Conditions: COVID-19
Keywords: sodium-glucose cotransporter-2 inhibitor (SGLT2i) dapagliflozin COVID-19
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1250
Healthy volunteers: no

Brief summary:
This is an international, multicenter, parallel-group, randomized, double-blind, placebo controlled, study in hospitalized adult patients with coronavirus disease 2019 (COVID-19) in the United States, Brazil, Mexico, Argentina, India, Canada, and United Kingdom. The study is evaluating the effect of dapagliflozin 10 milligrams versus placebo, given once daily for 30 days in addition to background local standard of care therapy, on reducing complications and all-cause mortality, or improving clinical recovery.

Detailed description:
COVID-19 can lead to multiorgan failure, especially in high-risk patients. Dapagliflozin, a sodium-glucose cotransporter-2 inhibitor (SGLT2i), favorably impacts many processes dysregulated during acute illness such as COVID-19, has significant cardio- and reno-protective benefits in cardiometabolic disease, and may provide similar organ protection in COVID-19.

The study population will include hospitalized patients with respiratory manifestations of COVID-19 of any duration, but without the need for mechanical ventilation. The eligible patients should have risk factors for developing serious complications of COVID-19, including hypertension, Type 2 diabetes, atherosclerotic cardiovascular disease, heart failure and/or chronic kidney disease stage 3 to 4.

Patients will be treated for 30 days, with either dapagliflozin 10 milligrams daily or placebo, each to be given in addition to the usual standard of care in the participating hospital.

The study assessments include only those that are absolutely critical for ensuring the safety of the patients, to measure efficacy outcomes, and collect biomarker data, so as not to place too high a burden on the study personnel and to minimize additional risk of exposure to severe acute respiratory syndrome coronavirus 2 (SARS CoV-2).

The dual primary efficacy endpoints of the study are time to first event of either complications or death from any cause, and improved clinical recovery through 30 days of follow-up. An extended follow-up period of 60 days (after the 30-day treatment period) is included, in order to examine longer-term trajectory of recovery from COVID-19 among trial participants.

The safety data will be monitored by an Independent Data and Safety Monitoring Committee.

Arms:
arm 1: Dapagliflozin 10 mg daily arm 2: Dapagliflozin matching placebo 10 mg daily

Interventions: intervention 1: Dapagliflozin 10 milligram (mg) intervention 2: Placebo
Intervention descriptions: intervention 1: Active Comparator: Dapagliflozin 10 mg intervention 2: Placebo Comparator

Protocol document:
Prot_000.pdf: 
Clinical Study Protocol 
 
Drug Substance dapagliflozin 
Version 4.0 
Study Number D1690C00081 
IND 149478 
EudraCT 2020-001473-79 
Date 20 November 2020 
CONFIDENTIAL AND PROPRIETARY 
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Clinical Study Protocol 
Drug Substance 
dapagliflozin 
Study Number 
D1690C00081 
 
 
Version 
4.0 
Date 
20 November 2020 
An International, Multicenter, Randomized, Double-blind, 
Placebo-controlled, Phase III Study Evaluating the Efficacy and 
Safety of Dapagliflozin in Respiratory Failure in Patients with 
COVID-19  
Short Title: DARE-19 (Dapagliflozin in Respiratory failure in 
patients with COVID-19) 
 
ClinicalTrials.gov Identifier:  NCT04350593


Clinical Study Protocol 
 
Drug Substance dapagliflozin 
Version 4.0 
Study Number D1690C00081 
IND 149478 
EudraCT 2020-001473-79 
Date 20 November 2020 
CONFIDENTIAL AND PROPRIETARY 
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PROTOCOL APPROVAL 
Study Title: 
An International, Multicenter, Randomized, Double-blind, Placebo-
controlled, Phase III Study Evaluating the Efficacy and Safety of 
Dapagliflozin in Respiratory Failure in Patients with COVID-19  
 
Short Title: DARE-19 (Dapagliflozin in Respiratory failure in 
patients with COVID-19) 
Protocol Number: 
ESR-20-20653 
Version: 
4.0 
Date of Issue: 
20 November 2020  
Sponsor Name 
and Address: 
 
 
 
 
 
 
 
Name  
Job Title 
Role 
 
 
 
 
 
 
 
 
 
 
I, the undersigned, have read and approve this protocol and agree on its content. It is 
confirmed that the information and guidance given in this protocol complies with scientific 
principles, the guidelines of Good Clinical Practice, the Declaration of Helsinki in the latest 
relevant version, and the applicable legal and regulatory requirements.  
 
 
 
 
 
 
  
 
 
 




Clinical Study Protocol 
 
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Version 4.0 
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Date 20 November 2020 
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• 
Glucose added to the standard of care metabolic panel in Section 4.2 and Table 1, footnote ‘c’ 
Changes to inclusion criteria: 
• 
‘Mild-moderate disease: SpO2≥94% with low-flow supplemental oxygen (3 liters or less)’ changed to 
‘…(5 liters or less)’ . Three liters is too restrictive as many stable patients are requiring higher oxygen 
support 
• 
‘Chest radiography or CT findings consistent with COVID-19’—a definition for the findings is replaced 
with ‘in the opinion of the investigator’, because the definition is too prescriptive 
• 
New criterion added: Hospital admission no more than 4 days prior to screening. This is to ensure that 
included patients are relatively recent admissions, as the intent is to administer the treatment as quickly 
as possible after the presentation 
• 
‘Confirmed SARS-CoV-2 infection by laboratory testing <72 hours prior to randomization…’ changed 
to ‘…testing within 10 days prior to screening…’, because 72 hours is too narrow a window given the 
clinical course of the disease 
Other changes: 
• 
An extended follow-up period of an additional 60 days of observational follow up (on top of the current 
active treatment duration of 30 days) has been added in response to a health authority request to consider 
following this patient population for longer than the 30-day treatment period. The intent of this extended 
observational follow-up period is to examine any potential longer-term effects of dapagliflozin 10 mg 
compared with placebo, after cessation of investigational product (added Sections 4.4and 8.5.7, and 
updated the Synopsis, Section1.2, Sections 1.4 and 5.1.4, Figure 1, and Table 1, including footnote ‘g’). 
Section 3.9.3 text updated to clarify that discontinued patients should be followed up to Day 90. 
• 
As soon as the pre-planned number of events has been reached, the database will be locked and 
unblinded for the analysis of 30-day treatment period data. After that, data collected on patients ongoing 
in the 60-day observational follow-up period will be unblinded (Section 8.1). 
• 
The proportion of patients randomized without a confirmed SARS-CoV-2–positive test will be closely 
monitored, and may be capped if it becomes greater than anticipated (added to Synopsis, Section 8.2 and 
as a footnote to the relevant inclusion criterion in Section 3.1). This is to ensure that the dominant 
majority of patients in the study are confirmed SARS-CoV-2– positive, given that this is the intended 
patient population. 
• 
IRT, instead of a call center, is providing the kit identification number (Sections 3.6 and 3.7). 
• 
Recruitment period updated from ‘approximately 3 months’ to ‘approximately 6 months’, and the 
estimated date of last patient completed updated from ‘3Q 2020’ to ‘4Q 2020’ in the Synopsis  and 
Section 9.3 to reflect the latest status. 
• 
Number and location of sites increased to approximately 90 sites in North America, Latin America, and 
Europe (Synopsis and Sections 1.2 and 1.3.2). 
• 
‘Refer to the Study Contact List for additional country fax numbers’ added to 
 contact 
details in Section 6.5. 
• 
Reference to the DAPA ACT HF-TIMI 68 clinical trial added (Sections1.1and 11). 
Clarifications: 
• 
In Table 1 (study plan), footnote ‘h’ added to clarify that concomitant medication is recorded at Day 15 
for previously discharged patients. Section 4.2 updated accordingly. 
• 
Made clear that all safety assessments in Section 5.2 should be recorded daily approximately between 
06:00 and 08:00 in the morning. 
• 
Removed the reference to daily collection of concomitant medications in Section7.7 to align with Table 
1. 
• 
The system for generating the randomization scheme was revised from ‘AZRand’ to ‘a validated 
system’, as AZRand will not be used (Section 3.5). 




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 
An episode of doubling s-Creatinine compared to baseline during index hospitalization 
 
or SAE with preferred term of acute kidney injury following discharge and through Day 30 
This is to identify all acute kidney injury events during the 30-day treatment period. 
Changes to the exploratory outcome measures in the Synopsis and Section 2.4: 
• 
Quantitative PCR for SARS-CoV-2 is removed as availability of quantitative PCR data is uncertain. 
Evaluation of quantitative PCR data, if available, will be pre-specified in the SAP. 
• 
‘Out of hospital’ is removed from ‘Total number of days alive, out of hospital, and not on renal 
replacement therapy’ to simplify the endpoint. It does not change the nature of the endpoint. Clarified 
that the total number of days not on renal replacement therapy refers to the index hospitalization only. 
• 
Phrase in brackets in ‘Change in NT-proBNP, hs troponin, D-dimer, LDH, ALT, lymphocyte count, CRP 
between Day 1 and Day 15 (or discharge from hospital, whichever is earlier)’replaces ‘(or last available 
assessment)’ to make the timepoint consistent with other exploratory outcome measures. 
Changes to sites and number of patients planned in the Synopsis and in Sections 1.4 and 8.2: 
• 
Number of patients to be randomized increased from 900 to approximately 1200 to provide adequate 
power for the dual primary endpoints. 
• 
Sites will also be located in India. 
• 
Recruitment period updated to ‘approximately 8 months’, and the estimated date of last patient 
completed updated to ‘1Q 2021’ in the Synopsis and Section 9.3 because of the increase in the number of 
patients and lower than expected recruitment rate. 
Changes to exclusion criteria in Section 3.2. 
• 
Criteria 1 and 2 are updated to simplify the description of mechanical ventilation and include BiPAP.  
Other changes 
• 
Global Clinical Lead changed to Anna Maria Langkilde on protocol approval page. 
• 
Section 1.1 is updated with the latest information about COVID-19 and to reflect the unpredictable and 
fast-evolving pandemic necessitating a change in the primary objective. When referring to the SARS-
CoV-2 infection in the study, the term verified is removed since verification is not protocol mandated. 
• 
Section 1.2 is updated with the latest information about COVID-19 that supports the changes to the 
primary endpoint. 
• 
India is added to ‘Patients with T2DM will be monitored in the hospital as part of standard of care, which 
in North America, Latin America, Europe, and India includes blood glucose monitoring.’ in 
Section 1.3.2. 
• 
‘T2DM’ and ‘T1DM’ replaced with ‘clinical studies in various clinical settings’ in the statement about 
the safety profile of dapagliflozin in Section 1.3.2, since dapagliflozin has been studied also in patients 
with HF and CKD without diabetes, etc. 
• 
Randomization will be stratified within each country to ensure balanced treatment allocation (Synopsis 
and Section 3.5).  
• 
Attempts to contact a patient who cannot be reached should continue to be documented but not in the 
medical records (Section 3.9.3). 
• 
Removed the constraint that ‘Incorrect enrollment’ as a reason for withdrawal is only valid for screen 
failures in Section 3.10.1. This is to more accurately reflect study procedures. 
• 
Removed the statement ‘If a patient withdraws from the study, he or she may request destruction of any 
samples taken, and the Investigator must document this in the site study records.’ to more accurately 
reflect study procedures. 
• 
Expected standard of care laboratory assessment broadened to allow for other means of acid-base 
monitoring (per local standard of care) than a basic metabolic panel (Table 1). Made clear that the 
associated footnote ‘c’ refers to daily assessment while hospitalized. 
• 
Time points for assessments are replaced with cross-references to the study plan in Sections 4.2, 5.1.3, 
and 5.1.4 to avoid inconsistencies. 


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• 
‘New/worsened organ dysfunction’ removed from the list of time-to-event endpoints in Section 5.1.2 
because the analysis of this endpoint will automatically be included as a component of one of the dual 
primary endpoints, and will be pre-specified in the SAP.  
• 
Definitions of reportable SAEs, DAEs, and/or key safety events are added (Section 6.4.2). 
• 
Text referring to reportable SAEs, DAEs, and key safety events are updated in Sections 5.2.3 and 6.4. 
• 
 ‘
’ is replaced by ‘The Sponsor or delegate’ in retaining the right to request additional 
information about unresolved events, in Section 6.4.4 to more accurately reflect the trial conduct. 
• 
Fatal events due to disease progression must be reported as SAEs, added to Section 6.4.1. 
• 
Causality assessment in relation to other medication is not assessed so is removed from Section 6.4.5. 
• 
Overdose Section 6.7 is revised so that only an overdose associated with a SAE is to be reported. 
• 
Executive Committee will make final decisions, not recommendations, with regard to early stopping or 
modifications to the study in Section 6.9. 
• 
Orogastric tube as an option for administration of investigational product during mechanical ventilation 
added in the Synposis and in Section 7.2. 
• 
Removed the accountability of the study personnel for returned investigational product since patients are 
not asked to return their unused investigational product (Section 7.6). 
• 
This is no longer an event-driven study, so references to it being event-driven are removed from the 
Synopsis and Section 8.2. The study will remain blinded until the 30-day database lock (updated in 
Section 8.1).  
• 
The methods for statistical analysis are revised in Section 8.5 to reflect the dual primary endpoint. 
Clarifications:  
• 
‘Mild to moderate COVID-19’ removed from target population description in the Synopsis as ‘mild to 
moderate’ description is not aligned with the FDA definition of severity of the disease. 
• 
Made clear that allocation of IP is blinded in Section 1.3.1. 
• 
Made clear that patients must have SpO2 ≥ 94% while receiving low-flow supplemental oxygen (5 liters 
or less) to meet inclusion criterion number 7 in Section 3.1. Removed ‘mild to moderate disease’ as it is 
not aligned with the FDA definition of severity of the disease, and defining severity of disease is not 
necessary for this criterion. 
• 
Removed reference to weekly monitoring of blinded safety data by the IDSMC in Section 3.7.1—the 
monitoring frequency is included in the IDSMC charter. 
• 
Made clear in Section 3.7.1 that, in addition to the Sponsor, the Sponsor representatives are blinded in all 
data transfers provided to the IDSMC. 
• 
A footnote is added to the NEWS 2 row in the study plan (Table 1) to clarify that NEWS 2 is only 
collected while the patient is hospitalized. 
• 
A footnote is added to the SAEs row in the study plan (Table 1) to cross-reference the definition of a 
reportable event. 
• 
Stipulated a ± 3-day window for the Day 15 and Day 30 follow-up calls after hospital discharge in 
Section 4.3. 
• 
Stipulated a ± 7-day window for the Day 60 and Day 90 follow-up calls after hospital discharge in 
Section 4.4 and Table 1. 
• 
Made clearer throughout Section 6.4 that only reportable events are recorded.  
• 
Made clear that reportable events are recorded on a daily basis during index hospitalization and at 
Discharge, as well as during pre-specified post discharge phone follow up visits in Section 6.4. 
Administrative: 
• 
Additional definition of stage 3 to 4 CKD (ie, eGFR ≥ 25 mL/min/1.73m2) is removed in Section 1.2, as 
it is not fully consistent with the inclusion criterion and is not a necessary detail for this section. 
• 
The title of Section 5.1.1 is changed from ‘Endpoint Event’ to ‘Primary Endpoint Events’. 
• 
HbA1c is removed from Table 2 in Section 5.1.5. It had been included in the list of lab variables in error. 
• 
Typographical error is corrected in the Levey et al 2009 citation in Section 5.1.5. 


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• 
The time period for collection of AEs corrected to ‘through Day 90’ (to include the additional 60-day 
observational period) in Section 6.4.1. 
• 
The time period for follow up of unresolved AEs corrected to ‘through Day 90’ in Section 6.4.4. 
• 
personnel or delegate’ is corrected to ‘The Sponsor or delegate’ as responsible for 
generating the randomization scheme in Sections 3.5 and 3.6 to more accurately reflect trial conduct. 
• 
‘Any discrepancy between dispensed and returned investigational product should be explained’ is 
removed from Section 7.6 because the patient is not required to return investigational product. 
• 
Section 3.7.1.1 renumbered as Section 3.7.1. 
• 
 is corrected to ‘Sponsor or delegate’ in being responsible for providing reports of any 
serious and unexpected adverse drug reactions from any other study conducted, to the PI in Section 10.3, 
to more accurately reflect trial conduct. 
 


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Version 4.0 
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Date 20 November 2020 
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PROTOCOL SYNOPSIS 
 
An International, Multicenter, Randomized, Double-blind, 
Placebo-controlled, Phase III Study Evaluating the Efficacy and 
Safety of Dapagliflozin in Respiratory Failure in Patients with 
COVID-19 
 
 
International Co-ordinating Investigator 
 
 
 
 
 
Study Site(s) and Number of Patients Planned 
Approximately 1200 patients will be randomized to the study at approximately 90 sites in 
North America, Latin America, India, and Europe. 
Study period 
 
Phase of development 
Estimated date of first patient enrolled 
2Q 2020 
Phase III 
Estimated date of last patient completed 
1Q 2021 
 
 
Study Design 
This is an international, multicenter, parallel-group, randomized, double-blind, 
placebo-controlled, study in hospitalized adult patients with COVID-19. The study is 
evaluating the effect of dapagliflozin 10 mg versus placebo, given once daily for 30 days in 
addition to background local standard of care therapy, in reducing complications or all-cause 
mortality, or improving clinical recovery. The study will recruit approximately 1200 patients 
with a fixed follow-up.  
It is anticipated that the recruitment period will be approximately 8 months. When enrolled, 
patients can be screened twice if they do not fully meet the inclusion/exclusion criteria on the 
first screening. They must not be randomized more than once. Patients will be followed up for 
their 30-day treatment period, and will continue to take investigational product and be 


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followed up by telephone (at Day 15 and/or Day 30) if discharged from hospital. After the last 
dose of investigational product at Day 30, patients are followed up for an extended additional 
(observational) period of 60 days (total duration of follow up 90 days), with telephone visits 
on Day 60 and Day 90. 
Objectives 
All of the objectives are assessed during the 30-day treatment period. 
Primary objective: 
Outcome measure: 
To determine whether dapagliflozin 10 mg is 
superior to placebo, in terms of reducing 
complications or all-cause mortality, or 
improving clinical recovery in patients 
hospitalized with COVID-19. 
Dual primary endpoints of: 
 
Prevention of COVID-19 complications or death 
During the 30-day treatment period, time to first 
occurrence of new/worsened organ dysfunction during 
index hospitalization or death from any cause. 
New/worsened organ dysfunction is defined as at least one 
of the following:  
• 
Respiratory decompensation requiring initiation of 
mechanical ventilation (includes invasive or 
non-invasive ventilation, CPAP, or BiPAP), and/or 
initiation of ECMO 
• 
New or worsening congestive HFa 
• 
Requirement for vasopressor therapy and/or inotropic 
or mechanical circulatory support 
• 
Ventricular tachycardia or fibrillation lasting at least 
30 seconds and/or associated with hemodynamic 
instability or pulseless electrical activity, or 
resuscitated cardiac arrest 
• 
Doubling of s-Creatinine or initiation of renal 
replacement therapy 
 
Improving clinical recovery 
Hierarchical composite outcome measure: 
1 
Death from any cause through Day 30 
2 
New/worsened organ dysfunction (as defined above) 
3 
Clinical status at Day 30 for patients still hospitalized 
and without any worsening organ dysfunction (using 
points 3 to 5 of a 7-point ordinal scaleb) 
4 
Hospital discharge before Day 30 and alive at Day 30 
 
a 
Congestive HF is defined as at least one of the following 1) initiation of new intravenous therapy for heart 
failure 2) reinstitution of previous intravenous therapy for heart failure 3) increase in current intravenous 
therapy for heart failure. This is based on modification on previous definition of in-hospital worsening heart 
failure (McMurray et al 2007) 
b 
7-point Patient Clinical Status scale: 
1 
Not hospitalized, no limitations on activities 


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2 
Not hospitalized, limitation on activities 
3 
Hospitalized, not requiring supplemental oxygen 
4 
Hospitalized, requiring supplemental oxygen 
5 
Hospitalized, on high flow oxygen devices 
6 
Hospitalized, on invasive mechanical ventilation or ECMO 
7 
Death 
BiPAP Bilevel positive airway pressure; COVID-19 Coronavirus disease 2019; CPAP Continuous positive 
airway pressure; ECMO extracorporeal membrane oxygenation; HF Heart failure. 
 
Secondary objectives: 
Outcome measures: 
To compare the effect of dapagliflozin 10 mg 
versus placebo on time to hospital discharge 
Time to hospital dischargea 
To compare the effect of dapagliflozin 10 mg 
versus placebo on total number of days alive and 
free from respiratory decompensation requiring 
mechanical ventilation 
Total number of days alive and free from respiratory 
decompensationa requiring initiation of mechanical 
ventilation (includes invasive or non-invasive ventilation, 
CPAP, or BiPAP) from randomization through Day 30 
To compare the effect of dapagliflozin 10 mg 
versus placebo on total number of days alive, not 
in ICU, and free from respiratory decompensation 
requiring mechanical ventilation 
Total number of days alive, not in the ICU, and free from 
respiratory decompensationa requiring initiation of 
mechanical ventilation (includes invasive or non-invasive 
ventilation, CPAP, or BiPAP) from randomization 
through Day 30 
To compare the effect of dapagliflozin 10 mg 
versus placebo on a composite kidney endpoint  
Time to composite of acute kidney injuryb or initiation of 
renal replacement therapyc, or death from any cause 
through Day 30 
To compare the effect of dapagliflozin 10 mg 
versus placebo in reducing the incidence of 
all-cause mortality 
Time to death from any cause through Day 30 
a 
Refers to index hospitalization only 
b 
Acute kidney injury defined as:  
 
An episode of doubling s-Creatinine compared to baseline during index hospitalization 
 
or SAE with preferred term of Acute kidney injury following discharge and through Day 30 
c 
Renal replacement therapy defined as: 
 
Initiation of renal replacement therapy during index hospitalization  
 
or SAE with a preferred term for renal replacement therapy (ie, Haemodialysis, Haemofiltration, 
Continuous haemodiafiltration, Dialysis, Peritoneal dialysis, Dialysis device insertion, Renal 
replacement therapy, or Artificial kidney device user) following discharge and through Day 30 
BiPAP Bilevel positive airway pressure; COVID-19 Coronavirus disease 2019; CPAP Continuous positive 
airway pressure; ECMO Extracorporeal membrane oxygenation; ICU Intensive care unit; SAE Serious adverse 
event. 
 


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Safety objective: 
Outcome measure: 
To evaluate the safety and tolerability of 
dapagliflozin compared to placebo in patients 
hospitalized with COVID-19 
• 
Serious adverse events from randomization to Day 30a 
• 
Acute kidney injury defined as:  
 
An episode of doubling of s-Creatinine compared 
to baseline during index hospitalization 
 
or SAE with preferred term of acute kidney 
injury following discharge and through Day 30 
• 
Incidence of diabetic ketoacidosis from randomization 
through Day 30 
a 
SAEs will be collected through Day 90 but comparison of treatment groups will be assessed based on the 
data obtained through Day 30. For the definition of reportable SAEs, see Section 6.4.2. 
COVID-19 Coronavirus 2019; SAE Serious adverse event. 
 
Exploratory objective: 
Outcome measures: 
To compare the effect of dapagliflozin 10 mg to 
placebo on the components of the primary 
endpoint, biomarkers, and patient’s clinical status 
• 
Change in NT-proBNP, hs troponin, D-dimer, 
LDH, ALT, lymphocyte count, CRP between Day 1 
and Day 15 (or discharge from hospital, whichever 
is earlier) 
• 
Qualitative PCR for SARS-CoV-2 in 
oropharyngeal/nasopharyngeal swab at baseline 
(while hospitalized); and Day 15 (if still 
hospitalized) or discharge from hospital 
• 
Change in NEWS 2 from Day 1 to Day 15 (or 
discharge from hospital, whichever is earlier). 
• 
Patient’s clinical status (on a 7-point ordinal scale) 
at Day 15 (or discharge from hospital, whichever is 
earlier) 
• 
Total number of days alive and not on renal 
replacement therapya  
• 
Proportion of patients with acute coronary 
syndromeb 
a 
Refers to index hospitalization only 
b 
Acute coronary syndrome defined as: during index hospitalization, abnormal troponin level above 99th 
percentile of the local laboratory reference range or, if abnormal at baseline, further rise in troponin levels 
accompanied by at least 1 of the following: 1) ischemic symptoms 2) ischemic ST-segment changes on 
ECG (Thygesen et al 2018) 
NEWS 2 is a standardized assessment of acute-illness severity and can prompt critical care intervention. It is 
used as an adjunct to clinical judgment. 
ALT Alanine aminotransferase; COVID-19 Coronavirus disease 2019; CRP C-reactive protein; 
ECG Electrocardiogram; hs troponin High-sensitivity cardiac troponin; LDH lactate dehydrogenase; NEWS 2 
National Early Warning Score 2; NT-proBNP N-terminal-pro B-type natriuretic peptide; PCR Polymerase chain 
reaction; SARS-CoV-2 Severe acute respiratory syndrome-coronavirus-2. 
 
Target Patient Population 
The target population includes male and female adult patients (≥18 years) currently 
hospitalized with SARS-CoV-2 infection and COVID-19, and with a medical history of at 
least one of the following: hypertension, type 2 diabetes mellitus, atherosclerotic 
cardiovascular disease, heart failure, or chronic kidney disease stage 3/4. Patients with type 1 


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diabetes mellitus are excluded. 
To ensure balance within countries, stratification will be employed. Given the unpredictable 
and rapidly-shifting incidence of COVID-19 across different countries, balanced 
representation across countries cannot be ensured. 
The proportion of patients randomized without a confirmed SARS-CoV-2–positive test will be 
closely monitored, and may be capped if it becomes greater than anticipated. 
Duration of Treatment 
Eligible patients will be randomized to start treatment with either dapagliflozin 10 mg or 
placebo daily (double-blind) as soon as possible. 
Investigational product will be administered for 30 days, with follow-up assessments every 
24 hours until either hospital discharge, Day 30, or death. Patients discharged from hospital 
will continue with their treatment for the remainder of the 30 days and be followed up by 
telephone on Day 15 and/or Day 30. After the last dose of investigational product at Day 30, 
patients are followed up for an extended additional (observational) period of 60 days (total 
duration of follow up 90 days), with telephone visits on Day 60 and Day 90. 
Investigational Product, Dosage and Mode of Administration 
Patients will be randomized 1:1 to either dapagliflozin 10 mg or placebo once daily per oral 
use. Every attempt should be made to maintain patients on dapagliflozin 10 mg or matching 
placebo during the course of the study. The investigational product should be taken as soon as 
possible after randomization and then once daily in the morning, at approximately the same 
time every day, during the 30-day treatment period. 
For patients requiring a mechanical ventilator, the tablet will be crushed and flushed with 
water down the patient’s nasogastric (or orogastric) tube. The tube will then be rinsed with 
water to ensure all the tablet has been consumed. 
Statistical Methods 
The primary objectives are to determine the superiority of dapagliflozin versus placebo in 
reducing the incidence of complications or all-cause mortality (prevention of worsening 
COVID-19) or improving clinical recovery in patients hospitalized with COVID-19. The 
treatment effect on prevention of worsening COVID-19 or clinical recovery will be tested as 
dual primary endpoints.  
The treatment effect on prevention will be assessed as the time to first event of the composite 
endpoint of complications or all-cause mortality, analyzed using a Cox proportional hazards 


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model. The treatment effect on recovery will be evaluated by a hierarchical composite 
endpoint, using a win ratio analysis method.  
It is estimated that a sample size of approximately 1200 patients will provide adequate power 
to detect the treatment effect on prevention or recovery, when the dual endpoints are tested 
with alpha split between these outcomes. 
All patients randomized will be included in the full analysis set according to their randomized 
investigational product assignment, irrespective of the treatment actually received. The full 
analysis set will be considered the primary analysis set for the primary, secondary, and 
exploratory efficacy variables. 
All patients who received at least 1 dose of randomized treatment will be included in the 
safety population. Patients will be analyzed according to the treatment actually received. The 
safety analysis set will be considered the primary analysis set for all safety variables. 
Interim analysis for safety only will be performed by an independent data and safety 
monitoring committee after the first 100 patients have completed the 30-day treatment period; 
no interim efficacy analyses are planned.  


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TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
PROTOCOL APPROVAL ......................................................................................................... 2 
VERSION HISTORY ................................................................................................................ 3 
PROTOCOL SYNOPSIS .......................................................................................................... 9 
TABLE OF CONTENTS ......................................................................................................... 15 
LIST OF TABLES ................................................................................................................... 18 
LIST OF FIGURES ................................................................................................................. 18 
LIST OF APPENDICES .......................................................................................................... 18 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................. 19 
1 
INTRODUCTION ................................................................................................ 21 
1.1 
Background and Rationale for Conducting this Study ......................................... 21 
1.2 
Rationale for Study Design, Doses and Control Groups ...................................... 24 
1.3 
Benefit/risk and Ethical Assessment ..................................................................... 25 
1.3.1 
Potential Benefits to Subjects ............................................................................... 25 
1.3.2 
Potential Risks to Subjects ................................................................................... 25 
1.3.2.1 
Protection Against Risks ....................................................................................... 27 
1.3.3 
Conclusion ............................................................................................................ 27 
1.4 
Study Design ......................................................................................................... 28 
2 
STUDY OBJECTIVES......................................................................................... 29 
2.1 
Primary Objective ................................................................................................. 29 
2.2 
Secondary Objectives ........................................................................................... 30 
2.3 
Safety Objectives .................................................................................................. 31 
2.4 
Exploratory Objectives ......................................................................................... 31 
3 
SUBJECT 
SELECTION, 
ENROLMENT, 
RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL ...................... 32 
3.1 
Inclusion Criteria .................................................................................................. 32 
3.2 
Exclusion Criteria ................................................................................................. 33 
3.3 
Subject Enrolment and Randomization ................................................................ 34 
3.4 
Procedures for Handling Incorrectly Enrolled or Randomized Subjects.............. 35 
3.5 
Methods for Assigning Treatment Groups ............................................................ 35 
3.6 
Methods for Ensuring Blinding ............................................................................ 35 
3.7 
Methods for Unblinding ....................................................................................... 36 
3.7.1 
Unblinding for Independent Data and Safety Monitoring Committee ................. 36 
3.8 
Restrictions (Not Applicable) ............................................................................... 36 


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3.9 
Discontinuation of Investigational Product .......................................................... 36 
3.9.1 
Evaluation of Volume Status and Investigational Dose Reduction/interruption .. 37 
3.9.2 
Investigational Product Restart ............................................................................. 37 
3.9.3 
Procedures for Discontinuation of Investigational Product .................................. 38 
3.10 
Criteria for Withdrawal ......................................................................................... 38 
3.10.1 
Screen Failures...................................................................................................... 38 
3.10.2 
Withdrawal of the Informed Consent ................................................................... 39 
3.11 
Discontinuation of the Study ................................................................................ 39 
4 
STUDY PLAN AND TIMING OF PROCEDURES ............................................ 39 
4.1 
Screening and Enrollment Period (Day 0) ............................................................ 43 
4.2 
Treatment Period (Day 1 to Day 30) .................................................................... 43 
4.3 
Follow-up Period after Hospital Discharge .......................................................... 44 
4.4 
Extended Follow-up Period after Day 30 ............................................................. 45 
5 
STUDY ASSESSMENTS..................................................................................... 45 
5.1 
Efficacy Assessments ............................................................................................ 45 
5.1.1 
Primary Endpoint Events ...................................................................................... 45 
5.1.2 
Time to Event Endpoints ...................................................................................... 46 
5.1.3 
National Early Warning Score 2 ........................................................................... 46 
5.1.4 
Patient Clinical Status ........................................................................................... 46 
5.1.5 
Laboratory Assessments ....................................................................................... 47 
5.2 
Safety Assessments ............................................................................................... 48 
5.2.1 
Physical Examination (not applicable) ................................................................. 48 
5.2.2 
Vital Signs ............................................................................................................. 48 
5.2.3 
Adverse Events ..................................................................................................... 48 
6 
SAFETY REPORTING AND MEDICAL MANAGEMENT .............................. 49 
6.1 
Definition of Adverse Events................................................................................ 49 
6.2 
Definitions of Serious Adverse Event................................................................... 49 
6.3 
Definition of Suspected Unexpected Serious Adverse Event ............................... 50 
6.4 
Recording of Adverse Events ............................................................................... 50 
6.4.1 
Disease Progression .............................................................................................. 50 
6.4.2 
Definition of Reportable Events ........................................................................... 50 
6.4.3 
Time Period for Collection of Adverse Events ..................................................... 51 
6.4.4 
Follow-up of Unresolved Adverse Events ............................................................ 51 
6.4.5 
Variables ............................................................................................................... 51 
6.4.6 
Causality Collection.............................................................................................. 52 
6.4.7 
Adverse Events Based on Signs and Symptoms .................................................. 52 
6.4.8 
Adverse Events Based on Examinations and Tests .............................................. 53 
6.5 
Reporting of Serious Adverse Events to the IRB/IEC and/or the Regulatory 
Authority ............................................................................................................... 53 
6.6 
Reporting of Serious Adverse Events to Company .............................................. 54 


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6.7 
Overdose ............................................................................................................... 55 
6.8 
Pregnancy ............................................................................................................. 55 
6.8.1 
Maternal Exposure ................................................................................................ 55 
6.9 
Study Governance and Oversight ......................................................................... 55 
6.9.1 
Executive Committee............................................................................................ 55 
6.9.2 
Independent Data and Safety Monitoring Committee .......................................... 56 
6.9.3 
Scientific Advisory Committee (not applicable) .................................................. 56 
7 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS .................... 56 
7.1 
Identity of Investigational Product(s) ................................................................... 56 
7.2 
Dose and Treatment Regimens ............................................................................. 56 
7.3 
Labeling ................................................................................................................ 57 
7.4 
Storage .................................................................................................................. 57 
7.5 
Compliance ........................................................................................................... 57 
7.6 
Accountability....................................................................................................... 57 
7.7 
Concomitant and Other Treatments ...................................................................... 57 
7.7.1 
Other Concomitant Treatment .............................................................................. 58 
7.8 
Post-study Access to Study Treatment .................................................................. 58 
8 
STATISTICAL ANALYSES ................................................................................. 58 
8.1 
Statistical Considerations...................................................................................... 58 
8.2 
Sample Size Estimate ........................................................................................... 58 
8.3 
Definitions of Analysis Sets.................................................................................. 60 
8.3.1 
Full Analysis Set ................................................................................................... 60 
8.3.2 
Safety Analysis Set ............................................................................................... 60 
8.4 
Outcome Measures for Analyses .......................................................................... 60 
8.4.1 
Primary Outcome Measures ................................................................................. 60 
8.4.2 
Secondary Outcome Measure ............................................................................... 60 
8.4.3 
Safety Outcome Measure ...................................................................................... 61 
8.4.4 
Exploratory Outcome Measure ............................................................................. 61 
8.5 
Methods for Statistical Analyses .......................................................................... 61 
8.5.1 
Analysis of the Primary Variable(s) ...................................................................... 61 
8.5.2 
Analysis of the Secondary Variable(s) .................................................................. 62 
8.5.3 
Subgroup Analysis ................................................................................................ 62 
8.5.4 
Interim Analysis .................................................................................................... 62 
8.5.5 
Sensitivity Analysis .............................................................................................. 62 
8.5.6 
Exploratory Analysis ............................................................................................ 62 
8.5.7 
Analysis of the Observational Data ...................................................................... 62 
9 
STUDY AND DATA MANAGEMENT ............................................................... 63 
9.1 
Training of Study Site Personnel .......................................................................... 63 
9.2 
Monitoring of the Study ....................................................................................... 63 
9.2.1 
Source Data ........................................................................................................... 63 


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9.2.2 
Research Agreement(s) ......................................................................................... 64 
9.2.3 
Archiving of Study Documents ............................................................................ 64 
9.3 
Study Timetable and End of Study ....................................................................... 64 
9.4 
Data Management ................................................................................................. 64 
10 
ETHICAL AND REGULATORY REQUIREMENTS ......................................... 65 
10.1 
Ethical Conduct of the Study ................................................................................ 65 
10.2 
Subject Data Protection ........................................................................................ 65 
10.3 
Ethics and Regulatory Review.............................................................................. 65 
10.4 
Informed Consent ................................................................................................. 66 
10.5 
Changes to the Protocol and Informed Consent Form.......................................... 67 
10.6 
Audits and Inspections .......................................................................................... 67 
11 
LIST OF REFERENCES ...................................................................................... 68 
 
LIST OF TABLES 
Table 1 
Study Plan Detailing the Procedures ........................................................... 40 
Table 2 
Laboratory Variables ................................................................................... 47 
Table 3 
Investigational Product ................................................................................ 56 
Table 4 
2.5% Alpha (80% Power, Time-to-event Analysis) .................................... 59 
 
LIST OF FIGURES 
Figure 1 
Study flow chart .......................................................................................... 28 
 
LIST OF APPENDICES 
Appendix A 
Additional Safety Information .................................................................... 74 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this Clinical Study Protocol. 
Abbreviation or special 
term 
Explanation 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ASCVD 
Atherosclerotic cardiovascular disease 
AST 
Aspartate aminotransferase 
BiPAP 
Bilevel positive airway pressure 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CKD 
Chronic kidney disease 
CoV 
Coronavirus 
COVID-19 
Coronavirus disease 2019 
CPAP 
Continuous positive airway pressure 
CRF 
Case Report Form 
CRP 
C-reactive protein 
CSP 
Clinical Study Protocol 
CT 
Computed tomography 
DCI 
Data collection instruments 
DKA 
Diabetic ketoacidosis 
ECMO 
Extracorporeal membrane oxygenation 
eCRF 
Electronic case report form  
eGFR 
Estimated glomerular filtration rate 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HF 
Heart failure 
HR 
Hazard ratio 
hs troponin 
High-sensitivity troponin 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation 


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Abbreviation or special 
term 
Explanation 
ICU 
Intensive care unit 
IDSMC 
Independent data and safety monitoring committee 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
LDH 
Lactate dehydrogenase 
LVEF 
Left ventricular ejection fraction 
LSLV 
Last subject last visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
NEWS 2 
National Early Warning Score 2 
NIH 
National Institute of Health 
NSAID 
Non-steroidal anti-inflammatory drug 
NT-proBNP 
N-terminal-pro B-type natriuretic peptide 
O2 SAT 
Oxygen saturation 
PI 
Principal investigator  
PLTs 
Platelets 
RBC 
Red blood cell 
SAE 
Serious adverse event  
SAP 
Statistical analysis plan 
SARS 
Severe acute respiratory syndrome 
SDV 
Source data verification 
SGLT2 
Sodium-glucose co-transporter 2 
SGLT2i 
Sodium-glucose co-transporter 2 inhibitors 
SpO2 
Blood oxygen saturation 
SD 
Standard deviation 
T2DM 
Type 2 diabetes mellitus 
US 
United States 
WBC 
White blood cell 
WHO 
World Health Organization 
WP 
Win proportion 
WR 
Win ratio 


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1 
INTRODUCTION 
1.1 
Background and Rationale for Conducting this Study 
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in 
Wuhan, China, in December 2019 as the cause of an outbreak of COVID-19, a type of viral 
pneumonia. The following COVID-19 pandemic has since then affected millions of people 
worldwide. Early epidemiologic data indicated that ~12% of SARS-CoV-2-positive patients 
develop symptoms requiring hospitalization, and of these, nearly 24% may need intensive care 
(CDC 2020, Guan et al 2020). In the US, approximately 14% of COVID-19 infected patients 
have required hospitalization and about 14% of the hospitalized patients (2% of the total) have 
been admitted to ICUs (NIH COVID-19 Treatment Guidelines). Hospital admission occurs at 
a median time of Day 7 from the onset of symptoms, and many recover with supportive care 
(Huang et al 2020). In others, progressive deterioration is seen. Although respiratory failure is 
a key manifestation in most patients with COVID-19, it is increasingly being recognized that 
COVID-19 is a systemic disease in which cardiovascular and kidney complications are 
common, and may be key drivers of poor outcomes, including death (Arentz et al 202, Guzik 
et al 2020, Li et al 2020, Madjid et al 2020, Ronco et al 2020). As an example, nearly 80% of 
patients hospitalized with COVID-19 have evidence of cardiac involvement (Puntmann et al 
2020). In addition, average NT-proBNP among critically ill patients in one of the initial 
reports from the US was ~4700 pg/mL (higher than what is typically seen in trials of patients 
with HF and reduced ejection fraction). It is possible (and likely), based on these findings, that 
HF may be a significant component of the disease process. Furthermore, nearly 30% of 
patients had evidence of acute myocardial injury (Shi et al 2020). The risk of disease 
progression, need for intensive care, and death was dramatically higher in COVID-19 patients 
that develop cardiac injury versus those that do not (risk of death is 51% versus 14%). 
Collectively, these findings suggest that cardiovascular complications are prominent in 
patients hospitalized with COVID-19 and appear to be key drivers of poor outcomes and 
death. It thus follows that prevention of these complications may lead to lower risk of disease 
progression and death. 
Risk factors for adverse outcomes associated with COVID-19 include older age and presence 
of cardiometabolic comorbidities such as T2DM, ASCVD, hypertension, HF and CKD 
(Arentz et al 202, Grasselli et al 2020, Guan et al 2020, NIH COVID-19 Treatment 
Guidelines). Individuals that have a combination of such underlying health conditions, and 
with evidence of acute cardiac involvement and/or kidney injury, have a high risk of death due 
to COVID-19 (Guo et al 2020, Pranata et al 2020, Ronco et al 2020, Shi et al 2020, Vrsalovic 
and Vrsalovic Presecki 2020). The underlying mechanisms for this greater risk are not yet 
fully understood, but compromised baseline organ function and metabolism combined with 
greater susceptibility to endothelial injury, inflammatory insults and tissue hypoxia are likely 


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to play a role (Ayres 2020, Guzik et al 2020, Kang et al 2020, Madjid et al 2020). 
Currently, remdesivir is the only drug approved for treatment of hospitalized patients with 
COVID-19 by the FDA. Dexamethasone has been authorized for emergency use in 
hospitalized COVID-19 patients, and remdesivir and dexamethasone are recommended 
therapies in the NIH guidelines (NIH COVID-19 Treatment Guidelines). Remdesivir is an 
anti-viral therapy (with limited supply) recommended to be used for 5 days or until hospital 
discharge in hospitalized patients with COVID-19 who require supplement oxygen but who do 
not require mechanical or high-flow device ventilation. Dexamethasone, an anti-inflammatory 
drug, is also recommended for treatment up to 10 days or until discharge in hospitalized 
COVID-19 patients. The evidence is stronger for a positive effect of this treatment when the 
patients are mechanically ventilated. 
Over the past several months, the unpredictable nature of the evolving global pandemic and 
the change in available medications for treatment of COVID-19 resulted in lower rates of 
complications and death than what was observed during the pandemic’s initial phase. As a 
consequence, faster and more complete recovery has now become an important treatment goal 
on par with prevention of complications and death in patients hospitalized with COVID-19. 
Dapagliflozin inhibits SGLT2, the major transporter responsible for renal sodium and glucose 
reabsorption in the proximal convoluted tubule of the kidney. In addition to the primary 
action, SGLT2 inhibitors including dapagliflozin have been shown to provide substantial 
cardiorenal protection in patient populations similar to those at risk for COVID-19 
complications, namely, patients with T2DM, ASCVD, HF, and CKD. SGLT2 inhibitors were 
shown to reduce the risk of cardiovascular and kidney events in patients with T2DM in 4 large 
outcome trials investigating empagliflozin, canagliflozin and dapagliflozin (Neal et al 2017, 
Perkovic et al 2019, Wiviott et al 2019, Zinman et al 2015). In the DAPA-HF trial, 
dapagliflozin reduced the risk of death and worsening of HF by 26% in patients with HFrEF, 
with identical effects in patients with and without T2DM (McMurray et al 2019, Petrie et al 
2020). These benefits were observed within days and were significant by 28 days of treatment 
(Sabatine et al 2019). SGLT2 inhibitors also consistently reduce the risk of kidney disease 
progression and acute kidney injury (Neal et al 2017, Perkovic et al 2019, Wiviott et al 2019, 
Zinman et al 2015). Recently released results from the DAPA-CKD trial demonstrate a 
statistically significant and clinically meaningful benefit of dapagliflozin on the risk of 
worsening of renal function or death in adult patients with CKD; with and without T2DM 
(Heerspink et al 2020). 
The mechanisms that could explain the protective effects of SGLT2 inhibitors overlap 
substantially with those involved in COVID-19. Firstly, the decrease in glucose and insulin 
levels, shift of energy metabolism to increased lipid oxidation with reduced reliance on 


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glucose, and inhibition of glycolysis may be especially important in COVID-19, as SARS-
CoV-2 may depend on the glycolytic pathway for its replication, stimulating lipogenesis that 
appears to be one of the key drivers of cellular damage (Codo et al 2020, Daniele et al 2016). 
Secondly, SGLT2 inhibitors improve endothelial function within 48 hours of treatment, 
probably because of reduced oxidative stress, and have significant anti-inflammatory effects 
with reduction of C-reactive protein and interleukin-6 (Bonnet and Scheen 2018, Solini et al 
2017). In addition, experimental studies have shown reduced activation of the NLRP3 
inflammasome, and protection against septic acute kidney injury on SGLT2 inhibitor 
treatment (Kim et al 2020, Maayah et al 2020). SGLT2 inhibitors also increase erythropoiesis 
resulting in increased haematocrit, which together with improved endothelial function may 
improve oxygen delivery to tissues (Ghanim et al 2020, Lambers Heerspink et al 2013, Solini 
et al 2017). Moreover, SGLT2 inhibitors reduce the extracellular volume in patients with fluid 
overload, such as those with CKD and HF (Griffin et al 2020, Ohara et al 2020), and appear to 
rapidly reduce pulmonary artery pressure in patients with HF, leading to hemodynamic 
decongestion (Mullens et al 2020). Taken together, SGLT2 inhibitors may favorably impact 
multiple processes, including but not limited to energy metabolism, endothelial function, 
oxidative stress, inflammation, and autophagy, that are dysregulated during a major acute 
illness such as COVID-19 (Aragón-Herrera et al 2019,  Esterline et al 2018, Ferrannini 2017, 
Kim et al 2020, Packer 2020, Tanaka et al 2018). Such metabolic restoration may help to 
prevent multi-organ damage in the setting of COVID-19, and could provide critical and 
complementary efficacy to other therapeutic approaches across various stages of the disease 
course, including remdesivir and dexamethasone, in patients hospitalized with COVID-19 but 
not yet critically ill (Ayres 2020). 
Therefore, we hypothesize that dapagliflozin, a potent, highly-selective, and orally-active 
inhibitor of human renal SGLT2, has the potential to afford end-organ protection against 
SARS-CoV-2-mediated injury (ie, lowering the risk of cardiovascular and kidney 
complications and multi-organ failure), thereby, reducing the risk of morbid complications and 
improving clinical recovery. Our dual primary objectives are, therefore, aligned to capture 
both critical components of treatment benefit (prevention of complications and improving 
clinical recovery). Finding a therapeutic effect for either or both dual primary endpoints 
would, therefore, be considered a significant and clinically meaningful benefit for patients 
hospitalized with COVID-19. If found to be effective, SGLT2i are already approved (for 
different indications) and available in most countries, and have a well-established safety 
profile, having been studied in tens of thousands of patients, and having been prescribed to 
millions around the world since their introduction in 2011. 
In this study, patients hospitalized with SARS-CoV-2 infection that are at high risk for 
complications will be treated with dapagliflozin or matching placebo for 30 days to investigate 
the effects on risk of complications and all-cause death, or improvement in clinical recovery in 


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adult patients hospitalized with COVID-19 compared to placebo. 
1.2 
Rationale for Study Design, Doses and Control Groups 
This is a randomized, multicenter, double-blind, placebo-controlled, parallel-group, Phase III 
study in countries with high prevalence of COVID-19 (countries in North America, Latin 
America, and Europe, plus India). Randomization and double-blinding study treatment will 
minimize potential bias. 
Patients with serious COVID-19 complications, including death, frequently have 
cardiometabolic disease (hypertension, T2DM, ASCVD, HF, and/or kidney disease at 
baseline) (Arentz et al 202, Grasselli et al 2020, Guan et al 2020, NIH COVID-19 Treatment 
Guidelines). Individuals that have a combination of such underlying health conditions, and 
with evidence of acute cardiac involvement and/or kidney injury, have a high risk of death due 
to COVID-19 (Guo et al 2020, Pranata et al 2020, Ronco et al 2020, Shi et al 2020 Vrsalovic 
and Vrsalovic Presecki 2020). These findings suggest that cardiovascular and kidney 
complications are prominent in patients hospitalized with COVID-19 and appear to be key 
drivers of poor outcomes and death. It thus follows that prevention of these complications may 
lead to either lower risk of disease progression or improved clinical recovery. In summary, the 
patients at highest risk of COVID-19 complications appear to be those with cardiometabolic 
disease at baseline and the rate of cardiorenal complications in the setting of COVID-19 is 
high—especially in patients with pre-existing cardiovascular and kidney disease. 
SGLT2 inhibitors may favorably impact multiple processes, including but not limited to 
energy metabolism, endothelial function, oxidative stress, inflammation, and autophagy, that 
are dysregulated during a major acute illness such as COVID-19 (Aragón-Herrera et al 2019,  
Esterline et al 2018, Ferrannini 2017, Kim et al 2020, Packer 2020, Tanaka et al 2018). Such 
metabolic restoration may help to prevent multi-organ damage or improve clinical recovery in 
the setting of COVID-19, and could provide critical and complementary efficacy to other 
therapeutic approaches across various stages of the disease course. 
The study population will include hospitalized patients with respiratory manifestations of 
COVID-19 of any duration, but without the need for mechanical ventilation. The eligible 
patients should have a medical history including risk factors for developing serious 
complications of COVID-19. These risk factors include patients with a history of 
hypertension, T2DM, ASCVD, HF and/or CKD stage 3 to 4. Patients with reduced renal 
function usually present a clinical profile of increased intra glomerular pressure, hypertension, 
proteinuria and fluid/sodium overload. Existing data demonstrate that SGLT2 inhibition can 
improve all these abnormalities (Kosiborod et al 2017, McMurray et al 2019, Neal et al 2017, 
Perkovic et al 2019, Wiviott et al 2019, Zinman et al 2015). Thus, patients with HF and 
reduced renal function could be expected to benefit from treatment with dapagliflozin. 


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Patients will be treated for 30 days, with either dapagliflozin 10 mg daily or placebo, each to 
be given in addition to the usual standard of care in the participating hospital. In the natural 
course of the disease, serious complications of COVID-19 can occur up to 10 to 15 days after 
the start of symptoms, so the treatment period of 30 days should be sufficient to assess 
efficacy. Per the protocol, treatment with dapagliflozin or matching placebo will continue even 
if mechanical ventilation becomes necessary. In that case, the tablets will be crushed and 
given to the patient via the gastric tube. The 10-mg dose of dapagliflozin has a 
well-characterized efficacy and safety profile in the T2DM clinical development program and 
is the recommended dose in the majority of countries worldwide. All patients will be treated 
according to local guidelines on standard of care treatment for patients with COVID-19. 
The study assessments include only those that are absolutely critical for ensuring the safety of 
the patients, to measure efficacy outcomes, and collect biomarker data, so as not to place too 
high a burden on the study personnel and to minimize additional risk of exposure to 
SARS-CoV-2.  
The dual primary efficacy endpoints of the study are time to first event of either complications 
or death from any cause, and improved clinical recovery through 30 days of follow-up. An 
extended follow-up period of 60 days (after the 30-day treatment period) is included, in order 
to examine longer-term trajectory of recovery from COVID-19 among trial participants.  
The safety data will be monitored by an Independent Data and Safety Monitoring Committee 
and an interim safety analysis of the first 100 patients will be performed. 
1.3 
Benefit/risk and Ethical Assessment 
Dapagliflozin has global marketing approval in more than 90 countries. More detailed 
information about the known and expected benefits and risks and reasonably expected AEs of 
dapagliflozin may be found in the Investigator’s Brochure. The following is a summary of 
benefit-risk considerations relevant to the COVID-19 target population. 
1.3.1 
Potential Benefits to Subjects 
All patients in the study are expected to be treated optimally according to background local 
standard of care therapy, including treatments to control co-morbidities. Dapagliflozin or 
matching placebo will be administered in addition to these treatments. 
These patients are hospitalized and will receive close medical attention, irrespective of blinded 
treatment allocation. 
1.3.2 
Potential Risks to Subjects 
The safety profile of dapagliflozin is already well established from prior clinical studies in 


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various clinical settings. These studies have demonstrated that dapagliflozin is generally safe 
and well tolerated. 
Dapagliflozin, as an inhibitor of SGLT2, increases urinary glucose excretions, which is 
commonly believed to increase the risk of urinary tract infections. Urinary tract infections 
have been reported in dapagliflozin-treated patients in a slightly higher proportion than in 
placebo-treated patients in some global Phase III studies, although the rates of urinary tract 
infections (and serious urinary tract infections) observed in large clinical trials of dapagliflozin 
and other SGLT2i have been similar to placebo (Wiviott et al 2019, McMurray et al 2019). 
Increased urinary glucose excretion may also lead to an increased risk of developing genital 
infections. Genital infections are considered common side effects (in ≥1/100 to <1/10 
patients). 
Dapagliflozin reduces BP and may reduce blood volume from its diuretic effect, which could 
be a concern in patients with COVID-19, but could also be an important mechanism of a 
potential treatment effect. A pooled analysis of patients with T2DM and HF in the 
dapagliflozin development program, showed no increase of volume depletion events, but an 
increase in renal events, mainly creatinine increases, in patients treated with dapagliflozin 
(n=171) compared with patients treated with placebo (n=149). About half of the patients were 
on loop diuretics (Kosiborod et al 2017). In the dapagliflozin T2DM program, the rate of 
events related to volume depletion and impaired renal function has been similar between 
dapagliflozin and placebo.  
Dapagliflozin has not been shown to induce hypoglycemia in non-diabetic patients. In clinical 
pharmacology studies, healthy subjects have been treated with single oral doses of up to 
500 mg and multiple oral doses of 100 mg up to 14 days without any hypoglycemic events. 
However, in patients with T2DM and on insulin or sulfonylurea medication, there is an 
increased risk of hypoglycemia. Patients with T2DM will be monitored in the hospital as part 
of standard of care, which in North America, Latin America, Europe, and India includes blood 
glucose monitoring. 
There have been reports of ketoacidosis, including DKA, in patients with T2DM taking 
dapagliflozin and other SGLT2 inhibitors. Diabetic ketoacidosis is considered a rare (in 
≥1/10000 to <1/1000 patients) adverse drug reaction for dapagliflozin in patients with T2DM. 
Patients treated with dapagliflozin who present with signs and symptoms consistent with 
ketoacidosis, including nausea, vomiting, abdominal pain, malaise, and shortness of breath, 
should be assessed for ketoacidosis, even if blood glucose levels are below 14 mmol/L 
(250 mg/dL). If ketoacidosis is suspected, interruption of dapagliflozin treatment should be 
considered, and the patient should be evaluated promptly.  


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Predisposing factors to ketoacidosis include a low beta-cell function reserve resulting from 
pancreatic disorders (eg, type 1 diabetes, history of pancreatitis, or pancreatic surgery), insulin 
dose reduction, reduced caloric intake, or increased insulin requirements caused by infections, 
illness or surgery and alcohol abuse. Dapagliflozin should be used with caution in patients in 
these circumstances. 
1.3.2.1 
Protection Against Risks 
Appropriate measures are in place to monitor and minimize potential risks to participating 
patients, including the use of an IDSMC that will continuously evaluate safety data. Patients 
with type 1 diabetes mellitus and patients with a history of DKA are excluded from this study. 
Careful, frequent monitoring of acid-base balance of diabetes patients with T2DM during 
hospitalization is important and represents a standard of care in most institutions. Should there 
be an abnormal increase in anion gap and/or reduced bicarbonate levels, measurement of 
blood levels of ketones, lactate, and analysis of pH must be performed if DKA is suspected. 
Also, if careful monitoring of acid-base balance according to Table 1 can’t be performed, 
dosing of study medication should be temporarily interrupted until monitoring can be 
resumed. At discharge, patients with diabetes should be instructed about symptoms associated 
with DKA and to seek immediate health care contact if such symptoms occur. 
A diagnosis of DKA should only be made in a clinical setting consistent with DKA (based on 
patient history, symptoms, and physical exam) and in the absence of more likely alternative 
diagnoses and causes of acidosis (such as lactic acidosis). The following biochemical data 
should support diagnosis: 
• 
Ketonemia ≥3.0 mmol/L and/or significant ketonuria (more than 2+ on standard urine 
sticks) in the absence of elevated lactate (lactate should be <2 mmol/L to be considered a 
potential DKA) 
and 
• 
At least one of the following criteria suggesting high anion gap metabolic acidosis: 
(a) Arterial or Venous pH ≤7.3 
(b) Serum bicarbonate ≤18 mEq/L 
(c) Anion gap [Na – (Cl + HCO3)] >10 
 
1.3.3 
Conclusion 
Considering the nonclinical and clinical experience with dapagliflozin and the precautions 
included in the study protocol, participation in this study should present a minimal and thus 
acceptable risk to eligible patients. This clinical study will test the hypothesis that 
dapagliflozin is superior to placebo in reducing the risk of complications or death, or 


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improving clinical recovery in patients hospitalized with COVID-19. The results could offer 
substantial benefit to patients with COVID-19, a global patient population with very high risk 
and an urgent unmet need for effective treatments. 
1.4 
Study Design 
This is an international, multicenter, parallel-group, randomized, double-blind, 
placebo-controlled, Phase III study in approximately 1200 hospitalized adult COVID-19 
patients. The study is evaluating the effect of dapagliflozin 10 mg versus placebo, given once 
daily for 30 days in addition to background local standard of care therapy, including 
treatments to control co-morbidities. The screening period should be as short as possible (no 
more than 2 days), and patients should start investigational product the same day as 
randomization. Following last dose of investigational product at Day 30 patients are followed 
up for an extended additional (observational) period of 60 days. 
Figure 1 
Study flow chart 
(a) Discharged patients will be asked to attend telephone visits at Day 15 and Day 30 
Adult patients 
hospitalized 
with 
confirmed or 
strongly 
suspected 
COVID-19 
1:1 randomization 
to dapagliflozin 
10 mg/day or 
matching 
placebo, given in 
addition to 
standard of care 
treatment  
Dapagliflozin 
10 mg daily 
Matching 
placebo daily 
All patients have 
daily 
assessments 
until hospital 
discharge, death 
or end of 30-day 
treatment period 
(a) 
Screening 
30-day treatment period 
60-day 
observational 
follow-up 
Extended 
follow-up 
period after 
last dose. 
Patients are 
contacted at 
Day 60 and 
Day 90 
 


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2 
STUDY OBJECTIVES 
All objectives are assessed during the 30-day treatment period. 
2.1 
Primary Objective 
Primary objectives: 
Outcome measure: 
To determine whether dapagliflozin 10 mg is 
superior to placebo, in terms of reducing 
complications or all-cause mortality, or improving 
clinical recovery in patients hospitalized with 
COVID-19. 
 
Dual primary endpoints of: 
 
Prevention of COVID-19 complications or death 
During the 30-day treatment period, time to first 
occurrence of new/worsened organ dysfunction during 
index hospitalization or death from any cause. 
New/worsened organ dysfunction is defined as at least 
one of the following:  
• 
Respiratory decompensation requiring initiation of 
mechanical ventilation (includes invasive or non-
invasive ventilation, CPAP, or BiPAP), and/or 
initiation of ECMO 
• 
New or worsening congestive HFa 
• 
Requirement for vasopressor therapy and/or 
inotropic or mechanical circulatory support 
• 
Ventricular tachycardia or fibrillation lasting at 
least 30 seconds and/or associated with 
hemodynamic instability or pulseless electrical 
activity, or resuscitated cardiac arrest 
• 
Doubling of s-Creatinine or initiation of renal 
replacement therapy 
 
Improving clinical recovery 
Hierarchical composite outcome measure: 
1 
Death from any cause through Day 30 
2 
New/worsened organ dysfunction (as defined 
above) 
3 
Clinical status at Day 30 for patients still 
hospitalized and without any worsening organ 
dysfunction (using points 3 to 5 of a 7-point ordinal 
scaleb) 
4 
Hospital discharge before Day 30 and alive at 
Day 30 
a 
Congestive HF is defined as at least one of the following 1) initiation of new intravenous therapy for heart 
failure 2) reinstitution of previous intravenous therapy for heart failure 3) increase in current intravenous 
therapy for heart failure. This is based on modification on previous definition of in-hospital worsening heart 
failure (McMurray et al 2007) 
b 
7-point Patient Clinical Status scale: 
1 
Not hospitalized, no limitations on activities 
2 
Not hospitalized, limitation on activities 
3 
Hospitalized, not requiring supplemental oxygen 


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4 
Hospitalized, requiring supplemental oxygen 
5 
Hospitalized, on high flow oxygen devices 
6 
Hospitalized, on invasive mechanical ventilation or ECMO 
7 
Death 
BiPAP Bilevel positive airway pressure; COVID-19 Coronavirus disease 2019; CPAP Continuous positive 
airway pressure; ECMO extracorporeal membrane oxygenation; HF Heart failure. 
 
2.2 
Secondary Objectives 
Secondary objectives: 
Outcome measures: 
To compare the effect of dapagliflozin 10 mg 
versus placebo on time to hospital discharge 
Time to hospital dischargea 
To compare the effect of dapagliflozin 10 mg 
versus placebo on total number of days alive and 
free from respiratory decompensation requiring 
mechanical ventilation 
Total number of days alive and free from respiratory 
decompensationa requiring initiation of mechanical 
ventilation (includes invasive or non-invasive ventilation, 
CPAP, or BiPAP) from randomization through Day 30 
To compare the effect of dapagliflozin 10 mg 
versus placebo on total number of days alive, not 
in ICU, and free from respiratory decompensation 
requiring mechanical ventilation 
Total number of days alive, not in the ICU, and free from 
respiratory decompensationa requiring initiation of 
mechanical ventilation (includes invasive or non-invasive 
ventilation, CPAP, or BiPAP) from randomization 
through Day 30 
To compare the effect of dapagliflozin 10 mg 
versus placebo on a composite kidney endpoint  
Time to composite of acute kidney injuryb or initiation of 
renal replacement therapyc, or death from any cause 
through Day 30 
To compare the effect of dapagliflozin 10 mg 
versus placebo in reducing the incidence of all-
cause mortality 
Time to death from any cause through Day 30 
a 
Refers to index hospitalization only 
b 
Acute kidney injury defined as:  
 
An episode of doubling s-Creatinine compared to baseline during index hospitalization 
 
or SAE with preferred term of Acute kidney injury following discharge and through Day 30 
c 
Renal replacement therapy defined as: 
 
Initiation of renal replacement therapy during index hospitalization  
 
or SAE with a preferred term for renal replacement therapy (ie, Haemodialysis, Haemofiltration, 
Continuous haemodiafiltration, Dialysis, Peritoneal dialysis, Dialysis device insertion, Renal 
replacement therapy, or Artificial kidney device user) following discharge and through Day 30 
BiPAP Bilevel positive airway pressure; CPAP Continuous positive airway pressure; ICU Intensive care unit; 
SAE Serious adverse event. 
 


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2.3 
Safety Objectives 
Safety objective: 
Outcome measure: 
To evaluate the safety and tolerability of 
dapagliflozin compared to placebo in patients 
hospitalized with COVID-19. 
• 
Serious adverse events from randomization to Day 30a 
• 
Acute kidney injury defined as:  
 
An episode of doubling s-Creatinine compared to 
baseline during index hospitalization 
 
or SAE with preferred term of acute kidney injury 
following discharge and through Day 30 
• 
Incidence of diabetic ketoacidosis from randomization 
through Day 30 
a 
SAEs will be collected through Day 90 but comparison of treatment groups will be assessed based on the 
data obtained through Day 30. For the definition of reportable SAEs, see Section 6.4.2. 
COVID-19 Coronavirus 2019; SAE Serious adverse event. 
 
2.4 
Exploratory Objectives 
Exploratory objective: 
Outcome measures: 
To compare the effect of dapagliflozin 10 mg to 
placebo on the components of the primary 
endpoint, biomarkers, and patient’s clinical status. 
• 
Change in NT-proBNP, hs troponin, D-dimer, 
LDH, ALT, lymphocyte count, CRP between Day 1 
and Day 15 (or discharge from hospital, whichever 
is earlier) 
• 
Qualitative PCR for SARS-CoV-2 in 
oropharyngeal/nasopharyngeal swab at baseline 
(while hospitalized); and Day 15 (if still 
hospitalized) or discharge from hospital 
• 
Change in NEWS 2 from Day 1 to Day 15 (or 
discharge from hospital, whichever is earlier). 
• 
Patient’s clinical status (on a 7-point ordinal scale) 
at Day 15 (or discharge from hospital, whichever is 
earlier) 
• 
Total number of days alive and not on renal 
replacement therapya 
• 
Proportion of patients with acute coronary 
syndromeb 
a 
Refers to index hospitalization only 
b 
Acute coronary syndrome defined as: during index hospitalization, abnormal troponin level above 99th 
percentile of the local laboratory reference range or, if abnormal at baseline, further rise in troponin levels 
accompanied by at least 1 of the following: 1) ischemic symptoms 2) ischemic ST-segment changes on 
ECG (Thygesen et al 2018) 
NEWS 2 is a standardized assessment of acute-illness severity and can prompt critical care intervention. It is 
used as an adjunct to clinical judgment. 
ALT Alanine aminotransferase; COVID-19 Coronavirus disease 2019; CRP C-reactive protein; 
ECG Electrocardiogram; hs troponin High-sensitivity cardiac troponin; LDH lactate dehydrogenase; NEWS 2 
National Early Warning Score 2; NT-proBNP N-terminal-pro B-type natriuretic peptide; PCR Polymerase chain 
reaction SARS-CoV-2 Severe acute respiratory syndrome-coronavirus-2. 


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3 
SUBJECT SELECTION, ENROLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
In this study, patients will be recruited from sites with adult patients hospitalized with 
confirmed or strongly suspected COVID-19. Each patient should meet all of the inclusion 
criteria and none of the exclusion criteria for this study in order to be randomized to 
investigational product. Under no circumstances can there be exceptions to this rule. Patients 
can be re-screened once, but must be considered screen failures if they still do not meet the 
entry requirements (Section 3.3). 
In this study, “enrolled” patients are those who sign the ICF. “Randomized” patients are those 
who undergo randomization and receive a randomization number.  
3.1 
Inclusion Criteria 
For inclusion in the study patients should fulfill the following criteria based on local 
regulations: 
1 
Provision of informed consent prior to any study specific procedures. The ICF process is 
described in Section 10.4 
2 
Male or female patients aged ≥18 years on the day consent given 
3 
Currently hospitalized 
4 
Hospital admission no more than 4 days prior to screening 
5 
Confirmed SARS-CoV-2 infection by laboratory testing within 10 days prior to 
screening, or strongly suspected SARS-CoV-2 infection on presentation* 
6 
Chest radiography or CT findings that, in the opinion of the investigator, are consistent 
with COVID-19  
7 
SpO2 ≥ 94% while receiving low-flow supplemental oxygen (5 liters or less) 
8 
Medical history of at least one of the following:  
(a) hypertension 
(b) T2DM 
(c) atherosclerotic cardiovascular disease 
(d) heart failure (with either reduced or preserved LVEF) 
(e) CKD stage 3 to 4 (eGFR between 25 to 60 mL/min/1.73 m2) 
 
*Note that the proportion of patients randomized without a confirmed SARS-CoV-2–positive 
test will be closely monitored, and may be capped if it becomes greater than anticipated. 


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3.2 
Exclusion Criteria 
Patients should not enter the study if any of the following exclusion criteria are fulfilled: 
1 
Respiratory decompensation requiring mechanical ventilation (includes invasive or 
non-invasive ventilation, CPAP, or BiPAP)  
2 
Expected need for mechanical ventilation (includes invasive or non-invasive ventilation, 
CPAP, or BiPAP) within the next 24 hours 
3 
Anticipated transfer to another hospital facility, which is not another study site, within 
72 hours 
4 
Expected survival of less than 24 hours at the time of presentation, in the judgement of 
the Investigator 
5 
eGFR <25 mL/min/1.73 m2 or receiving renal replacement therapy/dialysis 
6 
Evidence of oliguria (urine output <500 mL in 24 hours or <0.5 mL/kg/hour) or serum 
creatinine ≥1.5x baseline pre-hospitalization value, if available at the time of screening  
7 
Systolic BP <95 mmHg and/or requirement for vasopressor treatment and/or inotropic or 
mechanical circulatory support at Screening 
8 
History of type 1 diabetes mellitus 
9 
Currently receiving or has received in the last 14 days, experimental immune modulators 
and/or monoclonal antibody therapies for COVID-19** 
10 History of diabetic ketoacidosis 
11 Current treatment with any SGLT2i (eg, dapagliflozin, canagliflozin, empagliflozin, 
ertugliflozin) or having received treatment with any SGLT2i within 4 weeks prior to 
screening  
12 History of hypersensitivity to dapagliflozin 
13 Any other condition that in the judgment of the investigator would jeopardize the patient's 
participation in the study or that may interfere with the interpretation of study data or if 
the patient is considered unlikely to comply with study procedures, restrictions and 
requirements 
14 Women of childbearing potential: Current or planned pregnancy or currently lactating.  
(a) Women of childbearing potential are defined as any female who has experienced 
menarche and who is NOT permanently sterile or post-menopausal 
(b) Post-menopausal is defined as 12 consecutive months with no menses without an 
alternative medical cause 
(c) Women of childbearing potential, who are sexually active, must agree to use a 
medically-accepted method of birth control for the duration of the study. Acceptable 
birth control methods include:  


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• 
Surgical sterilization (such as a hysterectomy or bilateral tubal ligation) 
• 
Progesterone hormonal contraceptives (birth control pills or implants) 
• 
Barrier methods (such as a condom or diaphragm) used with a spermicide 
• 
An intrauterine device 
15 Involvement in the planning and/or conduct of the study (applies to both Investigator staff 
and/or staff at the study site) 
16 Previous enrolment in the present study. (Note: the study design allows 2 attempts to meet 
the randomization criteria after enrolment.) 
17 Current participation in another interventional clinical trial (with an investigational drug) 
that is not an observational registry 
 
**Note that use of rescue therapies including immune modulators, monoclonal antibody 
therapies, antiviral therapies, and other agents that are approved or being used through 
open-label compassionate/expanded use programs or in accordance with the local standard of 
care is permitted during the study. 
Procedures for withdrawal of incorrectly enrolled patients are in Section 3.4. 
3.3 
Subject Enrolment and Randomization 
Investigator(s) or designee should keep a record (the patient’s screening log) of patients who 
entered pre-study screening. 
The Investigator(s) or designee will: 
1 
Obtain informed consent from the potential patient or their guardian/legal representative 
before any study specific procedures are performed 
2 
Assign potential subject a unique enrolment number 
3 
Determine patient eligibility (see Sections 3.1 and 3.2). More than 1 attempt to meet the 
randomization criteria is allowed 
4 
Assign eligible patient a unique randomization code 
5 
If a patient withdraws from participation in the study, then his/her 
enrolment/randomization code cannot be reused 
 
Randomization codes will be assigned strictly sequentially as patients become eligible for 
randomization (see Section 3.5). 


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3.4 
Procedures for Handling Incorrectly Enrolled or Randomized 
Subjects 
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive investigational product. There can be no exceptions to this rule. Patients 
who are enrolled, but subsequently found not to meet all the eligibility criteria must not be 
randomized or initiated on treatment (note that more than 1 attempt to meet the randomization 
criteria is allowed). 
Where a patient does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on treatment, the Investigator should inform the Sponsor immediately, and 
a discussion should occur between the Sponsor and the Investigator regarding whether to 
continue or discontinue the patient from treatment. The Sponsor must ensure all decisions are 
appropriately documented. 
3.5 
Methods for Assigning Treatment Groups 
All patients will be randomly assigned to investigational product centrally using an Interactive 
Response Technology system. Randomization to investigational product will be performed in 
balanced blocks to ensure approximate balance between the treatment groups (1:1). The 
Sponsor or delegate is responsible for generating the randomization scheme for this study 
using a validated system. Before the study starts, the instructions for accessing and using the 
Interactive Response Technology system will be provided to each site. 
Investigational product (dapagliflozin or placebo) should be administered the same day the 
investigational product kit number is assigned and as soon after randomization as possible. 
To ensure balanced randomization, stratification will be employed by country.  
3.6 
Methods for Ensuring Blinding 
The blinding of treatment is ensured by using a double-blind technique of matching placebo. 
The IRT will provide the Investigator with the kit identification number to be allocated to the 
patient when investigational product is dispensed. 
No member of the extended Sponsor study team, personnel at study sites, 
 study 
team, or the Sponsor’s delegate handling study data will have access to the randomization 
scheme during the study. The Sponsor or delegate generating the randomization scheme and 
the Supply Chain Study Management may be able to access the randomization scheme as 
appropriate. Neither the patient nor any of the Investigator’s staff/designee who are involved 
in the treatment or clinical evaluation and monitoring of the patients will be aware of the 
treatment received. In the event that the treatment allocation for a patient becomes known to 


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the Investigator or other study staff involved in the management of study subjects, the 
Investigator must notify the Sponsor immediately.  
3.7 
Methods for Unblinding  
Individual treatment codes, indicating the treatment randomization for each randomized 
patient, will be available to the Investigator(s) or pharmacists at the study site from the IRT. 
Instructions for code breaking/unblinding are provided to each study site. 
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the patient requires knowledge of the treatment randomization. The date and 
reason that the blind was broken must be recorded in the source documentation and eCRF as 
applicable. The Investigator is to document and report the action to the Sponsor or Sponsor 
representative, without revealing the treatment given to the patient. 
The Sponsor or Sponsor representative retains the right to break the code for SAEs that are 
unexpected and are suspected to be causally related to the investigational product and that 
potentially require expedited reporting to regulatory authorities.  
3.7.1 
Unblinding for Independent Data and Safety Monitoring Committee 
An IDSMC will be established to monitor blinded safety data to ensure the safety of patients 
enrolled in this study, and to ensure the integrity of the study. An interim analysis of safety 
only (not efficacy) will occur when approximately 100 patients complete the 30-day treatment 
period. The IDSMC will be provided with partially unblinded data (data that are summarized 
by treatment group using masked treatment group labels). The IDSMC may choose to unblind 
the data for additional review as specified in the IDSMC charter. The Sponsor and Sponsor 
representatives will remain blinded to all data transfers provided to the IDSMC. Details about 
the IDSMC will be included in the IDSMC Charter (see Section 6.9.2). 
3.8 
Restrictions (Not Applicable) 
There are no restrictions affecting the patient’s daily life activities associated with 
participation in the study during the course of the study. 
3.9 
Discontinuation of Investigational Product 
If the patient temporarily or permanently discontinues from investigational product, it is 
important that the scheduled study visits, data collection and procedures continue according to 
the study protocol until study closure (see the Study plan in Table 1). 
Patients may be discontinued from investigational product in the following situations: 


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• Patient decision. The patient is at any time free to discontinue treatment, without prejudice 
to further treatment 
• Adverse event or other safety reasons that, in the opinion of the investigator, 
contraindicates further dosing with investigational product. 
• Severe non-compliance with the study protocol  
• DKA, consider temporarily interrupting investigational product if DKA is suspected. If 
DKA is confirmed, investigational product should be discontinued permanently 
• Positive pregnancy test (discontinue investigational product and notify the Sponsor) 
 
3.9.1 
Evaluation of Volume Status and Investigational Dose 
Reduction/interruption 
Dapagliflozin is a SGLT2i which by its mechanism of action reduces the reabsorption of 
glucose and sodium in the proximal tubules in the kidney. SGLT2 inhibition has a mild 
diuretic effect and an initial hemodynamic change with an initial increase in creatinine may 
occur. 
Unexpected acute declines in eGFR 
If an unexpected, acute decline in kidney function is observed, the patient should be evaluated.  
Volume depletion, hypotension, intercurrent medical problems and concomitant drugs may 
cause increases in blood creatinine. Urinary tract infection and urinary obstruction should be 
considered (the latter especially in men). Several drugs may cause a decline in kidney 
function, especially NSAIDs and certain antibiotics such as trimethoprim. If any drug is 
suspected of causing or contributing to worsening kidney function, their use should be 
re-considered. 
Volume depletion/hypotension 
Patients with clinically relevant symptoms/signs of suspected volume depletion and/or 
hypotension, should have their regular medication reviewed, and consideration given to 
reducing the dose of, or stopping concomitant non-essential medications, as assessed on an 
individual basis, including diuretics and drugs that lower BP (except essential treatments). The 
need for conventional diuretics (or the dose of diuretic used) should be re-evaluated in light of 
the patient’s symptoms and signs. In patients with HF, discontinuation of diuretic should only 
be undertaken cautiously. Hypotension may also occur with other BP lowering drugs and once 
again the need for (and dose of) non-essential agents of this type (eg, calcium channel 
blockers, alpha adrenoceptor antagonists and nitrates) should also be re-considered. 
3.9.2 
Investigational Product Restart  
Restart of randomized investigational product is always encouraged. If stopped, whenever 


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possible, randomized investigational product should be restarted. 
Every attempt should be made to maintain patients on dapagliflozin 10 mg or matching 
placebo during the course of the study. If the dose has been interrupted, the dose should be 
re-introduced as soon as, in the opinion of the investigator, the patient’s condition is stable. 
3.9.3 
Procedures for Discontinuation of Investigational Product 
At any time, patients are free to discontinue investigational product or withdraw from the 
study (ie, investigational product and assessments—see Section 3.10), without prejudice to 
further treatment. A patient that decides to discontinue investigational product will always be 
asked about the reason(s). If investigational product is in a patient’s possession, they should 
dispose of the study drug according to local regulations. 
Discontinuation from investigational product is not the same as complete withdrawal from the 
study. If a patient is completely withdrawn from study, see the procedures in Section 3.10.2.  
It is essential to collect data for all patients throughout the study. For that reason, a patient 
who discontinues investigational product should optimally continue to follow up study 
assessments up to and including Day 90. Alternatively, if the patient does not agree to this 
approach, modified follow-up should be arranged (eg, less frequent assessments, one contact 
at Day 30, or other means). Patients who agree to some kind of modified follow-up are still 
participating in the study. The modified visits and procedures that are done will be recorded in 
the eCRF. 
If a patient for some reason cannot be reached during the study, every attempt should be made 
to retrieve as much information regarding this patient as possible. The site should 
continuously try to reach the patient, the patient’s family, or pre-identified contact person and 
search for information regarding the patient’s status in applicable sources to protect the 
validity of data. These attempts should be documented. 
3.10 
Criteria for Withdrawal 
3.10.1 
Screen Failures 
Once enrolled in the study, patients can be re-screened one more time, if they do not fully 
meet the inclusion/exclusion criteria during the first attempt at screening. Ultimately, 
screening failures are patients who do not fulfill the eligibility criteria for the study, and, 
therefore, must not be randomized. These patients should have the reason for study 
withdrawal recorded as ‘Incorrect Enrollment’ (ie, patient does not meet the required 
inclusion/exclusion criteria). 


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3.10.2 
Withdrawal of the Informed Consent 
Patients are free to withdraw from the study at any time (investigational product and 
assessments), without prejudice to further treatment. Withdrawal of consent should only occur 
if the patient has received appropriate information about, and does not agree to, any kind of 
further assessments or contact, including modified follow-up options. Discontinuation of 
investigational product in itself is not considered withdrawal of consent. 
A patient who considers withdrawing from the study must be informed by the Investigator 
about modified follow-up options (eg, telephone contact, a contact with a relative or treating 
physician, or information from medical records).  
If a patient withdraws from participation in the study, then his/her enrollment and/or 
randomization code cannot be reused. Withdrawn patients will not be replaced. 
If the patient withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. A patient who 
withdraws consent will always be asked about the reason(s) and the presence of any AE. The 
Investigator will follow up patients as medically indicated. 
To ensure validity of study data, it is very important to collect as much data as possible 
throughout the study (including after hospital discharge) and especially vital status (dead or 
alive) (also for patients who have withdrawn their informed consent). Therefore, if informed 
consent has been withdrawn completely or the patient is non-contactable following hospital 
discharge, the investigator will attempt to collect information on all patients’ vital status from 
publicly available sources at study closure, in compliance with local privacy laws/practices. 
3.11 
Discontinuation of the Study 
The study may be stopped if, in the judgment of the Sponsor, patients are placed at undue risk 
because of clinically relevant findings. The judgment may be based on recommendations from 
the IDSMC, see IDSMC Charter for details. The study can also be stopped based on results of 
the interim analysis (see Section 8.5.4). 
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests. 
4 
STUDY PLAN AND TIMING OF PROCEDURES  
The schedule of assessments is shown in Table 1 and explained further in Sections 4.1 and 4.2.  


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Table 1 
Study Plan Detailing the Procedures 
Day number (week 1) 
Day number (week 2) 
Day number (week 3) 
Day number (week 4) 
Day 0 
(Screening 
and 
enrollment) 
1 
8 
16 
23 
2 
9 
17 
24 
3 
10 
18 
25 
4 
11 
19 
26 
5 
12 
20 
27 
6 
13 
21 
28 
7 
14 
22 
29 
 
15 
 
30 
Discharge 
from 
hospital 
Follow-up 
at Day 60 
and Day 90 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics  
X 
 
 
 
 
 
 
 
 
 
 
Weight and height 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
X 
 
 
 
 
 
 
 
Xa 
X 
X 
Vital signs (temperature, BP, 
pulse, O2 SAT) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Site laboratory assessmentb 
Xc 
Day 1b 
 
Day 3b 
 
 
 
 
Day 15b 
Xb 
 
Expected standard of care 
laboratory assessmentd (eg, 
basic metabolic panel and/or 
other means of acid-base 
monitoring per local standard 
of care) 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Oropharyngeal or 
nasopharyngeal swab 
X 
 
 
 
 
 
 
 
Day 15e 
Xe 
 
Local pregnancy test (female 
patients of child bearing 
potential only) 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
Randomization to study 
treatment 
 
Day 1 
 
 
 
 
 
 
 
 
 


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Table 1 
Study Plan Detailing the Procedures 
Day number (week 1) 
Day number (week 2) 
Day number (week 3) 
Day number (week 4) 
Day 0 
(Screening 
and 
enrollment) 
1 
8 
16 
23 
2 
9 
17 
24 
3 
10 
18 
25 
4 
11 
19 
26 
5 
12 
20 
27 
6 
13 
21 
28 
7 
14 
22 
29 
 
15 
 
30 
Discharge 
from 
hospital 
Follow-up 
at Day 60 
and Day 90 
New/worse organ dysfunction 
assessed (as defined in 
primary outcome) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
NEWS 2f 
 
Day 1 
 
 
 
 
 
 
X 
X 
 
Patient’s clinical status 
(7-point ordinal scale)g 
 
Day 1 
 
 
 
 
 
 
X 
X 
X 
Telephone follow up for 
discharged patientsg 
 
 
 
 
 
 
 
 
X 
 
 
Treatment dispensed 
 
X 
X 
X 
X 
X 
X 
X 
X 
Xh 
 
Serious adverse events and 
key safety eventsi 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs leading to discontinuation 
of IPj 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Telephone follow-up for all 
patients during extended 
follow-up periodk 
 
 
 
 
 
 
 
 
 
 
X 
a 
Recorded at Day 15 only for previously discharged patients. For all other patients, this is recorded at Day 30. 
b 
On Day 1, Day 3, Day 15, and Discharge only, laboratory assessment includes: renal panel (creatinine, BUN or urea, electrolytes, bicarbonate), 
NT-proBNP, hs troponin, D-dimer, CBC (RBC, WBC with differential, PLTs), LDH, ALT, AST, CRP and total bilirubin. All laboratory assessments will 
be done by site laboratories. 
c 
Screening laboratory assessment includes: glucose, renal panel (creatinine, BUN or urea, electrolytes, bicarbonate), NT-proBNP, hs troponin, D-dimer, 
CBC (RBC, WBC with differential, PLTs), LDH, ALT, AST, CRP, and total bilirubin. All laboratory assessments will be done by site laboratories. 
d 
Patients with diabetes should be evaluated daily while hospitalized with respect to acid-base balance to detect early change in bicarbonate levels and/or 
anion gap; acid-base monitoring may also include blood gas analysis, as applicable. If that happens, investigation of blood levels of ketones and lactate 
should be done. Glucose levels should be monitored per routine practice in these patients. 
e 
Oropharyngeal or nasopharyngeal swab will be obtained during screening and Day 15 (if patient still hospitalized) or Discharge from hospital. 


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f 
All patients are assessed at Day 1 (pre-randomization), Day 15 if hospitalized, Day 30 if hospitalized, and/or Discharge from hospital.  
g 
All patients are assessed at Day 1 (pre-randomization), Day 15, and Day 30 and/or Discharge from hospital. Hospitalized patients have all scheduled 
assessments. Discharged patients are followed up by telephone for SAEs, Patient’s clinical status, vital status, investigational product adherence, and 
subsequent hospitalization, if any. The window for the follow up phone call on Day 15 or Day 30 is ± 3 days. 
h 
The remaining investigational product is provided to the patient so that he/she can continue taking their investigational product until Day 30. 
i 
Events fulfilling the reportable SAE criteria and/or key safety events (see Section 6.4.2 for the definition of a reportable SAE or key safety event) will be 
collected from time of informed consent through Day 30. In addition, following the 30-day treatment period, all SAEs will continue to be collected through 
Day 90 (which includes the extended observational follow-up period of an additional 60 days). 
j 
If patient is still receiving IP. 
k 
All patients are followed up by telephone, if not still hospitalized, for concomitant medication, SAEs, Patient’s clinical status, vital status, and subsequent 
hospitalization, if any. The window for the follow-up phone call is ± 7 days. 
AE Adverse event; ALT Alanine aminotransferase; AST Aspartate aminotransferase; BP Blood pressure; BUN Blood urea nitrogen; CBC Complete blood count; 
CRP C-reactive protein; DAEs AEs leading to investigational product discontinuation; hs troponin High-sensitivity cardiac troponin; IP Investigational product; 
LDH lactate dehydrogenase; NEWS 2 National Early Warning Score 2; NT-proBNP N-terminal-pro B-type natriuretic peptide; O2 SAT Oxygen saturation level; 
PLTs Platelets, RBC Red blood cells; SAE Serious adverse event; WBC White blood cells.  
 


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4.1 
Screening and Enrollment Period (Day 0) 
Following hospital admission, participants will undergo screening and the following 
assessments and procedures will be completed. 
• Patient provides informed consent before any study procedures 
• Patient is enrolled and assigned an E-code  
• Demography (including smoking status), medical history, concomitant medication will be 
recorded 
• Vital signs (temperature, BP, pulse, O2 SAT, and body weight) and height will be 
recorded 
• Laboratory samples will be collected and sent to site laboratory (hemoglobin, glucose, 
renal panel (creatinine, BUN, electrolytes, bicarbonate), NT-proBNP, hs troponin, 
D-dimer, CBC (RBC, WBC with differential, PLTs), LDH, ALT, AST, CRP, and total 
bilirubin) 
• An oropharyngeal or nasopharyngeal swab will be collected and sent to the local site 
laboratory 
• Local pregnancy test (female patients of child bearing potential only) 
• The Investigator reviews the inclusion and exclusion criteria. Patients who do not meet 
these criteria must not be randomized in the study 
 
Patients can be re-screened one more time if they do not fully meet the eligibility criteria 
during their first screen. Patients who do not meet the inclusion/exclusion criteria must not be 
randomized in the study. Screening should take no more than 2 days. 
Procedures conducted as part of the patient’s routine clinical management and obtained before 
signing of the ICF may be used for screening or baseline purposes (eg, chest radiography or 
CT scan), provided the procedures meet the protocol-specified criteria and were performed 
within the time frame defined in the inclusion/exclusion criteria. 
Procedures will be performed according to the Study Plan (Table 1).  
4.2 
Treatment Period (Day 1 to Day 30) 
Eligible patients will be randomized to start treatment with either dapagliflozin 10 mg or 
placebo daily (double-blind) as soon as possible. 
Investigational product will be administered for 30 days, with follow-up assessments every 
24 hours until either hospital discharge, Day 30, or death.  


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The following assessments will be completed. 
• Concomitant medications at time points defined in the study plan in Table 1 
• Vital signs (temperature, BP, pulse, O2 SAT) at time points defined in the study plan in 
Table 1 
• Site laboratory assessments: 
(a) Renal panel (creatinine, BUN, electrolytes, bicarbonate), NT-proBNP, hs troponin, 
D-dimer, CBC (RBC, WBC with differential, PLTs), LDH, ALT and AST, CRP and 
total bilirubin at time points defined in the study plan in Table 1. 
(b) Expected standard of care basic metabolic panel (sodium, potassium, bicarbonate, 
anion gap, BUN, creatinine, glucose), and/or other acid-base monitoring per local 
standard for care to detect early change in bicarbonate levels and anion gap in 
diabetes patients (may also include blood gas analysis, as applicable). A venous or 
arterial blood gas analysis for pH, as well as blood levels of ketones 
(beta-hydroxybutyrate), and lactate should be investigated if DKA is suspected. This 
is performed at time points defined in the study plan in Table 1 
• An oropharyngeal or nasopharyngeal swab at time points defined in the study plan in 
Table 1 
• If the patient has experienced any potential endpoints: death, SAEs, developed 
new/worsened organ dysfunction (defined in Section 5.1) since the previous day (at time 
points defined in the study plan in Table 1) 
• A NEWS 2 assessment will be completed at time points defined in the study plan in Table 
1 
• Patient Clinical Status will be assessed using a 7-point scale (defined in Section 5.1) at 
time points defined in the study plan in Table 1 
 
4.3 
Follow-up Period after Hospital Discharge 
Patients discharged from hospital will continue with daily treatment for the remainder of the 
30 days, and are followed up by telephone at Day 15 and/or Day 30 (± 3 days). 
The following assessments will be completed: 
• Concomitant medications will be recorded 
• Follow up of ongoing reportable SAEs. Details of any new reportable SAEs will be 
recorded. 
• Vital status  
• Investigational product adherence 


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• Details of any re-hospitalization for the patient 
• Patient Clinical Status will be assessed using a 7-point scale (defined in Section 5.1) 
 
4.4 
Extended Follow-up Period after Day 30 
Following last dose of investigational product at Day 30, patients are followed up by 
telephone at Day 60 and Day 90 (± 7 days).  
The following assessments will be completed: 
• Concomitant medications will be recorded 
• Follow up of ongoing reportable SAEs. Details of any new reportable SAEs will be 
recorded. 
• Vital status  
• Details of any re-hospitalization for the patient 
• Patient Clinical Status will be assessed using a 7-point scale (defined in Section 5.1) 
 
5 
STUDY ASSESSMENTS 
The Investigator will ensure that data are recorded on the eCRFs as specified in the study 
protocol and in accordance with the instructions provided. If the eCRFs are not fully 
operational in time for patients being screened and enrolled, paper-based patient 
documentation will be used initially and data will be transferred into electronic systems when 
available. 
The Investigator ensures the accuracy, completeness, legibility, and timeliness of the data 
recorded and of the provision of answers to data queries according to the Research Agreement. 
The Investigator will sign the completed eCRFs. A copy of the completed eCRFs will be 
archived at the study site. 
5.1 
Efficacy Assessments 
5.1.1 
Primary Endpoint Events 
Endpoint events of death from any cause or developed new/worsened organ dysfunction 
through 30 days of follow up, defined as at least one of the items listed below, are identified 
from information received through review of medical records and laboratory data (see Table 1 
for timings).  


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• Respiratory decompensation requiring initiation of mechanical ventilationa (includes 
invasive or non-invasive ventilation, CPAP, or BiPAP), and/or initiation of ECMO 
• New or worsening congestive HF during current hospitalization 
• Requirement for vasopressor therapy and/or inotropic or mechanical circulatory support 
• Ventricular tachycardia or fibrillation lasting at least 30 seconds and/or associated with 
hemodynamic instability or pulseless electrical activity, or resuscitated cardiac arrest 
• Doubling of s-Creatinine or initiation of renal replacement therapya 
a 
Duration of mechanical ventilation and renal replacement therapy events will be collected. 
 
The hierarchical composite endpoint includes all the outcomes defined above. In addition, it 
includes the outcome of hospital discharge as well as any clinical status change in patients 
who are still hospitalized at Day 30 and did not experience any of the events described above. 
Clinical status change will be used as collected in Section 5.1.4 (points 3 to 5). 
5.1.2 
Time to Event Endpoints  
A number of efficacy endpoints, listed below, relate to the timing of an event. Patients are 
reviewed daily for the occurrence of each of these events. The date and time (24 hr) (time if 
known) of the event will be recorded. 
• Death from any cause 
• Hospital discharge 
• Composite kidney endpoint, defined as composite of acute kidney injury or initiation of 
renal replacement therapy, or death from any cause through Day 30 (See Section 2.2 for 
the definitions of acute kidney injury and renal replacement therapy) 
 
5.1.3 
National Early Warning Score 2 
The NEWS 2 can be used on all hospitalized patients to allow for the early detection of 
clinical deterioration and potential need for higher level of care. It determines the degree of 
illness of a patient and prompts critical care intervention. Patients with low NEWS 2 can 
continue receiving their usual care and observation. Patients with high NEWS 2 should be 
watched more attentively and considered for transfer to a higher care unit such as an ICU. 
A NEWS 2 assessment is recorded as specified in the Study Plan (Table 1). 
5.1.4 
Patient Clinical Status 
A 7-point scale is recorded as specified in the Study Plan (Table 1) to assess the clinical status 
of the patient: 


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1 
Not hospitalized, no limitations on activities 
2 
Not hospitalized, limitation on activities 
3 
Hospitalized, not requiring supplemental oxygen 
4 
Hospitalized, requiring supplemental oxygen 
5 
Hospitalized, on high flow oxygen devices 
6 
Hospitalized, on invasive mechanical ventilation or ECMO 
7 
Death 
 
5.1.5 
Laboratory Assessments 
Blood samples for determination of clinical chemistry and hematology, will be taken at the 
times indicated in the study plan (Table 1), if not already available as standard of care. 
The clinical chemistry and hematology will be performed at a local laboratory at or near to the 
Investigator site. Sample tubes and sample sizes may vary depending on laboratory method 
used and routine practice at the site. 
Table 2 
Laboratory Variables 
Hematology/hemostasis (whole blood) 
Clinical chemistry (serum or plasma) 
B-Hemoglobin (Hb) 
S/P-Creatininea 
B-Leukocyte count 
S/P-Bilirubin, total 
B-Leukocyte differential count (absolute count)—
Lymphocyte counta 
S/P-Aspartate transaminase (AST) 
B-Platelet count 
S/P-Alanine transaminase (ALT)a 
B-Hematocrit 
S/P-Blood urea nitrogen (BUN) or urea 
S/P-Bicarbonate 
S/P-Electrolytes 
S/P-Sodium 
 
S/P-Potassium 
 
S/P Glucose 
 
S/P CRPa 
 
S/P LDHa 
 
S/P NT-proBNPa 
S/P hs troponina 
P D-dimera 
 
Arterial/venous Blood gas 
 
Arterial/venous Anion gap 


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a 
Outcome measure and recorded in the eCRF 
CRP C-reactive protein; eCRF Electronic case report form; hs troponin High-sensitivity cardiac troponin, LDH 
lactate dehydrogenase; NT-proBNP N-terminal-pro B-type natriuretic peptide; P Plasma; S Serum. 
 
For calculation of eGFR using the CKD-EPI equation (Levey et al 2009): 
 
GFR=141x min(Scr/κ, 1)α x max(Scr/κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if 
black] 
 
Where: 
 
Scr is serum creatinine in mg/dL, 
 
κ is 0.7 for females and 0.9 for males, 
 
α is -0.329 for females and -0.411 for males, 
 
 min indicates the minimum of Scr/κ or 1, and 
 
 max indicates the maximum of Scr/κ or 1  
 
The equation does not require weight because the results are reported normalized to 1.73 m² 
body surface area, which is an accepted average adult surface area. 
The laboratory results should be signed and dated and retained at centre as source data for 
laboratory variables. 
5.2 
Safety Assessments 
All safety assessments in this section should be recorded daily approximately between 06:00 
and 08:00 in the morning. 
5.2.1 
Physical Examination (not applicable) 
There will be no physical examination performed in order to minimize the risk of exposure to 
the study personnel.  
5.2.2 
Vital Signs 
Vital signs (temperature, BP, pulse, O2 SAT) will be recorded daily according to the study 
plan (Table 1). 
5.2.3 
Adverse Events 
Occurrences of reportable SAEs, AEs leading to investigational product discontinuation 
(DAEs), and safety events of acute kidney injury (defined as an episode of doubling 
s-Creatinine compared to baseline during index hospitalization, or an SAE with the preferred 


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term of acute kidney injury following discharge and through Day 30) and DKA (as presented 
in Section 1.3.2.1), will be recorded by the study sites. Routine AEs will not be collected. See 
Section 6 for additional details of safety reporting. 
6 
SAFETY REPORTING AND MEDICAL MANAGEMENT 
The PI is responsible for ensuring that all staff involved in the study are familiar with the 
content of this section. 
6.1 
Definition of Adverse Events 
An AE is the development of an undesirable medical condition or the deterioration of a 
pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product. An undesirable medical condition 
can be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver) or the 
abnormal results of an investigation (eg, laboratory findings, electrocardiogram). In clinical 
studies, an AE can include an undesirable medical condition occurring at any time, including 
run-in or washout periods, even if no study treatment has been administered. 
The term AE is used to include both serious and non-serious AEs. 
6.2 
Definitions of Serious Adverse Event 
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, 
follow-up), that fulfils one or more of the following criteria: 
• Results in death 
• Is immediately life-threatening 
• Requires in-patient hospitalization or prolongation of existing hospitalization  
• Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions 
• Is a congenital abnormality or birth defect 
• Is an important medical event that may jeopardise the subject or may require medical 
intervention to prevent one of the outcomes listed above. 
 
Adverse events for malignant tumors reported during a study should generally be assessed as 
SAEs. If no other seriousness criteria apply, the ‘Important Medical Event’ criterion should be 
used. In certain situations, however, medical judgement on an individual event basis should be 
applied to clarify that the malignant tumor event should be assessed and reported as a 
non-serious AE. For example, if the tumor is included as medical history and progression 


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occurs during the study, but the progression does not change treatment and/or prognosis of the 
malignant tumor, the AE may not fulfill the attributes for being assessed as Serious, although 
reporting of the progression of the malignant tumor as an AE is valid and should occur. Also, 
some types of malignant tumors, which do not spread remotely after a routine treatment that 
does not require hospitalization, may be assessed as non-serious; examples include Stage 1 
basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy. 
The causality of SAEs (their relationship to all study treatment/procedures) will be assessed 
by the Investigator(s) and communicated to the Sponsor. 
For further guidance on the definition of an SAE, see Appendix A Additional Safety 
Information.  
6.3 
Definition of Suspected Unexpected Serious Adverse Event 
A suspected adverse reaction related to an investigational product that is both unexpected and 
serious. 
6.4 
Recording of Adverse Events 
Occurrences of reportable SAEs, DAEs and safety events of acute kidney injury and DKA, 
will be recorded on a daily basis during index hospitalization and at Discharge, as well as 
during pre-specified post-discharge phone follow up visits. 
6.4.1 
Disease Progression 
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the investigational product is being studied. It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease. 
Worsening of the patient’s condition that is directly attributable to the COVID-19 disease and 
which occurs during the original (index) hospitalization, is not considered an SAE and must 
not be reported as such unless it is a fatal event (a fatal event should always be reported as a 
an SAE). 
If the SAE occurs after the discharge from the primary (index) admission (during the 
follow-up period or re-admission), all events that fit the SAE criteria must be reported as such, 
regardless if they are directly attributable to the COVID-19 or not. 
6.4.2 
Definition of Reportable Events 
Reportable SAEs are all events leading to death and non-fatal SAEs that are not due to 
worsening of the patient’s condition directly attributable to COVID-19 during the index 
hospitalization. All SAEs occurring after discharge from the index hospitalization are 


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reportable SAEs. 
All DAEs (for patients receiving investigational product) and key safety events will be 
reported regardless of whether they fulfill the SAE criteria, are directly attributable to the 
COVID-19 disease, or whether they occur during index hospitalization or after discharge.  
6.4.3 
Time Period for Collection of Adverse Events 
Events fulfilling the reportable SAE criteria, DAEs (for patients receiving investigational 
product), and/or key safety events will be collected from time of informed consent through 
Day 30. In addition, following the 30-day treatment period, all SAEs will continue to be 
collected through Day 90 (which includes the extended observational follow-up period of an 
additional 60 days). 
6.4.4 
Follow-up of Unresolved Adverse Events 
Any AEs that are unresolved at Day 90 in the study are followed up by the Investigator for as 
long as medically indicated, but without further recording in the CRF. The Sponsor or delegate 
retains the right to request additional information for any patient with ongoing reportable 
AE(s)/SAE(s) at the end of the study, if judged necessary. 
6.4.5 
Variables  
The following variables will be collected for each reportable event (see Section 6.4.2 for the 
definition of reportable event) assessed in the study; 
• AE (verbatim) 
• The date when the AE started and stopped 
• Maximum intensity or intensity: 
1 
mild (awareness of sign or symptom, but easily tolerated) 
2 
moderate (disturbing but still tolerable) 
3 
severe (intolerable) 
• Investigator causality rating against the investigational product (yes or no) 
• Action taken with regard to investigational product 
• Outcome. 
 
In addition, the following variables will be collected for reportable SAEs: 
• Date AE met criteria for SAE 
• Date Investigator became aware of SAE 
• AE is serious due to 


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• Date of hospitalization 
• Date of discharge 
• Probable cause of death 
• Date of death 
• Autopsy performed 
• Causality assessment in relation to study procedure(s)  
• Description of SAE. 
 
It is important to distinguish between SAEs and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria in Section 6.2. An AE of severe intensity need 
not necessarily be considered serious. For example, nausea that persists for several hours may 
be considered severe nausea, but not a SAE unless it meets the criteria shown in Section 6.2. 
On the other hand, a stroke that results in only a limited degree of disability may be 
considered a mild stroke but would be a SAE when it satisfies the criteria shown in Section 
6.2. 
6.4.6 
Causality Collection 
The Investigator will assess causal relationship between investigational product and each AE, 
and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility 
that the event may have been caused by the investigational product?’ 
For SAEs causal relationship will also be assessed for other medication and study procedures. 
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’. 
A guide to the interpretation of the causality question is found in Appendix A Additional 
Safety Information to the Clinical Study Protocol. 
6.4.7 
Adverse Events Based on Signs and Symptoms 
All reportable SAEs, key safety events, and DAEs spontaneously reported by the patient or 
care provider or reported in response to the open question from the study personnel: ‘Have 
you had any health problems since the previous day/you were last asked?’, or revealed by 
observation will be collected and recorded in the CRF. When collecting reportable AEs, the 
recording of diagnoses is preferred (when possible) to recording a list of signs and symptoms. 
However, if a diagnosis is known and there are other signs or symptoms that are not generally 
part of the diagnosis, the diagnosis and each sign or symptom will be recorded separately. 
See Section 6.4.1 for the reporting of COVID-19-related signs and symptoms. 


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6.4.8 
Adverse Events Based on Examinations and Tests 
The results from protocol-mandated laboratory tests and vital signs will be summarized in the 
clinical study report. Deterioration as compared to baseline in protocol-mandated laboratory 
values and vital signs should only be reported as AEs if they fulfill the criteria for reportable 
SAEs, DAEs, or key safety events (see Section 6.4.2).  
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported if it fulfills the criteria for a reportable SAE, DAE, 
and/or key safety event, and the associated laboratory result/vital sign will be considered as 
additional information. Wherever possible the reporting Investigator uses the clinical, rather 
than the laboratory term (eg, anemia versus low haemoglobin value). In the absence of clinical 
signs or symptoms, clinically relevant deteriorations in non-mandated parameters should be 
reported if they fulfill the criteria for a reportable SAE, DAE, and/or key safety event. 
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE unless it fulfills the definition of a reportable SAE, DAE, 
and/or key safety event. 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported if it fulfills the criteria of a 
reportable SAE, DAE, and/or key safety event. 
6.5 
Reporting of Serious Adverse Events to the IRB/IEC and/or the 
Regulatory Authority 
Section 5.6 of the Investigator’s Brochure serves as the Reference Safety Information for this 
study.  
All reportable SAEs have to be reported, whether or not considered causally related to the 
investigational product. The Sponsor representative is responsible for informing the IRB/IEC 
and/or the Regulatory Authority of the SAE as per local requirements. 
If any reportable SAE occurs in the course of the study, then Investigators or other site 
personnel inform the appropriate Sponsor representatives within one day i.e., immediately but 
no later than 24 hours of when he or she becomes aware of it. 
The designated Sponsor representative works with the Investigator to ensure that all the 
necessary information is provided to the database within one calendar day of initial receipt 
for fatal and life-threatening events and within 5 calendar days of initial receipt for all other 
reportable SAEs. 


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For fatal or life-threatening reportable SAEs where important or relevant information is 
missing, active follow-up is undertaken immediately. Investigators or other site personnel 
inform Sponsor representatives of any follow-up information on a previously reported SAE 
within one calendar day ie, immediately but no later than 24 hours of when he or she 
becomes aware of it. 
The reference document for definition of expectedness/listedness is the Investigator’s 
Brochure for dapagliflozin. 
Sponsor and other site personnel must inform the FDA, via a MedWatch/AdEERs form, of 
any serious or unexpected AEs that occur in accordance with the reporting obligations of 
21 CFR 312.32. It is the responsibility of the Sponsor to compile all necessary information 
and ensure that the FDA receives a report according to the FDA reporting requirement 
timelines. 
 reporting information:  
via email: 
  
via Fax (US Fax number: 
; UK and EU Fax Number: 
). Refer 
to the Study Contact List for additional country fax numbers. 
6.6 
 Reporting of Serious Adverse Events to Company 
Investigators or other site personnel inform Sponsor representatives of the reportable SAE. 
The Sponsor is responsible for informing
 of the SAE. All reportable SAEs have 
to be reported to 
 whether or not considered causally related to the investigational 
product.  
Reportable SAEs related to the investigational product must be provided to 
 on an 
ongoing basis as individual case reports.  
Reportable SAEs unrelated to the investigational product must be provided to
 as 
individual case reports on an ongoing basis. 
At the end of the study a final unblinded summary line listing of all reportable SAEs notified 
to the regulatory authority and/or 
 during the study, must be provided to 
 to enable reconciliation of safety information held 
 for its product(s). 
Send SAE reports (individual case reports and line listings) and accompanying cover page to 
  
SAEs that do not require expedited reporting to the Regulatory Authority/IRB/IEC still need 
to be reported to 
as individual case reports on an ongoing basis. 


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Suspected Unexpected Serious Adverse Reactions must be reported to
at the 
same time these events are notified to the Regulatory Authority. 
may request that the Sponsor either provide a copy of the randomization code/ 
code break information or unblind those SAEs which require expedited reporting. 
6.7 
Overdose 
Dapagliflozin has been well tolerated at doses of up to 500 mg/day in single dose testing in 
healthy volunteers and up to 100 mg/day in repeat dose testing for 14 days in healthy 
volunteers and patients with T2DM. For further information, refer to the Investigator’s 
Brochure. If an overdose is suspected, monitoring of vital functions as well as treatment 
should be performed as appropriate. 
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.5. 
6.8 
Pregnancy 
Pregnancies and outcomes of pregnancy in patients that are participating in this study should 
be reported to Sponsor and 
. 
6.8.1 
Maternal Exposure 
If a patient becomes pregnant during the course of the study investigational product should be 
discontinued immediately. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital abnormalities/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs.  
If pregnancy occurs in a study subject during the course of the study, then the Investigator or 
other site personnel informs the Sponsor within one day ie, immediately but no later than 24 
hours of when he or she becomes aware of it. 
The designated Sponsor representative works with the Investigator to ensure that all relevant 
information is provided to the Sponsor data entry site within 1 or 5 calendar days for SAEs 
(see Section 6.5) and within 30 days for all other pregnancies in study subjects. 
6.9 
Study Governance and Oversight 
6.9.1 
Executive Committee 
Together with the Sponsor, the Executive Committee will be responsible for the final overall 
study design, including the development of the study protocol and eCRF, supervision of the 


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study conduct and progress, development of any protocol amendments needed during the 
study, liaison with the IDSMC as needed, development of the SAP, interpretation of the final 
data and reporting (presentations at international congresses and publications in peer reviewed 
journals) of the study. The Executive Committee will make final decisions with regard to early 
stopping or modifications of the study based on the information received from the IDSMC. 
The Executive Committee will be comprised of the overall study PI (Chair), designated 
international academic leaders, and non-voting members of 
 and will operate 
under an Executive Committee Charter.  
6.9.2 
Independent Data and Safety Monitoring Committee 
The IDSMC is the independent data and safety monitoring group for the study, operating 
under an IDSMC charter. It is an external expert group which, on a regular basis, reviews 
accumulating study data, evaluates the treatments for excess adverse effects, determines 
whether the basic study assumptions remain valid, judges whether the overall integrity and 
conduct of the study remain acceptable, and makes recommendations to the Executive 
Committee. The IDSMC will carry out an interim analysis of safety on the first 100 patients 
who complete the 30-day treatment period in the study. 
6.9.3 
Scientific Advisory Committee (not applicable) 
There will be no Scientific Advisory Committee for the study. 
7 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS 
7.1 
Identity of Investigational Product(s) 
Table 3 
Investigational Product 
Investigational product 
Dosage form and strength 
Manufacturer 
Dapagliflozin 10 mg 
Green, plain, diamond shaped, 
film coated tablets 10 mg 
 
Matching placebo for 
dapagliflozin 10 mg 
Green, plain, diamond shaped, 
film coated tablets placebo 
 
 
Dapagliflozin and its matching placebo tablets will be packed in bottles. The tablets may 
contain lactose, which may cause discomfort in lactose-intolerant individuals. 
7.2 
Dose and Treatment Regimens 
At randomization (Day 1), eligible patients will be randomly assigned to 1 of 2 treatments: 
• Dapagliflozin 10 mg, given once daily per oral use 


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• Placebo—one tablet to match dapagliflozin 10 mg, given once daily per oral use 
 
The investigational product should be taken as soon as possible after randomization and then 
once daily in the morning, at approximately the same time every day, during the treatment 
period of 30 days. If the patient, for any reason is not administered the investigational product 
in the morning, any other time point during the day may be applied, provided the 
investigational product is routinely administered in approximately 24-hour intervals. For 
patients requiring a mechanical ventilator, the tablet will be crushed and flushed with water 
down the patient’s nasogastric (or orogastric) tube. The tube will then be rinsed with water to 
ensure all the tablet has been consumed.  
7.3 
Labeling 
Labels will be prepared in accordance with GMP and local regulatory guidelines. The labels 
will fulfill GMP Annex 13 requirements for labeling. Label text will be translated into local 
language. 
7.4 
Storage 
All investigational product should be kept in a secure place under appropriate storage 
conditions. The investigational product label on the bottle specifies the appropriate storage 
conditions. 
7.5 
Compliance 
The administration of all investigational products should be recorded in the appropriate 
sections of the eCRF. 
7.6 
Accountability 
The investigational product provided for this study will be used only as directed in the study 
protocol. The study personnel will account for all investigational products dispensed to the 
patients. 
Any investigational product deliberately or accidentally destroyed must be recorded.   
For studies where investigational product is destroyed at site: study site personnel, will 
account for all investigational product received at the site, unused investigational product, and 
for appropriate destruction. Certificates of delivery, destruction, and return should be signed. 
7.7 
Concomitant and Other Treatments 
All patients will be treated according to local guidelines on standard of care treatment for 
patients with COVID-19 and existing co-morbidities (including treatment for hypertension, 


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ischemic heart disease, atrial fibrillation, diabetes, hyperlipidemia), and recorded in the CRF. 
There are no restricted medications and compassionate use of experimental medications is 
permitted. However, concomitant treatment with open label SGLT2i (eg, dapagliflozin, 
empagliflozin, canagliflozin, ertugliflozin, tofogliflozin and luseogliflozin and fixed-dose 
combinations containing these drugs), is prohibited.  
Background medications should be part of clinical practice and will not be provided by the 
Sponsor. 
7.7.1 
Other Concomitant Treatment 
Medication other than that described above, which is considered necessary for the patient’s 
safety and well-being, may be given at the discretion of the Investigator and recorded in the 
appropriate sections of the CRF. 
7.8 
Post-study Access to Study Treatment 
Patients will receive their last dose of investigational product on Day 30. Post-study treatment 
will not be provided by the Sponsor. Patients should receive standard of care therapy after 
Day 30, at the discretion of the Investigator. 
8 
STATISTICAL ANALYSES  
8.1 
Statistical Considerations 
All personnel involved with the analysis of the study will remain blinded until the 30-day 
database lock and protocol violations have been identified and documented. 
A comprehensive SAP will be developed
 and reviewed by the Sponsor prior to 
first patient randomized. Any subsequent amendments will be documented, with final 
amendments completed prior to unblinding of the data. 
The analysis will be performed by the Sponsor or its representative, and the results of the key 
study outcome will be independently validated by an
 biometrics team. 
All analyses described in Sections 8.5.1 to 8.5.6 will be carried out on data collected up to and 
including Day 30. As soon as the pre-planned number of patients have completed their 30-day 
treatment period, the database will be locked and unblinding performed for these analyses. 
After that, data collected on patients ongoing in the 60-day observational follow-up period 
will be unblinded. 
8.2 
Sample Size Estimate 
The primary objectives of the study are to determine the superiority of dapagliflozin versus 


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placebo in reducing the incidence of complications or all-cause mortality (prevention of 
worsening COVID-19) or improving clinical recovery. It is estimated that a sample size of 
approximately 1200 patients will provide adequate power to detect the treatment effect on 
prevention or recovery, when the dual endpoints are tested with alpha split between these 
endpoints.  
Since the original protocol was designed, the unpredictable nature of the evolving global 
pandemic and the change in standard of care for treatment of COVID-19 resulted in lower 
than expected event rates. As a consequence, faster and more complete recovery has now 
become an important treatment goal on par with prevention of complications and death in 
patients hospitalized with COVID-19, prompting the addition of ‘recovery’ to the primary 
objectives.  
The initial version of the protocol (CSP version 1.0, 10 April 2020) specified an event-driven 
approach with 380 events needed to detect HR of 0.75 with 80% power. In a fixed follow-up 
study that would have required 42% of initially randomized 900 patients to experience an 
event. The provision for a potential increase of sample size was included in the initial design 
and intended as a way of balancing the possible decrease in event rates, while the recruitment 
rate of 900 patients was anticipated to occur over a period of approximately 3 months. It is 
now estimated that around 10 to 20% of patients will develop COVID-19 related 
complications during the index hospitalization or will experience death during the 30-day 
treatment period, while 80 to 90% of patients will recover without experiencing worsening. 
Therefore, the sample size of approximately 1200 patients will provide approximately 100 to 
250 events for the first dual primary endpoint (prevention). 
With dual primary endpoints of prevention of COVID-19 complications or death and 
improvement in clinical recovery, an effect on any one will be sufficient evidence of the 
effectiveness of study medication. This is per the FDA guidance on Multiple Endpoints in 
Clinical Trials (FDA 2017). To control the type I error for dual primary endpoints, the 
allocated alpha of 5% will be split between them. Table 4 below shows the true hazard ratio 
required for 80% power for a hypothetical scenario of an even split of alpha (2.5% two-sided 
for each primary endpoint) depending on the number of events observed. Since no prior 
studies are available for SGLT2 inhibitors in the COVID-19 setting, possible scenarios of 
event rates and treatment effects are considered to infer the sample size (Table 4). 
Table 4 
2.5% Alpha (80% Power, Time-to-event Analysis) 
Number of Events 
Hazard Ratio (Dapagliflozin 
versus Placebo) required for 
80% power 
Minimal Detectable Hazard 
Ratio 
100 
0.54 
0.64 


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Table 4 
2.5% Alpha (80% Power, Time-to-event Analysis) 
Number of Events 
Hazard Ratio (Dapagliflozin 
versus Placebo) required for 
80% power 
Minimal Detectable Hazard 
Ratio 
150 
0.6 
0.69 
200 
0.65 
0.73 
250 
0.68 
0.75 
 
For the second dual primary endpoint (recovery) the sample size of 1200 patients will detect a 
win ratio (WR) of 1.23 with at least 80% power for hypothetical alpha of 2.5% (The power is 
calculated based on asymptotic normality property of the win proportion [WP] where 
WR = WP/[1-WP] and the estimated standard deviation (SD) for the WP is assumed to be 
SD = 1/sqrt[3] = 0.57735 [Kawaguchi et al 2011], as it is a conservative estimate.) This is 
based on an overall 1:1 allocation between dapagliflozin and placebo.  
Study-wise (overall) type I error multiplicity control strategy and the final allocation of alpha 
will be specified in the SAP, which will be finalized before database lock. 
8.3 
Definitions of Analysis Sets 
8.3.1 
Full Analysis Set 
All patients who have been randomized to study treatment will be included in the FAS 
irrespective of their protocol adherence and continued participation in the study. Patients will 
be analyzed according to their randomized investigational product assignment, irrespective of 
the treatment actually received. The FAS will be considered the primary analysis set for the 
primary, secondary, and exploratory efficacy variables. 
8.3.2 
Safety Analysis Set 
All patients who received at least 1 dose of randomized treatment will be included in the 
safety population. Patients will be analyzed according to the treatment actually received. The 
Safety analysis set will be considered the primary analysis set for all safety variables. 
8.4 
Outcome Measures for Analyses 
8.4.1 
Primary Outcome Measures 
The primary outcome measures are detailed in Section 2.1. 
8.4.2 
 Secondary Outcome Measure 
The secondary outcome measures are detailed in Section 2.2. 


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8.4.3 
Safety Outcome Measure 
The safety outcome measures are detailed in Section 2.3. 
8.4.4 
Exploratory Outcome Measure 
The exploratory outcome measures are detailed in Section 2.4. 
8.5 
Methods for Statistical Analyses 
For the primary endpoints the following 2 hypotheses will be tested with alpha allocated to 
each hypothesis to maintain an overall 5% 2-sided significance level: 
Prevention 
H0:HR [dapagliflozin:placebo] = 1 
versus  
H1:HR [dapagliflozin:placebo] ≠ 1 
Recovery 
H0:WR [dapagliflozin:placebo] = 1 
versus  
H1:WR [dapagliflozin:placebo] ≠ 1 
A strong type 1 error control rate will be applied in testing the primary and secondary efficacy 
endpoints. Details of the multiplicity plan, including allocation of alpha between the dual 
primary hypotheses, will be provided in the SAP. 
8.5.1 
Analysis of the Primary Variable(s) 
The first primary variable is the time to first event included in the primary composite 
endpoint.  
In this analysis treatments (dapagliflozin versus placebo) will be compared using a Cox 
proportional hazards model. The p-value, HR, and 95% confidence interval will be reported. 
The full details of the analysis model will be specified in the SAP. 
The contribution of each component of the primary composite endpoint to the overall 
treatment effect will be examined. Methods similar to those described for the primary analysis 
will be used to separately analyze the time from randomization to the first occurrence of each 
component of the primary composite endpoint. HR and 95% confidence intervals will be 


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reported. Kaplan-Meier estimates of the cumulative incidence to the first occurrence of any 
event in the primary endpoint will be calculated and plotted. 
The second primary variable is a hierarchical composite endpoint. In this analysis treatments 
(dapagliflozin versus placebo) will be compared using WR analysis methods. The p-value, 
WR, and 95% confidence interval will be reported. Contribution of each component will be 
reported as well. 
The primary analyses will be based on the intent-to treat principle using the FAS. The full 
details of the analyses methods will be specified in the SAP. 
8.5.2 
Analysis of the Secondary Variable(s) 
The secondary variables will be analyzed as specified in the SAP. 
8.5.3 
Subgroup Analysis  
Subgroup variables will include demography, baseline disease characteristics, and others. 
Subgroup analysis will be performed for both dual primary endpoints to examine treatment 
effects within relevant subgroups separately. The p-values for the subgroup analyses will not 
be adjusted for multiple comparisons as the tests are exploratory and will be interpreted 
descriptively.  
Treatment differences with 95% confidence intervals will be reported for each subgroup. HRs, 
WRs, and confidence intervals for overall analysis and subgroups will be presented with forest 
plots as well. Further details of the subgroup analysis, including the efficacy endpoints and the 
list of subgroup variables, will be provided in the SAP. 
8.5.4 
Interim Analysis 
Interim analysis for safety only will be performed by the IDSMC after the first 100 patients 
have completed the 30-day treatment period; no interim efficacy analyses are planned.  
8.5.5 
Sensitivity Analysis  
Details of the sensitivity analysis will be provided in the SAP. 
8.5.6 
Exploratory Analysis  
The exploratory variables will be analyzed as specified in the SAP. 
8.5.7 
Analysis of the Observational Data 
These analyses will be detailed in the SAP. 


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9 
STUDY AND DATA MANAGEMENT 
9.1 
Training of Study Site Personnel 
Before the first patient is entered into the study, a Sponsor representative will review and 
discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and train them in any study specific procedures and system(s) utilized. 
Training will conducted via Skype or another telecommunications application. 
The PI in each country will ensure that appropriate training relevant to the study is given to all 
of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved. 
The PI will maintain a record of all individuals involved in the study (medical, nursing and 
other staff). 
9.2 
Monitoring of the Study 
During the study, a Sponsor representative will have regular contacts with the study sites to: 
• Provide information and support to the Investigator(s) 
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the CRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks are 
being performed 
• As a part of the data collection process, the eCRF platform will have the ability for SDV 
to be performed remotely, obviating the need for onsite SDV. 
 
The Sponsor representative will be available at any time if the Investigator(s) or other staff at 
the site needs information and advice about the study conduct. 
9.2.1 
Source Data 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. Refer to the Research Agreement for location of source data. 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the Investigator for 15 years after study completion unless local regulations or 


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institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the Sponsor. No records may be transferred to 
another location or party without written notification to the Sponsor. 
9.2.2 
Research Agreement(s) 
The PIs in each county should comply with all the terms, conditions, and obligations of the 
Research Agreement, or equivalent, for this study. In the event of any inconsistency between 
this Clinical Study Protocol and the Research Agreement, the terms of Clinical Study Protocol 
shall prevail with respect to the conduct of the study and the treatment of subjects and in all 
other respects, not relating to study conduct or treatment of patients, the terms of the Research 
Agreement shall prevail. 
Agreements between the Sponsor and the PIs should be in place before any study-related 
procedures can take place, or patients are enrolled. 
9.2.3 
Archiving of Study Documents 
The Sponsor follows the principles outlined in the Research Agreement. 
9.3 
Study Timetable and End of Study 
The end of the study is defined as ‘the last visit of the last subject undergoing the study’—also 
known as LSLV. 
The study is expected to start in second quarter 2020, with LSLV in the first quarter 2021. 
The study may be terminated at individual centers if the study procedures are not being 
performed according to GCP, or if recruitment is slow. Sponsor may also terminate the entire 
study prematurely if concerns for safety arise within this study or in any other study with 
dapagliflozin. 
9.4 
Data Management 
Data management will be performed by 
 
, according to the Data Management Plan. Adverse events and medical/surgical 
history will be classified according to the terminology of the latest version the Medical 
Dictionary for Regulatory Activities (MedDRA). Medications will be classified according to 
WHO Drug Dictionary. Classification coding will be performed by 
. 
Data Collection Instruments 
Data collection instruments will be used in this study (eg, eCRFs). These instruments are used 
to transmit the information collected during the performance of this study to the Sponsor or 


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Sponsor’s designee and regulatory authorities. The Investigator must review the DCIs for 
completeness and accuracy and must approve all data, including any changes made.  
Furthermore, the Investigator retains full responsibility for the appropriateness and accuracy 
of all data collected in the DCIs. As a part of the data collection process, the eCRF platform 
will have the innate ability for remote SDV to be performed, obviating the need for onsite 
SDV. If the eCRF is not immediately available for logistical reasons, source documentation 
will be used and then the data transferred into the eCRF. 
The eCRF platform is 21 CFR Part 11 compliant, and complies with all applicable regulations, 
including the General Data Protection Regulation. 
Data validation 
Data queries will be raised for inconsistent, impossible or missing data. All entries to the study 
database will be available in an audit trail. 
The data will be validated as defined in the Data Management Plan. Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly. The Data Management Plan will also clarify the roles and 
responsibilities of the various functions and personnel involved in the data management 
process. 
When all data have been coded, validated, signed, and locked, clean file will be declared. Any 
treatment revealing data may thereafter be added and the final database will be locked. 
Serious Adverse Event Reconciliation 
Serious AE reconciliation will be done between the study database and the safety database. 
10 
ETHICAL AND REGULATORY REQUIREMENTS 
10.1 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP and applicable regulatory 
requirements. 
10.2 
Subject Data Protection 
The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy legislation. 
10.3 
Ethics and Regulatory Review 
An IRB or IEC should approve the final study protocol, including the final version of the ICF 


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and any other written information and/or materials to be provided to the patients. The 
Investigator will ensure the distribution of these documents to the applicable IRB/IEC, and to 
the study site staff. 
The opinion of the IRB/IEC should be given in writing. The Investigator should submit the 
written approval to the Sponsor before enrollment of any patient into the study.  
Sponsor should approve any modifications to the ICF that are needed to meet local 
requirements. 
If required by local regulations, the protocol should be re-approved by the IEC annually. 
Before enrolment of any patient into the study, the final study protocol, including the final 
version of the ICF, is approved by the national regulatory authority or a notification to the 
national regulatory authority is done, according to local regulations. 
The Sponsor will handle the distribution of any of these documents to the national regulatory 
authorities. 
Sponsor will provide Regulatory Authorities, IRB/IECs and PIs with safety updates/reports 
according to local requirements. 
For the United States, each PI is responsible for providing the IRB with reports of any serious 
and unexpected adverse drug reactions from any other study conducted with the 
investigational product. The Sponsor or delegate will provide this information to the PI so that 
he/she can meet these reporting requirements. 
10.4 
Informed Consent 
The PI(s) at each site will: 
• Ensure each patient is given full and adequate oral and written information about the 
nature, purpose, possible risk and benefit of the study 
• Ensure each patient is notified that they are free to discontinue from the study at any time 
• Ensure that each patient is given the opportunity to ask questions and allowed time to 
consider the information provided 
• Ensure each patient provides informed consent before conducting any procedure 
specifically for the study 
• Ensure the original, signed ICF(s) is/are stored in the Investigator’s Study File 
• Ensure a copy of the signed ICF is given to the patient 


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• Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described in the 
ICF that is approved by IRB/IEC. 
 
10.5 
Changes to the Protocol and Informed Consent Form 
Study procedures will not be changed without the mutual agreement of the PIs and the 
Sponsor. Any substantial changes to the study protocol will be documented in a study protocol 
amendment and, where required, in a new version of the study protocol (Revised Clinical 
Study Protocol). The amendment is to be approved by the relevant IRB/IEC and if applicable, 
also the national regulatory authority approval, before implementation. Local requirements are 
to be followed for revised protocols. 
Sponsor will distribute any subsequent amendments and new versions of the protocol to each 
PI(s). For distribution to IRB/EC see Section 10.3. 
If a protocol amendment requires a change to a site’s ICF, the Sponsor and the site’s IRB/EC 
are to approve the revised ICF before the revised form is used.  
If local regulations require, any administrative change will be communicated to or approved 
by each IRB/EC. 
10.6 
Audits and Inspections 
Authorized representatives of Sponsor, a regulatory authority, or an IRB/IEC may perform 
audits or inspections at the site, including SDV. The purpose of an audit or inspection is to 
systematically and independently examine all study-related activities and documents, to 
determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, GCP, guidelines of the ICH, and any applicable 
regulatory requirements. The Investigator will notify the Sponsor immediately if contacted by 
a regulatory agency about an inspection at the site. 


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11 
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Centers for Disease Control and Prevention. Severe Outcomes Among Patients with 
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Daniele et al 2016 
Daniele G, Xiong J, Solis-Herrera C, Merovci A, Eldor R, Tripathy D, et al. Dapagliflozin 
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Esterline RL, Vaag A, Oscarsson J, Vora J. MECHANISMS IN ENDOCRINOLOGY: SGLT2 
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Ghanim et al 2020 
Ghanim H, Abuaysheh S, Hejna J, Green K, Batra M, Makdissi A, et al. Dapagliflozin 
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Griffin et al 2020 
Griffin M, Rao VS, Ivey-Miranda J, Fleming J, Mahoney D, Maulion C, et al. Empagliflozin 
in Heart Failure: Diuretic and Cardiorenal Effects. Circulation. 2020;142(11):1028-39. 
Guan et al 2020 
Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al, for the China Medical Treatment 
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Guzik et al 2020 
Guzik TJ, Mohiddin SA, Dimarco A, Patel V, Savvatis K, Marelli-Berg FM, et al. COVID-19 
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Heerspink et al 2020 
Heerspink HJ, Stefansson BV, Correa‑Rotter R, Chertow, GM, Greene T, Hou FF, et al.-
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2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. 
Kang et al 2020 
Kang Y, Chen T, Mui D, Ferrari V, Jagasia D, Scherrer-Crosbie M, et al. Cardiovascular 
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Kawaguchi A, Koch GG, Wang X. Stratified multivariate Mann–Whitney estimators for the 
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Kim et al 2020 
Kim SR, Lee SG, Kim SH, Kim JH, Choi E, Cho W, et al. SGLT2 inhibition modulates 
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Kosiborod M, Gause-Nilsson I, J Xu J, Sonesson C, Johnsson E. Efficacy and safety of 
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Lambers Heerspink HJ, de Zeeuw D, Wie L, Leslie B, List J. Dapagliflozin a glucose-
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Madjid M, Safavi-Naeini P, Solomon SD, Vardeny O. Potential Effects of Coronaviruses on 
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Clinical Study Protocol 
 
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Appendix A Additional Safety Information 
A 1 
Further Guidance on the Definition of a Serious Adverse Event 
A 1.1 
Life Threatening 
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred, or it is suspected that use or continued use of the product would result in the 
subject’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure). 
A 1.2 
Hospitalization 
Outpatient treatment in an emergency room is not in itself a SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal edema). Hospital admissions and/or surgical operations 
planned before or during a study are not considered AEs if the illness or disease existed before 
the subject was enrolled in the study, provided that it did not deteriorate in an unexpected way 
during the study. 
A 1.3 
Important Medical Event or Medical Intervention 
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability or incapacity but may jeopardize the subject or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious. These 
should usually be considered as serious. 
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgment must be used. 
• Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment 
• Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine 
• Intensive treatment in an emergency room or at home for allergic bronchospasm 
• Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalization 
• Development of drug dependency or drug abuse 
 
A 1.4 
A Guide to Interpreting the Causality Question 
When making an assessment of causality consider the following factors when deciding if there 


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is a ‘reasonable possibility’ that an AE may have been caused by the drug. 
• Time Course. Exposure to suspect drug. Has the subject actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug? 
• Consistency with known drug profile. Was the AE consistent with the previous knowledge 
of the suspect drug (pharmacology and toxicology) or drugs of the same pharmacological 
class? Or could the AE be anticipated from its pharmacological properties? 
• De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug? 
• No alternative cause. The AE cannot be reasonably explained by another aetiology such as 
the underlying disease, other drugs, other host or environmental factors. 
• Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? Sponsor would not normally recommend or support a re-challenge. 
• Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship. 
 
In difficult cases, other factors could be considered such as: 
• Is this a recognized feature of overdose of the drug? 
• Is there a known mechanism? 
 
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship. 
The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’. 
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility. 
A 1.5 
Medication Error 
For the purposes of this study, a medication error is an unintended failure or mistake in the 
treatment process for an
 study drug that either causes harm to the participant or 
has the potential to cause harm to the participant. 


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A medication error is not lack of efficacy of the drug, but rather a human- or process-related 
failure while the drug is in control of the study site staff or participant. 

SAP_001.pdf: 
Statistical Analysis Plan  
Study Code D1690C00081 
Edition Number 5.0  
Date 3 March 2021 
 
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Statistical Analysis Plan 
 
Study Code 
D1690C00081 
 
 
 
 
Edition Number 
5.0 
 
Date 
3 March 2021  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Short Title: DARE-19 (Dapagliflozin in Respiratory failure in patients with 
COVID-19) 
 
 
 
 
Based on Clinical Study Protocol, version 4.0, 20 November 2020 
 
 
 
ClinicalTrials.gov Identifier: NCT04350593


Statistical Analysis Plan  
Study Code ESR-20-20653 
Edition Number 5.0  
Date 3 March 2021 
 
CONFIDENTIAL AND PROPRIETARY 
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Short Title: DARE-19 (Dapagliflozin in Respiratory failure in patients with 
COVID-19) 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan  
Study Code ESR-20-20653 
Edition Number 5.0  
Date 3 March 2021 
 
CONFIDENTIAL AND PROPRIETARY 
3 of 59 
 
 
 
 
 
Short Title: DARE-19 (Dapagliflozin in Respiratory failure in patients with 
COVID-19) 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan  
Study Code ESR-20-20653 
Edition Number 5.0  
Date 3 March 2021 
 
CONFIDENTIAL AND PROPRIETARY 
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TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
SIGNATURE OF STUDY STATISTICIAN ............................................................................ 2 
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN ..................................................... 3 
TABLE OF CONTENTS .......................................................................................................... 4 
LIST OF TABLES .................................................................................................................... 6 
LIST OF FIGURES ................................................................................................................... 6 
LIST OF ABBREVIATIONS ................................................................................................... 7 
AMENDMENT HISTORY ....................................................................................................... 9 
1 
STUDY DETAILS ............................................................................................... 14 
1.1 
Study Objectives ................................................................................................... 14 
1.1.1 
Primary Objective ................................................................................................. 14 
1.1.2 
Secondary Objectives ........................................................................................... 15 
1.1.3 
Safety Objectives .................................................................................................. 16 
1.1.4 
Exploratory Objectives ......................................................................................... 16 
1.2 
Definitions ............................................................................................................ 17 
1.2.1 
Study Closure ....................................................................................................... 17 
1.2.2 
Withdrawal of Informed Consent ......................................................................... 17 
1.2.3 
Discontinuation from Study Drug ........................................................................ 17 
1.2.4 
Vital Status............................................................................................................ 18 
1.2.5 
Follow-up Period after Hospital Discharge .......................................................... 18 
1.2.6 
Extended Follow-up Period after Day 30 ............................................................. 18 
1.2.7 
Lost to Follow-up ................................................................................................. 19 
1.3 
Study Design ......................................................................................................... 19 
1.3.1 
Randomization ...................................................................................................... 20 
1.4 
Number of Patients ............................................................................................... 20 
2 
ANALYSIS SETS ................................................................................................ 22 
2.1 
Definition of Analysis Sets ................................................................................... 22 
2.1.1 
Full Analysis Set ................................................................................................... 22 
2.1.2 
Safety Analysis Set ............................................................................................... 22 
2.2 
Violations and Deviations..................................................................................... 22 
3 
PRIMARY AND SECONDARY VARIABLES ................................................. 23 
3.1 
Estimands .............................................................................................................. 23 
3.2 
Primary Variables ................................................................................................. 24 
3.2.1 
Prevention Composite Endpoint ........................................................................... 24 
3.2.2 
Hierarchical Composite Endpoint ........................................................................ 25 
3.3 
Secondary Variables ............................................................................................. 25 
3.3.1 
Composite Kidney Endpoint ................................................................................ 25 


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3.3.2 
Total Number of Days Alive and Free from Mechanical Ventilation .................. 26 
3.3.3 
Total Number of Days Alive, Not in the ICU, and Free from Mechanical 
Ventilation ............................................................................................................ 26 
3.3.4 
Death from Any Cause ......................................................................................... 26 
3.3.5 
Discharge from Hospital ....................................................................................... 27 
3.4 
Safety Variables .................................................................................................... 27 
3.4.1 
Safety Data Restriction Specification ................................................................... 27 
4 
ANALYSIS METHODS ...................................................................................... 27 
4.1 
General Principles ................................................................................................. 27 
4.1.1 
Hypotheses ............................................................................................................ 28 
4.1.2 
Confirmatory Testing Procedure .......................................................................... 29 
4.1.2.1 
Multi-stage fallback procedure ............................................................................. 29 
4.1.2.2 
Significance level allocation for the testing procedure......................................... 30 
4.1.3 
Presentation of Time-to-event Analyses ............................................................... 31 
4.1.4 
Vital Status and Follow-up of the Prevention Endpoint ....................................... 31 
4.2 
Analysis Methods ................................................................................................. 32 
4.2.1 
Demographics and Baseline Characteristics ......................................................... 32 
4.2.2 
Prior, Baseline and Concomitant, Medications .................................................... 32 
4.2.3 
Analysis of Time-to-Event endpoints ................................................................... 33 
4.2.4 
Analysis of the Prevention Primary Composite Endpoint .................................... 33 
4.2.4.1 
Subgroup Analysis of the Prevention Composite Endpoint ................................. 33 
4.2.4.2 
Supplementary Analysis of the Prevention Composite Endpoint......................... 34 
4.2.4.3 
Sensitivity Analysis of the Prevention Composite Endpoint ................................ 36 
4.2.5 
Analysis of the Recovery Primary Endpoint (HCE)............................................. 38 
4.2.5.1 
Clinical interpretation of the recovery HCE (improvement in clinical status) ..... 39 
4.2.5.2 
Derivation of analysis values ................................................................................ 40 
4.2.5.3 
Handling of missing data ...................................................................................... 41 
4.2.5.4 
The primary analysis method  Stratified log-rank test........................................ 41 
4.2.5.5 
Exploratory analyses of the recovery HCE .......................................................... 42 
4.2.6 
Analysis of the Secondary Efficacy Variables ..................................................... 44 
4.2.6.1 
Time-to-Event Endpoints...................................................................................... 44 
4.2.6.2 
Analysis of Total Number of Days ....................................................................... 44 
4.2.7 
Analysis of Safety Variables ................................................................................ 48 
4.2.7.1 
Adverse Events ..................................................................................................... 48 
4.2.7.2 
Serious Adverse Events ........................................................................................ 49 
4.2.7.3 
Safety Events ........................................................................................................ 49 
4.2.7.4 
Laboratory Evaluation .......................................................................................... 49 
4.2.7.5 
Marked Laboratory Abnormalities ....................................................................... 49 
4.2.8 
Analysis of Exploratory Objectives ...................................................................... 50 
5 
INTERIM ANALYSES ........................................................................................ 51 
6 
OBSERVATIONAL PERIOD ............................................................................. 51 
7 
REFERENCES ..................................................................................................... 53 


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8 
APPENDIX .......................................................................................................... 55 
 
 
LIST OF TABLES 
Table 1 - 2.5% Alpha (80% Power, Time-to-event Analysis)................................................. 21 
Table 2 - Multiple testing procedure ....................................................................................... 29 
Table 3 - Characteristics and categories for subgroup analysis of the primary endpoint ........ 34 
Table 4 - Marked abnormality criteria for safety laboratory variables.................................... 50 
 
LIST OF FIGURES 
Figure 1 - Study flow chart ...................................................................................................... 19 
Figure 2 - Multiple testing procedure ...................................................................................... 31 
Figure 3 - Change in clinical status ......................................................................................... 39 
Figure 4 - Total number of days alive and free from MV  outpatient death ......................... 45 
Figure 5 - Total number of days alive and free from MV  death in hospital ......................... 45 
Figure 6 - Total number of days alive and free from MV - WoC ........................................... 46 
Figure 7 - Total number of days alive and free from MV - LTFU .......................................... 46 
 


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LIST OF ABBREVIATIONS 
Abbreviation or 
special term 
Explanation 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BiPAP 
Bilevel positive airway pressure 
CKD-EPI  
Chronic kidney disease epidemiology collaboration equation 
COPD 
Chronic obstructive pulmonary disease 
COVID-19 
Coronavirus disease 2019 
CPAP 
Continuous positive airway pressure 
CSP 
Clinical study protocol 
DAE 
Adverse event leading to treatment discontinuation 
DKA 
Diabetic ketoacidosis 
ECMO 
Extracorporeal membrane oxygenation 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
FAS 
Full analysis set 
HF 
Heart failure 
HR 
Hazard ratio 
hsCRP 
High sensitivity C-reactive protein 
ICF 
Informed consent form 
ICU 
Intensive care unit 
IP 
Investigational Product (dapagliflozin or matching placebo) 
ITT 
Intention-to-treat 
KM 
Kaplan-Meier 
LDH 
Lactate dehydrogenase 
LTFU 
Lost to follow-up 
MedDRA 
Medical Dictionary for Regulatory Activities 
NEWS 2 
National Early Warning Score 2 
NT-proBNP 
N-terminal pro b-type natriuretic peptide 
PCR 
Polymerase chain reaction 
PT 
Preferred term 


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Abbreviation or 
special term 
Explanation 
SAE 
Serious adverse event 
SAS 
Safety analysis set 
SGLT2i 
Sodium-glucose co-transporter 2 inhibitors  
SOC 
System organ class 
T2D 
Type 2 diabetes 
WoC 
Withdrawal of consent 
WR 
Win Ratio
 


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AMENDMENT HISTORY 
Date /Version 
Brief description of change 
14 April 2020 / 
Version 1.0 
Version 1.0 signed 


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1 August 2020 / 
Version 2.0 
The number of sites has been updated to 90, the list of countries has been 
changed as well [section 1.2.1] 
Extended follow-up of 60 days is added in accordance with the CSP updated 
version 3.0 [section 1.2.1] 
1.2.4] 
Recruitment assumption is removed, since it does not have an impact on 
power calculations. Previous version contained estimate of 800 patients 
needed with 900 being randomized. In the current version the estimate of 800 
patients has been removed and only the number 900 is retained. [section 1.4] 
Section on Estimands has been added [section 3.1] 
Censoring rule for the primary endpoint has been added [section 3.2] 
Censoring rule for the discharge from hospital has been modified to censor 
patients who die in hospital not at the time of death but at Day 30 [section 3.2] 
clarified as 
3.3.2] 
The definition of acute kidney injury has been updated to included events 
happening in outpatient setting [section 3.3.1] 
The endpoint of acute kidney injury has been updated to include death as a 
composite measure to account for intercurrent event due to death [section 
3.3.1] 
Updated to state that new/worsened organ dysfunction will not be included in 
the hierarchical testing, but analyzed as a component of the primary endpoint. 
As such repeated details about its derivation were moved to section 3.2 
Events of acute renal failure have been added to safety analysis [section 3.4] 
Clarification of calculation of study drug compliance added. Calculation of 
proportion of patient-days on study drug has been added [section 4.1] 
The fixed-sequence of testing the secondary endpoints has been clarified. 
New/worsened organ dysfunction is removed from the testing hierarchy 
[section 4.1.2] 
Detailed definition of prior, baseline and concomitant medications has been 
added [section 4.2.2] 
Use of proportionality assumption has been clarified and the handling of ties 
has been specified in the Cox regression analysis [section 4.2.3] 
A sensitivity analysis of the primary endpoint is redefined to exclude patients 
who were not tested for SARS-CoV-2 at randomization and tested negative 
when testing became available [section 4.2.4.3] 
Details for the tipping point analysis has been added [section 4.2.4.3] 
Detailed description of analysis methods for the Total Number of Days 
endpoints has been added [section 4.2.6.2] 
Clarification of definitions of time-to-event variables in testing hierarchy has 
been added [section 4.2.6] 
Actual exposure is introduced [section 4.2.7] 


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Date /Version 
Brief description of change 
Section on laboratory evaluations has been added [section 4.2.7.4] 
Marked abnormalities have been defined [section 4.2.7.5] 
 
1 November 2020 / 
Version 3.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Definition of the composite strategy of handling intercurrent events has been 
added [section 3.1] 
A sensitivity analysis has been added to incorporate into primary endpoint 
deaths happening after incomplete in-hospital event assessment [section 3.2] 
Safety Data Restriction Specification has been added to restrict analysis of 
safety objective only to 30-day treatment period [section 3.4.1] 
Clarification for derivation of patient-days with complete follow-up has been 
added [section 4.1.4] 
Sensitivity analysis for the difference in proportions has been added for the 
primary endpoint [section 4.2.4.3] 
Details of the tipping point analysis have been added [section 4.2.4.3] 
Sensitivity analysis for the difference in proportions has been added for the 
time-to-event endpoints [section 4.2.6] 
Figure 2 has been added for the interpretation of the hierarchical composite 
endpoint (HCE) [section 4.2.5] 
Derivation of the analysis values for the HCE analysis has been added [section 
4.2.5] 
Handling of missing data for the HCE analysis has been added [section 4.2.5] 
[section 4.2.6.2] 
Analysis of the observational period has been specified. [section 6] 
Details of the win ratio confidence interval calculation have been added 
[APPENDIX] 
 
 
 
 


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Date /Version 
Brief description of change 
1 February 2021/ 
Version 4.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary, Secondary, Safety and Exploratory objectives are updated based on 
the protocol amendment [sections 1.1.1, 1.1.2, 1.1.3, 1.1.4] 
Event driven study has been changed to a fixed sample size study, and sample 
size increased to approximately 1200 patients, based on the protocol 
amendment [section 1.2.1] 
Section is added to specify the data collection during the extended follow-up 
period [section 1.2.6] 
Sample size calculation has been changed to reflect the updated protocol 
accounting for the dual primary endpoints [section 1.4] 
Estimands, Primary variables, Secondary variables are updated to reflect the 
dual endpoint nature of the study, change of the Acute Kidney Endpoint to 
Composite Kidney Endpoint, according to the protocol amendment, and to 
reflect the changed order in testing sequence of secondary endpoints [section 
3.1, 3.2, 3.3.1-3.3.5] 
Pooling of countries for stratified analysis has been specified [section 4.1] 
The definition of compliance has been amended to distinguish between 
compliant and compliant while alive [section 4.1] 
Confirmatory testing procedure has been updated [section 4.1.2] 
Two additional supplementary analyses are added for the prevention 
composite endpoint  multiple event analysis and removing acute kidney 
injury from the composite [section 4.2.4.2] 
Sensitivity analysis is added for the prevention composite endpoint by baseline 
use of remdesivir [section 4.2.4.3] 
The hierarchical composite endpoint section has been amended to include the 
stratified log-rank test as the primary method of analysis and the win ratio 
from the stratified Cox regression as the main method of treatment effect 
estimate applied to the HCE [section 4.2.5] 
The hierarchical composite endpoint section has been amended to include the 
definition of recovery, sensitivity analyses by excluding patients with 
unconfirmed SARS-CoV-2 test or by baseline use of remdesivir [section 4.2.5]
amendment there are no changes from the protocol. 
Software implementation of the multi-state fallback procedure has been 
provided [APPENDIX] 
 
 
 
 
 
 
 
 
 
 
 


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Date /Version 
Brief description of change 
3 March 2021/ 
Version 5.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In the confirmatory testing procedure Death from any cause
hierarchy [section 4.1.2] 
Clarification has been added about reporting the individual events contributing 
to the composite endpoint if several of these components occur on the same 
day [section 4.2.4.2] 
The sensitivity analysis which includes deaths after incomplete event 
assessment has been added to section 4.2.4.3 in addition to being mentioned in 
section 3.2.1  
It has been clarified that type a) missingness will be handled for the primary 
analysis of the hierarchical composite endpoint [section 4.2.5.3] 
been updated to incorporate hierarchical structure of the outcomes (death vs 
survival). Analysis also incorporates patients with premature study 
discontinuation as censored [section 4.2.6.2] 
Software implementation of the primary analysis for HCE has been provided 
[APPENDIX] 
 
 
 


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1 
STUDY DETAILS 
1.1 
Study Objectives 
1.1.1 
Primary Objective 
Primary objective: 
Outcome measure: 
To determine whether dapagliflozin 10 mg is 
superior to placebo, in reducing disease 
progression, complications, and all-cause 
mortality in patients hospitalized with COVID-19.
Dual primary endpoints of: 
 
Prevention of COVID-19 complications or death 
During the 30-day treatment period, time to first 
occurrence of new/worsened organ dysfunction during 
index hospitalization or death from any cause. 
New/worsened organ dysfunction is defined as at least 
one of the following:  
 
Respiratory decompensation requiring initiation of 
mechanical ventilation (includes invasive or 
non-invasive ventilation, CPAP, or BiPAP), and/or 
initiation of ECMO 
 
New or worsening congestive HFa 
 
Requirement for vasopressor therapy and/or 
inotropic or mechanical circulatory support 
 
Ventricular tachycardia or fibrillation lasting at 
least 30 seconds and/or associated with 
hemodynamic instability or pulseless electrical 
activity, or resuscitated cardiac arrest 
 
Doubling of s-Creatinine or initiation of renal 
replacement therapy 
 
Improving clinical recovery 
Hierarchical composite outcome measure: 
1 
Death from any cause through Day 30 
2 
New/worsened organ dysfunction (as defined 
above) 
3 
Clinical status at Day 30 for patients still 
hospitalized and without any worsening organ 
dysfunction (using points 3 to 5 of a 7-point ordinal 
scaleb) 
4 
Hospital discharge before Day 30 and alive at 
Day 30 
 
a 
Congestive HF is defined as at least one of the following 1) initiation of new intravenous therapy for heart 
failure 2) reinstitution of previous intravenous therapy for heart failure 3) increase in current intravenous 
therapy for heart failure. This is based on modification on previous definition of in-hospital worsening heart 
failure (McMurray et al 2007) 
b 
7-point Patient Clinical Status scale: 
1 
Not hospitalized, no limitations on activities 
2 
Not hospitalized, limitation on activities 


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3 
Hospitalized, not requiring supplemental oxygen 
4 
Hospitalized, requiring supplemental oxygen 
5 
Hospitalized, on high flow oxygen devices 
6 
Hospitalized, on invasive mechanical ventilation or ECMO 
7 
Death 
BiPAP Bilevel positive airway pressure; COVID-19 Coronavirus disease 2019; CPAP Continuous positive 
airway pressure; ECMO extracorporeal membrane oxygenation; HF Heart failure. 
1.1.2 
Secondary Objectives  
Secondary objectives: 
Outcome measures: 
To compare the effect of dapagliflozin 10 mg 
versus placebo on time to hospital discharge. 
Time to hospital dischargea 
To compare the effect of dapagliflozin 10 mg 
versus placebo on total number of days alive 
and free from respiratory decompensation 
requiring mechanical ventilation 
Total number of days alive and free from respiratory 
decompensationa requiring initiation of mechanical 
ventilation (includes invasive or non-invasive ventilation, 
CPAP, or BiPAP) from randomization through Day 30 
To compare the effect of dapagliflozin 10 mg 
versus placebo on total number of days alive, 
not in ICU, and free from respiratory 
decompensation requiring mechanical 
ventilation 
Total number of days alive, not in the ICU, and free from 
respiratory decompensationa requiring initiation of 
mechanical ventilation (includes invasive or non-invasive 
ventilation, CPAP, or BiPAP) from randomization through 
Day 30 
To compare the effect of dapagliflozin 10 mg 
versus placebo on a composite kidney endpoint 
Time to composite of acute kidney injuryb or initiation of 
renal replacement therapyc, or death from any cause 
through Day 30 
To compare the effect of dapagliflozin 10 mg 
versus placebo in reducing the incidence of 
all-cause mortality 
Time to death from any cause through Day 30 
 
a 
Refers to index hospitalization only 
b 
Acute kidney injury defined as:  
 
An episode of doubling s-Creatinine compared to baseline during index hospitalization 
 
or SAE with preferred term of Acute kidney injury following discharge and through Day 30 
c 
Renal replacement therapy defined as: 
 
Initiation of renal replacement therapy during index hospitalization  
 
or SAE with a preferred term for renal replacement therapy (ie, Haemodialysis, Haemofiltration, 
Continuous haemodiafiltration, Dialysis, Peritoneal dialysis, Dialysis device insertion, Renal 
replacement therapy, or Artificial kidney device user) following discharge and through Day 30 
BiPAP Bilevel positive airway pressure; COVID-19 Coronavirus disease 2019; CPAP Continuous positive 
airway pressure; ECMO Extracorporeal membrane oxygenation; ICU Intensive care unit; SAE Serious adverse 
event. 
 


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1.1.3 
Safety Objectives 
Safety objective: 
Outcome measures: 
To evaluate the safety and tolerability of 
dapagliflozin compared to placebo in patients 
hospitalized with COVID-19. 
 
Serious adverse events from randomization to 
Day 30a 
 
Acute kidney injury defined as:  
 
An episode of doubling of s-Creatinine 
compared to baseline during index 
hospitalization 
 
or SAE with preferred term of acute kidney 
injury following discharge and through Day 30 
 
Incidence of diabetic ketoacidosis from 
randomization through Day 30 
a 
SAEs will be collected through Day 90 but comparison of treatment groups will be assessed based on the 
data obtained through Day 30. For the definition of reportable SAEs, see CSP Section 6.4.2. 
COVID-19 Coronavirus 2019; SAE Serious adverse event. 
 
1.1.4 
Exploratory Objectives 
Exploratory objective: 
Outcome measures: 
To compare the effect of dapagliflozin 10 mg to 
placebo on the components of the primary endpoint, 
status. 
 
Change in NT-proBNP, hs troponin, D-dimer, LDH, 
ALT, lymphocyte count, CRP between Day 1 and 
Day 15 (or discharge from hospital, whichever is 
earlier) 
 
Qualitative PCR for SARS-CoV-2 in 
oropharyngeal/nasopharyngeal swab at baseline 
(while hospitalized); and Day 15 (if still hospitalized) 
or discharge from hospital 
 
Change in NEWS 2 from Day 1 to Day 15 (or 
discharge from hospital, whichever is earlier). 
 
-point ordinal scale) at 
Day 15 (or discharge from hospital, whichever is 
earlier) 
 
Total number of days alive and not on renal 
replacement therapya  
 
Proportion of patients with acute coronary syndromeb 
a 
Refers to index hospitalization only 
b 
Acute coronary syndrome defined as: abnormal troponin level above 99th percentile of the local laboratory 
reference range or, if abnormal at baseline, further rise in troponin levels accompanied by at least 1 of the 
following: 1) ischemic symptoms 2) ischemic ST-segment changes on ECG (Thygesen et al 2018) 
NEWS 2 is a standardized assessment of acute-illness severity and can prompt critical care intervention. It is 
used as an adjunct to clinical judgment. 
ALT Alanine aminotransferase; COVID-19 Coronavirus disease 2019; CRP C-reactive protein; 
ECG Electrocardiogram; hs troponin High-sensitivity cardiac troponin; LDH lactate dehydrogenase; NEWS 2 
National Early Warning Score 2; NT-proBNP N-terminal-pro B-type natriuretic peptide; PCR Polymerase chain 
reaction SARS-CoV-2 Severe acute respiratory syndrome-coronavirus-2. 
 


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1.2 
Definitions 
1.2.1 
Study Closure 
The study is a fixed follow-up study with follow-up time of 30 days. Approximately 
1200 patients will be randomized at approximately 90 sites in North America (USA and 
Canada), Latin America (Argentina, Brazil, Mexico), India, and Europe (UK).  
An extended follow-up period of an additional 60 days of observational follow up (on top of 
the current active treatment duration of 30 days) will be conducted to examine any potential 
longer-term trajectory of recovery from COVID-19 among trial participants. All analyses 
described in the current SAP (except Section 6) will be carried out on data collected up to and 
including Day 30. As soon as the pre-planned number of patients have completed their 30 day 
treatment period, and the data is collected and cleaned, the database will be locked and 
unblinding performed for these analyses.  
Separate analyses will be done on extended follow-up period described in Section 6. 
1.2.2 
Withdrawal of Informed Consent 
Withdrawal of consent (WoC) should only occur if the patient has received appropriate 
information about, and does not agree to, any kind of further assessments or contact, including 
modified follow-up options. A patient who considers withdrawing from the study must be 
informed by the Investigator about modified follow-up options (eg, telephone contact, a 
contact with a relative or treating physician, or information from medical records).  
If the patient withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a WoC. A patient who withdraws consent 
will always be asked about the reason(s) and the presence of any adverse event (AE). The 
Investigator will follow up patients as medically indicated. To ensure validity of study data, 
efforts will be made to collect as much data as possible throughout the study (including after 
hospital discharge) and especially vital status (dead or alive) (also for patients who have 
withdrawn their informed consent). Therefore, if informed consent has been withdrawn 
completely or the patient is non-contactable following hospital discharge, the Investigator will 
study closure, in compliance with local privacy laws/practices. 
1.2.3 
Discontinuation from Study Drug 
Discontinuation from investigational product (IP) is not the same as complete withdrawal 
from the study. A patient who discontinues IP should optimally continue to follow up study 
assessments  up to and including Day 90. Alternatively, if the patient does not agree to this 
approach, modified follow-up should be arranged (eg, less frequent assessments, one contact 


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at Day 30, or other means). Patients who agree to some kind of modified follow-up are still 
participating in the study. The modified visits and procedures that are done will be recorded in 
the electronic case report form (eCRF). 
Data from patients who did not withdraw consent or events occurring before WoC for patients 
who withdraw consent will be included in the intention-to-treat (ITT) analyses irrespective of 
whether the event occurred before or following discontinuation of study drug.  
1.2.4 
Vital Status 
Known vital status at the end of the 30-day treatment period will be defined when the patient 
is dead or has date last known alive on or after Day 30. Vital status for 60 and 90 days will be 
summarized separately. 
For patients who have withdrawn consent, the investigator will attempt to collect vital status 
from publicly available sources at study closure in compliance with local privacy 
laws/practices. 
1.2.5 
Follow-up Period after Hospital Discharge 
Patients discharged from hospital will continue with daily treatment for the remainder of the 
30 days, and are followed up by telephone at Day 15 and/or Day 30 (± 3 days). 
The following assessments will be completed: 
 Concomitant medications will be recorded 
 Follow up of ongoing reportable serious AEs (SAEs). Details of any reportable SAEs 
will be recorded. 
 Vital status 
 Investigational product adherence 
 Details of any re-hospitalization for the patient 
 Patient Clinical Status will be assessed using a 7-point scale (defined in Section 1.1.2) 
 
1.2.6 
Extended Follow-up Period after Day 30 
Following last dose of investigational product at Day 30, patients are followed up by 
telephone at Day 60 and Day 90 (± 7 days).  
The following assessments will be completed: 
 Concomitant medications will be recorded 




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1.3.1 
Randomization 
In this study, patients will be recruited from sites with adult patients hospitalized with 
confirmed or strongly suspected COVID-19. Each patient should meet all of the inclusion 
criteria and none of the exclusion criteria for this study in order to be randomized to 
investigational product. Under no circumstances can there be exceptions to this rule. Patients 
can be re-screened once, but must be considered screen failures if they still do not meet the 
entry requirements (clinical study protocol [CSP], Section 3.3). 
informed consent form (ICF). 
number.  
All patients will be randomly assigned to investigational product centrally using an Interactive 
Response Technology system. Randomization to investigational product will be performed in 
balanced blocks to ensure approximate balance between the treatment groups (1:1). The 
Sponsor or delegate is responsible for generating the randomization scheme for this study 
using a validated system. Before the study starts, the instructions for accessing and using the 
Interactive Response Technology system will be provided to each site. 
Investigational product (dapagliflozin or placebo) should be administered the same day the IP 
kit number is assigned and as soon after randomization as possible. 
To ensure balanced randomization within countries, stratification will be employed by 
country. 
1.4 
Number of Patients 
The primary objectives of the study are to determine the superiority of dapagliflozin versus 
placebo in reducing the incidence of complications or all-cause mortality (prevention of 
worsening COVID-19) or improving clinical recovery. It is estimated that a sample size of 
approximately 1200 patients will provide adequate power to detect the treatment effect on 
prevention or recovery, when the dual primary endpoints are used for testing, with alpha split 
between these endpoints.  
Since the original protocol was designed, the unpredictable nature of the evolving global 
pandemic and the change in standard of care for treatment of COVID-19 resulted in lower 
than expected event rates. As a consequence, faster and more complete recovery has now 
become an important treatment goal on par with prevention of complications and death in 
patients hospitalized with COVID-
objectives.  


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The initial version of the protocol (CSP version 1.0, 2 April 2020) specified an event-driven 
approach with 380 events needed to detect HR of 0.75 with 80% power. In a fixed follow-up 
study that would have required 42% of initially randomized 900 patients to experience an 
event. The provision for a potential increase of sample size was included in the initial design 
and intended as a way of balancing the possible decrease in event rates, while the recruitment 
rate of 900 patients was anticipated to occur over a period of approximately 3 months. When 
the CSP was updated (version 4.0, 20 November 2020) it was estimated that around 10 to 20% 
of patients will develop COVID-19 related complications during the index hospitalization or 
will experience death during the 30-day treatment period, while 80 to 90% of patients will 
recover without experiencing worsening. Therefore, the sample size of approximately 1200 
patients would provide approximately 100 to 250 events for the first dual primary endpoint 
(prevention). 
With dual primary objectives of prevention of COVID-19 complications or death and 
improvement in clinical recovery, an effect on any one will be sufficient evidence of the 
effectiveness of study medication. This is per the FDA guidance on Multiple Endpoints in 
Clinical Trials (FDA 2017). To control the type I error for dual primary endpoints, the 
allocated alpha of 5% will be split between them. Table 1 below shows the true hazard ratio 
required for 80% power for a hypothetical scenario of an even split of alpha (2.5% two-sided 
for each primary endpoint) depending on the number of events observed (final alpha 
allocation is described in Section 4.1.2). Since no prior studies are available for SGLT2 
inhibitors in the COVID-19 setting, possible scenarios of event rates and treatment effects are 
considered to infer the sample size (Table 1). 
Table 1 - 2.5% Alpha (80% Power, Time-to-event Analysis) 
Number of Events 
Hazard Ratio 
(Dapagliflozin versus 
Placebo) required for 80% 
power 
Minimal Detectable 
Hazard Ratio 
100 
0.54 
0.64 
150 
0.6 
0.69 
200 
0.65 
0.73 
250 
0.68 
0.75 
 
For the second primary endpoint (recovery) the sample size of 1200 patients will detect a win 
ratio (WR) of 1.23 with at least 80% power for hypothetical alpha of 2.5% (The power is 
calculated based on asymptotic normality property of the win proportion [WP] where 
WR = WP/[1-WP] and the estimated standard deviation (SD) for the WP is assumed to be 


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SD = 1/sqrt[3] = 0.57735 [Kawaguchi et al 2011], as it is a conservative estimate.) This is 
based on an overall 1:1 allocation between dapagliflozin and placebo.   
2 
ANALYSIS SETS 
2.1 
Definition of Analysis Sets 
2.1.1 
Full Analysis Set 
All patients who have been randomized to study treatment will be included in the full analysis 
set (FAS) irrespective of their protocol adherence and continued participation in the study. 
Patients will be analyzed according to their randomized IP assignment, irrespective of the 
treatment actually received. The FAS will be considered the primary analysis set for the 
primary, secondary, and exploratory efficacy variables.   
2.1.2 
Safety Analysis Set 
All randomized patients who received at least 1 dose of randomized treatment will be included 
in the safety analysis set (SAS). Patients will be analyzed according to the treatment actually 
received. For any patients given incorrect treatment, ie, randomized to one of the treatment 
groups but actually given the other treatment, the treatment group will be allocated as follows: 
patients who got both incorrect and correct treatment will be analyzed according to their 
randomized treatment; patients who got only the incorrect treatment will be analyzed 
according to that treatment. 
The SAS will be considered the primary analysis set for all safety variables. 
2.2 
Violations and Deviations 
The important protocol deviations listed below will be summarized by randomized treatment 
group 
 Patients who were randomized but did not meet inclusion and exclusion criteria. 
 Patients who received the wrong study treatment at any time during the study. 
 Patients who received prohibited concomitant medication, which for this study is 
limited to open-label SGLT2 inhibitors taken in combination with IP.  
 
As the primary analysis is an ITT analysis, a protocol deviation will not imply exclusion from 
the primary analysis. 
 




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3.2 
Primary Variables 
3.2.1 
Prevention Composite Endpoint  
The analysis of the prevention endpoint is based on time from randomization to first 
occurrence of new/worsened organ dysfunction during index hospitalization or death from any 
cause.  New/worsened organ dysfunction is defined as at least one of the following: 
 Respiratory decompensation requiring initiation of mechanical ventilation (includes 
invasive or non-invasive ventilation, CPAP, or BiPAP), and/or initiation of ECMO 
 New or worsening congestive HF 
 Requirement for vasopressor therapy and/or inotropic or mechanical circulatory 
support 
 Ventricular tachycardia or fibrillation lasting at least 30 seconds and/or associated with 
hemodynamic instability or pulseless electrical activity, or resuscitated cardiac arrest 
 Doubling of s-Creatinine or initiation of renal replacement therapy 
 
Congestive HF is defined as at least one of the following 1) initiation of new intravenous 
therapy for HF 2) reinstitution of previous intravenous therapy for HF 3) increase in current 
intravenous therapy for HF. This is based on modification on previous definition of in-hospital 
worsening HF (McMurray et al 2007).  
The primary variable of interest is the onset of COVID-19 related new or worsened organ 
dysfunction in the hospital setting (ie, during index hospitalization), or death from any cause 
at any time during the 30-day treatment period. Therefore, if a patient is discharged from the 
hospital without an event of organ dysfunction, then the patient is assumed to have made a 
partial or full recovery from COVID-19 and is therefore no longer at high risk of developing 
COVID-19 related organ dysfunction in the outpatient setting. Thus, for the primary analysis 
(for both dual endpoints), after discharge only vital status will be considered in the analysis.  
For the prevention endpoint the censoring rule is the following, if a patient is discharged from 
the hospital without an event of organ dysfunction and is alive at Day 30, then this patient is 
censored at Day 30. The only instances that the censoring date will be truncated is when 
patients have incomplete vital status assessment after hospital discharge (are lost to follow-
up): the censoring date will be the date of hospital discharge or the last assessment of vital 
status after the discharge or the date of withdrawal of consent, if after withdrawal of consent 
the vital status is unknown. 


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Incomplete event assessment during the index hospitalization will serve as an additional 
censoring event. If it is known that some patients have died after incomplete event assessment, 
then a sensitivity analysis will be conducted to consider these deaths as events. 
The number and percentage of patients with complete follow-up of the prevention endpoint 
will be reported. 
In the analysis of components of the composite endpoint, date of death from any cause will be 
an additional point of censoring.  
3.2.2 
Hierarchical Composite Endpoint  
The efficacy variable is a composite of ordinal outcomes. All patients will be ranked based on 
the timing and severity of their events. Up to Day 30, all events described in the definition of 
the composite will be considered (not just the first events) to determine the ranks of patients as 
described in Section 4.2.5. 
 
3.3 
Secondary Variables 
The secondary endpoints are included in a hierarchical testing sequence following the primary 
endpoint as described in 3.3.1 to 3.3.5. 
3.3.1 
Composite Kidney Endpoint  
The efficacy analysis is based on time from randomization to composite of acute kidney 
injury, initiation of renal replacement therapy or death from any cause.  
Acute kidney injury is defined as:  
 An episode of doubling s-Creatinine compared to baseline during index hospitalization 
 or SAE with preferred term of Acute kidney injury following discharge and through 
Day 30 
 
Renal replacement therapy is defined as:  
 Initiation of renal replacement therapy during index hospitalization   
 or SAE with a preferred term for renal replacement therapy (ie, Haemodialysis, 
Haemofiltration, Continuous haemodiafiltration, Dialysis, Peritoneal dialysis, Dialysis 
device insertion, Renal replacement therapy, or Artificial kidney device user) 
following discharge and through Day 30 
 
 


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3.3.2 
Total Number of Days Alive and Free from Mechanical Ventilation 
The efficacy variable is the total number of days alive and free from respiratory 
decompensation (during index hospitalization only) requiring initiation of mechanical 
ventilation (includes invasive or non-invasive ventilation, CPAP, or BiPAP) from 
randomization through Day 30. 
The total number of days will be calculated as follows. The total follow-up time is defined for 
each patient as the 30 days after the randomization or until time of WoC or last contact for 
patients who are LTFU. The total time spent in hospital will be divided into combined 
duration of use of mechanical ventilation and of being free from mechanical ventilation. The 
time interval of being out of hospital and alive is considered as being free from mechanical 
ventilation. If a patient dies, the number of days from their death to the end of study will be 
assigned as days dead. Days in hospital with use of mechanical ventilation and days dead will 
then be subtracted from total follow-up time to arrive at days alive and free from mechanical 
ventilation for each patient. 
3.3.3 
Total Number of Days Alive, Not in the ICU, and Free from 
Mechanical Ventilation 
The efficacy variable is the total number of days alive, not in the ICU, and free from 
respiratory decompensation (during index hospitalization only) requiring initiation of 
mechanical ventilation (includes invasive or non-invasive ventilation, CPAP, or BiPAP) from 
randomization through Day 30. 
The total number of days will be calculated as follows. The total follow-up time is defined for 
each patient as the 30 days after the randomization or until time of WoC or last contact for 
patients who are LTFU. The total time spent in hospital will be divided into combined 
duration of being in ICU or using mechanical ventilation and of being out of ICU and free 
from mechanical ventilation. The time interval of being out of hospital and alive is considered 
as being out of ICU and free from mechanical ventilation. If a patient dies, the number of days 
from their death to the end of study will be assigned as days dead. Days in ICU or using 
mechanical ventilation and days dead will then be subtracted from total follow-up time to 
arrive at days alive, not in the ICU, and free from mechanical ventilation. 
3.3.4 
Death from Any Cause 
The efficacy variable is time to from randomization to death from any cause. All deaths on or 
prior to Day 30, including death after WoC will be included. Patients who are alive will be 
censored at the earliest of date last known alive and Day 30. 


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3.3.5 
Discharge from Hospital 
The efficacy variable is time from randomization to discharge from hospital. Since death is a 
competing event for the hospital discharge, censoring of patients at the time of death is not 
appropriate. Instead patients dying before hospital discharge will be censored at the end of 
follow-up, that is at day 30 (Dodd et al. 2011). Hospital discharge is a desirable outcome and 
intention of the treatment is to reduce (as opposed to time to negative outcomes, for example, 
organ worsening) the time to this event. Therefore, it is reasonable to assume that patients 
dying in hospital did not have the event during the entire follow-up period, since death 
precludes the happening of hospital discharge.  
3.4 
Safety Variables 
The safety and tolerability of dapagliflozin will be evaluated from reportable SAEs (see CSP 
Section 6.4.2), and safety events (acute kidney injury, DKA). Additionally, DAEs and events 
of 
cute renal failure , defined by narrow SMQ (Standardized MedDRA Queries) scope, 
will be summarized. Routine AEs will not be collected.  
3.4.1 
Safety Data Restriction Specification 
Because of the observational additional 60 days of follow-up, some AEs emerging during the 
30 days of follow-up will have resolution after Day 30. For analysis of all safety objectives 
only data from 30-days treated period will be used. Therefore, AEs still ongoing at the end of 
30 Day treatment period with outcome after day 30 will be considered as ongoing. For the 
analysis of observational data see Section 6.  
 
4 
ANALYSIS METHODS 
4.1 
General Principles 
No multiplicity adjustment will be made to confidence intervals as they will be interpreted 
descriptively and used as a measure of precision. P-values for variables not included in the 
confirmatory testing sequence or following a non-significant test in the sequence will be 
regarded as nominal. 
For stratified analyses countries contributing less than 5% of all randomized patients will be 
pooled together. 
 


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Baseline Laboratory Value 
For all laboratory variables, the baseline value is defined as the last value on or prior to date of 
randomization. Preference will be given to study-mandated laboratory values over standard of 
care laboratory values. 
eGFR 
The estimated glomerular filtration rate (eGFR) values will be calculated (in mL/min/1.73 m2) 
from the creatinine measurements using the chronic kidney disease epidemiology 
collaboration equation (CKD-EPI) formula (Levey at al 2009). Descriptive statistics will be 
presented based on laboratory data. 
Study Drug Compliance 
The percentage of study drug compliance (compliant and compliant while alive) for the 
overall treatment period will be derived. Compliant is defined as continuing taking the 
investigational product until and on Day 30, or died before Day 30 while being on study 
treatment. Compliant while alive is defined as being compliant and alive at Day 30. 
Additionally, patient-days on drug will be defined as days from first dose date until the 
earliest of drug discontinuation, death, WoC, or Day 30.  Proportion of patient-days on study 
drug will be calculated as total patient-days on study drug divided by total patient-days with 
maximum days on study drug, that is, time to death or Day 30. 
4.1.1 
Hypotheses 
For the primary endpoints the following 2 hypotheses will be tested with alpha allocated to 
each hypothesis to maintain an overall 5% 2-sided significance level: 
Prevention 
H0:HR [dapagliflozin:placebo] = 1 
versus  
H1:H
 1 
Recovery 
H0:WR [dapagliflozin:placebo] = 1 
versus  
H1:WR 
 1 


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Here HR (hazard ratio) is estimated from a Cox regression stratified by (pooled) countries and 
adjusted for sex and age, while WR (win ratio) will be estimated from the Cox regression 
applied to ranks of the Hierarchical Composite Endpoint (HCE, Section 4.2.5). Note that the 
statistical test for the latter will be done using the stratified log-rank test. A direct win ratio 
estimate will be provided as well, based on pairwise comparisons of patients in the active 
group with the patients in the placebo group, as a supplementary analysis.  
A strong type 1 error control will be applied in testing the primary and secondary efficacy 
endpoints (Section 4.1.2). 
4.1.2 
Confirmatory Testing Procedure 
4.1.2.1 
Multi-stage fallback procedure 
To control the overall type I error at a 2-sided 
0.05 level for multiplicity across primary and 
secondary endpoints (Table 2), a multi-stage fallback testing procedure (Dmitrienko et al 
2006) will be employed. Graphical representation of this testing procedure is given in Figure 2 
using the Bonferroni-based recycling framework developed in Burman et al 2009. Different 
weights will be allocated to the significance level for each hypothesis test in Table 2.  
Table 2 - Multiple testing procedure 
Hypothesis
Endpoint 
1  
The prevention composite endpoint (first occurrence of new/worsened 
organ dysfunction during index hospitalization or death from any cause 
through day 30). 
2  
The hierarchical composite endpoint (recovery). 
3  
The composite kidney endpoint. 
4  
Death from any cause. 
5  
Total number of days alive and free from respiratory decompensation.  
6  
Total number of days alive, not in the ICU, and free from respiratory 
decompensation.  
7  
Hospital discharge.  
 


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4.1.2.2 
Significance level allocation for the testing procedure 
The overall significance level 
 will be split to 0.015 for H1(prevention) and 0.035 for 
H2 (recovery) for the initial testing. If H1 is rejected then 0.005 will be recycled and H2 will 
be tested at 0.035+0.005=0.04, while 0.01 will be reserved for H3. If H2 is rejected at 0.04 
then H3 will be tested at full 0.05, otherwise H3 will be tested at 0.01. In the same way, if H2 
is rejected at 0.035, then 0.025 will be recycled and H1 will be tested at 0.04 while 0.01 will 
be reserved for H3. If H1 is rejected at 0.04 then H3 will be tested at full 0.05, otherwise H3 
will be tested at 0.01. If H3 is tested at full 0.05 (which can happen if and only if both H1 and 
H2 are rejected) and is rejected, then the testing procedure will continue for H4-H7 as a fixed 
sequence at full 0.05.  
Implementation of this testing procedure using SAS® software is given in Appendix A 2. 
As an example, consider the case of following p-values: 
At the initial allocation of significance level H2 will be rejected at 0.035, while H1 will 
not be rejected at 0.015. After recycling, H1 will be re-tested at 0.04 but will still not be 
rejected. H3 will be tested at 0.01, reserved from rejecting H2, and hence H3 will be rejected. 
Therefore, 0.01 can be recycled to test H1 at 0.04+0.01=0.05. At this level H1 will be rejected 
and hence the testing procedure can continue to hypotheses 4-7 at overall significance level 
0.05. 


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Figure 2 - Multiple testing procedure
4.1.3
Presentation of Time-to-event Analyses
In general, summary tables of time-to-event analyses will include the number and percentage
of patients with event per treatment group, event rate, HR with 95% confidence interval and 
p-value. The event rate will be derived as the number of patients with event divided by the 
total duration of follow-up across all patients in a given group, presented as patients with 
event per 100 patient months (1 month = 30 days).
Kaplan-Meier (KM) estimates of the cumulative proportion of patients with events will be 
calculated and plotted per treatment group, with the number of patients at risk indicated below 
the plot at specific time points. The KM plots will be presented for all time-to-event analyses, 
including the individual components of the composite endpoints.
4.1.4
Vital Status and Follow-up of the Prevention Endpoint
Potential endpoints will be collected from randomization throughout the study until and 
contact. The investigator will attempt to collect vital status (dead or 


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alive) on or after Day 30, including vital status from publicly available sources for patients 
who have withdrawn consent, in compliance with local privacy laws/practices. 
Known vital status at the end of the study will be defined when the patient is dead or has date 
last known alive on or after Day 30. In patient disposition, the number of patients who are 
dead, alive, or with unknown vital status will be reported separately for patients who did/did 
not withdraw consent. The term LTFU will be limited to only patients with unknown vital 
status. 
The number and percentage of patients who are not LTFU will be provided, as well as the 
number and percentage of patients with complete follow-up of the prevention composite 
endpoint. In addition, the proportion of patient-days with complete follow-up will be reported 
per treatment group. Patient-days with complete follow-up will be defined as days from 
randomization until the earliest of an event of the prevention composite endpoint, WoC, 
censoring due to incomplete event assessment (in cases where last complete event assessment 
is prior to Day 30), or Day 30. To calculate the proportion of patient-days with complete 
follow-up, the total patient-days with complete follow-up will be divided by the total patient-
days with maximum follow-up, that is the total days from randomization to first event or 
Day 30. 
4.2 
Analysis Methods  
4.2.1 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics, including medical history, will be summarized, 
using frequency distributions and summary statistics based on the FAS, for each treatment 
group as well as for all patients combined. No statistical test will be performed for comparison 
of any baseline measurement among treatment groups.  
4.2.2 
Prior, Baseline and Concomitant, Medications 
Prior medication is defined as medications started before index hospitalization. 
Baseline medication is defined as medications with at least one dose taken on or before date of 
randomization, during the index hospitalization.  
Concomitant medication is defined as medications taken post randomization, irrespective of 
study drug.  
The frequency of baseline and concomitant medication will be presented for the FAS per 
Anatomical Therapeutic Chemical (ATC) class and treatment group. 
COVID-19 related concomitant medications will be summarized separately. 


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Summaries of prohibited medication (as defined in CSP Section 7.7) will be presented. In this 
study prohibited medication is limited to open-label SGLT2 inhibitors taken in combination 
with investigational product. 
4.2.3 
Analysis of Time-to-Event endpoints 
For analysis of time to first event, data will be expressed as 2 variables: 
 A binary variable indicating whether the event in question occurred or the patient was 
censored 
 An integer variable for the number of days from randomization to the first occurrence 
of an event (start date of the event  randomization date + 1) or, for event-free patients, 
from randomization to censoring (censoring date  randomization date + 1) 
 
Event-free patients will be censored as described below for each respective endpoint. 
4.2.4 
Analysis of the Prevention Primary Composite Endpoint 
In the analysis of the prevention composite endpoint, treatments (dapagliflozin versus 
placebo) will be compared using a Cox proportional hazards model with a factor for treatment 
group, stratified by country (pooling together countries contributing less than 5% of all 
randomized patients) and adjusting for age and sex. The stratified Cox proportional hazards 
model is assuming proportionality of hazards in each stratum, meaning that baseline hazards 
in different strata can be different (which would be indicative of different event risks in 
different countries, during the time), but the effect of covariates over time and across strata is 
constant. The analysis will use the earliest of WoC, last clinical event assessment, and Day 30 
for censoring of patients without any primary event as described in Section 3.1. The Efron 
method for ties and p-value based on the Wald statistic will be used. The event rates, p-value, 
HR, and 95% confidence interval will be reported.   
Kaplan-Meier estimates of the cumulative proportion of patients with event will be calculated 
and plotted, for the composite endpoint and for the individual components. 
4.2.4.1 
Subgroup Analysis of the Prevention Composite Endpoint 
Exploratory subgroup analyses of the primary composite endpoint will be performed for the 
characteristics listed in Table 3. Analysis will be done separately by each level of the relevant 
subgroup variable, in a model stratified by (pooled) country and including age and sex as 
covariates. Furthermore, in a model across subgroups a test of interaction between randomized 
treatment group and the subgroup variable will be performed in a Cox model, stratified by 
(pooled) country and including as covariates age, sex, the relevant subgroup variable and the 
interaction between treatment and the subgroup variable. In addition to the number and 
percentage of patients with event, event rate estimate, HR with 95% confidence interval and 




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3. ECMO 
Cardiac decompensation 
4. New or worsened congestive HF 
5. Vasopressor therapy, inotropic or mechanical circulatory support 
6. Ventricular tachycardia or fibrillation, resuscitated cardiac arrest,  
Renal decompensation 
7. Doubling of s-Creatinine 
8. Initiation of renal replacement therapy 
Death 
9. All-cause mortality 
 
 In reporting the events of the composite the frequency of the first events will be summarized. 
If a subject has events of several types on the same day, then the subject is included in the 
category with the highest priority (in the following order  all-cause mortality, cardiac 
decompensation, renal decompensation, respiratory decompensation). The contribution of 
each component of the prevention composite endpoint to the overall treatment effect will be 
examined. In the analysis of the components, all first events of the given type will be included 
irrespective of any preceding non-fatal composite event of a different type. Consequently, the 
sum of the number of patients with events in the component analysis will be larger than the 
number of patients with composite events. Methods similar to those described for the analysis 
of the composite will be used to separately analyze the time from randomization to the first 
occurrence of each component of the prevention composite endpoint.  
In addition to analyzing the components, the following supplementary analyses will be 
conducted: 
1. Analyzing the composite using the second definition (b) below (Supplementary #1) of 
the respiratory decompensation. 
a. 
(Primary) Respiratory decompensation requiring initiation of mechanical ventilation 
(includes invasive or non-invasive ventilation, CPAP, or BiPAP), and/or initiation of 
ECMO. 
b. (Supplementary #1) Respiratory decompensation requiring mechanical ventilation 
(excluding CPAP and BiPAP), and/or initiation of ECMO. 
2. (Supplementary #2) Analyzing the composite by removing the respiratory 
decompensation component. Patients experiencing respiratory decompensation will be 
followed-up for  other components of the prevention composite endpoint. 


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3. (Supplementary #3) Analyzing the composite by removing AKI (Acute Kidney Injury) 
component. Patients experiencing AKI will be followed-up for other components of 
the prevention composite endpoint. 
4.  (Supplementary #4) Multiple event analysis using LWYY (Lin-Wei-Lang-Ying) 
method (see Lin et al 2000). There are 9 components in the prevention composite 
endpoint, hence a patient can have at most 9 events. Only multiple events of patients 
will be considered, repeated events of the same component of a patient will not be 
counted. 
4.2.4.3 
Sensitivity Analysis of the Prevention Composite Endpoint 
Analysis of proportions 
Sensitivity analysis of the prevention composite endpoint and components will be conducted 
by analysis of the difference in proportions of patients with an event using the Wald test for 2-
sample proportions. 
Unconfirmed SARS-CoV-2 Infection 
A sensitivity analysis will be performed of the primary analysis excluding patients who were 
not tested for SARS-CoV-2 at randomization and tested negative when testing became 
available.  
Baseline use of remdesivir 
A sensitivity analysis will be performed of the primary analysis by remdesivir use at 
randomization.  
Incomplete in-hospital event assessment 
If it is known that some patients have died after incomplete event assessment, then a 
sensitivity analysis will be conducted to consider these deaths as events. 
Missing Data and Informative Censoring 
The time-to-event analysis using the Cox regression depends on the assumption of 
non-informative or ignorable censoring, corresponding to the missing-at-random assumption. 
The missing data in this context are patients who are prematurely censored due to WoC, 
LTFU, or otherwise incomplete follow-up of endpoints. The amount of missing data will be 
described eg, in terms of the number of patients and patient time with incomplete follow-up as 
described in Section 4.1.4. 
The amount of incomplete follow-up is expected to be small. To assess the impact of missing 
data and the robustness of the results with regard to the assumption of non-informative 


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censoring, sensitivity analysis will be planned based on the evaluation of the missing 
follow-up and discussed in relation to the observed efficacy signal.  
A tipping point analysis will be performed for patients prematurely censored before Day 30 
(date of discharge for those patients that were discharged from hospital and have missing vital 
status assessment afterwards; the last assessment date of vital status after hospital discharge; 
date of withdrawal of consent for those patients that withdrew consent while in hospital). In 
all prematurely censored patients in the dapagliflozin group will be considered as having the 
event at their time of censoring, while the prematurely censored patients in the placebo group 
will be considered as censored at Day 30. This is the most unfavorable scenario for the 
dapagliflozin group, since all prematurely censored patients are considered as having the 
event, while in placebo group these patients are considered as having longer event free time 
than observed.  If the treatment effect is still observed, then no further analysis will be done, 
since this will mean that premature censoring did not affect the treatment effect. If there is no 
statistical significance in the worst case analysis, then events after initial censoring will be 
simulated in both treatment groups, using the observed event rates in each group, in the 
placebo group keeping the event rate constant, while gradually increasing the event rate in the 
dapagliflozin group, to find the event rate for which the significance is lost. Then, an 
increased event rate of the placebo group will be selected. The same procedure will be 
repeated by gradually increasing the event rate in the dapagliflozin group, to find the event 
rate for which the significance is lost. A shift table will be constructed for hazard ratios 
corresponding to various combinations of event rates in the dapagliflozin and the placebo 
groups.  
A hazard ratio corresponding to a combination of event rates in the dapagliflozin and placebo 
groups will be calculated as follows: event rates per treatment group (observed or increased) 
will be used to generate new event times for patients who were prematurely (before Day 30) 
censored, using exponential distribution. If for a patient the sum of the new event time and the 
time spent in the study (premature censoring time) is less than or equal to 30 then it will be 
assumed that the corresponding patient had an event, and the sum of the observed and 
simulated times will be used as the time of this event. If the sum of these times is greater than 
30 then this patient will be considered as censored at Day 30. After generating new event 
times for all patients who were prematurely (before Day 30) censored (using the previously 
observed events and new, simulated events), hazard ratio for the treatment effect in the 
dapagliflozin group will be calculated. This procedure will be repeated 100 times and 
corresponding hazard ratios and standard errors will be combined using the Rub
resulting hazard ratio will be reported in a shift table (possible values of event rates, Placebo × 
Dapa 10 mg). Statistically significant hazard ratios in the shift table will be marked. 


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4.2.5 
Analysis of the Recovery Primary Endpoint (HCE) 
To assess the  effect of dapagliflozin on clinical status change during the 30 days of follow-up, 
a hierarchical composite endpoint will be considered. Each patient will be ranked based on the 
timing and severity of the events. Up to Day 30, all events described in the definition of the 
prevention composite endpoint will be considered (not just the first events) to determine the 
ranks of patients. Patients will be ranked using the order below:  
Hierarchical composite outcome measure: 
1 Time to death from any cause 
2 Time to new/worsened organ dysfunction (as defined in the primary outcome 
measure) 
2.1 Patients experiencing more than one event of the primary composite outcome. 
2.2 Time to (only) new/worsened organ dysfunction. 
3 Clinical status at Day 30 for patients still hospitalized and without any worsening 
organ dysfunction using the scale below 
3.1 Hospitalized, on high flow oxygen devices 
3.2 Hospitalized, requiring supplemental oxygen 
3.3 Hospitalized, not requiring supplemental oxygen 
4 Time to hospital discharge 
 
Which will result in the following ranking (from lowest to highest, where a higher rank means 
a better outcome), or Categories: 
I. 
Patients dying during the study, [Ranking within this cohort will be based on the 
timing of the event, with patients dying sooner getting a lower rank]  
II. 
Patients who did not die but have more than one new or worsened organ 
dysfunction events, [Ranking within this cohort will be based on the number of 
events, with higher number getting a lower rank]  
A patient can have at most 8 events (there are 9 components in the prevention 
composite endpoint, the 9th is death which, if happened, will move the patient to 
category I), see Section 4.2.4.2. Only multiple events of different types will be 
considered, repeated events of the same component of a patient will not be 
counted. 
III. 
Patients who did not die but have only one new or worsened organ 
dysfunction event, [Ranking within this cohort will be based on the timing of the 
event, with patients having the event sooner getting a lower rank. Type of organ 
dysfunction will not be considered]  
IV. 
Patients without primary composite event but hospitalized at the end of 
follow-up (Day 30), [Ranking within this cohort, from low to high, includes 
patients on high-flow oxygen devices, patients requiring supplemental oxygen, and 
patients not requiring supplemental oxygen] 


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V. 
Patients alive at the end of follow up (Day 30), without primary composite 
event and are discharged from hospital before Day 30 will represent the highest 
cohort [Ranking within this cohort will be based on the time to discharge, with 
patients being discharged later getting a lower rank] 
 
The hierarchical composite endpoint (HCE) combines clinical deterioration (e.g. organ 
worsening as defined in the prevention composite endpoint, prolonged hospitalization or 
death) with clinical improvement (e.g., change in clinical status and hospital discharge) into a 
single metric, and all potential intercurrent events are accounted for in this endpoint.  
Figure 3 - Change in clinical status 
 
4.2.5.1 
Clinical interpretation of the recovery HCE (improvement in clinical status)  
It is hypothesized that dapagliflozin will prevent in-hospital (during the index hospitalization) 
new/worsened organ dysfunction events and death through Day 30, which will result in more 
events of clinical recovery (improvement in clinical status, see Figure 3). 
This hierarchical composite endpoint is similar to WHO suggested (8-point) COVID-19-
specific ordinal scale recovery endpoint (WHO 2020). But there are several important 
differences between the ordinal scale endpoint and the suggested HCE:  
 


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1. The ordinal scale endpoints are assessed at a prespecified timepoint (for example, at 
Day 15) while for ranking the HCE uses severity of all events that a patient 
experiences during the 30 days of follow-up. For example a patient discharged from 
hospital before Day 15 and experienced death soon after Day 15 will be categorized as 
recovered in the ordinal scale, but HCE will rank this patient based on the worst 
experienced event, namely death.  
2. The HCE takes into account in-hospital worsening of COVID-19 and not only the 
eventual discharge from hospital. For example, patients having in-hospital worsening 
before hospital discharge will be categorized as recovered in the ordinal scale, but 
HCE will rank this patient based on the worst experienced event, namely worsening of 
COVID-19. 
 
Therefore, the HCE is a recovery endpoint with a stricter definition of recovery (discharge 
from hospital without a worsening event and alive, or still in hospital without a worsening 
event and without oxygen support, see the 
 Figure 
3). Almost all patients enrolled in this study have the same baseline severity  hospitalized 
with COVID-19 with low-flow oxygen support. Recovery is represented on the clinical scale 
as improvement in clinical status compared to baseline:  
1. Discharge from hospital before day 30 without in-hospital worsening and alive at Day 
30; or  
2. Still in hospital at Day 30, but without in-hospital worsening during the 30 days of 
hospitalization and without oxygen support.  
 
Additionally, the timing of events is used to distinguish between those who recover or who 
experience worsening, thus making this endpoint more sensitive to capture treatment effect. 
4.2.5.2 
Derivation of analysis values 
Based on the ranking algorithm above, for all patients analysis values will be derived as 
follows:  
I. 
Patients dying during the study will have the category 400 with AVAL=400 -  
(study days from randomization to death). 
II. 
Patients who did not die but have more than one new or worsened organ 
dysfunction events will have the category 300 with AVAL=300 + (number of 
events),  
III. 
Patients who did not die but have only one new or worsened organ dysfunction 
event, will have the category 200 with AVAL=200 - (study days from 
randomization to organ dysfunction),  
IV. 
Patients without primary composite event but who are hospitalized at the end of 
follow-up will have the category 100 with AVAL=100 + ( 1 for patients not 


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requiring supplemental oxygen, 2 for patients requiring supplemental oxygen, and 
3 for patients on high-flow oxygen devices,).  
V. 
Patients alive at the end of follow up (Day 30), without primary composite event 
who  are discharged from hospital before Day 30 will be represented by the 
category 0 with values AVAL=  0 + (study days from randomization to hospital 
discharge).  
Note that the choice of values 100, 200, 300, 400 introduces the order between the 5 
categories described above.  The actual numerical values of these numbers will not affect 
the results since the analysis method described below is applicable for all ordinal random 
variables. 
4.2.5.3 
Handling of missing data 
With the ranking algorithm described above two types of missingness are associated: 
a) Events with missing date of occurrence (for example, if a patient is known to have died 
but the date of death is unknown).  
b) Missing occurrence of events (for example patients who are lost to follow-up or withdrew 
consent at any time during the study). 
For all analyses (primary and supplementary) type a) missingness will be handled by imputing 
ranks of these patients by assigning the median rank of the category to which this patient is 
categorized. For example, if it is known that the patient have died, then this patient is in the 
category I. Hence the median rank of the patients who have died can be used as an analysis 
value for the patient with the missing death date. Type b) missingness will be handled in the 
primary analysis by censoring (details below). 
 
4.2.5.4 
The primary analysis method  Stratified log-rank test 
The primary analysis method for the HCE will be stratified log-rank test which will be applied 
to AVAL described above (see APPENDIX for implementation). The p-value from this test 
will be used in the multiple testing procedure (Section 4.1.2). Stratification will be done using 
pooled strata, similar to the analysis of the prevention composite endpoint. The treatment 
effect will be characterized by a win ratio (WR) estimated from the stratified Cox regression 
model with the Efron method for ties. The win ratio is the odds that a patient in the 
dapagliflozin group will have a better clinical status during the 30 days of treatment than a 
patient in the placebo group. The null hypothesis is that WR=1 meaning that there is no 


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treatment effect on clinical status of patients, while WR >1 (WR < 1) would mean beneficial 
effect of dapagliflozin (placebo).  
The advantage of calculating the win ratio estimate from Cox regression is that it allows to 
incorporate type b) missingness as follows. 
Patients will be ranked based on the most severe event they had during the time they spent in 
the study using the same ranking algorithm as patients completing the 30-days of follow-up. 
But unlike patients completing the 30-day follow-up, patients with type b) missingness will be 
considered as censored in the log-rank test and Cox regression analysis. 
Note that type a) missingness will be handled by imputing ranks of these patients by assigning 
the median rank of the category to which this patient is categorized. 
 
Supplementary analysis  Win ratio (direct estimate) 
Win ratio based on direct comparison of analysis values of two treatment groups will be 
calculated as a supplementary analysis. Type a) missingness will be imputed (using median 
rank of the category), while patients with type b) missingness will have missing analysis 
values, hence will not be included in the analysis.  
Using the patient-level analysis values (AVAL described above), every patient in the 
dapagliflozin group will be compared with every patient in the placebo group. Each 
patient in the dapagliflozin group if 
the analysis value of the patient in the dapagliflozin group is lower, higher or equal to the 
analysis value of the patient in the placebo group, respectively. Within the dapagliflozin 
group, total number of wins will be divided by the total number of losses (ties are split evenly 
between wins and losses) to form the Win Ratio statistic of the dapagliflozin group against the 
placebo group (Pocock et al 2012). The confidence interval of the win ratio statistic will be 
calculated as described in Gasparyan et al 2020 (see APPENDIX).  
 
4.2.5.5 
Exploratory analyses of the recovery HCE 
An exploratory subgroup analysis will be conducted for the HCE using the same subgroups as 
in the subgroup analysis for the prevention composite endpoint (Table 3). 
The following exploratory analyses will be conducted. 


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Supplementary analysis  - different definition of respiratory decompensation 
The respiratory decompensation will be redefined as requiring initiation of mechanical 
ventilation (excluding CPAP and BiPAP), and/or initiation of ECMO. 
Sensitivity analyses 
Unconfirmed SARS-CoV-2 Infection 
A sensitivity analysis will be performed of the primary analysis excluding patients who were 
not tested for SARS-CoV-2 at randomization and tested negative when testing became 
available.  
Baseline use of remdesivir 
A sensitivity analysis will be performed of the primary analysis by use of remdesivir at 
randomization.  
Imputing ranks based on the most severe event 
In this analysis patients having type b) missingness will be imputed using their most severe 
event while in the study. For example, patients who are lost to follow-up cannot be 
categorized. But if they had an organ worsening before being lost to follow-up, then they can 
be categorized to category III for the sensitivity analysis. This analysis extends the follow-up 
time of the prematurely discontinued patients to Day 30 as it assumes that patients who 
prematurely discontinued the study would not have experienced more severe events than they 
had while in the study, if they had stayed in the study up to Day 30. Thus, in a sense it uses the 
last (most severe) observation. In deriving the win ratio, these patients, unlike the primary 
analysis, will not be censored but will contribute their rank as patients with complete follow-
up. The direct win ratio will be calculated as well and imputed ranks will be used in pairwise 
comparisons. 
Imputing ranks based on 
-
 
Another sensitivity analysis will be performed for patients with type b) missingness by 
-
(compared to their most severe event 
while in the study). For example, patients who had an organ worsening before being lost to 
follow-up, then they can be categorized to category II for this sensitivity analysis (instead of 
category III). This analysis assumes that patients who prematurely discontinued the study 
would have experienced a more (by one category) severe event than the most severe event 
they had experienced while in the study. 


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4.2.6 
Analysis of the Secondary Efficacy Variables 
4.2.6.1 
Time-to-Event Endpoints 
The time-to-event secondary variables included in the testing hierarchy are the following:  
 Time to hospital discharge.  
 Time to composite kidney endpoint. 
 Time to death from any cause. 
 
These endpoints will be analyzed in the same manner as the prevention composite endpoint. 
Analysis of the composite of kidney endpoint, in addition to stratification by (pooled) country 
will be adjusted for baseline eGFR.  
Additionally, an exploratory subgroup analysis (Table 3) will be conducted for the analysis of 
time to death from any cause, in the same way as the subgroup analysis for the prevention 
composite endpoint. 
Sensitivity analyses for the time-to-event endpoints will be conducted to analyze the 
difference in proportions of patients with an event using the Wald test for 2-sample 
proportions. 
4.2.6.2 
Analysis of Total Number of Days 
The endpoints based on total number of days (Sections 3.3.2 to 3.3.3) are similar to the 
endpoint 
 Ariti et al 2011 for patients with 
Heart Failure. The purpose of this endpoint is to characterize the whole burden of the disease 
by accounting for repeated events as well as lengths of events (e.g. duration of mechanical 
ventilation). Higher number is indicative of a more favorable outcome since it shows more 
days free from mechanical ventilation. Number of days dead is subtracted from total days in 
order to account for death being a competing event. Subtracting the days dead from the total 
follow-up time has the same meaning as combining the events of mechanical ventilation and 
death into a composite. The total days of using mechanical ventilator when added to the total 
 The four 
figures below show the calculation method of number of days alive and free from mechanical 
ventilation for an individual patient, depending on the presence of death and the type of 
censoring. The time interval of being out of hospital and alive is considered as being free from 
mechanical ventilation. 


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Figure 4 - Total number of days alive and free from MV  outpatient death 
 
Figure 5 - Total number of days alive and free from MV  death in hospital 
 
In the cases when patients withdraw their consent or are LTFU (presented in Figure 6 and 
Figure 7, respectively), the follow-up time for these patients will be defined as the timeframe 
from randomization to the time of LTFU or WoC. In other words, if a patient withdraws from 
the study or is LTFU, the total follow-up time for this patient will be the time spent in the 
study. Then, from the total follow-up time, as above, the periods of hospitalization with use of 
mechanical ventilation and days dead will be subtracted.  


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Figure 6 - Total number of days alive and free from MV - WoC 
 
Figure 7 - Total number of days alive and free from MV - LTFU 
 
with non-negative values.  
The primary analysis will be conducted where patients first will be compared based on the 
vital status at the end of 30-day follow-up period and then, within each category, based on the 
actual values of total number of days of each patient. The analysis values (AVAL) will be 
derived as follows: 
I. 
Patients who died during the 30-days of follow-up will be in the first group and 
will get the group rank 100. Within this group patients will be ranked based on the 
total number of days alive and free from MV derived above. That is, if X is the 
total number of days alive and free from MV for a subject who died during the 30-
days of follow-up period, then for this subject AVAL=100+X. 


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II. 
Patients who do not die during the 30-days of follow-up will be in the second 
group and will get the group rank 200. Within this group patients will be ranked 
based on the total number of days free from MV derived above. For these subjects 
AVAL=200+X, where X is the total number of days free from MV. 
Note that the assignment of values 100 and 200 introduces an order and their actual numeric 
values will not impact the analysis results, since for the win ratio analysis only ordinal (related 
to comparison) properties of variables are used. Using derived patient level analysis values, 
patients in two treatment groups will be compared and the patient with a higher analysis value 
. Because of a higher group rank of patients who are alive at Day 30, patients who 
die during the 30-day follow-up period cannot win in comparisons against patients who are 
alive at Day 30. Patients with missing vital status or who withdraw consent will be considered 
as censored and their total number of days X (calculated in Figure 6, Figure 7)  will be used to 
derive the AVAL using the rule of group II. 
To analyze this hierarchical endpoint, the win ratio (WR) approach will be used (patients will 
be compared using the AVAL, and the patient with higher AVAL will win ). The win ratio, 
its 95% confidence interval and the 2-sided p-value will be calculated from stratified Cox 
regression as in the analysis of primary recovery endpoint (see Section 4.2.5). 
The numeric values of total number of days 
 will be 
analyzed using direct win ratio approach as a supplementary analysis, as was suggested by 
Wang and Pocock 2016, while the 95% confidence interval for the WR and the corresponding 
p-value will be calculated using the theory of U-statistics (Gasparyan et al 2020, Koch et al 
1998, see APPENDIX). In this analysis patients who are lost-to-follow-up or withdrew 
consent will contribute as well (using their time spent in the study, see Figure 6, Figure 7). 
The difference from the primary analysis is that no ranking will be done based on the vital 
status. Therefore, in this analysis the endpoint will be a (non-hierarchical) composite endpoint 
where death during the study will have the same contribution as having mechanical ventilation 
at that point which lasts until the end of 30-days period. This will be supplementary to the 
hierarchical analysis and will have the advantage of providing numeric analysis values, which 
can be analyzed descriptively (using mean and standard deviation, for example). Number of 
patients with 
 days alive and free from mechanical ventilation =30  (patients 
who were alive at the end of 30-day treatment period and did not use mechanical ventilation 
during the study) will be summarized by treatment group. 
 


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Not in the ICU, and Free from Mechanical 
analyzed in the same manner, only time interval in the ICU will be 
subtracted from the total number of days alive and free from mechanical ventilation. 
4.2.7 
Analysis of Safety Variables 
Analysis Set 
For safety analyses, all summaries will be based on the SAS (Section 2.1.2). 
Exposure 
The total exposure to study drug will be defined as the length of period on study drug, 
calculated for each patient as date of last dose  date of first dose +1. 
An alternative measure where days of interruption are removed will be calculated and termed 
actual exposure. Study medication interruption is defined as a temporary medication 
discontinuation with an intent to restart at a later time. 
Total and actual exposure will be presented descriptively. 
Treatment Periods 
The summaries for the on-treatment period will include events with an onset date on or after 
first dose of randomized study drug and on or before 2 days after last dose of study drug, up to 
30 days of follow-up. Additional presentations will include all events with onset on or after 
first dose of study drug and up to 30 days of follow-up, regardless of whether patients are on 
or off study treatment at the time of the event (the  
treatment period). 
4.2.7.1 
Adverse Events  
Reportable SAEs (defined in CSP Section 6.4.2) and safety events of acute kidney injury and 
DKA will be recorded. 
narrow SMQ (Standardized MedDRA Queries) scope, will be summarized. Summaries of AEs 
will be limited to these categories. 
AEs will be classified according to Medical Dictionary for Regulatory Activities (MedDRA), 
using the most current version of MedDRA possible. 
Summaries by system organ class (SOC) and preferred term (PT) will be sorted by 
international order for SOC and by descending order of PT in the dapagliflozin treatment 
group. 
No statistical tests to compare crude AE frequencies between treatment groups will be 
performed. 


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A summary table will be provided of the total number and percentage of patients with an SAE. 
4.2.7.2 
Serious Adverse Events 
The number and percentage of patients with SAEs will be presented by SOC, PT, and 
treatment group. The most common SAEs will also be presented by PT and treatment group 
only.  
AEs with outcome of death will be presented separately by SOC and PT. 
4.2.7.3 
Safety Events 
Each category of safety event will be presented separately: acute kidney injury and DKA. 
4.2.7.4 
Laboratory Evaluation 
All summaries of clinical chemistry/hematology parameters will be presented in both 
conventional and SI units. Study mandated laboratory values and standard of care laboratory 
values will be analyzed separately as well as in overall assessment.  
The result and the change from baseline of each clinical chemistry/hematology tests, including 
estimated GFR , will be summarized by treatment group at each scheduled visit using 
descriptive statistics, including n, mean, SD, median and quartiles. 
4.2.7.5 
Marked Laboratory Abnormalities 
The number and percent of patients with a marked abnormality in clinical laboratory tests will 
be summarized over time by treatment group. 
Laboratory abnormalities will be evaluated based on marked abnormality (MA) criteria. The 
list of MAs is provided in Table 1 below. 
An on-treatment value will be considered an MA if either  
 the on-treatment value is beyond an MA limit AND the baseline value is not beyond 
the same limit,  
OR 
 both the baseline and on-treatment value are beyond the same MA limit AND the on-
treatment values is more extreme (farther from the limit) than was the baseline. 
Laboratory MAs occurring during the on-treatment period will be summarized by treatment 
group. The directions of changes (high or low) in MAs will be indicated in the tables.  


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Table 4 - Marked abnormality criteria for safety laboratory variables 
 
 
Marked Abnormality Criteria 
Clinical laboratory variables 
Units 
Low 
High 
Hematology 
Hematocrit 
< 0.20 
> 0.55 
Hematocrit 
 
> 0.60 
Hemoglobin  
g/L 
< 60 g/L 
> 180 g/L 
Hemoglobin  
g/L 
 
> 200 g/L 
Na (Sodium) 
mmol/L 
< 130 mmol/L 
> 150 mmol/L 
Na (Sodium) 
mmol/L 
< 120 mmol/L 
 
K (Potassium) 
mmol/L 
 2.5 mmol/L 
 6.0 mmol/L 
Creatinine 
µmol/L 
 
1.5X BL CREAT 
Creatinine 
µmol/L 
 
2X BL CREAT 
BL is the baseline measurement 
 
 
 
 
4.2.8 
Analysis of Exploratory Objectives 
The analysis of the exploratory variables will in the same fashion as the primary and 
secondary efficacy variables be based on the ITT principle, including data irrespective of 
whether the patient has discontinued study drug. 
The exploratory endpoints are  
 Change in NT-proBNP, hs troponin, D-dimer, LDH, ALT, lymphocyte count, CRP 
between Day 1 and Day 15 (or discharge from hospital, whichever is earlier) 
 Qualitative PCR for SARS-CoV-2 in oropharyngeal/nasopharyngeal swab at baseline 
(while hospitalized); and Day 15 (if still hospitalized) or discharge from hospital. 
 Change in NEWS 2 from Day 1 to Day 15 (or discharge from hospital, whichever is 
earlier). 
 
-point ordinal scale) at Day 15 (or discharge from 
hospital, whichever is earlier) 
 Total number of days alive, out of hospital, and not on renal replacement therapy 
(during index hospitalization only) 


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 Proportion of patients with ACS (acute coronary syndrome). 
Acute coronary syndrome is defined as: during index hospitalization, abnormal 
troponin level above 99th percentile of the local laboratory reference range or, if 
abnormal at baseline, further rise in troponin levels accompanied by at least 1 of the 
following: 1) ischemic symptoms 2) ischemic ST-segment changes on ECG. 
(Thygesen et al 2018) 
 
 
Proportions will be analyzed using 2-sample proportions tests. Endpoints with continuous 
values (like laboratory values) will be analyzed using generalized linear models with 
appropriate distributions, including fixed effects for treatment group and baseline values as a 
covariate. Endpoints with ordinal values will be analyzed using the WR approach. 
The total number of days endpoint will be analyzed similarly to the corresponding secondary 
endpoint (Section 4.2.6.2). 
5 
INTERIM ANALYSES 
Interim analysis for safety only will be performed by the Independent Data and Safety 
Monitoring Committee after the first 100 patients have completed the 30-day treatment 
period; no interim efficacy analyses are planned. 
6 
OBSERVATIONAL PERIOD 
All efficacy and safety objectives described in the CSP are based on the blinded and treated 
30-days of follow-up. As soon as the pre-planned number of patients has completed the 30-
day treatment period, and the data is collected and cleaned, the database will be locked and 
unblinded for the analysis of 30-day treatment period data. The primary clinical study report 
will be based on the 30-days of follow-up data. 
Following last dose of investigational product on Day 30, an extended follow-up period of an 
additional 60 days of observational follow-up (on top of the current active treatment duration 
of 30 days) will be conducted with telephone visits on Day 60 and Day 90, to examine longer-
term trajectory of recovery from COVID-19 among trial participants. The following 
assessments will be completed: 
 
Concomitant medications will be recorded 
 
Follow up of ongoing SAEs. Details of any new SAEs will be recorded. 
 
Vital status 
 
Details of any re-hospitalization for the patient 
 
Patient Clinical Status will be assessed using a 7-point scale, defined as  
 


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1. Not hospitalized, no limitations on activities  
2. Not hospitalized, limitation on activities  
3. Hospitalized, not requiring supplemental oxygen 
4. Hospitalized, requiring supplemental oxygen  
5. Hospitalized, on high flow oxygen devices  
6. Hospitalized, on invasive mechanical ventilation or ECMO  
7. Death  
 
Observational period will be analyzed descriptively. SAEs by System organ class/Preferred 
term, hospitalizations, concomitant medications and clinical status on the 7-point scale 
reported during the phone calls on Day 60 and Day 90 will be summarized.  Listings of patient 
level data on resolution of SAEs emerged during the 30-day treatment period, as well as 
clinical status change for patients still in hospital at the end of the 30-day treatment period will 
be provided. 


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7 
REFERENCES 
Ariti et al 2011 
Ariti CA, Cleland JG, Pocock SJ, Pfeffer MA, Swedberg K, Granger CB, et al. Days alive and 
out of hospital and the patient journey in patients with heart failure: insights from the 
candesartan in heart failure: assessment of reduction in mortality and morbidity (CHARM) 
program. AM Heart J 2011; 162(5), 900-906. 
Burman et al 2009 
 Statistics in medicine 28.5, 739-761, 2009. 
Cao et al 2020 
Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A trial of lopinavir ritonavir in adults 
hospitalized with severe Covid-19. N Engl J Med. 2020. doi: 10.1056/NEJMoa2001282. 
Dmitrienko et al 2006 
Dmitrienko A, Wiens B, Westfall P. Fallback tests in dose-response clinical trials. Journal of 
biopharmaceutical statistics, 16(5), 745-755, 2006. 
Dodd et al. 2011 
Dodd LE, Follmann D, Wang J, Koenig F, Korn LL, Schoergenhofer C, Proschan M, 
Hunsberger S, Bonnett T, Makowski M, Belhadi D. Endpoints for randomized controlled 
clinical trials for COVID-19 treatments. Clinical Trials. 2020:1740774520939938. 
Gasparyan et al 2020 
Gasparyan SB, Folkvaljon F, Bengtsson O, Buenconsejo J, Koch GG. Adjusted Win Ratio 
with Stratification: Calculation Methods and Interpretation. Stat Methods Med Res, DOI: 
10.1177/0962280220942558.  
ICH E9(R1) 2019 
ICH E9(R1). Harmonised Guideline Addendum on estimands and sensitivity analysis in 
clinical trials to the guideline on statistical principles for clinical trials. Final version. Adopted 
on 20 November 2019. 
FDA 2017 
FDA Guidance document. Multiple Endpoints in Clinical Trials Guidance for Industry. 
January 2017. Available at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/multiple-endpoints-clinical-trials-guidance-industry 
 


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Date 3 March 2021 
 
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Kawaguchi et al 2011 
Kawaguchi A, Koch GG, Wang X. Stratified multivariate Mann Whitney estimators for the 
comparison of two treatments with randomization based covariance adjustment. Statistics in 
Biopharmaceutical Research. 2011;3(2):217-31. 
Koch et al 1998 
Koch GG, Tangen CM, Jung JW, Amara IA. Issues for covariance analysis of dichotomous 
and ordered categorical data from randomized clinical trials and non-parametric strategies for 
addressing them. Statist. Med. 1998;
-92. 
Levey at al 2009 
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, Feldman HI, et al; CKD-EPI 
(Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate 
glomerular filtration rate. Ann Intern Med. 2009 May 5;150(9):604-12. 
Lin et al 2000 
Lin DY, Wei LJ, Yang I, Ying Z. Semiparametric regression for the mean and rate functions 
of recurrent events. Journal of the Royal Statistical Society: Series B (Statistical 
Methodology) 2000; 62(4):711 730. 
 
McMurray et al 2007 
McMurray JJ, Teerlink JR, Cotter G, Bourge RC, Cleland JG, Jondeau G, et al; VERITAS 
Investigators. Effects of tezosentan on symptoms and clinical outcomes in patients with acute 
heart failure: the VERITAS randomized controlled trials. JAMA. 
2007 Nov 7;298(17):2009-19. 
Pocock et al 2012 
Pocock SJ, Ariti CA, Collier TJ, Wang D. The win ratio: a new approach to the analysis of 
composite endpoints in clinical trials based on clinical priorities. European heart journal 2012, 
33(2), 176-182. 
Thygesen et al 2018 
Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, et al. Fourth Universal 
definition of Myocardial Infarction. Circulation. 2018;138(20):e618 51. 
doi: 10.1161/CIR.0000000000000617. 
Wang and Pocock 2016 
Wang D, Pocock S. A win ratio approach to comparing continuous non-normal outcomes in 
clinical trials. Pharmaceut. Statist. 2016;15:238 45. 


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WHO 2020 
WHO, R&D. 2020. WHO R&D blueprint novel coronavirus (COVID-19) therapeutic trial 
synopsis. https://www.who.int/blueprint/priority-diseases/key-action/COVID-
19_Treatment_Trial_Design_Master_Protocol_synopsis_Final_18022020.pdf 
8 
APPENDIX 
A 1 
Confidence Interval for the win ratio 
Confidence intervals for the win ratio will be calculated using the formulas from Section 2.2 
(Theorem 2) from Gasparyan et al 2020. Suppose that we have derived analysis values of the 
two treatment groups as described in Section 4.2.5. Below group 2 shows analysis values of 
the dapagliflozin group, while group 1 is for the analysis values of the placebo group (see 
Derivation of analysis values in Section 4.2.5) 
 
There are n1n2 possibilities of comparing a component of Y2 to a component of Y1: For each 
comparison we can have three results
2j < y1i (the analysis 
value of the active group is less than that of the placebo group) 
2j > y1i
y1i = y2j. Total number of wins of the active group plus half of ties divided by the total number 
of comparisons is called the Win Proportion (WP) of the active treatment against the placebo 
group. The win ratio of the active group against the placebo is the odds of the winning, that is 
WR=WP/(1-WP). While the win proportion can be calculated using the formulas below 
 
here 
 is an indicator taking the value 1 if the corresponding specification is satisfied, or 0 
otherwise. The quantities pj are defined as 
 
and called the individual win proportions of subject j in the active group against the placebo 
group. In the same way, we can define the win proportion of an individual i in the placebo 
group against the active group as 


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A confidence interval for the win proportion can be calculated from the asymptotic normality 
of the statistic  
 
here 
 
Then, applying the monotone transformation f(x)=x/(1-x) to the confidence interval of the win 
proportion, we will get a confidence interval and the corresponding p-value for the win ratio. 
A 2 
Multi-Stage Fallback testing Procedure 
Denote by 
 the p-values of the hypotheses 1-7. The following algorithm uses 
two-sided p-values, therefore the treatment effect estimate should be in the direction that 
favors treatment as well, in order to consider the specific hypothesis rejected. 
Step 1. 
Test the primary endpoints using the weight  
 
If any of these inequalities is true, proceed to the next step. 
Step 2. 
Then the following inequalities will be checked, where 
 denotes the 
indicator function which takes the value 1 if the underlying inequality is true and 0, 
otherwise. These indicator functions show how some part of 
can be recycled.  
 
 
 


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If any of these inequalities is true, proceed to the next step. 
Step 3. 
If H1 is rejected at 
, then  part of it 
 is recycled for H2 while 
 part of it is passed to H3 (
 If H2 is rejected at 
, then 
 part of it is recycled for H1 (
), while  part of it is reserved 
for H3 (
). If the initially non-rejected hypothesis is rejected at the recycled 
level, then the entire recycled mass is passed to H3 (hence it is tested at full ).  
Therefore, the significance level for H3 is 
 
 if only H1 is rejected, that is,  
but 
. 
 
, if only H2 is rejected that is 
 
 
, if both H1 and H2 are rejected, that is either  
 
or 
 
Step 4. 
It is possible to recycle the significance level if H3 is rejected, to test the 
remaining hypothesis H1 or H2 (whichever was not yet rejected). 
 
 
The significance level of H3 is: 
 
 if only H1 is rejected, that is,  
but 
. 
 
, if only H2 is rejected that is 
 
 
, if both H1 and H2 are rejected, that is either  
 


Statistical Analysis Plan  
Study Code ESR-20-20653 
Edition Number 5.0  
Date 3 March 2021 
 
CONFIDENTIAL AND PROPRIETARY 
58 of 59 
or 
 
Since these steps are recursive, only the last step can be done. If and only if H3 is tested at full 
 and 
the testing procedure will continue to H4-H7 as a fixed sequence testing 
procedure. 
The SAS software implementation is given below. A1-A7 show allocated significance levels 
for the hypotheses H1-H7. S1-S7 take value 1 if the corresponding hypothesis is rejected at 
the allocated level. 
data MTP; 
 
alpha=0.05; 
 
omega=0.3; 
 
gamma=1/3; 
 
theta=2/7; 
 
 
 
p1=0.044; 
 
p2=0.031; 
 
p3=0.007; 
 
p4=0.049; 
 
p5=0.051; 
 
p6=0.01; 
 
p7=0.002; 
 
 
 
I1=p1<=omega*alpha; 
 
I2=p2<=(1-omega)*alpha; 
 
I3=p3<=(1-gamma)*omega*alpha; 
 
 
 
a1=omega*alpha+(1-theta)*(1-omega)*alpha*I2+theta*(1-omega)*alpha*I2*I3; 
 
a2=(1-omega)*alpha+gamma*omega*alpha*I1+(1-gamma)*omega*alpha*I1*I3; 
 
if p1<=omega*alpha and p2 > (1-omega)*alpha+gamma*omega*alpha+(1-gamma)*omega*alpha  
 
 
then a3=(1-gamma)*omega*alpha; 
 
else if p1 > omega*alpha+(1-theta)*(1-omega)*alpha+theta*(1-omega)*alpha  
and p2 <=(1-omega)*alpha then a3=theta*(1-omega)*alpha; 
 
else if (p1<=omega*alpha  
and p2<=(1-omega)*alpha+gamma*omega*alpha*(1-gamma)*omega*alpha) or  
 
(p1<=omega*alpha+(1-theta)*(1-omega)*alpha+theta*(1-omega)*alpha  
and p2<=(1-omega)*alpha) then a3=alpha; 
 
else a3=0; 
 
 
 
a4=(a3=alpha)*(p3<=a3)*alpha; 
 
a5=(a4=alpha)*(p4<=a4)*alpha; 
 
a6=(a5=alpha)*(p5<=a5)*alpha; 
 
a7=(a6=alpha)*(p6<=a6)*alpha; 
 
 
 
if p1<=a1 then s1=1; 
 
if p2<=a2 then s2=1; 
 
if p3<=a3 then s3=1; 
 
if p4<=a4 then s4=1; 
 
if p5<=a5 then s5=1; 
 
if p6<=a6 then s6=1; 
 
if p7<=a7 then s7=1; 
run; 


Statistical Analysis Plan  
Study Code ESR-20-20653 
Edition Number 5.0  
Date 3 March 2021 
 
CONFIDENTIAL AND PROPRIETARY 
59 of 59 
A 3 
Implementation of the primary analysis for HCE 
The win ratio and its 95% confidence interval from Cox regression can be calculated as 
follows: 
proc phreg data=ADHCE; 
 
class TRTPN (ref="2"); 
 
model AVAL*CNSR(1)=TRTPN/rl ties=efron; 
 
strata STRATA; 
 
ods output parameterestimates=est(rename=(HazardRatio=WinRatio));  
run; 
 
The p-value is calculated from the stratified log-rank test as follows: 
PROC LIFETEST DATA=ADHCE notable; 
 
TIME AVAL*CNSR(1); 
 
STRATA STRATA/group=TRTP; 
 
ods output HomTests=LR(where=(TEST="Log-Rank")); 
RUN;