Extension Study in a Cohort of Adult Patients With SARS-CoV-2 Infection Requiring Hospital Admission and Received Treatment With Plitidepsin in the APLICOV-PC Study
Phase: PHASE1
Conditions: COVID-19 Infection
Sponsor: PharmaMar

 
 
 
 
 
 
 
 
 
Extension Study in a Cohort of Adult Patients With SARS-CoV-2 
Infection Requiring Hospital Admission and Received Treatment With 
Plitidepsin in the APLICOV-PC Study 
 
Study Protocol 
 
NCT05121740 
October 6, 2021 
 
 
 

CONFIDENTIAL 
 
 
Page 1/52  
 
 
COORDINATING INVESTIGATORS:  
José Felipe Varona 
Internal Medicine Department, Hospital Universitario HM Montepríncipe 
Pedro Landete 
Pneumology Service, Hospital Universitario la Princesa 
Pablo Guisado-Vasco 
Internal Medicine Department, Hospital Universitario Quironsalud Madrid 
Roger Paredes  
Department of Infectious Diseases, Hospital Germans Trias i Pujol 
 
PROTOCOL CODE: E-APLICOV-PC/ AV-APL-A-003-21 
 
EudraCT number: 2021-004966-37  
SPONSOR: Pharma Mar, SA 
Previous versions of the protocol/amendments  
(number and date):  
 
- Not applicable 
 
Current version (number and date):  
 
- Version 1.0 dated 06/Oct/2021 
CONFIDENTIAL: The information and data included in this protocol contain trade 
secrets and classified or confidential information that is the property of the sponsor. No 
person is authorised to make this information public without the written permission of the 
sponsor. These limitations will also apply to all information deemed classified or 
confidential that is provided in the future. This document may be disclosed and used by 
your team and collaborators, as necessary to carry out the clinical study. 
Extension study in a cohort of adult patients 
with SARS CoV2 infection requiring hospital 
admission and received treatment with 
plitidepsin in the APLICOV-PC study 

Protocol code: E-APLICOV-PC/ AV-APL-A-003-21 
 
EudraCT No.: 2021-004966-37 
Version 1.0 dated 06/Oct/2021 
 
 
 
CONFIDENTIAL 
 
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1. PROTOCOL SUMMARY 
1.1. Sponsor identification 
Name:  
Pharma Mar, SA 
 
Contact Person:  
 
José Jimeno MD PhD 
VP Global Head Virology & Inflammation  
email: jjimeno@pharmamar.com 
Tel: +34 91 846 6036 / +34 619 301 135 
 
 
Postal address:  
Avda. de los Reyes, 1 
Polígono Industrial “La Mina” 
28770 Colmenar Viejo 
Madrid, Spain 
Pharmacovigilance Contact:  
Hervé Dhellot 
EEA Qualified Person for Pharmacovigilance and Senior Pharmacovigilance 
Manager 
email: 
/ AEincoming@pharmamar.com 
Tel (24 hours): + 34 91 823 45 56 
Tel: 
 
Fax: 
Postal address:  
Avda. de los Reyes, 1 
Polígono Industrial “La Mina” 
28770 Colmenar Viejo 
Madrid, Spain 
Coordinating investigators:  
Dr. José Felipe Varona 
Hospital Universitario HM Montepríncipe 
Department of Internal Medicine 

Protocol code: E-APLICOV-PC/ AV-APL-A-003-21 
 
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Dr. Pedro Landete 
Hospital Universitario la Princesa  
Pneumology Service 
 
Dr. Pablo Guisado-Vasco 
Hospital Universitario Quironsalud Madrid 
Department of Internal Medicine 
 
Dr. Roger Paredes  
Hospital Germans Trias i Pujol 
Department of Infectious Diseases 
 
1.2. Study Title  
Extension study in a cohort of adult patients with SARS CoV2 infection requiring 
hospital admission and received treatment with plitidepsin in the APLICOV-PC 
study. 
1.3. Protocol code 
E-APLICOV-PC/ AV-APL-A-003-21 
1.4. Drug Research Ethics Committee (CEIm) 
Drug Research Ethics Committee of HM Hospitales  
1.5. Company Responsible for Monitoring 
APICES 
Av. Antonio López, 16 - 1ºA 
28320 - Pinto (MADRID) 
Tel: +34 91 816 6804 
Fax: +34 91 816 9172 
email: 
 
1.6. Investigational product 
Plitidepsin 
1.7. Clinical Trial Phase 
APLICOV-PC proof-of-concept study follow-up. 

Protocol code: E-APLICOV-PC/ AV-APL-A-003-21 
 
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1.8. Study objective  
Evaluate the incidence of post-COVID morbidity and characterise the 
complications profile in patients who participated in the APLICOV-PC study. 
1.9. Study design 
Multi-site extension study of the APLICOV-PC clinical study follow-up. 
The plitidepsin doses considered in this trial include the three doses specified in 
the APLICOV-PC study: 
- 
1.5 mg of plitidepsin administered as a 1.5-hour infusion, once a day for 3 
consecutive days (total dose 4.5 mg). 
- 
2.0 mg of plitidepsin administered as a 1.5-hour infusion, once a day for 3 
consecutive days (total dose 6.0 mg).  
- 
2.5 mg of plitidepsin administered as a 1.5-hour infusion, once a day for 3 
consecutive days (total dose 7.5 mg). 
1.10. 
Disease under study 
COVID-19 infection or SARS CoV2 infection. 
1.11. 
Endpoints 
Incidence of post-COVID-19 complications. 
1.12. 
Study population and total number of patients  
The main objective of the study is to evaluate the incidence of post-COVID 
morbidity and characterize the complications profile in patients who participated 
in the APLICOV-PC study.  
The maximum number of patients who can participate in the trial is limited to 42.  
1.13. 
Inclusion and exclusion criteria 
1.13.1. 
Inclusion criteria 
Patient who participated in the APLICOV-PC study treated with plitidepsin and 
who gives their consent.  
1.13.2. 
Exclusion criteria 
There are no exclusion criteria for this study.  

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1.14. 
Study schedule 
Inclusion start date: 10/2021 
Inclusion end date: December 2021 
The study will end with the last procedure performed on the last patient. It is 
estimated that all procedures will have ended in the month after the inclusion of 
the first patient in the study.  
 
 

Protocol code: E-APLICOV-PC/ AV-APL-A-003-21 
 
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2. TABLE OF CONTENTS 
 
1. 
PROTOCOL SUMMARY .......................................................................................................................................................... 2 
1.1. 
SPONSOR IDENTIFICATION ....................................................................................................................................................... 2 
1.2. 
STUDY TITLE ............................................................................................................................................................................. 3 
1.3. 
PROTOCOL CODE....................................................................................................................................................................... 3 
1.4. 
DRUG RESEARCH ETHICS COMMITTEE (CEIM).................................................................................................................. 3 
1.5. 
COMPANY RESPONSIBLE FOR MONITORING ....................................................................................................................... 3 
1.6. 
INVESTIGATIONAL PRODUCT .................................................................................................................................................. 3 
1.7. 
CLINICAL TRIAL PHASE ........................................................................................................................................................... 3 
1.8. 
STUDY OBJECTIVE .................................................................................................................................................................... 4 
1.9. 
STUDY DESIGN .......................................................................................................................................................................... 4 
1.10. 
DISEASE UNDER STUDY ........................................................................................................................................................... 4 
1.11. 
ENDPOINTS ................................................................................................................................................................................ 4 
1.12. 
STUDY POPULATION AND TOTAL NUMBER OF PATIENTS ................................................................................................... 4 
1.13. 
INCLUSION AND EXCLUSION CRITERIA .................................................................................................................................. 4 
1.13.1. Inclusion criteria ................................................................................................................................................................. 4 
1.13.2. Exclusion criteria ................................................................................................................................................................ 4 
1.14. 
STUDY SCHEDULE..................................................................................................................................................................... 5 
2. 
TABLE OF CONTENTS ............................................................................................................................................................. 6 
3. 
ABBREVIATIONS ........................................................................................................................................................................ 8 
4. 
STUDY CHARACTERISTICS ...............................................................................................................................................10 
4.1. 
STUDY IDENTIFICATION .........................................................................................................................................................10 
4.2. 
STUDY PHASE ..........................................................................................................................................................................10 
4.3. 
DESCRIPTION OF THE INVESTIGATIONAL PRODUCT ..........................................................................................................10 
4.4. 
SPONSOR INFORMATION ........................................................................................................................................................10 
4.5. 
DRUG RESEARCH ETHICS COMMITTEE (CEIM)................................................................................................................11 
4.6. 
COMPANY RESPONSIBLE FOR MONITORING .....................................................................................................................11 
4.7. 
EXPECTED DURATION OF THE STUDY ..................................................................................................................................12 
5. 
JUSTIFICATION AND OBJECTIVES ...............................................................................................................................12 
5.1. 
INTRODUCTION .......................................................................................................................................................................12 
5.2. 
JUSTIFICATION OF THE STUDY ..............................................................................................................................................17 
5.3. 
STUDY OBJECTIVES ................................................................................................................................................................18 
6. 
STUDY DESIGN ...........................................................................................................................................................................18 
6.1. 
DESIGN .....................................................................................................................................................................................18 
6.2. 
PRIMARY ENDPOINT ...............................................................................................................................................................18 
EVALUATION OF THE PRINCIPAL VARIABLE: .....................................................................................................................................18 
6.3. 
SECONDARY OUTCOMES .......................................................................................................................................................19 
7. 
SCREENING OF PATIENTS .................................................................................................................................................19 
7.1. 
INCLUSION CRITERIA ..............................................................................................................................................................19 
7.2. 
EXCLUSION CRITERIA.............................................................................................................................................................19 
7.3. 
RANDOMISATION PROCEDURES ...........................................................................................................................................19 
7.4. 
MASKING PROCEDURES.........................................................................................................................................................20 
8. 
WITHDRAWAL AND DISCONTINUATION CRITERIA ........................................................................................20 
8.1. 
REASON FOR WITHDRAWAL .................................................................................................................................................20 
8.2. 
REPLACEMENT OF SUBJECTS AND RESERVE SUBJECTS ....................................................................................................20 
9. 
INVESTIGATIONAL PRODUCT ........................................................................................................................................20 
9.1. 
DESCRIPTION OF THE INVESTIGATIONAL PRODUCT ..........................................................................................................20 
9.1.1. 
Description .........................................................................................................................................................................21 
9.1.2. 
Packaging ...........................................................................................................................................................................21 
9.1.3. 
Shipping and storage ........................................................................................................................................................21 

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9.2. 
DOSAGE AND ADMINISTRATION ..........................................................................................................................................21 
9.3. 
DURATION OF TREATMENT ...................................................................................................................................................21 
9.4. 
CRITERIA FOR DOSAGE MODIFICATION ...............................................................................................................................21 
9.5. 
TREATMENT ACCOUNTING AND COMPLIANCE ..................................................................................................................21 
9.6. 
PROHIBITED DRUGS ................................................................................................................................................................22 
9.7. 
DRUG INTERACTIONS .............................................................................................................................................................22 
10. 
EVALUATION CALENDAR ............................................................................................................................................23 
11. 
ADVERSE EVENTS ..............................................................................................................................................................24 
12. 
STATISTICAL CONSIDERATIONS .............................................................................................................................24 
12.1. 
GENERAL CONSIDERATIONS .................................................................................................................................................24 
12.2. 
SAMPLE SIZE ............................................................................................................................................................................24 
12.3. 
ANALYSIS POPULATIONS .......................................................................................................................................................24 
12.4. 
ANALYSIS OF THE PRIMARY ENDPOINT ...............................................................................................................................25 
13. 
DATA MANAGEMENT AND QUALITY ASSURANCE .....................................................................................26 
13.1. 
CLINICAL TRIAL MONITORING AND AUDITS .......................................................................................................................26 
13.2. 
AUDITS .....................................................................................................................................................................................26 
13.3. 
INSPECTIONS ............................................................................................................................................................................26 
13.4. 
REPORTING OF SERIOUS BREACHES .....................................................................................................................................26 
13.5. 
DATA MANAGEMENT .............................................................................................................................................................27 
13.6. 
ELECTRONIC CASE REPORT FORMS (ECRF) .....................................................................................................................27 
13.7. 
WEB-BASED ELECTRONIC CRF ...........................................................................................................................................28 
13.8. 
DATA RECORDING IN THE ELECTRONIC CRF.....................................................................................................................28 
13.9. 
QUERY MANAGEMENT ..........................................................................................................................................................28 
13.10. 
SOURCE DOCUMENTS .......................................................................................................................................................29 
13.11. 
USER IDENTIFIER ...............................................................................................................................................................29 
13.12. 
CHANGE CONTROL ............................................................................................................................................................29 
13.13. 
DOCUMENTATION STORAGE ...........................................................................................................................................29 
14. 
ADMINISTRATIVE CONSIDERATIONS ..................................................................................................................30 
14.1. 
LEGAL CONSIDERATIONS......................................................................................................................................................30 
14.2. 
REVIEW BY THE DRUG RESEARCH ETHICS COMMITTEE ................................................................................................30 
14.3. 
PROTOCOL MODIFICATIONS ..................................................................................................................................................31 
14.4. 
INFORMED CONSENT ..............................................................................................................................................................31 
14.5. 
CONFIDENTIALITY ..................................................................................................................................................................32 
14.6. 
INSURANCE POLICY ................................................................................................................................................................32 
14.7. 
PUBLICATIONS ........................................................................................................................................................................33 
15. 
ACCEPTANCE OF THE PROTOCOL BY THE SPONSOR...............................................................................34 
16. 
ACCEPTANCE OF THE PROTOCOL BY THE PRINCIPAL INVESTIGATOR .....................................35 
17. 
BIBLIOGRAPHIC REFERENCES .................................................................................................................................36 
ANNEX 1. DECLARATION OF HELSINKI...............................................................................................................................39 
ANNEX 2. LIST OF SITES / PRINCIPAL INVESTIGATORS ............................................................................................45 
ANNEX 3. SAMPLE PATIENT INFORMATION SHEET AND INFORMED CONSENT FORM .....................46 
ANNEX 4. NCI-CTCAE CRITERIA ...............................................................................................................................................47 
ANNEX 5. POST-COVID COMPLICATIONS ..........................................................................................................................48 
ANNEX 6. BARTHEL INDEX...........................................................................................................................................................49 
ANNEX 7. DYSPNOEA SCALE MMRC (MODIFIED MEDICAL RESEARCH COUNCIL) ...............................50 
ANNEX 8 CALCULATION OF PAO2 FROM SPO2 ..............................................................................................................51 
ANNEX 9 INSTRUCTIONS FOR THE 6 MINUTE WALK TEST. ...................................................................................52 
 
 

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3. ABBREVIATIONS 
 
Abbreviation 
Term 
AE 
Adverse Event 
AEMPS 
Spanish Agency for Medicines and Health Products 
AUC 
Area Under the Curve 
CEIm 
Drug Research Ethics Committee 
CK 
Creatine-phosphokinase 
CRF 
Case Report Form 
EC 
European Community 
ECG 
Electrocardiogram 
ECO 
Ecocardiogram 
eCRF 
Electronic Case Report Form 
eEF1A 
Eukaryotic elongation factor 
EU 
European Union 
FEV1 
Forced expiratory volume in 1 second 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
GOT 
Glutamic oxaloacetic transaminase 
GPT 
Glutamate-pyruvate transaminase 
HR 
Heart rate 
IC50 
Inhibitory concentration 50 
IC90 
Inhibitory concentration 90 
ICH 
International Council for Harmonisation 
ID 
Identification number 
LDH 
Lactate dehydrogenase 
mMRC 
Modified Medical Research Council 
MUGA 
Multigated acquisition scan 
PaFi Ratio 
Ratio of partial pressure arterial oxygen and fraction of 
inspired oxygen. 
PR 
PR interval  
Q1 
First quartile 
Q3 
Third quartile 
QT 
QT interval 

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Abbreviation 
Term 
RR 
Respiratory rate 
SAE 
Serious Adverse Event 
SAFI 
Ratio of percutaneous oxygen saturation to the fraction of 
inspired oxygen. 
SaO2 
Oxygen saturation 
WHO 
World Health Organisation 
WMA 
World Medical Association 
 
 
 
 

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4. STUDY CHARACTERISTICS 
4.1. Study identification 
Protocol code:  
E-APLICOV-PC/ AV-APL-A-003-21 
Title:  
Extension study in a cohort of adult patients with SARS CoV2 infection requiring 
hospital admission and received treatment with plitidepsin in the APLICOP-PC 
study. 
4.2. Study phase 
APLICOV-PC proof-of-concept study follow-up. 
4.3. Description of the investigational product 
Plitidepsin. 
4.4. Sponsor information 
Name:  
Pharma Mar, SA 
Contact Person:  
José Jimeno MD PhD 
VP Global Head Virology & Inflammation  
email: jjimeno@pharmamar.com 
Tel: +34 91 846 6036 / +34 619 301 135 
 
Postal address:  
Avda. de los Reyes, 1 
Polígono Industrial “La Mina” 
28770 Colmenar Viejo 
Madrid, Spain 
  
 

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Pharmacovigilance Contact:  
Hervé Dhellot 
EEA Qualified Person for Pharmacovigilance and Senior Pharmacovigilance 
Manager 
email: 
/ AEincoming@pharmamar.com 
Tel (24 hours): + 34 91 823 45 56 
Tel: 
Fax: 
 
Postal address:  
Avda. de los Reyes, 1 
Polígono Industrial “La Mina” 
28770 Colmenar Viejo 
Madrid, Spain 
Coordinating investigators:  
Dr. José Felipe Varona 
Hospital Universitario HM Montepríncipe 
Department of Internal Medicine 
 
Dr. Pedro Landete 
Hospital Universitario la Princesa  
Pneumology Service 
 
Dr. Pablo Guisado-Vasco 
Hospital Universitario Quironsalud Madrid 
Department of Internal Medicine 
 
Dr. Roger Paredes  
Hospital Germans Trias i Pujol 
Department of Infectious Diseases 
 
4.5. Drug Research Ethics Committee (CEIm) 
Drug Research Ethics Committee of HM Hospitales 
4.6. Company Responsible for Monitoring 
APICES 
Av. Antonio López, 16 - 1ºA 
28320 - Pinto (MADRID) 
Tel: +34 91 816 68 04 
Fax: + 34 91 816 91 72 
email: 
 

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4.7. Expected duration of the study 
Inclusion start date: 10/2021 
Inclusion end date: December 2021 
The study will end with the last procedure performed on the last patient. It is 
estimated that all procedures will have ended in the month after the inclusion of 
the first patient in the study. 
 
5. JUSTIFICATION AND OBJECTIVES  
5.1. Introduction 
COVID-19 
In December 2019, the World Health Organisation received information on a 
group of cases of pneumonia of unknown aetiology. The cause of this pneumonia 
was identified as a new virus in the Coronaviridae family (SARS CoV2) and the 
clinical picture associated with the virus has been named COVID-19. 
In January 2020 the first case was reported in Spain and in mid-February the first 
patient died of it. The growth of confirmed cases has not stopped since then.  
On 10 September 2021, the Coordination Centre for Health Alerts and 
Emergencies of the Ministry of Health reported that in Spain there have been 
4,907,461 cases and 85,290 deaths [1].  
COVID-19 is currently a public health emergency. The onset of a virus unknown 
until the end of 2019 has made it necessary to take measures taking into account 
the existing scientific knowledge with similar viruses and past situations.  
APLICOV-PC study 
The APLICOV-PC proof-of-concept study of plitidepsin [2] has fulfilled the 
primary safety objective. The characterised range of doses, of 1.5, 2.0 and 2.5 
mg/day x 3 consecutive days, confirms a positive therapeutic index in the study’s 
target population (adult patients with COVID-19 infection requiring hospital 
admission), as well as a good tolerance to the treatment, and the absence of any 
differences in the level of safety between the 3 evaluated doses.  
It is believed that the framework of pharmacological intervention proposed in the 
indicated group of patients could impact the natural course of the disease, based 
on:  

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- 
The dose range proposed according to the PK/PD model, anticipated that 
supra-pharmacological concentrations would be reached in distal 
anatomical compartments.  
 
- 
The in-vivo biodistribution of plitidepsin confirms that key organs in SARS 
CoV2 are exposed to therapeutic concentrations (Fig. 1).  
 
Figure 1. AUC0-t of the Total Radioactivity in SD Rats (Both Sexes) after a Single Administration 
of an I.V. Bolus dose of 14C1-Plitidepsin A 1.2 mg/m2 (0.2 mg/Kg). 
 
*For plasma AUC0-t, t=72 and 48 h in male and female rats, respectively.  
 

- 
The terminal half-life exceeding 30 hours supports a pharmacologically 
valid model of exposure, administering the medication over 3 consecutive 
days. With all the three dosage levels used (1.5 mg, 2.0 mg and 2.5 mg), 
plasma concentrations above IC50 were obtained throughout the 
treatment period and remained above IC90 for most of the administration 
interval. The accumulation after three repeated administrations is minimal. 
 
 
 

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Figure 2. Total plasma concentration profiles vs. plitidepsin time predicted for the administration 
schedule and doses used in the APLICOV-PC study.  
 
The horizontal lines represent the total plasma concentrations associated with lung concentrations 
equivalent to IC50, IC90 and 3xIC90 in vitro. 
 
The APLICOV-PC proof-of-concept study has validated the proposed hypothesis 
in terms of impact on viral load (Fig. 3), full recovery / discharge from hospital 
rapidly induced (Fig. 4) and very relevant impact on lymphocyte reconstitution 
and other relevant inflammatory parameters (Fig. 5). 
 
Figure 3. Effect of Plitidepsin and Remdesivir on viral load. 
 
 
 
 

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Figure 4. Time until discharge from hospital by dose and category (FDA)  
 
 
Figure 5. Inflammatory markers in APLICOV-PC patients: Effect of the Dose in Subjects with 
Moderate COVID-19 according to the FDA.  
 
 
 
Therefore, these results generated in the APLICOV-PC proof of concept study 
are deemed to be compatible with consideration as a tangible post-COVID clinical 
benefit, in which reference is made to the prevention/minimisation of 

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complications related to the SARS CoV2 infection. Also, it should be highlighted 
that 87% of the patients had a moderate to severe illness when they entered the 
APLICOV-PC study and, on day 15, 82% of the patients had already been 
discharged.  
The last patient was included in the APLICOV-PC study in November 2020. 
Therefore there is already an extensive margin of time for follow-up of almost 12 
months, which justifies this study's approach.  
The complications following SARS CoV2 infection represent a medical challenge. 
The evolutionary process following SARS CoV2 infection is critical in terms of the 
patient’s quality of life, the emergence/persistence of morbidities, and social and 
pharmacoeconomic impact [3-5]. The potential impact of plitidepsin in controlling 
the sequelae arising from the SARS CoV2 infection is deemed sufficiently 
clinically relevant to justify the creation of this study. 
Post-COVID 19 Syndrome 
SARS CoV2 infection is a systematic process that goes beyond affecting the 
respiratory tract. COVID-19 complications and sequelae are very varied and 
increasingly frequent and better documented. Post-COVID sequelae occur after a 
severe SARS CoV2 infection in patients who required hospitalisation admission. 
They are generally a consequence of structural damage to different organs by the 
infection itself and/or associated complications. Various studies point to the 
sequelae of this infection not only restricting the respiratory apparatus: sequelae 
have also been recorded in the cardiovascular system, in the kidneys and in the 
central and peripheral nervous system [6-11]. Psychiatric and psychological 
sequelae have also been documented [12].  
 
In patients who present a severe COVID-19 clinical picture, the main sequelae is 
the development of pulmonar fibrosis. According to a recent metaanalysis, 
approximately 30% of patients hospitalized with pneumonia due to SARS CoV2 have 
presented fibrotic changes that persist for the first 12 months after discharge from 
the hospital [13].  
 
It has been documented that patients with severe forms of COVID-19 presented 
significant heart injuries, including myocarditis related to infection, with a reduced 
systolic function and arrhythmias. Myocardial injury has been reported, which 
may be due to direct damage to the cardiomyocytes, systemic inflammation, 
myocardial interstitial fibrosis, and hypoxia [14]. Due to significant myocardial 
injuries in patients with severe clinical symptoms due to COVID-19, the morbidity 
and lethality of the illness could be high [15-17].  
 
In severe cases of COVID-19, the systemic hyper-inflammatory response could 
cause long-term cognitive damage, such as, for example, memory loss, attention 
deficit, slower processing speed associated with cognitive functioning, along with 
diffuse neuronal loss [18]. Various types of neuropsychiatric clinical signs have 
also been observed, such as encephalopathy, mood swings, psychosis, 
neuromuscular dysfunction or demyelinating processes. These may accompany 
an acute viral infection, or may emerge weeks, months, or even later, post-

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infection, in recovered patients [19-21]. According to an electronic follow-up record 
of 236,379 patients during the first six months following COVID-19 diagnosis, 
neuropsychiatric complications emerge in 34% of cases, not including cephalea. 
The most common complications include mood and anxiety disorders and psychoses 
(24%), neuropathies (2,1%), ischaemic heart disease (2.8%) and dementia (0.67%) 
[22]. On the other hand, the most frequent neurological symptoms are cephalea and 
cognitive changes, described in up to 68% and 81% of patients, respectively, with 
some sort of neurological symptom after week 12 following acute infection [23]. 
Cognitive changes that are usually reported are lack of concentration, attention, or 
difficulty planning tasks. 
 
The rapid drop in viral load of patients with COVID-19 infection may reduce the 
frequency of complications caused by the infection in the following months [24]. 
 
The WHO European Observatory on Health Systems and Policies estimates that 
10% of infected patients remain symptomatic for at least 12 weeks after infection, 
resulting in long-term sick leave, leaving sequelae that in 0.8% even last more 
than a year [25]. A study in Spain, based on Social Security data, shows that COVID 
caused 1.2 million registered sick leaves by March 2021, and its authors indicate that 
nearly 100,000 people needed 12 weeks or more to recover from post-COVID 
sequelae. The casualties were justified by almost 50 different symptoms ranging from 
fever, shortness of breath, fatigue, anxiety, dizziness or memory loss.  
 
On the other hand, data has been published from the COVERSCAN study conducted 
in the United Kingdom [25], which carried out serial Magnetic Resonance Imaging 
(MRI) scanning in a sample of 201 generally-healthy, middle-aged individuals, with 
COVID-19. The investigators found evidence of mild organ impairment of the heart 
(32%), lungs (33%), kidneys (12%), liver (10%), pancreas (17%), and spleen (6%) 
and reported that nearly 70% of the individuals suffered impairment in one or more 
organs 4 months after the initial symptoms of SARS-CoV2 infection, which was 
higher than age-matched healthy controls.  
5.2. Justification of the study 
As previously indicated, the APLICOV-PC proof of concept study demonstrated 
the antiviral activity of plitidepsin in terms of reducing viral load, inducing 
recovery, and impact on lymphocyte reconstitution and other inflammatory 
parameters. 
A percentage of patients, which varies between 10 and 25%, continue to show 
symptoms at 3 months after contracting the SARS CoV2 infection: For some of 
them this significantly restricts their life, requiring them to take long-term sickness 
leave from work, and leaving them with sequelae that may continue for more 
than one year.  
With this study, we intend to evaluate whether the treatment with plitidepsin, by 
attaining a reduction in the viral load and a faster recovery of the patient, could 
have a relevant impact on the emergence of sequelae resulting from the SARS 
CoV2 infection. 

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5.3. Study objectives 
Evaluate the incidence of post-COVID morbidity and characterise the 
complications profile in patients who participated in the APLICOV-PC study. 
  
6. STUDY DESIGN  
6.1. Design 
Multi-site extension study of the APLICOV-PC clinical study follow-up. 
The plitidepsin doses considered in this trial include the three doses specified in 
the APLICOV-PC study: 
- 
1.5 mg of plitidepsin administered as a 1.5-hour infusion, once a day for 3 
consecutive days (total dose 4.5 mg). 
- 
2.0 mg of plitidepsin administered as a 1.5-hour infusion, once a day for 3 
consecutive days (total dose 6.0 mg).  
- 
2.5 mg of plitidepsin administered as a 1.5-hour infusion, once a day for 3 
consecutive days (total dose 7.5 mg). 
  
6.2. Primary endpoint 
Incidence of complications related to COVID-19 infection.  
Evaluation of the principal variable:  
The following information will be gathered in this study: 
- 
Readmissions to hospitals and causes, from the last visit of the APLICOV-
PC study to the end of the extension study.  
- 
Need for oxygen therapy and duration of the same, from last visit of 
APLICOV-PC study until the end of the extension study. 
- 
Presence of complications (see annex 5) since last visit of APLICOV-PC 
study until the end of this extension study by the patient.  
 
Also, once the informed consent has been signed, the following tests will be 
carried out in the following 7 days: 
- 
Barthel Index [26], to assess the patient’s degree of autonomy when 
performing activities of daily living.  
- 
Evaluation of the dyspnea, according to the mMRC scale [27]. 
- 
Evaluation of functional capacity (6 minute walk test) [28].  
- 
Physical examination, including weight, height, BSA, pulse oximetry, PAFI 
(estimated annex 8). 

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- 
Full analysis, including inflammation markers. 
- 
Chest X-ray, in patients diagnosed with pneumonia upon admission to 
hospital, which led to their participation in the APLICOV-PC study.  
- 
Evaluation of pulmonary function, including dyspnea evaluation (mMRC 
and 6 minute walk test) (annexes 7 and 9) SaO2, PAFI (direct or 
estimated) (annex 8), spirometry (forced vital capacity, FEV1 and 
FEV1/CVF) and the diffusion test. 
- 
Electrocardiogram.  
- 
Heart Ultrasound/MUGA, in patients that suffered a relevant cardiac event 
while participating in the APLICOV-PC study or in those patients for which 
it was clinically indicated during follow-up. 
- 
Thus, an evaluation was made of both the ultrasound images and the 
results of the complementary (analytical or functional) tests necessary for 
interpreting the long-term evolution of the disease, from the start of the 
patient's participation in APLICOV-PC to the end of this study.  
  
6.3. Secondary outcomes 
Not applicable. 
 
7. SCREENING OF PATIENTS 
All patients who participated in and received plitidepsin in the APLICOV-PC study 
are eligible candidates for participating in this extension study. The investigative 
team will contact the patient to agree a date for the medical visit. The patient will 
be invited to participate in the study, and be handed the Patient Information 
Leaflet for the same, along with all additional information related to the study that 
is necessary for obtaining their informed consent. 
7.1. Inclusion criteria 
Patient who participated in the APLICOV-PC study, who has been treated with 
plitidepsin and gives their consent.  
7.2. Exclusion criteria 
There are no exclusion criteria for this study. 
7.3. Randomisation procedures 
Not applicable.  

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7.4. Masking procedures 
Not applicable. 
 
8. WITHDRAWAL AND DISCONTINUATION CRITERIA 
8.1. Reason for withdrawal 
Patients will be excluded or withdrawn from the study for any of the following 
reasons: 
- 
Withdrawal of consent by the patient. 
All cases of a patient's withdrawal from the study must be documented in the 
Case Report Form. 
8.2. Replacement of subjects and reserve subjects 
Not applicable. Given the characteristics of the study, those patients who do not 
agree to participate in the study, or who withdraw their consent, cannot be 
replaced. 
 
9. INVESTIGATIONAL PRODUCT 
9.1. Description of the investigational product 
Plitidepsin is licensed in Australia for the treatment of multiple myeloma.  
Plitidepsin is currently being investigated in a study to assess the efficacy and 
safety of the different doses vs a control arm in patients with moderate COVID-
19 infection (NEPTUNO). It is a randomized open-label phase III study in adult 
patients who require hospitalisation and oxygen supplement to treat a moderate 
COVID-19 infection. The study is designed to evaluate the safety and efficacy of 
plitidepsin at a low dose (1.5 mg x 3 days) and at a high dose (2.5 mg x 3 days), 
and it will be compared with the control arm.  
Also, plitidepsin was previously studied in the APLICOV-PC COVID-19 study, a 
proof of concept clinical trial to evaluate the safety of three doses of plitidepsin 
(1.5 mg, 2.0 mg and 2.5 mg administered over 3 consecutive days), in adult 
patients hospitalized for COVID-19 [2]. The aim of this study was to determine 
the safety and toxicological profile, as well as the efficacy, of each dosage level. 
The results of this clinical trial indicated a positive benefit-risk ratio for the 
treatment of COVID-19 infection, given the low incidence of adverse events 
related to the drug of grade ≥ 3, and the high proportion of discharges from 

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hospital on days 8 and 15, together with a significant drop in viral load, with no 
significant differences observed among the three dosage groups.  
9.1.1. Description 
Plitidepsin is a powder for concentrate for solution for infusion at a concentration 
of 2 mg/vial.  
9.1.2. Packaging 
Plitidepsin 2 mg is presented in a Type I clear glass vial with a bromobutyl rubber 
stopper covered with an aluminium seal. Each vial contains 2 mg of plitidepsin. 
The solvent for the reconstitution of macrogolglycerol ricinoleate (polyoxyl 35 
castor oil)/absolute ethanol/water for injection, 15%/15%/70% (v/v/v) is supplied 
in a Type I colourless glass vial. The ampoules have a volume of 4 ml. 
9.1.3. Shipping and storage  
Plitidepsin should be stored between 2ºC and 8ºC and the vials should be kept 
in the outer carton to protect them from light.  
The drug in these conditions is stable for 60 months. 
9.2. Dosage and administration 
The patients included in the extension study received no treatment whatsoever 
in relation to the study. To participate in the study, the patients must have 
previously participated in the APLICOV-PC proof of concept study and may have 
received:  
- 
1.5 mg of plitidepsin administered as a 1.5-hour infusion, once a day for 3 
consecutive days. 
- 
2.0 mg of plitidepsin administered as a 1.5-hour infusion, once a day for 3 
consecutive days.  
- 
2.5 mg of plitidepsin administered as a 1.5-hour infusion, once a day for 3 
consecutive days. 
9.3. Duration of treatment 
Not applicable.  
9.4. Criteria for dosage modification 
Not applicable.  
9.5. Treatment accounting and compliance 
Not applicable.  

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9.6. Prohibited drugs 
Not applicable. Patients who participate in this extension study may be receiving 
the medicines that their doctors deem necessary. 
9.7. Drug interactions 
Not applicable, as no medication is administered in this clinical trial. 

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10. 
 EVALUATION CALENDAR  
 
 
Baseline 
Up to day +7 
Informed consent1 
X 
 
Selection criteria2 
X 
 
PCR COVID-193 
 
X 
Medical history review4 
 
X 
Vital signs5 
 
X 
Physical examination  
 
X 
Symptoms/signs/complications of the 
disease 6 (annex 5) 
 
X 
Neurological examination 
 
X 
Pulmonary function7  
 
X 
Barthel scale 
 
X 
Electrocardiogram8 
 
X 
Haemogram and differential count9 
 
X 
Biochemistry10 
 
X 
Coagulation11 
 
X 
C-reactive protein 
 
X 
Chest x-ray12 
 
X 
SARS CoV2 IgG Serology  
 
X 
Ultrasound / MUGA13  
 
X 
Other pharmacological treatments 14 
X 
X 
Adverse events15  
 
X 
Hospital readmissions16 
X 
 
Need for oxygen therapy16 
X 
 
X-rays / complementary tests17  
X 
 
 
1  The patient will sign the informed consent before undergoing any specific study procedure that is not part of normal clinical 
practice. 
 
2  The patient must meet all the inclusion criteria in order to be included in the study. 
 
3 It will be confirmed via a PCR test that the patient has no COVID infection at the moment of being recruited to the study. 
 
4 The code assigned to the patient for participation in the (APLICOV-PC) reference study will be recorded. It will be confirmed if 
the patient has presented new COVID-19 episodes since the study ended, and if they have been vaccinated / the type of 
vaccine / received doses. Details of hospital readmissions and causes and the need for oxygen therapy were collected, from 
the last visit of the APLICOV-PC study to the signing of the informed consent form, and subsequently to the end of the study.  
 
5 Vital signs: temperature, arterial tension, heart rate, respiratory rate.  
 
6 Presence of complications (see annex 5) since the last visit of the APLICOV-PC study until the end of this extension study. 
 
7 Evaluation of pulmonary function, including dyspnea evaluation (mMRC and 6 minute walk test) (annexes 7 and 9) SaO2, PAFI 
(direct or estimated) (annex 8), spirometry (forced vital capacity and FEV1) and the diffusion test. 
 
8  The electrocardiogram: overall evaluation and measurement of PR, QT and RR intervals. Save the ECG in the patient’s history.
 
9 Complete blood count, including inflammation markers. 
 
10  It will include creatinine, ions, calcium, albumin, transaminases, bilirubin, alkaline phosphatase, LDH, CK, ferritin and troponin.
11 It will include D-dimer.  
 
12 A chest X-ray will be taken for patients diagnosed with pneumonia upon admission to hospital, which led to their participation 
in the APLICOV-PC study.  
 
13 A heart ultrasound / MUGA will be performed on patients who suffered a relevant cardiac event during their participation in 
the APLICOV-PC study.  
 
14 All pharmacological treatments received by the patient since the last visit of the APLICOV-PC study to the signing of the 
informed consent form, will be collected.
 
15  Serious and non-serious adverse events related to the study procedures, from the signing of the informed consent until the 
end of the patient's participation in the study, will be collected. 
 
16  If the patient so requested, their hospital readmissions/oxygen therapy, since the last visit of the APLICOV-PC study to the 
signing of the informed consent for the extension study, will be collected. 
 
17  Collection of ultrasound images or the results of complementary (analytical or functional) tests necessary for interpreting 
post COVID-19 evolution. 
  

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11. 
ADVERSE EVENTS 
No adverse effects were expected in this study, as no adverse events suspected of being 
related to plitidepsin in the treated patients have been reported since the APLICOV-PC 
study ended. However, if an adverse effect is observed that may be related to the study 
procedures, pharmacovigilance will be notified according to the current regulations.  
 
12. 
STATISTICAL CONSIDERATIONS 
12.1. 
General considerations 
This section describes the main analyses that will be carried out. The statistical analysis 
plan to be approved by the sponsor will include additional information on analyses, 
management of unavailable data and analytical methods. All data will be analysed with 
the SAS statistical analysis system, version 9.4. All analyses will be carried out mainly 
by descriptive statistical methods. Continuous endpoints will be described using 
maximum, minimum, Q1 and Q3, mean, median and standard deviation. Categorical 
endpoints will be described with frequencies and percentages as well as the exact 95% 
confidence interval of the relevant study variables. All results will be presented separately 
by treatment arm and severity of the information upon entry into the APLICOV-PC study.  
The final statistical study that will be the basis of the study’s final report, will cover the 
total population of patients once the extension study has ended.  
12.2. 
Sample size  
The main objective of the study is to evaluate the incidence of post-COVID morbidity and 
characterize its profile in patients who participated in the APLICOV-PC study. Given that 
a total of 45 patients received plitidepsin in said study, of which 3 died as a consequence 
of the progression of the disease, the maximum number of patients who could participate 
in the study is limited to 42.  
Assuming an average incidence of post-COVID complications of 15%, this study would 
have a power of 80% for detecting a reduction of 10%: if 3 or less patients presented 
post-COVID complications, the study would reject the null hypothesis (incidence of post-
COVID complications: 15%) and would accept the alternative (5%), with an alpha error 
of 0.05 (unilateral).  
12.3. 
Analysis populations 
All patients who sign an informed consent form and agree to undergo the battery of 
clinical examinations, imaging and laboratory tests specified in section 10 of the protocol, 
will be analysed in order to fulfil the objectives of the study.  

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12.4. 
Analysis of the primary endpoint 
The main objective of the study is to evaluate the incidence of post-COVID morbidity and 
characterize the complications profile in the cohort of patients who participated in the 
APLICOV-PC study.  
The number and percentage of patients who develop complications related to persistent 
illness, as judged by a physician, during the period between the end of the APLICOV-PC 
proof of concept study and the end of this extension study by the patient, as well as the 
percentage of patients who present complications. 
A description of the following endpoints will also be presented: 
- 
Number and percentage of patients who required readmission to hospital and 
causes, since last visit of APLICOV-PC study until the end of this extension study.  
- 
Need for oxygen therapy and duration of the same, since last visit of APLICOV-
PC study until the end of this extension study.  
- 
The maximum, minimum, Q1 and Q3, mean, median and standard deviation of 
the duration of the oxygen therapy will be provided. 
- 
Number and percentage of patients who presented complications (see annex 5).  
- 
Barthel Index [26]. A description will be provided with the frequency and 
percentage of each dependency category according to the score obtained:  
0-20: Total dependency  
21-60: Severe dependency  
61-90: Moderate dependency  
91-99: Slight dependency  
100: Independence 
- 
The maximum, minimum, Q1 and Q3, mean, median and standard deviation of 
the parameters related to pulmonary function will be provided: SaO2, PAFI, CVF, 
FEV1, FEV1/CVF and diffusion test. 
- 
The maximum, minimum, Q1 and Q3, mean, median and standard deviation of 
the results of the 6 minute walk test will be provided. 
- 
A description will be provided with the frequency and percentage of each category 
of the mMRC scale.  
- 
Number and percentage of patients with abnormalities in the chest X-ray, in 
patients who present pneumonia upon entry into the APLICOV-PC study, and 
description of the abnormalities.  
- 
Number and percentage of patients who presented abnormalities ≥G2 in the 
analytical parameters. 
- 
Number and percentage of patients who presented abnormalities in the ECG, and 
description of the abnormalities.  
- 
Number and percentage of patients who presented abnormalities in the heart 
Ultrasound/MUGA in patients who suffered a relevant cardiac event during their 
participation in the APLICOV-PC study, and description of the abnormalities.  
 

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The endpoints listed were correlated with the patients’ basal characteristics, the degree 
of severity of the illness, comorbidities, the plitidepsin dosage, the viral load and the 
clinical evolution documented in the APLICOV-PC study.  
 
13. 
 DATA MANAGEMENT AND QUALITY ASSURANCE 
13.1. 
Clinical trial monitoring and audits 
The sites participating in the study will be supervised by monitors appointed by the 
sponsor, with specific training for this clinical trial, making periodic visits to the site before, 
during and at the end of the trial. These monitoring visits will be carried out in accordance 
with the International Council for Harmonisation (ICH) E6 (R2) guidelines. Visits can be 
supplemented by telephone contact or written communication. In this study, remote 
verification of source data may be performed in agreement with the participating centres.  
Priority will be given to centralised monitoring and/or remote monitoring of the 
participating sites, avoiding overloading the site staff with tasks or reviewing source data 
and postponing, as far as possible, the verification of source data until it is possible to 
access the medical history directly. The sponsor will agree the conditions for such 
monitoring with the participating sites and teams.  
Procedures will be established to ensure the quality of any aspect related to the trial. 
13.2. 
Audits 
During the clinical trial, the Quality Department of Pharma Mar S.A. or external auditors 
contracted by the sponsor may make audit visits to the site, either in person or remotely. 
13.3. 
Inspections 
Participation in this clinical trial implies acceptance of possible inspection by national or 
foreign regulatory authorities.  
13.4. 
Reporting of serious breaches 
Any serious breaches of the authorised protocol or of Royal Decree 1090/2015 that occur 
in Spain must be reported by the sponsor without undue delay and no later than seven 
calendar days from detection of the breach to the Spanish Agency for Medicines and 
Medical Products (AEMPS) and the CEIm. 
For this purpose, a serious breach will be defined as any non-compliance that may 
significantly affect the safety and rights of the study subjects or the reliability and integrity 
of the data generated in the clinical trial. 
Only serious breaches will be reported to the AEMPS and the CEIm, and breaches that 
do not constitute a serious breach will not have to be reported. 

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Each investigator has to document and explain in the clinical history of the subjects any 
breach to the approved protocol and/or Royal Decree 1090/2015. Investigators can 
implement a protocol breach to eliminate an immediate safety risk to the subject without 
prior CEIm approval, but such a breach must be reported to the study monitor within one 
business day. These incidents will be evaluated and, if appropriate, an amendment to 
the protocol will be prepared.  
The monitor will document breaches during monitoring visits. The monitor will notify the 
investigator of the breach during the visit and the “Breach Form” document will be 
completed and signed by the investigator and monitor.  
13.5. 
Data management 
APICES will be responsible for processing and quality control of the data. Data 
management will be performed according to the Data Management Plan, standard 
operating procedures and the current regulations. 
Data management based on Good Clinical Practice (GCP) standards refers to the 
activities defined to achieve safe routines for the efficient input of information in the study 
database, avoiding errors. Routines include procedures for CRF handling, application 
design and management, data entry and verification, data validation, database quality 
control and documentation of activities performed, including information on discrepancies 
found during the process. The database, data input screens and programming will be 
designed by APICES in accordance with the clinical trial protocol. 
13.6. 
Electronic Case Report Forms (eCRF) 
The collection of study data will consist of the electronic recording of all the information 
required by the eCRF. APICES will provide the eCRF. 
All investigators agree to keep eCRFs filled in with truthful and accurate information as 
well as source documents that are part of medical records. 
All the requested information must be completed in each patient's eCRF. If a patient is 
included in the study but withdraws their consent, only the minimal data will be collected 
in the CRDe, such as demographic data and the date of informed consent, as well as the 
reason for the withdrawal, if the patient does not mind providing it. In general, no queries 
will be issued for the data of these patients indicated in the eCRF as “Not done” or “Not 
available”. 
For the patients included in the study, the information from the source documents will be 
included in each patient's eCRF by the staff of the investigation team of the site for this 
study and this information will be supervised by an APICES monitor. If the information 
requested on any variables is not available or does not apply, the reason must be 
included. Data should not be missing unless otherwise stated. Modifications to the eCRF 
must be made following the procedure described in the eCRF user guide and will be 
recorded in the eCRF. 

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Each completed eCRF must be reviewed, signed and dated by the Principal Investigator 
of the study without delay. The completed eCRF will be reviewed by the study monitor 
as soon as possible after completion. The site will be provided with an electronic copy of 
the final, approved and signed eCRF, which must be stored in the corresponding file. 
13.7. 
Web-based electronic CRF 
The data collected in this clinical trial will be entered into an application designed to 
collect study data. Access to the eCRF is password protected and includes internal 
quality controls, such as automatic data entry range controls, to identify inconsistent, 
incomplete or inaccurate data. The clinical data will be entered in the application based 
on the source documents. The profiles and data entry permits for the eCRF at each 
participating site will be established in advance. Only study staff from each site 
designated by the principal investigator will be authorised to enter the data in the eCRF. 
The principal investigator and the research team will receive the necessary training to 
complete the eCRF and will be informed, before the start of the study and before any 
study data are entered in the eCRF, of the security measures that they must take into 
account. 
13.8. 
Data recording in the electronic CRF 
All data must be entered in Spanish. The eCRFs must always reflect the latest 
observations of the patients participating in the study. Therefore, the eCRFs should be 
filled in as soon as possible during or after the patient's visit. The principal investigator of 
each participating site must check that all the data entered in the eCRFs are accurate 
and correct. 
If some evaluations are not carried out, or if certain information is not available, not 
applicable or unknown, the investigator or any other authorised person must state it in 
the eCRF. The investigator will approve the data by means of an electronic signature, 
and this approval will serve to confirm the accuracy of the recorded data. 
13.9. 
Query management 
The monitor will review the eCRFs and evaluate their completion and consistency. Each 
eCRF will be compared against the respective source documents to ensure that there 
are no discrepancies in critical data. The investigator or other authorised personnel will 
carry out the data entry, corrections and modifications. The monitor cannot fill in data in 
eCRFs. 
Once the clinical data of the eCRF have been recorded in the application, the corrections 
made to each of the variables will be recorded in the audit trail (e.g. the reason for any 
change, the name of the person who made the change, the time and date). If additional 
corrections to the data are required, the monitor in charge at the site or the data manager 
will include a query in the eCRF. The authorised site personnel will answer the queries 

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generated in the application. This entire process will be recorded in the audit trail along 
with the name of the person who made the change, the time and the date. 
13.10. 
Source documents 
The eCRF is essentially considered a data entry form and should not replace the original 
medical records (or source document) unless otherwise specified in the study protocol. 
Source documents are all documents used by the investigator or the hospital that relate 
to the patient's medical history, which verify the patient's existence, the inclusion criteria, 
and all the records that justify the patient's participation in the study. These include the 
inclusion of the patient, analyses, laboratory tests and images, the patient's file, 
questionnaires about symptoms, etc. 
Each investigator is responsible for maintaining source documents. These will be 
available for inspection by the study monitor at each monitoring visit, which may be 
carried out in person or remotely. All additional documentation completed in the eCRF, 
such as laboratory data, must be clearly identified with the study, visit and patient 
number. Any personal information (e.g. subject's name, initials) must be removed or 
redacted to preserve patient confidentiality. 
13.11. 
User identifier 
In each record included in the eCRF, the user's identification will be automatically added 
through their unique ID. The data for each of the patients included in the study will be 
electronically signed by the investigator to document their review and confirmation that 
the data are accurate. This will be done using the Investigator's ID and password; the 
date and time of signing will be automatically added at the time of the electronic signature. 
Should it be necessary to modify data in an eCRF, the correction must be made 
according to the procedures of the software used. 
13.12. 
Change control 
To comply with regulatory requirements, eCRF data will be electronically filed in the file 
of each participating site. All changes are recorded in a protected audit trail, and it will be 
necessary to enter the reason for the change. Once all data have been entered, verified 
and validated, the database will be locked to prevent further changes to the study data. 
13.13. 
Documentation storage 
Essential documents and eCRF data should be kept for 25 years after the end of the trial, 
or for a longer period if other requirements apply, such as if the study is presented as a 
basis for drug registration in which Annex I of Royal Decree 1345/2007, of October 11, 
must be complied with. 
The clinical history of the test subject must be kept in accordance with the provisions of 
Law 41/2002, of November 14, and according to the maximum period allowed by the 
hospital, institution or private practice. 

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14. 
 ADMINISTRATIVE CONSIDERATIONS 
The following administrative aspects are intended to guide the investigators participating 
in the study, but may be subject to changes based on the sponsor's procedures, 
legislation, or working documents or guidelines. 
14.1. 
Legal Considerations 
This clinical trial will be carried out in accordance with the ethical principles in the 
Declaration of Helsinki developed by the World Medical Association (WMA) and following 
the standards of good clinical practice and applicable legislation. 
The staff involved in conducting this trial will be trained and have sufficient experience to 
perform the necessary tasks. 
The study will be carried out in accordance with the protocol. The protocol, any 
amendment and the informed consent form will be approved by a CEIm before the start 
of the study, in accordance with current legislation. 
The decision of the CEIm on the execution of the study will be stated in writing. The 
investigator and/or sponsor are responsible for keeping the CEIm informed of any 
relevant information about the study drug. All protocol amendments will be agreed upon 
by the sponsor and the investigator. 
Administrative changes to the protocol are considered minor corrections and/or 
clarifications that have no impact on the way the study will be conducted. 
14.2. 
Review by the Drug Research Ethics Committee 
The ICH guidelines require the approval of the health authorities and a favourable opinion 
from an accredited Clinical Research Ethics Committee (in Spain CEIm) before patients 
can be included in clinical trials. Before the start of the study, the protocol, the informed 
consent form, the materials that will be used for patient recruitment (if applicable) and 
any other written information regarding the trial that is provided to the patient will be 
approved by the CEIm. The clinical trial can only be started when both the Health 
Authorities and the CEIm have considered that the expected benefits for the study 
patients and society justify the risks; in addition, this criterion must be continuously 
reviewed to continue with the trial with guarantees. 
APICES will obtain the favourable opinion of the CEIm on behalf of the sponsor and the 
investigators. All regulatory approvals will be signed by the President of the CEIm, or the 
person appointed by them, and must identify the name and address of the CEIm, the trial 
protocol using the protocol title and/or code, and the date of approval or date on which 
the favourable opinion is granted. Documentation related to authorisation by the CEIm 
and the health authorities and CEIm compliance with ICH E6 (R2) guidelines will be kept 
at the site and will be available for review. 

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14.3. 
Protocol modifications 
Any change to the approved protocol will require an amendment to the protocol. The 
investigator should not make any changes to the study without the favourable opinion of 
the CEIm and the authorisation of the health authorities (if applicable), except when 
necessary to eliminate an imminent and obvious risk for the patients or in the case of 
administrative changes. Modifications to the protocol to eliminate an imminent and 
obvious risk can be implemented immediately, but must subsequently be documented in 
an amendment, notified to the CEIm and the relevant health authorities within the 
required period. 
Any major modifications to the protocol must be sent to the CEIm and the health 
authorities for approval before the changes proposed in the amendment can be applied. 
Depending on the magnitude of the change, recruitment could be temporarily suspended. 
The sponsor does not have to notify minor modifications to the health authorities or the 
CEIm. However, a record will be kept of minor modifications, filed with the study 
documentation and notified when sending another notification or when a major 
modification is submitted. Documentation related to minor modifications will be available 
for inspection in the study file at the site or at the sponsor's facilities. 
14.4. 
Informed consent 
Before the patient is included in the study or before any specific procedure is carried out, 
informed consent must be obtained in writing from the patient or their legal 
representative, in accordance with ICH E6 guidelines.  
For obtaining and documenting informed consent, the investigator must comply with 
applicable legislation, and must adhere to the standards of Good Clinical Practices as 
well as the ethical principles of the Declaration of Helsinki. The patient information leaflet 
and the informed consent form and any revisions thereof must be approved by the CEIm 
before being given to patients who are deemed eligible to participate in the study or to 
their legal representatives.  
The sponsor will provide the investigation team of each participating centre with the 
patient information leaflet and the informed consent form approved by the CEIm. 
Before performing any study procedure on the patient, it is the responsibility of the 
principal investigator (or person appointed by them) to obtain consent, freely given in 
writing, from the patient or their legal representative after adequately explaining the 
objectives, methods, expected benefits and potential risks of the study and before any 
protocol-specific screening procedure is performed or study drug is administered. 
Patients or their legal representatives should have the opportunity to ask questions and 
receive the requested information, and they will have sufficient time to decide whether or 
not they want to participate in the study. Once the investigator makes sure that the patient 
understands the implications of participating in the study, they will be asked to sign the 
informed consent in order to obtain their consent to participate in the study. 

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The informed consent form must be personally signed and dated by the patient or their 
legal representative and by the study doctor who carried out the informed consent 
process (Principal Investigator or appointed person).  
The acquisition of written informed consent must also be documented in the patient's 
medical history. 
The investigator must provide a copy of the signed informed consent form to the patient 
or their legal representative. Another original copy of the document will be filed in the 
investigator's study file at the site. 
If the informed consent form is reviewed and modified during the study, active 
participating subjects must sign the document reviewed and approved by the CEIm. 
The patient participating in the clinical trial, or their legal representative, can withdraw 
consent at any time, without giving any explanation and without this entailing any harm 
to the patient. 
14.5. 
Confidentiality  
The collection and processing of personal data of the patients included in this clinical trial 
will be limited to the data that are necessary to investigate the efficacy, safety, quality 
and usefulness of the study medication used in this trial. 
It is the investigator's responsibility to keep sufficient information to allow patient 
identification. 
The trial monitor, sponsor auditors, CEIm and Competent Authorities should have direct 
access to all trial-related information and agree to keep the identity of study patients 
confidential. 
The data must be collected and processed with the appropriate precautions to guarantee 
confidentiality and compliance with the current legislation regarding data privacy. 
Explicit consent of the patients or their representatives for the treatment of personal data 
will be obtained before data collection, if necessary, and this consent will include the 
transfer of the data to other companies and countries. 
Pharma Mar SA will comply 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 with Organic 
Law 03/2018 on protection of personal data and guarantee of digital rights. 
14.6. 
Insurance policy  
The sponsor has contracted an insurance policy to cover the responsibilities of the 
investigators and the other parties participating in the study in accordance with the 
applicable regulatory requirements. 

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14.7. 
Publications  
Before the investigators of this study send a manuscript or abstract for publication or 
publicly disclose information related to the study drug or products, they will provide this 
publication to Pharma Mar SA at least 60 days beforehand for review and approval, to 
guarantee that confidential data and data ownership are protected. 
If Pharma Mar SA determines that any patentable aspect is disclosed in the proposed 
publication or communication, it will withhold the publication or communication for a 
period of time that it deems appropriate. If the study is part of a multi-site study, the first 
publication of the study will be carried out with the overall results of the study, taking into 
account the investigators and institutions of all participating centres that have contributed 
data, analysis and comments. However, if such publication of the global results is not 
presented within 12 months after the end of the study in all the sites, the study could be 
published individually according to the procedure established above. 
The order of the co-authors will reflect the relative contribution of each of them in the 
development of the study and in the analysis. In general, the first author will be the 
investigator who has recruited the largest number of patients with information that is 
ultimately available for data analysis. Pharma Mar SA staff who have fully participated in 
the study should be considered for co-authorship in the publication. 
 
 
 

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15. 
ACCEPTANCE OF THE PROTOCOL BY THE SPONSOR 
 
 
Clinical trial title: Extension study in a cohort of adult patients with SARS CoV2 infection 
 
requiring hospital admission and received treatment with plitidepsin in the 
 
APLICOP-PC study 
Protocol Code: E-APLICOV-PC/ AV-APL-A-003-21 
Version (number and date): 1.0 of 6 October 2021 
 
 
 
Position 
(pre-printed name) 
 Signature  
 Signature Date 
(DD-Mmm-YYYY) 
 
 
 
Position 
(pre-printed name) 
 Signature  
 Signature Date 
(DD-Mmm-YYYY) 
 
 
 
Position 
(pre-printed name) 
 Signature 
 Signature Date 
(DD-Mmm-YYYY) 
 
 
 
 

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16. 
ACCEPTANCE OF THE PROTOCOL BY THE PRINCIPAL 
INVESTIGATOR  
 
Clinical trial title: Extension study in a cohort of adult patients with SARS CoV2 infection 
requiring hospital admission and received treatment with plitidepsin in the APLICOP-PC 
study 
Protocol Code: E-APLICOV-PC/ AV-APL-A-003-21 
Version (number and date): 1.0 of 6 Octuber 2021 
I have read and carefully reviewed the study protocol. Having read and understood the 
requirements and conditions of the study protocol, I agree to carry out the clinical study 
according to the international principles of Good Clinical Practice and the requirements 
of the regulatory authorities for the verification of the original documents and the 
audit/inspection of the study. I agree to use the study material, including the medication, 
only as specified in the protocol. 
I understand that the changes made to the protocol must be made in the form of an 
amendment with the sponsor's prior written approval. I understand that any breach of the 
protocol may lead to early termination of the study. 
 
 
Signature of the Principal Investigator 
 
Signature Date 
(DD-Mmm-YYYY) 
 
 
 
 
 
Investigator's name (uppercase) 
 
 
 
 
 
 
 
 

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17. 
 BIBLIOGRAPHIC REFERENCES 
 
1. Ministry of Health, Consumer Affairs and Social Welfare. Current situation of 
coronavirus in Spain [Last time visited 10-sep-2021] 
https://www.mscbs.gob.es/profesionales/saludPublica/ccayes/alertasActual/nCo
v/documentos/Actualizacion_451_COVID-19.pdf 
2. Varona, J.F., et al., Plitidepsin has a positive therapeutic index in adult patients 
with COVID-19 requiring hospitalization. medRxiv, 2021.  
3. Scordo, K.A., M.M. Richmond, and N. Munro, Post-COVID-19 Syndrome: 
Theoretical Basis, Identification, and Management. AACN Adv Crit Care, 2021: 
p. e1-e8.  
4. Cares-Marambio, K., et al., Prevalence of potential respiratory symptoms in 
survivors of hospital admission after coronavirus disease 2019 (COVID-19): A 
systematic review and meta-analysis. Chron Respir Dis, 2021. 18: p. 
14799731211002240.  
5. Zaccone, G., et al., Myocardial Involvement in COVID-19: an Interaction 
Between Comorbidities and Heart Failure with Preserved Ejection Fraction. A 
Further Indication of the Role of Inflammation. Curr Heart Fail Rep, 2021. 
6. Carfì A, Bernabei R, Landi F, Group for the GAC-19 P-ACS. Persistent 
Symptoms in Patients After Acute COVID-19. JAMA 2020;324:603–5. 
7. Sudre CH, Murray B, Varsavsky T, et al. Attributes and predictors of long 
COVID. Nat Med 2021. doi: 10.1038/s41591-021-01292-y. 
8. Salehi S, Reddy S, Gholamrezanezhad A. Long-term Pulmonary Consequences 
of Coronavirus Disease 2019 (COVID-19): What We Know and What to Expect. 
J Thorac Imaging 2020;35:W87–9. 
9. Munblit D, Bobkova P, Spiridonova E, et al. Risk factors for long-term 
consequences of COVID-19 in hospitalised adults in Moscow using the ISARIC 
Global followup protocol: StopCOVID cohort study. medRxiv 2021 
2021.02.17.21251895. 
10. Huang C, Huang L, Wang Y, et al. 6-month consequences of COVID-19 in 
patients discharged from hospital: a cohort study. Lancet 2021;397:220–32. 
11. Vindegaard N, Benros ME. COVID-19 pandemic and mental health 
consequences: Systematic review of the current evidence [published online 
ahead of print, 2020 May 30]. Brain Behav Immun. 2020;S0889-1591(20)30954-
5. doi:10.1016/j.bbi.2020.05.048. 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260522/  
12. Ojha V, Mani A, Pandey NN, Sharma S, Kumar S. CT in coronavirus disease 
2019 (COVID-19): a systematic review of chest CT findings in 4410 adult 
patients [published online ahead of print, 2020 May 30]. Eur Radiol. 2020;1-10. 

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doi:10.1007/s00330-020-06975-7. 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261039/  
13. Fabbri L, Moss S, Khan F, Chi W, Xia J, Robinson K, et al. Post-viral 
parenchymal lung disease of COVID-19 and viral pneumonitis: A systematic 
review and meta-analysis. medRxiv [Internet]. 2021 March 17, 
http://dx.doi.org/10.1101/2021.03.15.21253593. 
14. Babapoor-Farrokhran, S., Gill, D., Walker, J., Rasekhi, R. T., Bozorgnia, B., & 
Amanullah, A. (2020). Myocardial injury and COVID-19: Possible mechanisms. 
Life sciences, 253, 117723. https://doi.org/10.1016/j.lfs.2020.117723  
15. Aggarwal, G., Cheruiyot, I., Aggarwal, S., Wong, J., Lippi, G., Lavie, C. J., Henry, 
B. M., & Sanchis-Gomar, F. (2020). Association of Cardiovascular Disease With 
Coronavirus Disease 2019 (COVID-19) Severity: A Meta-Analysis. Current 
problems in cardiology, 45(8), 100617. 
https://doi.org/10.1016/j.cpcardiol.2020.100617 Panamerican Health 
Organization • www.paho.org • © OPS/OMS, 2020 - 17 –  
16. Clerkin, K. J., Fried, J. A., Raikhelkar, J., Sayer, G., Griffin, J. M., Masoumi, A., 
Jain, S. S., Burkhoff, D., Kumaraiah, D., Rabbani, L., Schwartz, A., & Uriel, N. 
(2020). COVID-19 and Cardiovascular Disease. Circulation, 141(20), 1648–
1655. https://doi.org/10.1161/CIRCULATIONAHA.120.046941  
17. Bansal M. (2020). Cardiovascular disease and COVID-19. Diabetes & metabolic 
syndrome, 14(3), 247–250. https://doi.org/10.1016/j.dsx.2020.03.013  
18. Cothran, T. P., Kellman, S., Singh, S., Beck, J. S., Powell, K. J., Bolton, C. J., & 
Tam, J. W. (2020). A brewing storm: The neuropsychological sequelae of 
hyperinflammation due to COVID-19. Brain, behavior, and immunity, S0889-
1591(20)31209-5. Advance online publication. 
https://doi.org/10.1016/j.bbi.2020.06.008  
19. Rogers, J. P., Chesney, E., Oliver, D., Pollak, T. A., McGuire, P., Fusar-Poli, P., 
Zandi, M. S., Lewis, G., & David, A. S. (2020). Psychiatric and neuropsychiatric 
presentations associated with severe coronavirus infections: a systematic review 
and meta-analysis with comparison to the COVID-19 pandemic. The Lancet. 
Psychiatry, 7(7), 611–627. https://doi.org/10.1016/S2215-0366(20)30203-0  
20. Polak, S. B., Van Gool, I. C., Cohen, D., von der Thüsen, J. H., & van Paassen, 
J. (2020). A systematic review of pathological findings in COVID-19: a 
pathophysiological timeline and possible mechanisms of disease progression. 
Modern pathology: an official journal of the United States and Canadian 
Academy of Pathology, Inc, 1–11. Advance online publication. 
https://doi.org/10.1038/s41379-020-0603-3  
21. Troyer, E. A., Kohn, J. N., & Hong, S. (2020). Are we facing a crashing wave of 
neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and 
potential immunologic mechanisms. Brain, behavior, and immunity, 87, 34–39. 
https://doi.org/10.1016/j.bbi.2020.04.027  

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22. Taquet M, Geddes JR, Husain M, Luciano SH, Harrison PJ. 6-month 
neurological and psychiatric outcomes in 236.379 survivors of COVID-19: a 
retrospective cohort study using electronic health records. Lancet Psychiatry. 
2021;8:416–27, http://dx.doi.org/10.1016/S2215-0366(21)00084-5. 
23. Graham EL, Clark JR, Orban ZS, Lim PH, Szymanski AL, Taylor C, et al. 
Persistent neurologic symptoms and cognitive dysfunction in nonhospitalized 
Covid-19 “long haulers”. Ann Clin Transl Neurol. 2021;8:1073–85, 
http://dx.doi.org/10.1002/acn3.51350. 
24. In the wake of the pandemic: preparing for Long COVID (2021). 
https://www.euro.who.int/en/about-us/partners/observatory/publications/policy-
briefs-and-summaries/in-the-wake-of-the-pandemic-preparing-for-long-covid-
2021.  
25. European Observatory on Health Systems and Policies, Rajan, Selina, Khunti, 
Kamlesh, Alwan, Nisreen, Steves, Claire. et al. (2021). In the wake of the 
pandemic: preparing for long COVID. World Health Organisation. Regional 
Office for Europe. https://apps.who.int/iris/handle/10665/339629  
26. Mahoney FI, Barthel DW. Functional evaluation: the Barthel Index. Md State 
Med J 1965;14:61–5. 
27. Mahler DA, Wells CK. Evaluation of clinical methods for rating dyspnea. Chest. 
1988 Mar;93(3):580-6. doi: 10.1378/chest.93.3.580. PMID: 3342669. 
28. ATS Committee on Proficiency Standards for Clinical Pulmonary Function 
Laboratories. ATS statement: guidelines for the six-minute walk test. Am J 
Respir Crit Care Med. 2002 Jul 1;166(1):111-7. doi: 
10.1164/ajrccm.166.1.at1102. Erratum in: Am J Respir Crit Care Med. 2016 May 
15;193(10):1185. PMID: 12091180. 
 
 

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Annex 1. Declaration of Helsinki 
WMA Declaration of Helsinki - Ethical principles for medical research involving human subjects 
Adopted by the 
18th WMA General Assembly, Helsinki, Finland, June 1964 
and amended by the 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington DC, USA October 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
Introduction 
1. 
The World Medical Association (WMA) has developed the Declaration of Helsinki 
as a statement of ethical principles for medical research involving human subjects, 
including research on identifiable human material and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs 
should be applied with consideration of all other relevant paragraphs. 
2. 
Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research 
involving human subjects to adopt these principles.  
General principles 
3. 
The Declaration of Geneva of the WMA binds the physician with the words, “The 
health of my patient will be my first consideration,” and the International Code of 
Medical Ethics declares that, “A physician shall act in the patient’s best interest 
when providing medical care.” 
4. 
It is the duty of the physician to promote and safeguard the health, well-being and 
rights of patients, including those who are involved in medical research. The 
physician’s knowledge and conscience are dedicated to the fulfilment of this duty.  
5. 
Medical progress is based on research that ultimately must include studies involving 
human subjects. 
6. 
The primary purpose of medical research involving human subjects is to understand 
the causes, development and effects of diseases and improve preventive, 
diagnostic and therapeutic interventions (methods, procedures and treatments). 
Even the best proven interventions must be evaluated continually through research 
for their safety, effectiveness, efficiency, accessibility and quality. 
7. 
Medical research is subject to ethical standards that promote and ensure respect 
for all human subjects and protect their health and rights. 
8. 
While the primary purpose of medical research is to generate new knowledge, this 
goal can never take precedence over the rights and interests of individual research 
subjects. 

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9. 
It is the duty of physicians who are involved in medical research to protect the life, 
health, dignity, integrity, right to self-determination, privacy, and confidentiality of 
personal information of research subjects. The responsibility for the protection of 
research subjects must always rest with the physician or other health care 
professionals and never with the research subjects, even though they have given 
consent. 
10. Physicians must consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable 
international norms and standards. No national or international ethical, legal or 
regulatory requirement should reduce or eliminate any of the protections for 
research subjects set forth in this Declaration. 
11. Medical research should be conducted in a manner that minimises possible harm 
to the environment.  
12. Medical research involving human subjects must be conducted only by individuals 
with the appropriate ethics and scientific education, training and qualifications. 
Research on patients or healthy volunteers requires the supervision of a competent 
and appropriately qualified physician or other health care professional. 
13. Groups that are underrepresented in medical research should be provided 
appropriate access to participation in research. 
14. Physicians who combine medical research with medical care should involve their 
patients in research only to the extent that this is justified by its potential preventive, 
diagnostic or therapeutic value and if the physician has good reason to believe that 
participation in the research study will not adversely affect the health of the patients 
who serve as research subjects. 
15. Appropriate compensation and treatment for subjects who are harmed as a result 
of participating in research must be ensured. 
Risks, Burdens and Benefits 
16. In medical practice and in medical research, most interventions involve risks and 
burdens. 
Medical research involving human subjects may only be conducted if the 
importance of the objective outweighs the risks and burdens to the research 
subjects. 
17. All medical research involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and groups involved 
in the research in comparison with foreseeable benefits to them and to other 
individuals or groups affected by the condition under investigation. 
Measures to minimise the risks must be implemented. The risks must be 
continuously monitored, assessed and documented by the investigator. 
18. Physicians may not be involved in a research study involving human subjects 
unless they are confident that the risks have been adequately assessed and can be 
satisfactorily managed. 

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When the risks are found to outweigh the potential benefits or when there is conclusive 
proof of definitive outcomes, physicians must assess whether to continue, modify or 
immediately stop the study. 
 
Vulnerable Groups and Individuals 
19. Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered 
protection. 
20. Medical research with a vulnerable group is only justified if the research is 
responsive to the health needs or priorities of this group and the research cannot 
be carried out in a non-vulnerable group. In addition, this group should stand to 
benefit from the knowledge, practices or interventions that result from the research. 
Scientific Requirements and Research Protocols 
21. Medical research involving human subjects must conform to generally accepted 
scientific principles, be based on a thorough knowledge of the scientific literature, 
other relevant sources of information, and adequate laboratory and, as appropriate, 
animal experimentation. The welfare of animals used for research must be 
respected. 
22. The design and performance of each research study involving human subjects must 
be clearly described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and 
should indicate how the principles in this Declaration have been addressed. The 
protocol should include information regarding funding, sponsors, institutional 
affiliations, potential conflicts of interest, incentives for subjects and information 
regarding provisions for treating and/or compensating subjects who are harmed as 
a consequence of participation in the research study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-
trial provisions. 
 
Research Ethics Committees 
23. The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins. This 
committee must be transparent in its functioning, must be independent of the 
investigator, the sponsor and any other undue influence and must be duly qualified. 
It must take into consideration the laws and regulations of the country or countries 
in which the research is to be performed as well as applicable international norms 
and standards but these must not be allowed to reduce or eliminate any of the 
protections for research subjects set forth in this Declaration. 

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The committee must have the right to monitor ongoing studies. The investigator 
must provide monitoring information to the committee, especially information about 
any serious adverse events. No amendment to the protocol may be made without 
consideration and approval by the committee. After the end of the study, the 
investigators must submit a final report to the committee containing a summary of 
the study’s findings and conclusions. 
 
Privacy and Confidentiality 
24. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
Informed Consent 
25. Participation by individuals capable of giving informed consent as subjects in 
medical research must be voluntary. Although it may be appropriate to consult 
family members or community leaders, no individual capable of giving informed 
consent may be enrolled in a research study unless he or she freely agrees. 
26. In medical research involving human subjects capable of giving informed consent, 
each potential subject must be adequately informed of the aims, methods, sources 
of funding, any possible conflicts of interest, institutional affiliations of the 
investigator, the anticipated benefits and potential risks of the study and the 
discomfort it may entail, post-study provisions and any other relevant aspects of the 
study. The potential subject must be informed of the right to refuse to participate in 
the study or to withdraw consent to participate at any time without reprisal. Special 
attention should be given to the specific information needs of individual potential 
subjects as well as to the methods used to deliver the information. 
After ensuring that the potential subject has understood the information, the 
physician or another appropriately qualified individual must then seek the potential 
subject’s freely-given informed consent, preferably in writing. If the consent cannot 
be expressed in writing, the non-written consent must be formally documented and 
witnessed. 
All medical research subjects should be given the option of being informed about 
the general outcome and results of the study. 
27. When seeking informed consent for participation in a research study the physician 
must be particularly cautious if the potential subject is in a dependent relationship 
with the physician or may consent under duress. In such situations the informed 
consent must be sought by an appropriately qualified individual who is completely 
independent of this relationship. 
28. For a potential research subject who is incapable of giving informed consent, the 
physician must seek informed consent from the legally authorised representative. 
These individuals must not be included in a research study that has no likelihood of 
benefit for them unless it is intended to promote the health of the group represented 
by the potential subject, the research cannot instead be performed with persons 

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capable of providing informed consent, and the research entails only minimal risk 
and minimal burden. 
29. When a potential research subject who is deemed incapable of giving informed 
consent is able to give assent to decisions about participation in research, the 
physician must seek that assent in addition to the consent of the legally authorised 
representative. The potential subject’s dissent should be respected. 
30. Research involving subjects who are physically or mentally incapable of giving 
consent, for example, unconscious patients, may be done only if the physical or 
mental condition that prevents giving informed consent is a necessary characteristic 
of the research group. In such circumstances the physician must seek informed 
consent from the legally authorised representative. If no such representative is 
available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving subjects with a 
condition that renders them unable to give informed consent have been stated in 
the research protocol and the study has been approved by a research ethics 
committee. Consent to remain in the research must be obtained as soon as possible 
from the subject or a legally authorised representative. 
31. The physician must fully inform the patient which aspects of their care are related 
to the research. The refusal of a patient to participate in a study or the patient’s 
decision to withdraw from the study must never adversely affect the patient-
physician relationship. 
32. For medical research using identifiable human material or data, such as research 
on material or data contained in biobanks or similar repositories, physicians must 
seek informed consent for its collection, storage and/or reuse. There may be 
exceptional situations where consent would be impossible or impracticable to obtain 
for such research. In such situations the research may be done only after 
consideration and approval of a research ethics committee. 
Use of Placebo 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best proven intervention(s), except in the following 
circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is 
acceptable; or 
Where for compelling and scientifically sound methodological reasons the use of 
any intervention less effective than the best proven one, the use of placebo, or no 
intervention is necessary to determine the efficacy or safety of an intervention and 
the patients who receive any intervention less effective than the best proven one, 
placebo, or no intervention will not be subject to additional risks of serious or 
irreversible harm as a result of not receiving the best proven intervention. 
Extreme care must be taken to avoid abuse of this option. 
 
 
 

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Post-Trial Provisions 
34. In advance of a clinical trial, sponsors, investigators and host country governments 
should make provisions for post-trial access for all participants who still need an 
intervention identified as beneficial in the trial. This information must also be 
disclosed to participants during the informed consent process. 
 
Research Registration and Publication and Dissemination of Results 
35. Every research study involving human subjects must be registered in a publicly 
accessible database before recruitment of the first subject. 
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations 
with regard to the publication and dissemination of the results of research. 
Researchers have a duty to make publicly available the results of their research on 
human subjects and are accountable for the completeness and accuracy of their 
reports. All parties should adhere to accepted guidelines for ethical reporting. 
Negative and inconclusive as well as positive results must be published or 
otherwise made publicly available. Sources of funding, institutional affiliations and 
conflicts of interest must be declared in the publication. Reports of research not in 
accordance with the principles of this Declaration should not be accepted for 
publication. 
 
Unproven Interventions in Clinical Practice 
37. In the treatment of an individual patient, where proven interventions do not exist or 
other known interventions have been ineffective, the physician, after seeking expert 
advice, with informed consent from the patient or a legally authorised 
representative, may use an unproven intervention if in the physician’s judgement it 
offers hope of saving life, re-establishing health or alleviating suffering. This 
intervention should subsequently be made the object of research, designed to 
evaluate its safety and efficacy. In all cases, new information must be recorded and, 
where appropriate, made publicly available. 

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Annex 2. List of Sites / Principal Investigators 
Attached in a separate document. 

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Annex 3. Sample Patient Information Sheet and Informed Consent 
Form 
Attached in a separate document. 
 
 
 
 

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Annex 4. NCI-CTCAE criteria  
 
The common terminology criteria for the classification of adverse events version 5.0  
(NCI-CTCAE v. 5.0) can be consulted at the following Internet address: 
 
 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_
Quick_Reference_8.5x11.pdf 
 
  

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Annex 5. Post-COVID complications  
 
 
 
 
List of post-COVID complications 
 
COMPLICATIONS  
HAVE HAD 
Duration  
Worst grade 
Fatigue/asthenia 
YES/NO 
Start/end date  
 
General malaise 
YES/NO 
Start/end date  
 
Headaches 
YES/NO 
Start/end date  
 
Low mood 
YES/NO 
Start/end date  
 
Muscle aches and pains 
YES/NO 
Start/end date  
 
Joint pains 
YES/NO 
Start/end date  
 
Attention deficit 
YES/NO 
Start/end date  
 
Chest pressure 
YES/NO 
Start/end date  
 
Anxiety 
YES/NO 
Start/end date  
 
Febricula 
YES/NO 
Start/end date  
 
Cough 
YES/NO 
Start/end date  
 
Memory lapses 
YES/NO 
Start/end date  
 
Diarrhoea 
YES/NO 
Start/end date  
 
Palpitations 
YES/NO 
Start/end date  
 
Dizziness 
YES/NO 
Start/end date  
 
Tingling in extremity 
YES/NO 
Start/end date  
 
Others (specify) 
YES/NO 
Start/end date  
 
 
List based on the survey carried out by the Spanish Society of General Practitioners and Family Doctors. 
 
 
 

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Annex 6. Barthel Index 
 
 
 
 
Mahoney FI, Barthel DW. Functional evaluation: the Barthel Index. Md State Med J 1965;14:61–5. 
 
 

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Annex 7. Dyspnoea scale mMRC (modified Medical Research Council) 
 
 
Grade 
Severity of symptom 
0 
I only get breathless with strenuous exercise 
1 
I get short of breath when hurrying on level ground or walking up a slight hill 
2 
On level ground, I walk slower than people of the same age because of 
breathlessness, or have to stop for breath when walking at my own pace 
3 
I stop for breath after walking about 100 metres or after a few minutes on level 
ground 
4 
I am too breathless to leave the house or I am breathless when dressing 
 
 
Mahler DA, Wells CK. Evaluation of clinical methods for rating dyspnea. Chest. 1988 Mar;93(3):580-6. 
doi: 10.1378/chest.93.3.580. PMID: 3342669. 
  
 

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Annex 8 Calculation of PaO2 from SpO2  
 
It will be necessary to evaluate the PaO2/FiO2 ratio, to discriminate between ‘Moderate’ 
and ‘Severe’ categories, according to FDA guidance.  
As most patients will only have determinations of oxyhemoglobin percent saturation with 
a pulse oximeter (SpO2), it will be necessary to implement a method for the estimation 
of the PaO2/FiO2 ratio to evaluate disease severity.  
The Ellis inversion of the Severinghaus equation provides a useful nonlinear method for 
imputing PaO2 from SaO2. This technique has been used in cohorts of mostly 
nonintubated patients with pneumonia (3-5) and in patients with acute respiratory distress 
syndrome (6).  
 
 
 
 
Ellis solution for the Severinghaus equation  
(S= SpO2 from pulse oximetry)  
________________________________________________________________________  
References  
1.  Ellis R.K. Determination of Po2 from saturation. J Appl Physiol. 1989;67(2):902.  
2.  Severinghaus J.W. Simple, accurate equations for human blood O2 dissociation computations. J Appl 
Physiol. 1979;46(3):599-602.  
3.  Lanspa M.J., Jones B.E., Brown S.M., Dean N.C. Mortality, morbidity, and disease severity of patients 
with aspiration pneumonia. J Hosp Med. 2013;8(2):83-90.  
4.  Dean N.C., Jones J.P., Aronsky D. Hospital admission decision for patients with community-acquired 
pneumonia: variability among physicians in an emergency department. Ann Emerg Med. 
2012;59(1):35-41.  
5.  Brown S.M., Jones B.E., Jephson A.R., Dean N.C., Infectious Diseases Society of America/American 
Thoracic Society Validation of the Infectious Diseases Society of America/American Thoracic Society 
2007 guidelines for severe community-acquired pneumonia. Crit Care Med. 2009;37(12):3010-3016.  
6.  Brown SM, Grissom CK, Moss M, et al. Nonlinear Imputation of Pao2/Fio2 From Spo2/Fio2 Among 
Patients 
With 
Acute 
Respiratory 
Distress 
Syndrome. 
Chest. 
2016;150(2):307-313. 
doi:10.1016/j.chest.2016.01.003 
 
 
 
 

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Annex 9 Instructions for the 6 minute walk test.  
 
See article and erratum in separate documents.  
 
ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: 
guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002 Jul 1;166(1):111-7. doi: 
10.1164/ajrccm.166.1.at1102. Erratum in: Am J Respir Crit Care Med. 2016 May 15;193(10):1185. PMID: 
12091180.