a trial, the investigator must inform the Institution where 
the trial is conducted and the investigator/institution must promptly inform the CEIm by 
providing written justification of the reasons for the termination or suspension. 
If the Ethics Committee (CEIm) terminates or withdraws the favourable opinion of a trial, the 
investigator shall inform the institution and the investigator/institution shall promptly inform 
the sponsor of this fact and provide written justification as to the cause of such termination or 
suspension. 
 
8. Description of the treatment. 
 
8.1. 
Characteristics of the Research Product 
Methylprednisolone boluses are currently a common treatment in diseases with a serious 
component of infamation such as lupus nephritis. That is why its application in the 
inflammation phase of COVID could be useful, since these patients have a severe 
inflammatory profile. The response to intermediate doses of dexamethasone suggests a 
possible effect of treatment with higher doses. 
The risks of corticosteroid treatment at the bolus dose in the short term are similar to those of 
administration of intermediate doses, with an increased risk of bacterial superinfection, 
baseline glycemic decompensation, or risk of psychosis or arousal. Use in cycles of a few 
days has no long-term side effects such as hypertension, dyslipidemia or osteoporosis. 
The chosen pattern is the same as that used in acute inflammatory diseases, such as lupus 
nephritis.  In case of lack of stock, it could be decided to use other glucocorticoid preparations 
in doses equivalent to that of methyl-prednisolone, according to the following table: 
Table 2. Guidelines equivalences to methylprednisolone in different studiess. 
Active substance 
Agenda 
Equivalence in  
methyl-prednisoitin the 
Equivalence in 
prednisona  
Dexamethasone 
6 mg/24h 
30 mg/24h 
37,5mg/24h 


 
 
 
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Metilprednisolona 
250mg/24h 
N/A 
312,5 mg/24h 
Hidrocortisona 
50-100mg/6h 
20-40 mg/12h 
25-50 mg/12h 
Reference: doses calculated according to "Steroid Conversion Calculator", accessible in 
https://www.mdcalc.com/steroid-conversion-calculator#evidence 
Patients with a confirmed diagnosis of SARS-CoV-2 who have pulmonary involvement and 
are at risk of developing adult respiratory distress syndrome will be included. 
There are studies that have evaluated observationally the treatment with GC boluses in this 
pathology in which there seems to be a beneficial effect when compared with the usual 
treatment (Callejas-Rubio, Rodríguez-Baño, Ruiz-Irastorza). 
 
8.2. 
Treatment groups and selected doses. 
Patients continue with the treatment that is considered standard in their center and 
associate glucocorticoids in 2 possible regimens (group membership is done randomly) 
1) RECOVERY guideline. Intravenous administration of 6mg of dexamethasone every 24h 
for 10 days. It can be given both orally and intravenously at the same dose 
 
2) BOWLING GUIDELINE. Intravenous administration of 250mg of methylprednisolone 
every 24 hours for 3 days. 
 
The standard treatment in each group is as described, but given the pandemic situation and 
the risk of stock depletion, in the case of the RECOVERY regimen the use of 
methylprednisolone 30 mg could be assessed as an alternative to dexamethasone 6 mg, as 
well as in the case of the bolus regimen, the use of dexamethasone 50 mg could be assessed 
as an alternative in case of stock depletion. 
 
Method of administration 
Once the patient has been included in the study, it is recorded in the data collection 
notebook and randomization is performed. Once the treatment group is known, the doctor 
prescribes the treatment according to the usual procedure in the center according to the 
protocol.  
The pharmacy of the center prepares the medication according to the medical schedule, for 
intravenous administration in the case of methylprednisolone or intravenous or oral 
according to the medical criteria for dexamethasone.  
 


 
 
 
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8.3. 
Justification character low level of intervention. 
The investigational products are marketed drugs and will be used according to the guidelines 
of the SmPC, so that the study cannot be classified as a low level of intervention. In addition, 
procedures outside of standard practice that were not performed on thesepatients outside 
the study will not be performed. (Annex 2) 
On the other hand, on 18 September 2020, the AEMPS published, with reference MUH 
28/2020, that the Committee for Medicinal Products for Human Use (CHMP) P has 
concluded that, for the treatment of patients   with COVID-19, dexamethasone can be 
administered orally or administered as an injection or infusion (drip) intravenously. In all 
cases, the recommended dose in adults and adolescents is 6 milligrams once a day for up to 
10 days.  In this way, the use of dexamethasone as a new indication in patients with COVID-
19 is possible. 
 
 
8.4. 
Concomitant treatments 
8.3.1. 
Concomitant treatment allowed (Standard Treatment) 
Although this is a pragmatic study in real practice and some degree of heterogeneity is 
accepted in standard treatment, minimum requirements are considered to be able to include 
patients in the study. Thus, as standard treatment is accepted: 
a) Supplemental oxygen. For use in patients with hypoxemia. The target for 
oxygen therapy should not exceed 92% in patients at risk of respiratory failure 
with hypercapnia and 96% in all other patients. 
b) Antibiotic treatment. Standard treatment protocols should not recommend the 
administration of empirical antibiotic treatment on a routine basis. Its 
administration should only be recommended when risk of bacterial pneumonia 
is considered as co-infection. The antibiotic regimen will correspond to the 
usual treatment guide of the center. 
c) Prophylaxis or thromboembolism treatment with low molecular weight 
heparins. Thrombotic prophylaxis is recommended in all admitted patients and 
the use of therapeutic doses in patients with confirmed thromboembolic disease. 
The use of extended prophylaxis guidelines could be assessed according to the 
recommendations of the Spanish society of thrombosis and hemostasis. 


 
 
 
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d) Remdesivir. The use of remdesivir is accepted if it is done according to the 
recommendations of the Ministry of Health. 
e) Other antiviral drugs or drugs that block viral activity. The protocols should not 
incorporate the following drugs: Hydroxychloroquine or chloroquine, 
lopinavir-ritonarvir. 
f) Serum therapy. The use of serum therapy is allowed in those indications defined 
in the protocols. 
g) Other concomitant medications without antiviral or immunosuppressive effect 
(eg: antihypertensives, analgesics, lipid-lowering agents, antiplatelet agents,...). 
There is no limitation to the use of these drugs. 
 
8.3.2. 
Concomitant treatments prohibited. 
Other immunosuppressants. The concomitant use of other immunosuppressants is NOT 
allowed in the first 48 hours of evolution. If immunosuppressants are prescribed during the 
study, patients in whom they are initiated with the third or subsequent dose of CG should 
be maintained. The use of these drugs in these patients will be considered as an event. 
 
9. Development of the study. 
9.1. 
Study schedule. 
Recruitment is planned to begin in December 2020.  
The overall duration of the study is estimated at approximately 9 months, from the start of the 
recruitment period (6 months of recruitment) to the last follow-up visit (3 months of follow-
up). This study is expected to be completed in September 2021. 
 
 
 
 
9.2. 
Calendar of visits. 
 


 
 
 
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Processes to be carried out 
SCR 
Day 4-6 
Day 12-
16 
Day 28 
3 months 
Premature 
withdrawal 
Informed consent 
X 
 
 
 
 
 
Inclusion criteria 
X 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
Medical history comorbidities 
X 
 
 
 
 
 
Physical examination 
X 
X 
X 
X 
X* 
X* 
 COVID Clinical Evaluation 
X 
X 
X 
X 
X 
X 
WHO scale of 10 categories  
X 
X 
X 
X 
X* 
X* 
Concomitant medication  
X 
X 
X 
X 
X 
X 
Biochemistry and blood count 
X 
X 
X 
X 
X* 
X* 
Adverse events 
X 
X 
X 
X 
X 
X 
Rx the TC  
X 
 
X 
 
X* 
X* 
ECG 
X 
 
 
 
 
 
* Only in case of being a face-to-face visit.  
 
 
9.3. 
Description of the visits and the procedures to be carried out in 
each visit. 
9.3.1. Study visits 
− Selection/Randomization. 
− Day 4-6 (any day between 4 and 6). 
− Day 12-16 (any day between the 12th and the 16th). 
− Day 28 (window allowed: day 24 to day 30). 
− 3 months (window allowed: ±2weeks). This visit can be made in person or by 
telephone at medical discretion, depending on the patient's condition and 
the usual practice of the center.  
− Visit to discharge or premature withdrawal.  This visit can be done in person 
or by telephone. 
 
9.3.2. Study Procedures 
− Chronopathology of COVID-19 infection. During the screening visit, the 
date of onset of symptoms and the date of the first confirmatory diagnostic test 


 
 
 
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will be collected. In addition, if the diagnostic RT-PCR was not performed in 
the last 10 days, it will be necessary to repeat it and confirm the positivity. 
− Medical history comorbidities (including hypertension, diabetes mellitus, 
dyslipidemia, heart failure, ischemic heart disease, stroke, chronic obstructive 
pulmonary disease, bronchial asthma, hypopnea sleep apnea syndrome, 
hypoventilation, chronic kidney disease, chronic liver disease, neoplasia, 
transplant, human immunodeficiency virus infection, autoimmune disease, 
dementia, smoker) 
− Clinical evaluation of COVID, assessment of own symptoms, date of onset of 
symptoms and evolution of them. 
− WHO scale of 10 categories (Annex 1). 
− Physical examination (includes general assessment of the patient, degree of 
hydration, nutrition, vital signs and respiratory situation, cardiopulmonary 
ascultation, abdominal examination and a neurological assessment of alertness). 
− Concomitant medication registration  (start and end date, active substance 
and dose). 
− Biochemistry and blood count (determination of blood count, coagulation 
with D-dimer, biochemistry including creatinine, ions, AST, ALT, BT, BD, 
LDH, PCR, ferritin, blood gases and IL-6). 
− Adverse events, medication-related or non-medication-related. 
− Chest X-ray (X-ray) or Computed Tomography (CT) (Brixia scale – Annex 
1). 
− Electrocardiogram (ECG), according to the usual practice of the center. 
− Both the 3-month follow-up visit and the premature withdrawal visit can be 
done in person or by telephone. If the visit is carried out in person, in addition 
to the assessment of the COVID clinic, the registration of  concomitant 
medication and the registry of adverse events, the following procedures would 
be carried out: 
• 
WHO scale of 10 categories (Annex 1). 
• 
Physical examination. 
• 
Biochemistry and blood count. 


 
 
 
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• 
Chest X-ray (X-ray) or Computed Tomography (CT) (Brixia12 scale  – 
Annex 1). 
 
10. Study variables and parameters 
10.1. 
Variable Principal: 
• Death after 28 days 
 
 
10.2. 
Secondary Variables 
• 
Admission to the Intensive Care Unit at 28 days 
• 
Need for noninvasive mechanical ventilation or high-flow oxygen at 28 days. 
• 
Need for mechanical ventilation and intubation at 28 days. 
• 
Use of other immunosuppressive drugs. 
• 
Time to discharge (days of hospitalization from start of treatment) 
• 
Baseline at 3 months of treatment according to the WHO 10-category scale  . 
 
10.3. 
Security variables 
• 
Nosocomial infection (superadded infection developed at least 3 days after 
administration of the first dose of steroids) with microbiological confirmation by 
culture. When there is no microbiological confirmation, the diagnosis is established at 
the discretion of the physician. 
• 
Hyperglycemia in non-diabetic patients or decompensation of diabetes mellitus in 
previously controlled patients. To define this event, the presence of at least one 
glycemic value greater than 180 mg/dl in the laboratory at any point of evolution or a 
value greater than 150 mg/dl in fasting capillary glycemia during the days that the 
patient receives treatment with glucocorticoids is established. 


 
 
 
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• 
Episodes of psychosis defined as the presence of euphoria, behavioral changes, 
aggressiveness, alteration of thought with disorganization of this or presence of 
hallucinations or delusions. 
• 
Any other treatment-related adverse reaction that,  in medical judgment, isrelevant to 
the safety of the drug under study. 
 
11. Statistical considerations 
11.1. 
Estimation of sample size. 
 
Initial estimates:  
28-day mortality in patients requiring 
oxygen who received intermediate-
dose glucocorticoids 
Mortality at 21-28 days in patients 
requiring oxygen and receiving boluses of 
glucocorticoids (observational studies, 
indirect evidence) 
GLUCOCOVID data 17% 
RECOVERY data 23.3% 
METCOVID data 37% 
Data Granada 8% 
SAM-COVID data: 10% 
Crossing Data: 9.1% 
Estimate: 23% 
Estimate: 10% 
 
The following values apply: alpha error 5%, beta error 20%. 
 
Estimated sample size: two groups of 145 patients (290 in total) 
 
 
11.2. 
Data Management 
11.2.1. Electronic Data Collection Notebook (CRDe) 
The data collected will be recorded in an electronic Data Collection Notebook (CRDe), 
whose veracity will be validated by the designated monitors. In the CRD, each patient will 
be identified by an alphanumeric code that identifies the patient. At all times, the data 
protection provisions of Organic Law 3/2018 on the Protection of Personal Data and 
guarantee of digital rights will be respected. 


 
 
 
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11.2.2. Identification 
Each patient receives an identification number when randomized. Only the pharmacy and 
principal investigator at each facility know the correspondence between the study 
identification number and the patient's medical record number (NHC). 
It corresponds to the principal investigator of each center, who will be responsible for 
maintaining the list with the allocation of patients and their medical history number. 
 
11.2.3. Record in medical records 
Participation in the study will be included in the evolution of the clinical history of each 
center. All study data shall be recorded in the study so that all data collected in the CRDe 
can be verified. The data will be obtained from the personal interview with the patient and 
access to their complete medical history.  
In the event that the patient does not attend any of the planned visits, the researcher will 
contact him by telephone to confirm that this absence is not due to a conscious 
abandonment of the follow-up. If you do not contact him, you will access the local or 
regional digital medical record to know if there have been events related to the study that 
have been evaluated in another health center. 
 
11.3. 
Statistical analysis 
The categorical variables will be presented as frequency and percentage and the continuous 
variables as mean and standard deviation. 
Death after 28 days, intubation or admission to the ICU will be presented as proportions. 
The difference in proportions will be estimated with a 95% confidence interval. 
An analysis per protocol will be performed, considering those patients who have received at 
least 2 doses of the assigned drug. In addition, an intention-to-treat analysis will be carried 
out.  
In the event that there is a depletion of stock and any of the guidelines are replaced by one 
of the alternatives proposed in point 8.2, no adjustment would be made in the analysis since 
the equivalence of dose and dosage between the original dose and the substitution is 
established. 


 
 
 
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For the analysis of the main outcome, death at 28 days, survival analysis will be performed 
and the Hazard ratio of the Cox regression, with the log-rank statistic, will be used to 
estimate the mortality relationship.  
An alpha error of 5% is set.  
In case there was a lack of balance in the age of the patients between the groups, age-
adjusted analyses would be performed, establishing 2 groups: < 70 years and ≥ 70 years. 
Two interim efficacy and  safety analyses are established with 100 and 200 patients 
2 analyses of the results are established according to: 
a) Time of evolution (<7 days from the onset of symptoms, ≥ 7 days from the onset of 
symptoms). 
b) Presence of a state of high inflammation. The patient is considered to have a high 
degree of inflammation when he meets any of the following laboratory criteria: 
• 
Ferritin greater than or equal to 1000 mg/dl 
• 
IL-6 greater than or equal to 20 pg/ml 
• 
PCR mayor o igual a 150 mg/l 
• 
D-dimer greater than or equal to 1000 mg/dl 
Finally, since no age criterion is established to exclude older patients, a sensitivity analysis 
will be performed, leaving out those patients who had orders of no intubation or non-
invasive mechanical ventilation prior to being included in the study. 
For statistical analysis, the IBM SPSS statistics, version 21 program will be used. 
 
11.4. 
Responsibilities 
• 
Coordination between the different groups for data management tasks is the 
responsibility of the promoter. 
• 
Only authorised and adequately trained persons shall have access to the electronic data 
collection system. 
• 
Data controllers shall ensure access to the system to all authorised persons. 
• 
The promoter shall be responsible for the consistency of the eCRD data against the 
source data. 


 
 
 
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• 
Verification of eCRD data and source data will be the responsibility of the study 
monitor or, failing that, of the sponsor. 
 
 
 
 
12. Security Assessment. 
12.1. 
Definitions. 
• 
Adverse Event (AA): An adverse event is any unwanted medical reaction experienced 
by the patient at any time during the course of the study, whether or not considered 
related to the study treatment. This definition includes the development of a new 
disease and the exacerbation of pre-existing disorders other than the indication under 
study. 
• 
Adverse Reaction (AR): An RA is any harmful and unintended reaction to an 
investigational drug, regardless of the dose administered. 
• 
Serious Adverse Event (SAA) and Serious Adverse Reaction (RAG): AEs or RAs are 
considered serious if, at any dose, may result in death, threaten the life of the subject, 
require hospitalization of the patient or prolong an existing hospitalization, cause 
permanent or significant disability or disability, or result in a congenital anomaly or 
malformation. Suspicions of medically important AA or RA are also considered 
serious, even if they do not meet the above criteria, including important medical 
events that require intervention to prevent one of the consequences described above 
from occurring. In addition, all suspected transmission of an infectious agent through 
a medicinal product shall be reported as serious. 
The concept "threatening the life of the subject" in the definition refers to the fact 
that, in the opinion of the researcher, the patient at the time of AA or RA is at real risk 
of death; it does not mean that AA/RA hypothetically could have caused death if it 
had been more intense. 
The concept of "requiring hospitalization" will exclude both hospitalizations planned 
for scheduled treatments and those that have been planned or anticipated before the 
study begins in relation to a pre-existing medical condition. 


 
 
 
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• 
Unexpected Adverse Reaction (RAI): Any RA whose nature, intensity or 
consequences do not correspond to the reference safety information. 
• 
Unexpected Serious Adverse Reaction (RAGI): AGR (previously defined), the nature, 
severity or consequences of which do not correspond to the reference safety 
information. 
 
12.2. 
Causality Criteria 
 
• 
Related OA: The temporal relationship of AA to the medication under study indicates 
a possible causal relationship and cannot be explained by factors such as the patient's 
clinical status, therapeutic interventions. 
• 
Unrelated OA: The temporal relationship of AA with study medication indicates an 
unlikely causal relationship, or other factors (medication or concomitant conditions), 
other therapeutic interventions provide a satisfactory explanation for AA. 
 
12.3. 
Reference Security Information 
In this study the reference safety information (SRI) will be the information available in the 
corresponding Summary of Product Characteristics of the drugs under study: 
1. RECOVERY guideline. Intravenous administration of 6mg of dexamethasone every 24h 
for 10 days. It can be given both orally and intravenously at the same dose. 
2. BOWLING GUIDELINE. Intravenous administration of 250mg of methylprednisolone 
every 24 hours for 3 days. 
 
12.4. 
Security variables and parameters 
The assessment of the safety of the drugs under study will be carried out through clinical 
examination (physical, analytical and / or radiological) and by collecting serious adverse 
effects and those that may be directly related to the medication under study, such as: 
• 
Nosocomial infection (superadded infection developed at least 3 days after 
administration of the first dose of steroids) with microbiological confirmation by 


 
 
 
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culture. When there is no microbiological confirmation, the diagnosis is established 
at the discretion of the physician.  
• 
Hyperglycemia in non-diabetic patients or decompensation of diabetes mellitus in 
previously controlled patients. To define this event, the presence of at least one 
glycemic value greater than 180 mg/dl in the laboratory at any point of evolution or a 
value greater than 150 mg/dl in fasting capillary glycemia during the days that the 
patient receives treatment with glucocorticoids is established.  
• 
Episodes of psychosis defined as the presence of euphoria, behavioral changes, 
aggressiveness, alteration of thought with disorganization of this or presence of 
hallucinations or delusions.  
• 
Any other treatment-related adverse reactions that, in their medical judgment, are 
relevant to the safety of the study drug. 
 
12.5. 
Information on Adverse Events 
All adverse events shall be recorded in the data collection log. For each adverse event, the 
start and resolution dates, intensity, duration and consequence on study treatment (e.g. 
discontinuation) will be recorded. The severity of the adverse event and its relationship to 
the study will be assessed according to specific guidelines. Any action taken or results 
obtained (e.g. hospitalisation, withdrawal of treatment, etc.) will also be recorded. 
The investigator or a collaborator will question and/or examine the subject in relation to the 
incidence of adverse events. 
Adverse events will be collected once the subject has been recruited. If a subject suffers an 
adverse event after signing the informed consent document (inclusion), but before assigning 
the treatment (recruitment), the event will NOT be recorded unless the researcher considers 
that it has a causal relationship with some procedure of the protocol. 
Over the course of the study, the facility staff will again note any changes that occur in the 
disorder and nature of the possible adverse events. 
 
12.6. 
Assessment of the intensity of adverse events and their relationship 
to treatment 
The following definitions shall be applied to assess the intensity of adverse events: 


 
 
 
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• 
Mild: the sign, symptom or event is known, but it is easily tolerated. 
• 
Moderate: there is enough discomfort to interfere with usual activity and may 
warrant intervention. 
• 
Severe: it is disabling and produces inability to perform usual activities or significantly 
affects the clinical state and warrants intervention. 
• 
Life-threatening: immediate risk of death. 
• 
Death 
 
12.7. 
Assessment of the imputability of adverse events and serious 
adverse events with the study treatment: Imputability criteria. 
The sponsor will classify adverse events, based on their causal relationship with the drug, 
according to the Karch and Lasagna Algorithm (1977), as: 
• Definitive: there is a reasonable time sequence between the administration of the drug 
and the appearance of AA. This event coincides with the RA described for the drug, 
improves with its suppression, reappears after its readministration and cannot be 
explained by alternative causes.  
• Probable: there is a reasonable time sequence between the administration of the drug 
and the appearance of AA. This event coincides with the ARs described for the drug, 
improves after discontinuation of treatment and cannot be explained by other 
alternatives.  
• Possible: there is a reasonable time sequence between the administration of the drug 
and the appearance of AA. This event coincides with the RA described for the drug 
but can be explained by alternative causes.  
• Conditional or Unlikely: there is a reasonable temporal sequence between the 
administration of the drug and the appearance of AA. This event does not coincide 
with the RA described for the drug and can be explained by alternative causes.  
• Unrelated: there is no reasonable time sequence between the administration of the 
drug and the appearance of AA. This event does not coincide with the RA described 
for the drug and can be explained by alternative causes.  


 
 
 
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For expedited notification purposes, the definitive, probable and possible categories of 
Karch and Lasagna's (1977) algorithm will be considered as related and the conditional or 
improbable category of said algorithm  as unrelated. 
The determination of the possible relationship with the treatment of the study is the 
responsibility of the principal investigator of the research center or the person designated 
by it and, once notified, will be reviewed by the sponsor of the study and / or person to 
whom it delegates. 
 
12.8. 
Monitoring of adverse events 
Subjects with adverse events should be monitored using appropriate clinical assessments 
and laboratory tests as indicated by the investigator. All adverse events should be followed 
until satisfactory resolution or stabilization. All measures taken and the results of the 
monitoring should be recorded in the relevant section of the data collection booklet. If 
laboratory abnormalities are clinically significant and cause clinical symptoms or meet the 
criteria for serious adverse event, the diagnosis shall be reported as such a serious adverse 
event. 
 
12.9. 
AAG Notification, Expedited Notification, and Pregnancy Notification 
Although the safety data collected in the corresponding Summary of Product Characteristics 
of the investigational drugs indicate their tolerance profile, the limited data on the doses 
used in this study make us take measures to control the safety of the product. Therefore, 
any adverse event that meets the severity criteria defined throughout the study follow-up 
will be collected and reported. 
 
12.10. 
Reporting of Serious Adverse Events 
The principal investigator or collaborator shall report to the Pharmacovigilance 
Department FV-UICEC-HUC, all serious adverse events (as defined below), whether or not 
considered treatment-related or expected, within 24 hours (one working day), of their 
knowledge and through the corresponding notification form. Serious adverse events 
occurring should be reported at any time after the patient is included in the study (defined 
as the time the subject signs informed consent) and up to 30 days after the subject 
concludes or leaves the study. A subject is considered complete: after the conclusion of 
the last visit or contact (e.g., telephone contact with the investigator or a collaborator), 


 
 
 
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as indicated in the protocol assessment schedule, or after the last dose of study 
medication, whichever is later. Withdrawal is defined as the date on which a subject 
and/or investigator determines that the subject can no longer meet the study 
requirements at any subsequent visits and assessments. 
 
The reporting investigator will complete and sign the AAG notification form for the study 
that will be faxed or emailed to: 
 
PhD Patricia Rodríguez Fortúnez 
Head of Pharmacovigilance UICEC of the University Hospital of the Canary Islands 
(HUC) 
Telephone: 922 678 117 Fax: 922 677 284 
Email: patricia.rodriguez@scren.es 
 
PV staff will review the form received and, if appropriate, request additional information 
from the investigator. The investigator will provide information to the sponsor or to 
whoever assumes the tasks delegated by the sponsor (FV-UICEC-HUC Unit) whenever 
requested and, in any case, when his initial assessment changes in terms of severity or 
causality. The reporting of follow-up information shall follow the notification procedure 
described above. 
The staff of FV-UICEC-HUC shall keep a detailed record of all AAGs or of special interest 
communicated to them by investigators. 
In the event of a medication error or the investigational medicinal product is used outside 
the provisions of the protocol during the development of the study, the investigator will 
notify the FV-UICEC-HUC within 24 hours of becoming aware of it. The circuit for 
notification and form will be the same as for AAGs. 
AEs that meet the severity criteria described in the definitions section will be considered 
serious. Clinically significant events that do not result in death, are life-threatening or 
require hospitalization may be considered serious adverse pharmacological experiences 
when, based on appropriate medical judgment, they may endanger the individual or 
require medical or surgical intervention to prevent one of the outcomes listed in this 


 
 
 
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definition. Examples of such medical events are allergic bronchospasm requiring intensive 
treatment, at home or in an emergency unit, blood dyscrasias or seizures that do not 
result in hospitalization, or development of dependence or substance abuse. 
It is also necessary to report changes to laboratory tests that are considered clinically 
relevant, unless otherwise indicated in this section of the protocol. 
 
12.10.1. Expedited notification of RAGIs 
The FV-UICEC-HUC department is responsible for notifying the AEMPS and the 
Autonomous Communities where the test is carried out, all the RAGI that are collected in 
the study, following the procedure indicated in the current legislation. 
The maximum period for reporting an individual case of suspected RAGI will be 15 
calendar days from the moment the sponsor became aware of it. When the suspicion of 
RAGI has caused the death of the patient, or endangered his life, the sponsor will send 
the information within 7 calendar days from the moment he becomes aware of it. You will 
complete this information, if possible, within 8 days. 
This information should include an assessment of the significance and implication of the 
findings, including relevant previous experience with the same or similar medicinal 
products. 
Likewise, the competent body of each of the Autonomous Communities where the test is 
carried out must be notified of the suspicions of RAGI that occurred in the health centers 
of their Community. In both cases, the RAGI notification form will be used for this purpose. 
 
12.10.2. Expedited notification of other relevant security information 
The FV-UICEC-HUC department shall notify as soon as possible and no later than 15 days 
after becoming aware of it any information that could modify the benefit/risk ratio of the 
investigational medicinal product (for example: increase in the percentage of occurrence 
of expected RAGs, RAGIs occurring after the end of a clinical trial,  new developments 
related to the conduct of the trial or the development of the investigational medicinal 
product, any recommendations of the data monitoring committee relevant to the safety 
of the subjects, etc.). 
 


 
 
 
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12.10.3. Pregnancy Notification 
In the event that any pregnancy occurs during the development of the study, the 
investigator will notify the sponsor or whoever assumes the tasks delegated by the 
sponsor within 24 hours of his knowledge. The pregnancy will also be monitored to 
document its outcome and the health status of the newborn. If the outcome of pregnancy 
meets criteria for SAA or if the newborn has a serious event, the procedures described for 
reporting SAA will be followed. Notification will be made using AAG's specific notification 
form which will be faxed or emailed to the same contact who will receive AAG 
notifications. 
 
12.11. 
Periodic safety report 
The annual safety reports that will include the RAGIs and AAGs collected in the study since 
the patient is randomized, will be sent by FV-UICEC of the University Hospital of the Canary 
Islands to the AEMPS (Clinical Trials Area of the General Subdirectorate of Medicines for 
Human Use), to the corresponding Autonomous Communities and to the CEIm, within the 
deadlines established in current legislation. 
The submission of the annual safety report and other safety reports by the sponsor shall, in 
any case, comply with the criteria and procedure specified in Articles 43, 45 and 53 of 
Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 
2014. 
 
12.12. 
Report to researchers 
The sponsor will present to investigators safety information that could impact the safety of 
patients enrolled in the study as soon as possible. In addition, the researcher will be 
informed throughout the study about any safety aspects, including protocol modifications 
due to safety reasons. 
 
12.13. 
Discontinuation of study drugs due to adverse events 
Certain events or conditions may necessitate temporary or permanent discontinuation of 
study medication. Patients presenting with such events or conditions will remain "in the 
study" and will be followed until the end of the study. Any patient who temporarily 
discontinues study medication should restart it as soon as possible. Study guidelines will be 


 
 
 
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discontinued and replaced by out-of-study guidelines with continued follow-up in patients. 
If the administered drug is permanently discontinued, subsequent therapy is at the 
discretion of the investigator. 
• 
Temporal Discontinuation: Criteria for Temporal Discontinuation of Study Drugs: The 
development of toxicity that, depending on its nature and severity, requires 
temporary discontinuation of study medication until toxicity resolves as indicated in 
the toxicity management section above, as well as the development of another 
medical condition that discourages administration of the study drug. The decision to 
temporarily discontinue study medication in this situation will be left to the discretion 
of the investigator. The period during which the patient is not taking the study 
medication will be as short as possible. 
• 
Permanent Discontinuation: Criteria for Permanent Discontinuation of Study Drugs: 
The development of toxicity that requires permanent discontinuation of any study 
drug, refusal of the patient to continue treatment, when in the opinion of the 
investigator continuing study therapy is not the best option for the patient and 
completion of the study.  
 
13. Quality Control and Assurance 
In order to ensure data quality, the sponsor shall: 
• 
Provide quality instruction and training to research staff prior to the start of the study. 
Training topics include, but are not limited to: PCB certificates, AA reports, details of 
the study and its procedures, study documentation, informed consent, and patient 
recruitment. 
• 
Perform regular monitoring in accordance with the International Conference on 
Harmonization (ICH) for Good Clinical Practice (GCP). The data will be evaluated with 
respect to compliance with the protocol and accuracy in relation to the source documents. 
Monitors will verify that the clinical trial is conducted, that data is generated, 
documented and reported in compliance with protocol, good clinical practice and any 
applicable local regulatory requirements. 
Direct access to the data will be granted to the principal investigators, monitors, members of the 
evaluating CEIm and the AEMPS, as well as to the authorities that are necessary, in order to allow 
monitoring and surveillance related to the study, audits and inspections. At each center, they will 
be able to review the study records and compare them directly with the source documents, they 
could discuss how to conduct the study with the investigator, and verify that the facilities remain 
acceptable. Audit reports will be treated confidentially 


 
 
 
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14. Ethical and legal aspects. 
The trial will be conducted in accordance with the recommendations for clinical trials and drug 
evaluation in man, contained in the Declaration of Helsinki of 1964, revised in Tokyo, Venice, 
Hong Kong, South Africa, Edinburgh, Washington, Tokyo and Seoul (2008) and in the 
Document of instructions of the Spanish Agency of Medicines and Health Products for the 
conduct of clinical trials in Spain (Version 9 of July 27, 2018). The researcher will carry out the 
study in compliance with the ethical principles of the Declaration of Helsinki. 
The study/trial must adhere to the protocol, which guarantees compliance with Good Clinical 
Practices, described in the ICH Harmonized Tripartite Guidelines of Good Clinical Practices. 
This study/trial will be submitted for evaluation by a Research Ethics Committee with 
medicines and will be notified to the Spanish Agency for Medicines and Health Products 
(AEMPS). 
 
14.1. 
Patient Information and Informed Consent Sheet (HIP-CI) 
The investigator will explain to each patient (witness or legal representative) the nature of the 
study and the purposes, procedures, estimated duration, possible risks and benefits of their 
participation in the study / trial and possible inconveniences that this may cause. All patients 
will be informed of the voluntary nature of their participation and that they may withdraw at 
any time, without affecting their future medical care or their relationship with the doctor 
responsible for their treatment. 
The patient will have sufficient time to read and understand the explanations included in the 
patient information sheet before giving informed consent. No patient may be included in the 
study before having obtained informed consent in the manner indicated in accordance with 
the standards of good clinical practice.  
The patient will not be tested or treated by the study before informed consent is obtained.  
 
14.2. 
Audit and monitoring. 
Regulatory authorities, the CEIm, and the sponsor or a designated representative may 
request access to all original documents, patient data collection notebooks, and other study 
documentation to conduct an on-site audit or inspection. The researcher must ensure direct 
access to these documents and collaborate at all times in carrying out these activities. In 


 
 
 
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such procedures, due protection of private personal identification data will be attended to 
in accordance with the data protection law. 
The objective of this audit is to systematically evaluate all activities and documentation 
related to the trial in order to determine if these activities have been carried out and if the 
data have been analyzed and reported in accordance with the protocol, Good Clinical 
Practice Standards, International Conference on Harmonization (ICH) Guidelines and legal 
requirements. 
Monitoring. 
Before starting the study, at the start visit of each center or at a meeting of researchers, a 
representative of the Sponsor will review the protocol and the data collection notebooks 
with the researchers and other personnel involved in the study.  During the study, the 
monitor will regularly visit the center, to compare the data collected in the CRD with the 
source documents, check adherence to the protocol and the Standards of Good Clinical 
Practice. The investigator and trial personnel should be available to assist the monitor during 
these visits.  
No data revealing the identity of patients should leave the participating center.  
 
14.3. 
Failure to comply with protocol. 
Serious breaches of the authorised protocol should be reported to the sponsor without 
undue delay and at the latest within three calendar days from the date on which it became 
aware of the non-compliance. The sponsor will communicate it to the Spanish Agency of 
Medicines and Health Products and the CEIm. For these purposes, a serious non-compliance 
is one that may significantly compromise the safety and rights of the subjects or the 
reliability and robustness of the data obtained in the clinical trial.  
Where immediate deviation from the protocol is required to avoid immediate risks to 
patients, the investigator shall contact the sponsor, circumstances permitting, to discuss 
planned action. Any deviation from the protocol should be documented in detail in the CRD 
and in the original documentation. 
 


 
 
 
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15. Data Management and Archiving of Records 
The confidentiality of individual patient data will be respected at all times. The original data will 
be kept in the corresponding Service and only the researchers of the study / trial or the inspectors 
will have access to them, in case of inspection by the Spanish Health Authorities. 
Patients in the study/trial will be identified by a patient code. The investigator will inform patients 
that the data obtained during the study/trial will be stored and analyzed electronically, in 
compliance with Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 
April 2016 on the protection of natural persons with regard to the processing of personal data and 
on the free movement of such data and on the free movement of such data and on Organic Law 
3/2018,  of December 5, Protection of Personal Data and guarantee of digital rights. 
The researcher is the only person who can and should know the origin of the data obtained and 
who can associate them with the patient. 
The personal data (full name, address, place of work, NIF) of the researchers will be recorded in 
a computerized file, with the sole purpose of facilitating the organizational and logistical aspects 
necessary for the development of the study / trial. 
In compliance with the regulations described above, the data file will be treated confidentially 
and researchers may exercise their rights of access, rectification, cancellation and opposition with 
respect to the registered personal data, if they request it by writing to the Data Protection Officer 
of the promoter in protecciondedatos@ibsal.es. 
 
16. Financing and Insurance 
This is a non-commercial study. The trial will be funded by the sponsor and will be carried out 
with  the means and staff of the sponsor himself.  
 
Sure. 
Because the clinical trial has been requested as a low-intervention clinical trial, the sponsor takes 
advantage of the insurance coverage established by RD 1090/2015, of December 4, for this type 
of trial. 
 
 


 
 
 
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17. Difficulties and limitations of the study 
The main problem is the very nature of the pandemic due to SARS-CoV-2 infection, which has 
already surprised the health authorities in its evolution in several stages. This makes it very 
difficult to establish a fixed and stable recruitment line. 
Another limitation of the study is due to the pragmatic nature of this, since it could happen that 
it was necessary to add some treatment or remove it from the standard of treatment given the 
speed with which the knowledge of the disease evolves. 
 
 
18. Publication Policy 
Regardless of the results of the study, the sponsor agrees to present them to the medical 
community through scientific publications, congresses or other means. 
Any formal presentation or publication of the results of the study shall be considered a joint 
publication of the investigator(s) and the sponsor. 
 
19. Bibliographical references. 
1. 
RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in 
Hospitalized Patients with Covid-19 - Preliminary Report. N Engl J Med. Published 
online July 17, 2020. doi:10.1056/NEJMoa2021436 
2. 
Tomazini B, Maia I, Cavalcanti A, et al. Effect of Dexamethasone on Days Alive and 
Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress 
Syndrome and COVID-19: The CoDEX Randomized Clinical Trial. JAMA. 
doi:10.1001/jama.2020.17021 
3. 
Dequin P, Heming N, Meziani F, et al. Effect of Hydrocortisone on 21-Day Mortality or 
Respiratory Support Among Critically Ill Patients With COVID-19: A Randomized 
Clinical Trial. JAMA. doi:10.1001/jama.2020.16761 
4. 
Angus D, Derde L, Al-Beidh F, et al. Effect of Hydrocortisone on Mortality and Organ 
Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 
Corticosteroid 
Domain 
Randomized 
Clinical 
Trial. 
 
JAMA. 
doi:10.1001/jama.2020.17022 


 
 
 
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5. 
Corral-Gudino L, Bahamonde A, Arnaiz-Revillas F, et al. GLUCOCOVID: A 
Controlled Trial of Methylprednisolone in Adults Hospitalized with COVID-19 
Pneumonia. 
Infectious 
Diseases 
(except 
HIV/AIDS); 
2020. 
doi:10.1101/2020.06.17.20133579 
6. 
Prado-Jeronimo CM, Farias MEL, Val FFA, et al. Methylprednisolone as Adjunctive 
Therapy for Patients Hospitalized With COVID-19 (Metcovid): A Randomised, Double-
Blind, Phase IIb, Placebo-Controlled Trial. Clin Infect Dis. Published online August 12, 
2020. doi:10.1093/cid/ciaa1177 
7. 
Callejas Rubio JL, Luna Del Castillo J de D, de la Hera Fernández J, Guirao Arrabal E, 
Colmenero Ruiz M, Ortego Centeno N. Effectiveness of corticoid pulses in patients with 
cytokine storm syndrome induced by SARS-CoV-2 infection. Med Clin (Engl Ed). 
2020;155(4):159-161. doi:10.1016/j.medcle.2020.07.002 
8. 
Rodríguez-Baño J, Pachón J, Carratalà J, et al. Treatment with tocilizumab or 
corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre 
cohort study (SAM-COVID-19). Clin Microbiol Infect. Published online August 27, 
2020. doi:10.1016/j.cmi.2020.08.010 
9. 
Ruiz-Irastorza G, Pijoan J-I, Bereciartua E, et al. Second week methyl-prednisolone 
pulses improve prognosis in patients with severe coronavirus disease 2019 pneumonia: 
An observational comparative study using routine care data. PLoS ONE. 
2020;15(9):e0239401. doi:10.1371/journal.pone.0239401 
10. Panettieri RA, Schaafsma D, Amrani Y, Koziol-White C, Ostrom R, Tliba O. Non-
genomic Effects of Glucocorticoids: An Updated View. Trends in Pharmacological 
Sciences. 2019;40(1):38-49. doi:10.1016/j.tips.2018.11.002 
11. Stellato C. Post-transcriptional and Nongenomic Effects of Glucocorticoids. Proc Am 
Thorac Soc. 2004;1(3):255-263. doi:10.1513/pats.200402-015MS 
12. Borghesi A, Maroldi R. COVID-19 outbreak in Italy: experimental chest X-ray scoring 
system for quantifying and monitoring disease progression. Radiol Med. 
2020;125(5):509-513. doi:10.1007/s11547-020-01200-3 
13. Blenkinsop A, Parmar M, Choodari-Oskooei B. Assessing the impact of efficacy 
stopping rules on the error rates under the multi-arm multi-stage framework. Clin Trials. 
2019; 16(2):132-141. doi: 10.1177/174077451882355125. 
14. WHO Working Group on the Clinical Characterisation and Management of COVID-19 
infection. A minimal common outcome measure set for COVID-19 clinical research. 
Lancet 
Infect 
Dis 
2020; 
20: 
e192–97. 
doi: 
https://doi.org/10.1016/S1473-
3099(20)30483-7 


 
 
 
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ANNEX 1: Scales of measurement 
 
A. Serious situation. WHO Proposal14 
 
Patient status 
Descriptor 
Scale 
 
Not infected. No virus detected 
0 
Ambulant. 
Mild illness 
Asymptomatic, independent, virus detected 
1 
Symptomatic, independent 
2 
Symptomatic, needs help 
3 
Hospitalized. 
Moderate disease 
Hospitalized. Does not require Oxygen 
4 
Hospitalized. Precise oxygen either by nasal glasses, or 
by conventional mask 
5 
Hospitalized. Severe 
illness 
High-flow oxygen or noninvasive mechanical 
ventilation 
6 
Mechanical intubation, 
pO2/FiO2 ≥150 or SpO2/FiO2 ≥200 
7 
Mechanical intubation, vasopressors, or 
pO2/FIO2 <150 (SpO2/FiO2 <200) 
8 
Mechanical intubation, 
pO2/FiO2 <150 + 
vasopressors, dialysis, or ECMO 
9 
Deceased 
Deceased 
10 
 
 
 
 
 
 


 
 
 
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B. Severity scale Rx Brixia Score (0 to 18 points)12. 
 
Lung 
area 
Normal 
Interstitial 
infiltrate 
Interstitial and alveolar 
infiltrate with predominance 
of the former 
Interstitial and alveolar 
infiltrate with predominance 
of the second 
Top 
right 
0 
1 
2 
3 
Middle 
right 
0 
1 
2 
3 
Lower 
right 
0 
1 
2 
3 
Top left 
0 
1 
2 
3 
Middle 
left 
0 
1 
2 
3 
Bottom 
left 
0 
1 
2 
3 
Total 
 
 
 
 
 
 
 


 
 
 
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ANNEX 2: Justification for the low-level nature of intervention.  
 
It is requested that the CEIm evaluator of the trial rate it as: 
 
Clinical trial of low level of intervention according to the  provisions of  RD 1090/2015 and 
European Regulation No. 536/2014 for the following conditions: 
 
1. The use of the investigational medicinal product is evidence-based and supported by 
published scientific data on the safety and efficacy of such medicinal products in one of the 
Member States concerned. 
 
1.1.1. The use of corticosteroids in COVID-19 pneumonia is validated mainly according 
to the results of the RECOVERY clinical trials (ISRCTN50189673) conducted by the 
British National Health System (NHS), as well as the meta-analysis conducted by 
the World Health Organization (doi:10.1001/jama.2020.17023). 
 
2. The complementary diagnostic or follow-up procedures entail an additional risk or burden 
for the safety of the subjects that is minimal compared to that of routine clinical practice in 
one of the Member States involved, since they are the usual ones carried out in the 
Prevention Services Involved. 
3. Low-intervention clinical trials are often crucial to evaluate standard treatments and 
diagnoses and optimize the use of medicines, thereby contributing to a high level of public 
health:  
3.1. There is currently no effective solution for the treatment of COVID pneumonia, because 
despite the improvement in prognosis with the use of the RECVOERY dexamethasone 
regimen, the case fatality rate is still 23% in non-critical patients. 
3.2. Although there is the possibility of application of dexamethasone in intermediate 
doses, it seems logical that an alternative can be offered with higher doses of 
corticosteroids from which patients with COVID pneumonia can be benefited. 
 
 
 
 
 


 
 
 
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Additional information: 
 
Clinical trials assessing the usefulness of intermediate doses in patients with COVID-19 
pneumonia 
 
• 
RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in Hospitalized 
patients with Covid-19 - Preliminary Report. N Engl J Med. Published online July 17, 
2020. doi:10.1056/NEJMoa2021436 
• 
Tomazini B, Maia I, Cavalcanti A, et al. Effect of Dexamethasone on Days Alive and 
Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress 
Syndrome 
and 
COVID-19: 
The 
CoDEX 
Randomized 
Clinical 
Trial. 
JAMA. 
doi:10.1001/jama.2020.17021 
• 
Dequin P, Heming N, Meziani F, et al. Effect of Hydrocortisone on 21-Day Mortality or 
Respiratory Support Among Critically Ill Patients With COVID-19: A Randomized Clinical 
Trial. JAMA. doi:10.1001/jama.2020.16761 
• 
Angus D, Derde L, Al-Beidh F, et al. Effect of Hydrocortisone on Mortality and Organ 
Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid 
Domain Randomized Clinical Trial.  JAMA. doi:10.1001/jama.2020.17022 
• 
Corral-Gudino L, Bahamonde A, Arnaiz-Revillas F, et al. GLUCOCOVID: A Controlled Trial 
of Methylprednisolone in Adults Hospitalized with COVID-19 Pneumonia. Infectious 
Diseases (except HIV/AIDS); 2020. doi:10.1101/2020.06.17.20133579 
• 
Prado-Jeronimo CM, Farias MEL, Val FFA, et al. Methylprednisolone as Adjunctive 
Therapy for Patients Hospitalized With COVID-19 (Metcovid): A Randomised, Double-
Blind, Phase IIb, Placebo-Controlled Trial. Clin Infect Dis. Published online August 12, 
2020. doi:10.1093/cid/ciaa1177 
 
 
Meta-analyses assessing the usefulness of corticosteroids in patients with COVID-19 pneumonia 
 
• 
The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. 
Association Between Administration of Systemic Corticosteroids and Mortality Among 
Critically Ill Patients With COVID-19. A Meta-analysis. JAMA. 2020;324(13):1330-1341. 
doi:10.1001/jama.2020.17023 
 
 
Observational studies assessing the usefulness of high doses of corticosteroids in COVID-19 
pneumonia 
 


 
 
 
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• 
Callejas Rubio JL, Luna Del Castillo J de D, de la Hera Fernández J, Guirao Arrabal E, 
Colmenero Ruiz M, Ortego Centeno N. Effectiveness of corticoid pulses in patients with 
cytokine storm syndrome induced by SARS-CoV-2 infection. Med Clin (Engl Ed). 
2020;155(4):159-161. doi:10.1016/j.medcle.2020.07.002 
• 
Rodríguez-Baño J, Pachón J, Carratalà J, et al. Treatment with tocilizumab or 
corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre 
cohort study (SAM-COVID-19). Clin Microbiol Infect. Published online August 27, 2020. 
doi:10.1016/j.cmi.2020.08.010 
• 
Ruiz-Irastorza G, Pijoan J-I, Bereciartua E, et al. Second week methyl-prednisolone pulses 
improve prognosis in patients with severe coronavirus disease 2019 pneumonia: An 
observational 
comparative 
study 
using 
routine 
care 
data. 
 
PLoS 
ONE. 
2020;15(9):e0239401. doi:10.1371/journal.pone.0239401 
 
 

ICF_001.pdf: 
 
                
               Version 1.3, January 07, 2021 
EudraCT: 2020-005026-28 
Sponsor: Instituto de Investigación Biomédica de Salamanca (IBSAL) 
 
INFORMATION AND INFORMED CONSENT SHEET 
Title 
MP3-pulses COVID-19. METHYLPREDNISOLONE PULSES 
VERSUS DEXAMETHASONE RECOVERY REGIMEN IN 
PATIENTS WITH PNEUMONIA DUE TO SARS-COV-2 
CORONAVIRUS INFECTION 
Protocol Code  
MP3-pulses-COVID-19 
Principal Investigator 
 
Service 
 
 
Introduction  
We are writing to inform you about a research study in which you are invited to participate. 
Participation is voluntary. Please take the time to read the information below and refer to what 
you want. Ask the researcher in this study if anything is unclear to you or if you want to learn 
more. 
As you know, he is hospitalized for a confirmed condition or very compatible with coronavirus 
infection.  
This is still a poorly understood disease. So far, there is no treatment specifically directed against 
this virus. However, there are several medications that have been found to be effective in some 
patients. These treatments, and other general measures, are being administered to you, in a 
way that is tailored to your clinical situation. 
After infection with the virus, the body's defense systems organize a response to try to eliminate 
it. That response sometimes leads to inflammation of some organs, especially the lungs. For this 
reason, medications, such as corticosteroids, are sometimes used in this disease to try to 
decrease the harmful part of the inflammation.   
At the end of June 2020, a large clinical trial (RECOVERY) conducted by the British public health 
system was the first to clearly demonstrate that corticosteroids are useful in the management 
of this disease when patients notice shortness of breath and require supplemental oxygen. Since 
then, this treatment has been common in all patients with COVID-19 pneumonia.  
However, even though we know the usefulness of corticosteroid treatment, we still need to 
know what the ideal dose and duration of treatment is and whether the use of higher doses 
could be even more beneficial for the patient. 
Objective of the study 
The aim of the study is to compare the effect of high-dose methylprednisolone boluses versus 
the dexamethasone intermediate-dose regimen (the one used in the RECOVERY trial) in COVID-
19 patients with non-critical respiratory failure. 


 
                
               Version 1.3, January 07, 2021 
EudraCT: 2020-005026-28 
Sponsor: Instituto de Investigación Biomédica de Salamanca (IBSAL) 
 
This research study has been approved by the Ethics Committee for Research with Medicines of 
the Salamanca Health Area and is carried out in accordance with current legislation, Royal 
Decree 1090/2015 of 4 December and European Regulation 536/2014 of 16 April, which regulate 
clinical trials with medicines.  and in accordance with the standards of good clinical practice.  
Study Procedures and Potential Risks and Discomforts 
The study will compare the outcome of a limited number of patients divided into 2 groups. Both 
groups will be treated with glucocorticoids. One of them at the dose tested in the RECOVERY 
trial for 10 days. The other group will receive higher doses, but for only three days, known as 
methylprednisolone boluses. 
The study has been reviewed and approved by the appropriate committees in order to ensure 
its quality and the safety of the patients included.  
During the study, your doctor will inform you of the need to receive steroid treatment. You will 
then be assigned to one of two study groups: 
1) 
Group 1: dexamethasone 6 mg for 10 days, the first three intravenously and the rest 
either orally or intravenously depending on the patient  
2) 
Group 2: 3 boluses of intravenous methylprednisolone. You will also continue with all 
other treatments indicated for your particular case. 
This assignment will be made 1:1 randomly, you have an equal chance of getting one or the 
other treatment arm. In addition, the assignment is done centrally, so neither you nor the doctor 
know a priori the branch of treatment that you may have.   
Your doctor will monitor your progress and may always modify the treatment, or cancel the 
study, if he or she considers it preferable in terms of your evolution. Subsequently, you will 
collect the main data from your story to analyze the results. That data will be encrypted, with 
no possibility of you being identified. 
The rest of the treatment will be included in your hospital's COVID-19 management protocol. 
No diagnostic laboratory or imaging tests other than those that would normally be performed 
during the admission of a patient with COVID-19 infection will be performed. During admission, 
you will have at least 2 x-rays and 3 analysis determinations. 
In addition, 28 days after the start of treatment, a follow-up visit will be made to see your 
progress, in which some more tests will be carried out, such as blood tests and imaging tests. 
Similarly, at 12 weeks or if you are removed from the study, of your own volition or by decision 
of your doctor, prematurely at any time during your participation, you will have another follow-
up visit. This visit can be carried out in person or by phone, if the doctor and you consider it 
appropriate, so, in addition to asking you about your condition, you could be given some more 
tests such as blood tests and imaging tests if the visit is face-to-face.  


 
                
               Version 1.3, January 07, 2021 
EudraCT: 2020-005026-28 
Sponsor: Instituto de Investigación Biomédica de Salamanca (IBSAL) 
 
Given the current situation of the global health crisis, in the event of a lack of stock of any of the 
active ingredients in the study, it could be decided to use other glucocorticoid preparations in 
doses equivalent to that of methyl-prednisolone, according to the following table: 
Active ingredient 
Guideline 
Equivalence in  
methyl-
prednisolona 
Equivalence in 
prednisone  
Dexamethasone 
6 mg/24h 
30 mg/24h 
37.5mg/24h 
Methylprednisolona 
250mg/24h 
N/A 
312.5 mg/24h 
Hydrocortisone 
50-100mg/6h 
20-40 mg/12h 
25-50 mg/12h 
 
In both arms of the study, or in the case of administering any of the other glucocorticoid 
preparations, the risks inherent to the use of corticosteroids may appear, such as mainly the 
increased risk of infection added to the infection by the virus itself (rare), increased blood 
glucose levels (rare) or mood disorders (very rare). Other side effects of corticosteroids such as 
high blood pressure, dyslipidemia, diabetes or osteoporosis are not expected in this study given 
the short duration of treatment. Participation in this study would not cause any discomfort, and 
does not involve additional health risk. 
If you do not agree to participate, your doctor will continue your current treatment and may 
eventually consider administering the 10-day dose of dexamethasone as well. 
Voluntary Participation and Withdrawal 
You are free to decide whether or not you want to take part in this study, participation is 
completely voluntary. If you choose to participate, you still have the ability to withdraw at any 
time, without explanation, and without any penalty or negative consequences for you. If you 
change your mind about your data, you have the right to request its destruction or 
anonymization, through your doctor/researcher. However, you should be aware that the data 
obtained in the analyses carried out up to that point may be used for the purposes requested 
and may be kept in compliance with the corresponding legal obligations. 
If you do not participate in the study, you will receive treatment according to standard clinical 
practice, and there is even the possibility that, if your doctor decides to do so, you may receive 
one of the drugs offered in this study.  If you want, the study doctor will give you more 
information. 
Potential Benefits 
You may not get any health benefits from taking part in this study. However, the information 
gained from this trial may contribute to medical progress and could help other patients suffering 
from their disease in the future. 
You will not receive any financial benefit from the transfer of the data provided, nor will you 
have rights to possible commercial benefits from the discoveries that may be made as a result 
of the research carried out. 


 
                
               Version 1.3, January 07, 2021 
EudraCT: 2020-005026-28 
Sponsor: Instituto de Investigación Biomédica de Salamanca (IBSAL) 
 
Data protection and confidentiality 
All information about your results will be treated as strictly confidential. Both the Centre and 
the Promoter are responsible for the processing of your data and undertake to comply with the 
data protection regulations in force, currently Organic Law 3/2018, of 5 December, on the 
Protection of Personal Data and Guarantee of Digital Rights and Regulation (EU) 2016/679 of the 
European Parliament and of the Council of 27 April 2016 on Data Protection (GDPR). The data 
collected for the study will be identified by a code, so that no information that could identify 
you is included, and only the research team will be able to relate this data to you. The research 
team will analyse your data based on the legitimate interest of achieving the purposes of the 
study. Subsequently, your personal information will only be retained by the health care center 
and the research team for other scientific research purposes if you have given your consent to 
do so and if permitted by applicable law and ethical requirements. 
If the results of the study are susceptible to publication in scientific journals, at no time will 
personal data of the participants in this research be provided. We inform you that you have the 
right to access, rectify or cancel your data, and you can limit the processing of data that is 
incorrect, request a copy or transfer to a third party of the data you have provided for the study. 
To exercise their rights, or in the event that the participant wishes to provide further information 
on the processing of their personal data, the principal investigator of the study whose details 
are specified at the end of this document may be contacted by the Data Protection Officer of 
the 
Regional 
Health 
Management 
(dpd@saludcastillayleon.es) 
or 
our 
centre 
(dpd.husa@saludcastillayleon.es). You also have the right to contact the Data Protection Agency 
if you are not satisfied. 
 
 
 
 
 
 
 
 
 
 
 
 


 
                
               Version 1.3, January 07, 2021 
EudraCT: 2020-005026-28 
Sponsor: Instituto de Investigación Biomédica de Salamanca (IBSAL) 
 
 
Information on results  
At your request, at the end of the study and in accordance with article 27 of Law 14/2007 on 
Biomedical Research, you may be provided with information on the results of this research work. 
I authorize those responsible for the project to use my data for the purposes and in the manner 
described in this document.  
        □ IF □ NO 
I consent to the future use of the data that have been collected in this research study to conduct 
other research related to the medical specialty or research area of this study 
        □ IF □ NO 
I consent to my medical records being accessed again in the future to collect data that is 
considered important for other research related to the medical specialty or research area of this 
study 
        □ IF □ NO 
 
 
 
Contact details of the research team: 
If you have any questions or need more information, please contact:   
Name:  
Telephone:  
 
 


 
                
               Version 1.3, January 07, 2021 
EudraCT: 2020-005026-28 
Sponsor: Instituto de Investigación Biomédica de Salamanca (IBSAL) 
 
INFORMED CONSENT 
Title 
MP3-pulses COVID-19. METHYLPREDNISOLONE PULSES 
VERSUS DEXAMETHASONE RECOVERY REGIMEN IN 
PATIENTS WITH PNEUMONIA DUE TO SARS-COV-2 
CORONAVIRUS INFECTION 
Protocol Code  
MP3-pulses-COVID-19 
Principal Investigator 
 
Service 
 
 
I (First and Last Name) ________________________________ 
I have read the information sheet that has been given to me about the study. 
I've been able to ask questions about the study. 
I have received enough information about the study. 
I have spoken with the Investigator __________________ 
I understand that my participation is voluntary. 
I understand that I can withdraw from the study: 
 
 
1º Whenever you want 
 
2º Without having to give explanations 
 
3º Without having any negative repercussions 
I voluntarily agree to participate in the clinical trial and authorize the use of all information 
obtained. I understand that I will receive a signed copy of this informed consent. 
 
 
 
______   
 
 
 
 
 
 
        _________ 
Participant's signature  
 
 
 
 
 
 
 
Date 
 
 
 
 
 
_______________ 
 
       
 
 
 
 
 
 
Researcher's name and signature 
 
 
 
 
 
 
Date 


 
                
               Version 1.3, January 07, 2021 
EudraCT: 2020-005026-28 
Sponsor: Instituto de Investigación Biomédica de Salamanca (IBSAL) 
 
INFORMED CONSENT IN THE PRESENCE OF A WITNESS* 
Title 
MP3-pulses COVID-19. METHYLPREDNISOLONE PULSES 
VERSUS DEXAMETHASONE RECOVERY REGIMEN IN 
PATIENTS WITH PNEUMONIA DUE TO SARS-COV-2 
CORONAVIRUS INFECTION 
Protocol Code  
MP3-pulses-COVID-19 
Principal Investigator 
 
Service 
 
 
_____________________________________________________________________________ 
(Patient's name and surname) 
 
I (Name and Surname of Witness)_________________________________________________ 
I confirm that the patient has read (or has been read to them  if they are unable to do so on 
their own), the information sheet that has been given to them about the study. 
He was able to ask questions about the study. 
You have received enough information about the study. 
Have you spoken with the Investigator _________________________________ 
You understand that your participation is voluntary. 
You understand that you may withdraw from the study: 
 
 
1º Whenever you want 
 
2º Without having to give explanations 
 
3º Without having any negative repercussions 
You voluntarily agree to participate in the clinical trial and authorize the use of all information 
obtained. You understand that you will receive a signed copy of this informed consent. 
 
 
 
______   
 
 
 
 
 
 
        _________ 
Signature of the witness 
 
 
 
 
 
 
 
 
Date 
 
 
_______________ 
 
       
 
 
 
 
 
 
Researcher's name and signature 
 
 
 
 
 
 
Date 


 
                
               Version 1.3, January 07, 2021 
EudraCT: 2020-005026-28 
Sponsor: Instituto de Investigación Biomédica de Salamanca (IBSAL) 
 
*When the patient is unable to sign and gives oral consent. The witness may be a family member or 
healthcare worker.  
INFORMED CONSENT FOR LEGAL REPRESENTATIVE 
Title 
MP3-pulses COVID-19. METHYLPREDNISOLONE PULSES 
VERSUS DEXAMETHASONE RECOVERY REGIMEN IN 
PATIENTS WITH PNEUMONIA DUE TO SARS-COV-2 
CORONAVIRUS INFECTION 
Protocol Code  
MP3-pulses-COVID-19 
Principal Investigator 
 
Service 
 
 
_____________________________________________________________________________ 
(Patient's name and surname) 
 
I 
(Name 
and 
Surname 
of 
Legal 
Representative) 
______________________________________________________________ 
I have read the information sheet that has been given to me about the study. 
He was able to ask questions about the study. 
You have received enough information about the study. 
Have you spoken with the Investigator _________________________________ 
I understand that your participation is voluntary. 
I understand that you may withdraw from the study: 
 
 
1º Whenever you want 
 
2º Without having to give explanations 
 
3º Without having any negative repercussions 
I voluntarily agree to participate in the clinical trial and authorize the use of all information 
obtained. I understand that we will receive a signed copy of this informed consent. 
 
 
 
______   
 
 
 
 
 
 
        _________ 
Signature of the legal representative 
 
 
 
 
 
 
Date 
 
 
_______________ 
 
       
 
 
 
 
 
 
Researcher's name and signature 
 
 
 
 
 
 
Date 


 
                
               Version 1.3, January 07, 2021 
EudraCT: 2020-005026-28 
Sponsor: Instituto de Investigación Biomédica de Salamanca (IBSAL) 
 
INFORMED CONSENT IN THE PRESENCE OF A WITNESS* 
Title 
MP3-pulses COVID-19. METHYLPREDNISOLONE PULSES 
VERSUS DEXAMETHASONE RECOVERY REGIMEN IN 
PATIENTS WITH PNEUMONIA DUE TO SARS-COV-2 
CORONAVIRUS INFECTION 
Protocol Code  
MP3-pulses-COVID-19 
Principal Investigator 
 
Service 
 
 
_____________________________________________________________________________ 
(Patient's name and surname) 
 
I (Name and Surname of Witness)_________________________________________________ 
I confirm that the patient has read (or has been read to them  if they are unable to do so on 
their own), the information sheet that has been given to them about the study. 
He was able to ask questions about the study. 
You have received enough information about the study. 
Have you spoken with the Investigator _________________________________ 
You understand that your participation is voluntary. 
You understand that you may withdraw from the study: 
 
 
1º Whenever you want 
 
2º Without having to give explanations 
 
3º Without having any negative repercussions 
You voluntarily agree to participate in the clinical trial and authorize the use of all information 
obtained. You understand that you will receive a signed copy of this informed consent. 
 
 
 
______   
 
 
 
 
 
 
        _________ 
Signature of the witness 
 
 
 
 
 
 
 
 
Date 
 
 
 
_______________ 
 
       
 
 
 
 
 
 
Researcher's name and signature 
 
 
 
 
 
 
Date 


 
                
               Version 1.3, January 07, 2021 
EudraCT: 2020-005026-28 
Sponsor: Instituto de Investigación Biomédica de Salamanca (IBSAL) 
 
 
REVOCATION OF CONSENT 
 
Title 
MP3-pulses COVID-19. METHYLPREDNISOLONE PULSES 
VERSUS DEXAMETHASONE RECOVERY REGIMEN IN 
PATIENTS WITH PNEUMONIA DUE TO SARS-COV-2 
CORONAVIRUS INFECTION 
Protocol Code  
MP3-pulses-COVID-19 
Principal Investigator 
 
Service 
 
 
 
D/Dña ____   
 
I 
voluntarily 
revoke 
the 
consent 
given 
on 
________________________________________________________________ 
 
 
 
 
 
______   
 
 
 
 
 
 
        _________ 
Participant's signature  
 
 
 
 
 
 
 
Date 
 
 
 
 
 
_______________ 
 
       
 
 
 
 
 
 
Researcher's name and signature 
 
 
 
 
 
 
Date