Rationale It is very likely that the most severe manifestations of COVID-19 may be linked to
an excessive and aberrant hyper-inflammatory host immune response along with pro-thrombotic
derangements of haemostatic system, two processes mutually reinforcing.

Steroids exert potent anti-inflammatory activity by inhibition of leucocytes extravasation,
function of macrophages and antigen-presenting cells, production of TNF alpha, interleukin-1
and nitric oxide. A Chinese report on 201 patients with COVID-19 pneumonia pointed out a
survival benefit of more than 15% among patients with ARDS who received Methylprednisolone
compared to those who did not .

The use of Low Molecular Weight Heparin (LMWH) or Unfractionated Heparin (UFH) at
prophylactic doses has been demonstrated to be associated with a reduced 28-day in more
severe patients with Sepsis Induced Coagulopathy (SIC) score ≥4 (40.0% vs 64.2%, P=0.029), or
D-dimer > 6 fold of upper limit of normal (32.8% vs 52.4%, P=0.017) . This finding agrees
with the already described immune-modulatory properties and protective action of glycocalyx
from shedding displayed by heparin. Despite the biological plausibility, no good evidence is
available on the efficacy and safety of heparin on sepsis patients, and many issues have to
be addressed, regarding the proper timing, dosages and administration schedules of
anticoagulant drugs.

Targeting inflammatory responses along with thrombosis prevention may be a promising
therapeutic option to improve outcomes in patients with COVID-19.

Study objective The primary objective is to assess the hypothesis that an adjunctive therapy
with steroids and unfractionated heparin or with steroids and molecular weight heparin (LMWH)
are more effective in reducing any-cause mortality in critically-ill patients with pneumonia
from COVID- 19 infection compared to low molecular weight heparin (LMWH) alone. Mortality
will be measured at 28 days. A possible result showing the efficacy of the composite
treatment in reducing the mortality rate among critically ill patients with pneumonia from
COVID-19 infection will lead to a revision of the current clinical approach to this disease.

Study setting The study will involve 8 Italian Academic and non-Academic Intensive Care
Units. The recruitment of 210 participants will be completed in around 10 months.

Interventions Patients who satisfy all inclusion criteria and no exclusion criteria will be
randomly assigned to a LMWH group (Group 1), LMWH+steroids (group 2) or UFH+steroid group
(Group 3). The study in conceived as open-label: the patients and all the health-care
personnel will be aware of the assigned group. The treatments will be initiated as soon as
possible after randomization (maximum allowed starting time 12h after randomization). In both
groups, before enrolment in the study it will be allowed the administration of low-dosages
steroids for ARDS treatment (maximum 320 mg of Metilprednisolone per day for a maximum of 2
days).

- LMWH group (group 1): Patients in this group will be administered enoxaparin at standard
prophylactic dose.

- LMWH + steroids group (group 2): Patients in this group will receive enoxaparin at
standard prophylactic dose and methylprednisolone.

- UFH + steroid group (group 3): Patients in this group will receive unfractionated
heparin at therapeutic dosages and methylprednisolone.

Unfractionated heparin will be administered intravenously in UFH + steroid group at
therapeutic doses. The infusion will be started at an infusion rate of 18 IU/kg/hour and then
modified to attain APTT Ratio in the range 1.5-2.0. aPTT will be periodically checked at
intervals no longer than 12 hours. The treatment with unfractionated heparin will be
administered up to ICU discharge. After ICU discharge anticoagulant therapy may be
interrupted or switched to prophylaxis with LMWH in the destination ward up to clinical
judgement of the attending physician.

Enoxaparin will be administered in both LMWH group and LMWH + steroids group at standard
prophylactic dose (i.e., 4000 UI once day, increased to 6000 UI once day for patients
weighting more than 90 kg). The treatment will be administered subcutaneously daily up to ICU
discharge. After ICU discharge it may be continued or interrupted in the destination ward up
to clinical judgement of the attending physician.

Methylprednisolone will be administered in both LMWH + steroids group and UHF + steroids
group intravenously with an initial bolus of 0,5 mg/kg followed by administration of 0,5
mg/kg 4 times daily for 7 days, 0,5 mg/kg 3 times daily from day 8 to day 10, 0,5 mg/kg 2
times daily at days 11 and 12 and 0,5 mg/kg once daily at days 13 and 14.

Concomitant medications: Depending on their clinical status, patients will be treated
according to the principles of the Good Clinical Practice and clinical judgement of the
attending physician. No other pharmacological therapy or treatment will be influenced from
the study protocol. There are no restrictions to concomitant treatments provided to patients
in this study. All relevant concomitant medications and treatments taken or administered in
the 24 hours before screening and during the study period will be recorded. Upon clinical
judgement of the attending physicians, the patients can receive rescue administration of
high- dose steroids or immune-modulatory drugs. Need and timing of rescue treatments
administration will be recorded.

Criteria for discontinuing or modifying allocated interventions: The duration of study
therapy will be until ICU discharge for LMWH and UFH and 7 days for Methylprednisolone.
Patients may be prematurely discontinued from study protocol at the discretion of the
Investigator, should any untoward effect occur (including an AE or clinically significant
laboratory abnormality that, in the opinion of the Investigator, warrants the subject's
permanent discontinuation of study protocol-directed care).

Data collection and management Every patient who meets the inclusion criteria will be
included and randomised in the three groups. The study data will be collected along the
entire study period in a dedicated electronic Case Report Form (eCRF). The eCRF will be
provided by the steering committee with proper options to minimize data entry errors: the
datasheet will incorporate un-amendable fixed intervals of values (for continuous variables)
and pre-defined coding system (for binary or categorical variables). Data entry will be
performed and double-checked from a dedicated researcher in each centre; in order to limit
collection errors, 10% of all records will be randomly re- checked from the PI in each
participating centre. The data collection will be also checked by a Clinical Monitor, by
phone calls as agreed with the investigators. The study Monitor will be responsible for
performing the monitoring in accordance with good clinical practice (GCP) guidelines. The
investigators will agree on monitoring phone calls to assess the progress of the study,
verify adherence to the protocol, check the eligibility of patients, the accuracy and
completeness of the eCRF, check the correlation between the data reported into eCRF and those
recorded in the hospital documents (medical records, patient registries, etc.), check for the
correct reporting of adverse events, verify that evaluations planned and documentation of the
study are properly stored and handled. Data will be collected and stored in on hardware
supports in every participant centre and sent to the coordinating centre at the end of the
study and protected by password to prevent unintentional modifications or deletion. Each
satellite centre will monthly communicate and report via e-mail with the coordinating centre
about number of recruited patients, eventual missing data or missing visit or any kind of
problem correlated to data collection. Data related to the study will be stored for eventual
further analysis or study purpose for 10 years after the end of the study. All the data about
the included patients will be extrapolated from the clinical documentation and recorded in an
eCRF from adequately trained researcher.

Demographic information (gender, age) and co-morbidities, will be registered at the
inclusion, severity of critical illness (quantified by the Simplified Acute Physiology Score
II, SAPS II) will be calculated by the data from the first 24 h of ICU stay. During the study
duration clinical and laboratory parameters will be evaluated and recorded following the
scheduled timeline: SOFA score and its components, vital signs such as mean arterial pressure
(MAP), hearth rate (HR), respiratory rate (RR), systemic temperature, diuresis, fluid
balance, data from routine laboratory test such as haemoglobin, platelets count, white blood
cells count, troponin, coagulative parameters (INR, PT, aPTT), parameters for liver and renal
function (AST, ALT, bilirubin, creatinine), oxygen inspired fraction, blood gas analysis
results (BGA), ventilation mode, need of adjunctive therapy for ARDS (i.e. prone position,
Nitric oxide, ECMO), blood cells count, C-reactive protein (PCR), procalcitonin (PCT),
interleukin-6 (IL-6), immunoglobulin titers (IgG, IgM, IgA) , occurrence of ICU-acquired
(from 48 hours after ICU admission) blood, respiratory and urinary-tract infection and the
implicated microorganisms, reactivation of viral infections (CMV-DNA titres). Other recorded
parameters will include duration and mode of ventilatory support in days, duration and type
of antiviral, antibiotic and antifungal therapy in days, need of vasoactive drugs, use of
immune-modulatory drugs or other adjunctive treatment for COVID-19 pneumonia. As a blood-bank
for possible further biochemical investigations (e.g. cytokines titers, different
biomarkers), for each patient who will be included in the study a blood sample of about 6 ml
will be collected at baseline, day 7 and 28 or at ICU discharge and stored, after
centrifugation, at -70°C in the local laboratory of each site.

Methods for statistical analysis All patients enrolled in the study will be entered in the
full analysis set independently of his/her treatment time. The intention to treat population
will be considered for primary analysis. A descriptive statistical analysis will be performed
to describe every relevant variable. In general, categorical data will be presented using
counts and percentages, whilst continuous variables will be presented using the number of
patients, mean, standard deviation, median, minimum, and maximum. Denominators for
calculation of percentages will be taken as the number of non-missing responses in the
specified analysis population and treatment group unless otherwise stated, and percentages
will be rounded to one decimal. Minima and maxima will usually be reported to the same level
of accuracy as the raw data; means, medians and standard deviations will be presented to one
further decimal place; standard errors (if presented) will be presented to 2 decimal places
more than the raw data. 97.5 % confidence interval will be calculated for primary outcome and
for the relevant secondary ones. All data recorded in the CRF will be listed. Distribution of
SAPSII and SOFA score (total and for single organ) at admission, P/F ratio distribution at
baseline and at day 3, biomarkers PCR, PCT and IL-6 P/F ratio distribution at baseline and at
day 3 will be summarized. The comparison between 1. LMHW + steroids group and LMWH group 2.
UHF + steroids group and LMWH group with binary outcomes will be performed by using Relative
Risks (RRs), whereas for continuous data, the difference of means (DMs) will be used.
Comparisons involving time to event data will be displayed by using Kaplan-Maier survival
curves and summarised by Hazard Ratios (HRs). All measures of association will be presented
with their confidence intervals. A result will be considered as statistically significant if
its p-values will be less than 0.025 (2.5%). The analyses will be performed by using STATA
software. As the study has not been sized to assess the difference between LMHW + steroids
group and UHF + steroids group, the results obtained from this comparison will be reported
and will be interpreted with caution. The main analyses will not take into account the
factors of stratification.

Data monitoring An independent Data Safety Monitoring Board (DSMB), consisting of 2 experts
in clinical research in intensive care and 1bio-statistic will be established before patient
enrolment. The DSMB Charter will be prepared by the steering committee and signed by the
members of the DSMB before the trial commences. The DSMB will have access to all results and
make the appropriate considerations about the appropriateness of the sample size, the
efficiency and quality of data collection system, eventual occurrence of suspected
protocol-related adverse event. The DSMB has the right to stop the trial for safety reasons.

Analyses ad interim Considering a statistical approach based on two phases, an interim
analysis is planned after the randomization of 90 patients (50% of sample size) for the
double objective of monitoring safety and verifying the accuracy of the assumptions made for
sample size estimation regarding the primary end-point event rate in relation to the
anticipated survival benefit. With the interim analysis we will be able to evaluate whether
there is a substantial superiority of one treatment. The obtained results will be evaluated
by the DSMB and by the steering committee and, in case of significant differences in survival
among the groups, all patients will be switched to the most promising treatment.

Harms All the patients, regardless the inclusion in the study and the randomization group,
will benefit from the best standard of care following the principles of Good Clinical
Practice. All the included patients will be intensively monitored following the standard
procedures of intensive care medicine and any suspected protocol-related adverse event will
be reported to the steering committee, the data safety and monitoring board, other
participating centres and the competent authorities. In Beyond suspected protocol-related
adverse event, the data safety and monitoring board will have access to all results of the
trial and make the appropriate considerations about the appropriateness of the sample size,
the efficiency and quality of data collection system and has the right to stop the trial for
safety reasons or futility.

Ethics and dissemination The study will be conducted in line with the protocol, the
Declaration of Helsinki (1964) and subsequent amendments and updates (Fortaleza, Brazil,
October 2013). Moreover, it is the responsibility of the investigator to ensure that the
study will be done in line with to the requirements of Good Clinical Practice (GCP) and the
applicable regulatory requirements.

Research ethics approval The entire study protocol, including informative material for the
patients and modules for the informed consent, have been approved by the Ethics Committee of
Italian National institute for Infectious diseases (Istituto Nazionale per le Malattie
Infettive Lazzaro Spallanzani -IRCCS).

The study will not start before obtaining a favourable opinion from the EC, the Competent
Authority Authorization and any other authorization required by local regulation. Every
intention to modify any element of the original protocol after the first approval will be
promptly notified to the Ethics Committee and will be applied only after its written
authorization. Investigator/sponsor will be responsible to submit to the Ethics Committee any
amendments to the protocol.

Consent and confidentiality Before inclusion in the study, conscious patients must be
informed of the purpose and of clinical procedures required by the protocol. The
investigators will explain the purpose, risks and benefits associated with study
participation. In addition, patients will be informed of his right to withdraw from the study
at any time without explanation and without losing the right to future medical care. If the
patient will be unable to comprehend or to give his consent (because of compromised
neurological status), the following consent options are acceptable: (i) A priori consent by a
legal representative (ii) delayed consent from a legal representative; (iii) Delayed consent
from the patient; (iv) waiver of consent; (v) consent provided by an ethics committee or
other legal authority. Which options are available at individual participating sites will be
determined by the relevant ethics committee and subject to applicable laws. The approach to
patients unable to provide an informed consent before enrolment will be to consider whether
participation is in the best interests of each individual patient and as soon as it is
practical and reasonable to do so, to seek the advice of persons interested in the patient's
welfare (e.g. family member) to establish that study participation is consistent with the
patient's wishes. All participants who recover sufficiently will be given the opportunity to
provide informed consent for ongoing study participation and for the use of data collected
for the study. Every patient is free to leave the study protocol at any state of the study
and can request to retire his consent and, consequently, to ask the elimination of all his
data from the database. In order to comply with legal requirements regarding privacy and the
processing of sensitive personal data, Legislative Decree 30/06/2003 n. 196 on the protection
of personal data and 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 repealing Directive 95/46/EC
(General Data Protection Regulation), each patient will be given an information sheet on the
study they participate in and will be asked for sign the consent to the processing of
personal data. Data about personal and private information, included sensible data, will be
treated following current legislation on data protection; patients will be identified with a
coding system and data registered in anonymous form. Collected data will be processed by the
Investigator for the exclusive purposes of fulfil to the present study requirements, and in
anonymous form, aggregate in the study database with data obtained from the other patients
participating, solely on the basis of finalizing the study and achievement objectives.
Obtained data will not be disclosed except in strictly anonymous and aggregated form.

Direct access to the original medical records may be requested only by commissioning DMC of
the study and will be accessible by the PI, its delegate to perform monitoring on the conduct
of the trial, the EC or by the regulatory Authorities, such as personnel of the Italian
Ministry of Health and the Italian Medicines Agency (AIFA) to verify that the information
entered in the documents of the study are correct and methods that guarantee the privacy and
confidentiality of the data are respected. Such verification activities will be always
carried out under the supervision of the SC, executed professionally and to guarantee the
privacy of the subject.

Dissemination policy The Circ. Min. Health N° 6 of 09/02/2002 obliges each researcher who
gets any results of interest to public health, to publish the results within 12 months from
the end of the study. All the patients will freely agree or disagree to participate to the
study in the belief that the results will be useful to improve knowledge about their
pathologies, for health benefit from themselves or other patients. To respect their will and
in the maximum interest of honest clinical research, the investigators agree on the need to
ensure the wide publication and diffusion of their results in a consistent and responsible
way under their responsibility. The study coordinator is the official data owner. The
steering committee has the right to present methods and results of the study at public
symposia and conferences. The principal publications from the trial will be in the name of
Investigators with full credit assigned to all collaborating investigators and institutions.