The Fondazione Genomic SARS-CoV-2 Study
Phase: NA
Conditions: COVID-19, Genetic Predisposition
Sponsor: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico



Department of Services and Preventive Medicine UOC 
Transfusion Center Tel. 02 55036595
- Director: Dr. Daniele Prati
RESPONSIBILITIES (role of promoter and collaborators)
InternalCollaborations
Department
Participant'sname
Role in the study
Department
Transfusion and Hematology,
IRCCS Ca' Granda Foundation
Maggiore Policlinico Hospital,
University of Milan,
directed by dr. Daniele Prati
Of
Medicine
Daniele Prati
Guido Baselli
Serena Pelusi
Giuseppe Lamorte
study coordination,
data analysis and interpretation,
recruitment and characterization
of controls
Scientific Direction, IRCCS Ca' 
Granda Foundation Ospedale 
Maggiore Policlinico
Filippo Martinelli-Boneschi
Monica Miozzo,
Luigia Scudeller,
Silvano Bosari
genotyping,
data analysis and interpretation,
biobanking,
study funding.
UOC Adult Resuscitation and 
Intensive Care, IRCCS Ca' 
Granda Foundation Ospedale 
Maggiore Policlinico and 
University of Milan
Alberto Zanella
Giacomo Grasselli
Antonio Pesenti
patients recruitment and
characterization
substudy management.
IRCCS Ca' Granda Maggiore 
Hospital Foundation
“COVID-19 Network” Polyclinic
Valter Monzani,
Francesco Blasi,
Andrea Gori,
Alessandra Bandera,
Flora Peyvandi,
George Constantine,
Anna Ludovica Fracanzani,
Marina Baldini
Leonardo Terranova
patientsrecruitment
characterization.
and
UOC High Intensity Pediatrics
Paola Marchisio
patientsrecruitment
and
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Department of Services and Preventive Medicine UOC 
Transfusion Center Tel. 02 55036595
- Director: Dr. Daniele Prati
Treatment, IRCCS Ca' Granda 
Ospedale Maggiore Policlinico 
Foundation
characterization.
UOC General Medicine,
IRCCS Ca' Granda Ospedale 
Maggiore Policlinico Foundation
Maria Carrabba
patients
characterization,
management.
recruitment
and
substudy
UOC Laboratory Medicine, 
Fondazione IRCCS Ca' Granda 
Ospedale Maggiore Policlinico
Ferruccio Ceriotti
samplescollection,
laboratorycharacterization.
External Collaborations (biological samples analysis, data analysis, diagnostic procedures)
Institution
Department
Participant'sname
Role in the study
University of Oslo
Department of
Gastroenterology,
Tom Hemming Karlsen
study funding,
data analysis
University of Kiel
Department of
Molecular Medicine
Andre Franke
genotyping
genetic analysis
and
Humanitas University and 
Research Hospital
Stefano Duga, Rossana
Asselta
data analysis, controls
for collaborative
studies
San Gerardo Hospital,
Bicocca University
Pietro Invernizzi, Andrea
Blonde
controls for
collaborative studies
3

Department of Services and Preventive Medicine UOC 
Transfusion Center Tel. 02 55036595
- Director: Dr. Daniele Prati
LIST OF ABBREVIATIONS
IEC:IndependentEthics Committee
THERE:Informed Consent
CRF:Case Report Form
GCP:Good Clinical Practice
GWAS:Genome-wide association studies
PNS:single nucleotide polymorphisms
GRS:genetic risk score
4

Department of Services and Preventive Medicine UOC 
Transfusion Center Tel. 02 55036595
- Director: Dr. Daniele Prati
Summary
Summary................................................................ .................................................. .................................................. ....... 5
BACKGROUND AND OVERVIEW OF THE PROJECT................................................ ................................................. 7
Hypothesis ................................................ .................................................. .................................................. 8
Purpose and aims ................................................. .................................................. .......................................... 8
Project timeline ................................................ .................................................. .......................................... 11
STUDY PROTOCOL ................................................ .................................................. .......................................... 11
Objectives ................................................ .................................................. ................................................. 11
Study Design ................................................ .................................................. ................................................ 11
Participants (eligibility) ................................................ .................................................. ................................ 12
Houses ................................................ .................................................. .................................................. ... 12
Mild/moderate infection controls........................................................ .................................................. ............ 12
Healthy controls (general population controls) ................................................ ........................................... 12
Study flowchart ................................................ .................................................. ...................................... 13
Genomic study, laboratory methods................................................. .................................................. ............ 13
Potential biases and pitfalls................................................ .................................................. ................................ 14
Study variables and data sources ................................................. .................................................. ................. 15
Houses ................................................ .................................................. .................................................. ... 15
Mild/moderate infections controls ................................................ .................................................. .......... 15
Healthy controls................................................ .................................................. ...................................... 15
Statistical issues................................................ .................................................. ...................................... 16
Sample size ................................................ .................................................. ............................................ 16
Statistical analysis plan................................................. .................................................. .......................... 17
Ethical considerations................................................ .................................................. .................................... 17
Regulatory standards................................................ .................................................. ................................ 17
Institutional review board / independent ethics committee .......................................................... .......................... 17
Patient information ................................................ .................................................. .................................... 18
5

Department of Services and Preventive Medicine UOC 
Transfusion Center Tel. 02 55036595
- Director: Dr. Daniele Prati
Funding ................................................ .................................................. .................................................. ... 19
Insurance ................................................ .................................................. .................................................. 19
Confidentiality ................................................ .................................................. .......................................... 19
Publication................................................ .................................................. ................................................ 19
REFERENCES................................................. .................................................. .................................................. 21
6

Department of Services and Preventive Medicine UOC 
Transfusion Center Tel. 02 55036595
- Director: Dr. Daniele Prati
BACKGROUND AND OVERVIEW OF THE PROJECT
The Lombardy region in Northern Italy is now in the midst of an outbreak of severe acute respiratory disease
syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19)1. The
COVID-19 epidemic situation needs little introduction and represent a global world-wide emergency with
mortality rates rapidly increasing in Europe and the US. Evidence is accumulating that the majority of
individuals infected by SARS-CoV-2 are asymptomatic and the major source of viral spread3, and that a
considerable fraction of these has active viral replication4.5.Furthermore,disease behavior is variable,
with the majority of patients experiencing only mild symptoms or no symptoms at all. Some patients
develop severe pulmonary affection, with aggressive and extensive inflammatory destruction of lung
parenchyma and associated inflammatory responses and superinfections, driving large fractions of the
COVID-19 related mortality. What exactly drives this development of severe lung disease remains
unknown, but old age, obesity, diabetes and other co-morbidities increase the risk, while the role played
by specific medications is still uncertain. Variation in virus genetics and patient immunology are also likely
. As to the latter point, we hypothesize that host genetics may play a role in determining
development of severe lung disease in SARS-CoV-2 infection.
Genome-wide association studies (GWAS) have been applied to decipher the genetic predisposition in
thousands of disease traits since the study design was invented in 2005. The genetic signals detected vary
from very strong effects that can be detected in a few hundred individuals, to very weak effects requiring
cohorts of tens of thousands for detection. By 2020, the study design is now a robust, off-the-shelf, easy-
to-perform industry-standard screening tool for genetic predisposition, even available through “consumer
genetics” online-based companies. The study design is simple: testing for genetic variants throughout the
genome (single nucleotide polymorphisms, SNPs) using SNP microarrays, comparing their frequencies in
patients versus controls (or across other variables). For inflammatory phenotypes in particular, GWAS has
proven an efficient tool, delineating hundreds of susceptibility loci in many conditions, some of which has
provided novel and surprising disease insights.
7

Department of Services and Preventive Medicine UOC 
Transfusion Center Tel. 02 55036595
- Director: Dr. Daniele Prati
GWAS serves two purposes. Most importantly they allow to determine biological factors involved in disease
development, thus potentially guiding drug development and therapy. This would be particularly relevant
during the current COVID-19 emergency, when hundreds of trials have begun and there is an urgent need
to prioritize well-conducted collaborative studies based on robust pathophysiological data. Secondly, and
increasingly popular, they allow for the calculation of a “polygenic risk score” to predict disease
development. Both aspects appear crucial to clarify for COVID-19 lung disease: (a) are there genetic
signatures suggesting which biological mechanisms are involved that may suggest relevant therapeutic
approaches, and (b) can we predict those at risk (or those with very low risk)?
The Fondazione IRCCS Ca' GrandaOspedale Maggiore Policlinico is the main public clinical research
institute in Italy and has taken a leading role in the medical management of the COVID-19 epidemics
in Milan and the Lombardy region. Due to the high volume of patients treated, the ongoing
characterization of a large cohort of individuals who acquired the infection without developing
symptoms (CoDS study), and scientific leadership in the field of human genetics, the Foundation is in
a unique position to conduct a genomewide association study for the identification of the inherited
determinants of the susceptibility to severe COVID-19.
Hypothesis
Host genetic factors contribute to development of severe pulmonary disease in patients with SARS-CoV-2
infection.
Purpose and aims
The purpose of the entire project is to identify genetic determinants of the predisposition to develop
respiratory failure in persons infected by SARS-CoV-2; knowledge of these factors may educate the
biological understanding of the development of severe lung disease in SARS-CoV-2 infection. Such an
understanding may inform treatment trials of potential utility towards more effective management of this
patient group. A polygenic risk score may also be useful in identifying high/low risk patients, eg among
health-care providers and vulnerable individuals with significant comorbidities.
8

Department of Services and Preventive Medicine UOC 
Transfusion Center Tel. 02 55036595
- Director: Dr. Daniele Prati
Specific aims of the project are:
1. To identify the main common genetic determinants of severe COVID-19 by conducting a GWAS:
in first phase we will compare the first 1,000 cases (SARS-CoV-2 positive patients with severe lung
affection)to 5,000 historical healthy controls from the same geographic area, in order to provide
initial data informing the research in the field in a timely fashion. This will be conducted in close
collaboration with the University of Kiel COVID-19 genomic initiative. Later on, we will proceed
to assess objectives 1 and 2 in the full cohort, including also infected controls who did not
developed clinically significant symptoms.
2. To provide extensive genetic characterization of all patients managed at the Foundation in order
to facilitate other groups working on specific projects (eg on candidate genes such as
SERPINA1andACE2by the Intensive Care and Cardiology Units and others that may emerge from
upcoming projects), in a large population and in a very timely fashion, and without incurring in any
additional expenses for the Fondazione research network, and coordinate research efforts.
3. To provide a coordination to manage the collaboration with other research consortia in the field,
eg the “An anonymized GWAS to urgently query host genetic predisposition to severe COVID-19
(SARS-CoV-2 infection) lung disease, and the COVID-19 Host Genetic Initiative
(https://www.covid19hg.org). Indeed, collaboration among large networks analyzing several
thousand cases will be ultimately necessary to clarify the genetic basis of COVID-19 susceptibility,
and large collaborative networks are essential instruments for conducting human genetic research.
Secondary aims:
1. To develop a genetic risk score (GRS) to stratify disease risk, based on both genomewide
significant loci and candidate variants (including those regulating immune response and viral
receptors).
9

Department of Services and Preventive Medicine UOC 
Transfusion Center Tel. 02 55036595
- Director: Dr. Daniele Prati
2. To assess the impact of genetic risk variants on disease outcomes, specific clinical characteristics, and
response to specific therapeutic approaches (pharmacogenomic analysis) in patients who
developed respiratory failure.
3. To examine the possible role of rare genetic variants in determining the predisposition to severe
COVID-19 in individuals who developed severe respiratory failure requiring ventilation despite age
< 50 years and lack of comorbidities and risk factors (in collaboration with COVID-19 Host genetic
initiative and other international research networks).
4. To analyze the predisposition to develop severe COVID-19 in pediatric patients.
10

Department of Services and Preventive Medicine UOC 
Transfusion Center Tel. 02 55036595
- Director: Dr. Daniele Prati
Project timeline
Milestones
Planning
Basal samples collection
03/23/2020
Ethical committee submission
04/09/2020
Phase 1 analysis - start
04/05/2020
Phase 1 analysis – initial report
01/06/2020
Phase 2 analysis
01/09/2020 - 06/09/2021
Final study report (main outcomes)
09/31/2021
Additional analyzes (secondary outcomes), and
planning of additional steps
03/06/2020 – 06/02/2022
STUDY PROTOCOL
We will conduct a genomewide association study to identify common genetic variants predisposing to the
development of severe SARS-CoV-2 infection.
Objectives
1)To identify differences in genetic background between patients with severeSARS-CoV-2 infection and 
healthy controls from the same geographic area
ENDPOINTS: SNPs as identified by GWAS
2) To identify differences in genetic background between patients with severe versus mild or moderate SARS-CoV-2 
infection
ENDPOINTS: SNPs as identified by GWAS
Study Design
Cross-sectional study, with non-standard study-specific biological testing.
The study consists of two phases as reported in the project timeline:
11

Department of Services and Preventive Medicine UOC 
Transfusion Center Tel. 02 55036595
- Director: Dr. Daniele Prati
1. In the first phase of the study, we will compare the first 1,000 cases (SARS-CoV-2 positive patients
with severe lung affection) to 5,000 historical healthy controls from the same geographic area, in
order to provide initial data informing the research in the field in a timely fashion. This will be
conducted in close collaboration with the University of Kiel COVID-19 genomic initiative.
2. In the second phase of the study, we will proceed to analyze the full cohort, including also infected
controls who did not develop clinically significant symptoms.
Participants (eligibility)
1. Cohort 1: Cases
SARS-CoV-2 positive patients (no age limit) with severe lung affection defined by hospitalization and
respiratory failure requiring support of any kind (ranging from O2support via non-invasive ventilation to full
respirator/ECMO) at the Fondazione IRCCS Ca' Granda. These patients will be selected among those
enrolled in the “COVID-19 Network”, “EPIDEMIOLOGICAL AND CLINICAL CHARACTERISTICS OF PATIENTS
HOSPITALIZED IN ITALIAN INTENSIVE THERAPY AFFECTED BY 2019-NCOV: COHORT STUDY
MULTI-CENTRIC RETROSPECTIVE-PROSPECTIVE: 2019-nCoV_ICU”,and other COVID-19 research
registries sponsored by the IRCCS Ca' Granda Foundation.
−
Informed consent
2. Cohort 2: Mild/moderate infection controls
−
blood donors (age 18-70 years) donating between 24/02/2020 and 18/05/2020(~7,500 donors) which
will be confirmed to have been infected with SARS-CoV-2 without developing clinically significant
symptoms, identified in the CoDS project “COVID-19 Donor Study” sponsored by the Foundation
−
confirmed to be exposed to the virus (by means of positive viremia and/or IgM/G antibodies).
−
informed consent
3. Cohort 3: Healthy controls (general population controls)
Healthy control data of Italian individuals available from previous multi-ethnic assessments (n=5,000, age 14-80 
years). These data are already present within a database at the University of Kiel comprising more than 50,000 
cases and are available for the analysis of this study.
12

Department of Services and Preventive Medicine UOC 
Transfusion Center Tel. 02 55036595
- Director: Dr. Daniele Prati
Study flowchart
Baselines
Timing
04/01/2020 – 09/30/2020
ROUTINE ASSESSMENT:
Clinical evaluation
X
Medical historyto
X
Clinical outcomesb
X
Basic biochemical panelb
X
Collection of blood sample for DNA extraction
X
toIncluding family history, lifestyle evaluation, physical activity, alcohol and smoking, risk factors for communicable
disorders, comorbidities.
bas specified in the research registries in which the patients are enrolled.
Genomic study, laboratory methods
In the first phase of the study, identified peripheral blood samples from severely affected cases (cases,
cohort 1) will be sent to the Department of Molecular Medicine of the University of Kiel: Dr.Andre Franke
will be responsible for storage and analysis of the samples. Genotyping will be performed by Illumina
GlobalScreeningArray-24 v3.0 + Multi-Disease array (Illumina), at the Department of Molecular Medicine
of the University of Kiel. At the end of the analyses, any leftover of biological samples will be sent back to
IRCCS Ca' Granda Foundation.
In the second phase of the study, DNA will be extracted from identified peripheral blood samples from
mild/moderate infection controls (cohort 2) at the Genomic platform of the Fondazione IRCCS Ca' Granda.
Deidentified DNA samples will be sequenced at the Fondazione IRCCS Ca' Granda by using the same
approach. Prof. Luca Valenti in collaboration with Monica Miozzo (Scientific direction) will be responsible for
the genomic analyzes of these samples at the Fondazione IRCCS Ca' Granda.
13

Department of Services and Preventive Medicine UOC 
Transfusion Center Tel. 02 55036595
- Director: Dr. Daniele Prati
The genetic risk profile (common inherited variants) will be evaluated at genomewide level by Illumina
Infinium Global screening array (Illumina), and frequency distributions of common genetic variants will be
compared between donors who cleared the infection without developing severe symptoms and patients
admitted for respiratory failure (enrolled by the COVID-19 research networks of the Fondazione IRCCS Ca'
Granda).
Substudy:to examine the possible role of rare genetic variants in determining the predisposition to severe
COVID-19, DNA (isolated from the same biological samples of the main study) of individuals who
developed severe respiratory failure requiring ventilation despite age < 50 years and lack of comorbidities
and risk factors will be further sequenced and analyzed by Whole exome sequencing (WES) at the
Department of Molecular Medicine of the University of Kiel (Dr.Andre Franke).
Any leftover of biological samples will be stored atBiobank POLI-MI for additional 15 years under the
responsibility of Dr.Luca Valenti.
Potential biases and pitfalls
Samples of insufficient quality due to low call rate (<0.95%) or outlying heterozygosity will be excluded. TO
set of LD-pruned SNPs with MAF>40% were used to estimate identity by descent (IBD) and ancestry and
any closely related individuals excluded. Principal component analysis will be used to exclude samples with
non-European ancestry. SNPs with a minor allele frequency less than 0.1%, Hardy-Weinberg equilibrium P
< 10−7, call rate lower than 95% will be excluded as well.
In order to be able to compare data to other cohorts to increase the sample power and allow replication,
we will proceed to single nucleotide polymorphisms (SNP) imputation in the cases was carried out using
the Michigan Imputation Server (https://imputationserver.sph.umich.edu/start.html#!pages/home ). Each
cohort was uploaded to the Michigan Imputation Server and imputed to the Haplotype Reference
Consortium (HRC 1.1r 2016) reference panel. Imputed genotypes will be filtered by an r2score of at least
0.8, and only overlapping well-imputed SNPs between the two cohorts will be retained.
14

Department of Services and Preventive Medicine UOC 
Transfusion Center Tel. 02 55036595
- Director: Dr. Daniele Prati
In case during the planned analyzes we will need a larger sample size to answer the research questions, we
will actively involve cases from collaborating hospitals and the international collaborative network.
Study variables and data sources
A biorepository (serum samples and buffy coats for DNA extraction) is being established and maintained
within the Fondazione IRCCS PoliclinicoPOLI-MI Biobank (at the coordinating Unit).
Cohort 1: Cases
Extensive clinical data with prospective follow-up and samples of these individuals are
alreadybeingcollectedwithin the “Register for the evaluation of epidemiological characteristics and
patient clinicshospitalizedat the COVID-19 units: COVID-19 network” and “characteristics
epidemiological and clinical findings of patients hospitalized in Italian intensive care units affected by 2019-nCoV:
multicenter retrospective-prospective cohort study: 2019-nCoV-ICU”. We will also involve collaborating
centers in Lombardy and Northern Italy.
Cohort 2: mild/moderate infections controls
All donors undergo clinical evaluation, including updating of medical history, and biochemical testing at
each blood donation. For each blood donation, the possible development of flu-like symptoms in the two
weeks following blood donation will be recorded as well. All donors are indeed asked to report the
development of any symptom potentially related to COVID-19 in the 14 days after the procedure, by
contacting a dedicated phone number, and all calls are managed by medical personnel of the Transfusion
center. All these events, as well as all the other data that will be collected for this study, are registered in
the EMONET 15 informatics system.
Cohort 3: healthy controls
> 5,000 historical healthy controlsfromthe same geographic area (data derived from previous studies
conducted at other institutions), in order to provide initial data informing the research in the field in a
timely fashion. This will be conducted in close collaboration with the University of Kiel and Oslo COVID-19
15

Department of Services and Preventive Medicine UOC 
Transfusion Center Tel. 02 55036595
- Director: Dr. Daniele Prati
genomic initiative, which includes collaborators from the Milan area (San Gerardo and
HumanitasHospitals).
Statistical issues
Sample size
Group
Sample size
Source/notes
Cases
2000
Ca' Granda ICU and medicine departments
Mild/moderate controls
2000
based on an estimated cumulative prevalence of 
SARS-CoV-2 infection >10% in Lombardy at the time 
of project writing, we estimate to enroll at least 
1,000 controls for the study (blood donors).
Healthy controls
5000 (including
collaborating centres)
Historic data
The study is originally scoped toward 2,000 cases, but if more samples are collected, the experiment will
be expanded (for which there is both capacity and funding).
The study is a case-control cross-sectional study. Two main comparisons will be performed:
1) cases vs healthy controls (phase 1)
2) cases vs mild/moderate infections (phase 2)
In the hypothesis that we will recruit 2,000 cases and consider 5,000 controls, we will have >99% power to
detect a 4-fold increase in the risk of severe COVID-19 for variants that have a minor allele frequency >30%
in the population (two sided, for a significance threshold of P values   < 10-8generally employed in GWAS),
and a good power (>80%) to detect an impact of rarer variants or of variant with smaller size effects.
Associations with very weak effect sizes may be missed with the crude approach, but for this study this
compromise is acceptable to achieve feasibility and speed.
16

Department of Services and Preventive Medicine UOC 
Transfusion Center Tel. 02 55036595
- Director: Dr. Daniele Prati
Statistical analysis plan
Statistical association analysis will be performed using logistic regression / linear mixed models, based
association methods with standard tools (eg SAIGE, BOLT-LMM, PLINK etc.)) and appropriate correction
for population stratification confounders, and incorporating patient age and gender as co-variables. For
strong genetic signals (egHLAin many immune mediated diseases,IL28Bin HCV infection,complement
factor Hpolymorphisms in age-related macular degeneration) only a few hundred patients have been
required to achieve genome-wide significant findings.
The comparison will be carried out on imputed genotypes, firstly from the set obtained from imputing
both cases and controls together, and then again from the set obtained by imputing all cohorts separately
and then combining stringently filtered genotypes. LocusZoom plots will be examined for visualization of
the signal around significantly associated SNPs.
For each trait the analysis will be performed with no clinical covariates and then again with the following
additional covariates: presence of arterial hypertension, diabetes, chronic obstructive pulmonary disease,
type of respiratory support.
Ethical considerations
Regulatory standards
This study will be conducted by Good Clinical Practice (GCP) rules; in accordance with the ethical principles
that have their origin in the Declaration of Helsinki and with the respect to the European clinical practice,
in compliance with all international guidelines and national law regulation in Italy.
Institutional review board / independent ethics committee
The protocol and the informed consent document must be submitted to the Independent Ethics
Committee (IEC) for review and will receive IEC approval/favourable opinion before initiation of the study.
During the study, any amendments to the protocol must also be approved by IEC. A progress report is sent
to the IEC at least annually, and a summary of the study's outcome is sent at the end of the study.
17

Department of Services and Preventive Medicine UOC 
Transfusion Center Tel. 02 55036595
- Director: Dr. Daniele Prati
Patient information
Participants enrolled will be required to consent to the deidentification of personal data for the study.
Information form and the module for the acquisition of informed consent for the handling of sensitive data
will be given to the patient.Specific written informed consents will be obtained by all included participants,
who will be confirmed to be exposed to SARS-CoV-2 (as detected by the presence of viremia and/or
seroconversion), to participate in genetic and biomarkers studies.
The investigator will fulfill the current regulations for research and documentation of informed consent, the
standards of Good Clinical Practice and the ethical principles derived from the Declaration of Helsinki. The
approval by the Ethics Committee will be required whether an update of the informed consent form will be
needed during the study.
According to the recommendations of the Declaration of Helsinki and local regulations, each patient will
be adequately informed about the aims, methods, expected benefits, potential risks and related problems
to the study. Furthermore, patients will be informed of their right to refuse consent to the use of their
sensitive data or to withdraw it at any time, without having any effect on their medical care.
The patient will have all the time necessary for the evaluation of the information received before providing
their informed consent to the use of sensitive data. The investigator will have to obtain spontaneously
informed consent in writing by the patient, before using them in any way for the study. The written
consent to the handling of sensitive data must be subscribed by the date and signature of the patient and
by the investigator's or his representative's ones.
The investigator has to give to the patient a signed copy of informed consent; the original form will be
retained with the other documents of the study protocol; the module for the acquisition of informed
consent to the treatment of sensitive data will be attached to the clinical folder. The collaborator will be
appointed to review the original forms of all patients' informed consent.
18

Department of Services and Preventive Medicine UOC 
Transfusion Center Tel. 02 55036595
- Director: Dr. Daniele Prati
Funding
The study will be funded by Institutional funding dedicated to testing the safety of blood products, and the
specific research funding dedicated to the COVID-19 emergency from the Scientific Direction, Foundation
IRCCS Ca' GrandaOspedale Maggiore Policlinico.
Genotyping and genetic analyzes performed at the Department of Molecular Medicine of the University of
Kielwill be supported by funding by University of Oslo.
Insurance
No additional blood sampling (samples will derive from leftovers of donations) or clinical data will be
required in addition to those already collected during the regular clinical practice. The internal institutional
insurance policy will cover for any undesirable effects due to the participation in the study.
Confidentiality
According to the ICH guidelines for the Good Clinical Practice, the monitoring team must check the CRF
entries against source documents. The personnel bound by professional secret must maintain the
confidentiality of all personal identity or personal medical information (according to the confidentiality
and personal data protection rules). The confidentiality of records that could identify subjects should be
protected, only initials of the name and the first name will be registered with an inclusion coded number
for the study (no name nor address nor identifying data).
Publications
Communications, reports, and publication of the results of the study will be under the responsibility of the
principal investigator of the study. A summary of the results of the study will be written and provided on
request of the participating patients.
Intellectual property rights of study results
The Promoter of the study and the Participating Centers acknowledge and accept that during the
implementation of the Project, to the extent strictly necessary for the performance of the Project, know-
19

Department of Services and Preventive Medicine UOC 
Transfusion Center Tel. 02 55036595
- Director: Dr. Daniele Prati
how, technical material and/or goods protected by industrial and/or intellectual property rights or
susceptible to protection, developed prior to the commencement of the Project by the Promoter and the
Participating Centres, shall be and shall remain their exclusive ownership. Nothing in this protocol shall be
constructed as a grant of rights under such intellectual property.
The results arising from the research activities will be jointly owned by the Promoter of the study and the
Participating Centers in proportion to their respective contribution, being understood that the provision of
biological samples underlying the research project, related clinical information and related medical know-
how by the Study Promoter will be considered as an essential contribution.
In cases of innovative results, which are subject to patent protection (or similar rights) and/or economic
exploitation, ownership of such Invention shall be owned based on inventorship contribution. In case of
joint ownership, the Promoter of the study and the Participating Centers will regulate, in fair and good
condition, the protection and the exploitation of the results.
20

Department of Services and Preventive Medicine UOC 
Transfusion Center Tel. 02 55036595
- Director: Dr. Daniele Prati
REFERENCES
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3. Li R, Pei S, Chen B, et al. Substantial undocumented infection facilitates the rapid dissemination of
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4. Zhang W, Du RH, Li B, et al. Molecular and serological investigation of 2019-nCoV infected patients:
implication of multiple shedding routes. Emerg Microbes Infect 2020;9:386-9.
5. Huang C, Wang Y, Li X, et al. Clinical characteristics of patients infected with 2019 novel coronavirus in
Wuhan, China. Lancet 2020;395:497-506.
6. Shang G, Biggerstaff BJ, Yang B, Shao C, Farrugia A. Theoretically estimated risk of severe acute
respiratory syndrome transmission through blood transfusion during an epidemic in Shenzhen, Guangdong,
China in 2003. TransfusApher Sci 2007;37:233-40.
7. Xu L, Liu J, Lu M, Yang D, Zheng X. Liver injury during highly pathogenic human coronavirus
infections. Liver Int 2020.
8. Casadevall A, Pirofski LA. The convalescent evening option for containing COVID-19. J ClinInvest 2020.
9. Chinazzi M, Davis JT, Ajelli M, et al. The effect of travel restrictions on the spread of the 2019 novel
coronavirus (COVID-19) outbreak. Science 2020.
10. Prati D, Capelli C, Zanella A, et al. Influence of different hepatitis C virus genotypes on the course of
asymptomatic hepatitis C virus infection. Gastroenterology 1996;110:178-83.
11. Prati D, Capelli C, Silvani C, et al. The incidence and risk factors of community-acquired hepatitis C
in a cohort of Italian blood donors. Hepatology 1997;25:702-4.
12. Prati D, Capelli C, Zanella A, et al. Asymptomatic hepatitis G virus infection in blood donors.
Transfusion 1997;37:1200-4.
Grasselli G, Pesenti A, Cecconi M. Critical Care Utilization for the COVID-19 Outbreak in Lombardy,
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Department of Services and Preventive Medicine UOC 
Transfusion Center Tel. 02 55036595
- Director: Dr. Daniele Prati
13. Prati D, Zanella A, Zanuso F, et al. Sustained response to interferon-alpha2a monotherapy of young people
blood donors with minimal-to-mild chronic hepatitis C. The Donor Surveillance Study Group. J
ViralHepat2000;7:352-60.
14. Prati D, Taioli E, Zanella A, et al. Updated definitions of healthy ranges for serum alanine
aminotransferase levels. Ann Intern Med 2002;137:1-10.
15. Zeuzem S, Diago M, Gane E, et al. Peginterferon alfa-2a (40 kilodaltons) and ribavirin in patients
with chronic hepatitis C and normal aminotransferase levels. Gastroenterology 2004;127:1724-32.
16. Spreafico M, Raffaele L, Guarnori I, et al. Prevalence and 9-year incidence of hepatitis E virus
infection among north italian blood donors: Estimated transfusion risk. J ViralHepat 2020.
17. Spreafico M, Berzuini A, Foglieni B, et al. Poor efficacy of nucleic acid testing in identifying occult
HBV infection and consequences for safety of blood supply in Italy. J Hepatol 2015;63:1068-76.
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