DARE-19: Dapagliflozin in Respiratory Failure in Patients With COVID-19

• Sponsor: Saint Luke's Health System (Other)
• Overall Status: Completed
• CT.gov ID: NCT04350593
• Collaborator: Saint Luke's Hospital of Kansas City (Other), AstraZeneca (Industry), George Clinical Pty Ltd (Industry)
• Enrollment: 1,250
• Locations: 95
• Arms: 2
• Actual Duration (Months): 13.6
• Patients Per Site: 13.2
• Patients Per Site Per Month: 1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
COVID-19	Drug: Dapagliflozin 10 milligram (mg); Drug: Placebo	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1250 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official 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
• Actual Study Start Date: Apr 22, 2020
• Actual Primary Completion Date: Mar 31, 2021
• Actual Study Completion Date: Jun 11, 2021

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Dapagliflozin 10mg Dapagliflozin 10 mg daily	Drug: Dapagliflozin 10 milligram (mg); Active Comparator: Dapagliflozin 10 mg; Other Names: Farxiga
Placebo Comparator: Placebo Dapagliflozin matching placebo 10 mg daily	Drug: Placebo; Placebo Comparator

Outcome Measures

Primary Outcome Measures

1. 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. [Randomization through Day 30]

   Time to first occurrence of new/worsened organ dysfunction during index hospitalization or death from any cause. Event rates are presented as the number of subjects with event per 100 patient month (30 days) of follow-up. Unit of Measure: Patients with events per 100 patient-months (pt-mos) at risk. 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 extracorporeal membrane oxygenation (ECMO) New or worsening congestive heart failure 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

2. Improving Clinical Recovery: Hierarchical Composite Outcome Measure Including Death From Any Cause Through Day 30, New/Worsened Organ Dysfunction, Clinical Status at Day 30 and Hospital Discharge Before Day 30 and Alive at Day 30. [Randomization through Day 30]

   The number of patients experiencing improvement by day 30 compared with baseline (discharged from hospital without a worsening event and alive, or still in hospital without a worsening event and without oxygen support) in the hierarchical composite endpoint analysis. Hierarchical composite outcome measure includes: Death from any cause through Day 30 New/worsened organ dysfunction Clinical status at Day 30 for patients still hospitalized and without any worsening organ dysfunction Hospital discharge before Day 30 and alive at Day 30

Secondary Outcome Measures

1. Time to Hospital Discharge [Randomization through Day 30]

   Time to hospital discharge (refers to index hospitalization only). Median time to hospital discharge is presented in days.

2. Total Number of Days Alive and Free From Respiratory Decompensation Requiring Initiation of Mechanical Ventilation (Includes Invasive or Non-invasive Ventilation, CPAP, or BiPAP) [Randomization through Day 30]

   Total number of days alive and free from mechanical ventilation (includes invasive or non-invasive ventilation, CPAP, or BiPAP) is calculated for each patient as total follow-up time (30 days) substracted days in hospital with mechanical ventilation and days dead.

3. Total Number of Days Alive, Not in the ICU, and Free From Respiratory Decompensation Requiring Initiation of Mechanical Ventilation (Includes Invasive or Non-invasive Ventilation, CPAP, or BiPAP) [Randomization through Day 30]

   Total number of days alive, not in the ICU and free from mechanical ventilation (includes invasive or non-invasive ventilation, CPAP, or BiPAP) is calculated for each patient as total follow-up time (30 days) substracted days in ICU and days dead.

4. Time to Composite of Acute Kidney Injury or Initiation of Renal Replacement Therapy, or Death From Any Cause [Randomization through Day 30]

   Acute kidney injury is defined as an episode of doubling s-creatinine compared to baseline during index hospitalization or SAE. Initiation of renal replacement therapy is defined as initiation of renal replacement therapy during index hospitalization or SAE. Event rates are presented as the number of subjects with event per 100 patient month (30 days) of follow-up. Unit of Measure: Patients with events per 100 patient-months (pt-mos) at risk.

5. Time to Death From Any Cause [Randomization through Day 30]

   Time to death from any cause. Event rates are presented as the number of subjects with event per 100 patient month (30 days) of follow-up. Unit of Measure: Patients with events per 100 patient-months (pt-mos) at risk.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Provision of informed consent

2. Male or female patients aged ≥18 years

3. Currently hospitalized

4. Hospital admission no more than 4 days prior to screening

5. Confirmed severe acute respiratory syndrome coronavirus 2 (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 computerized tomography (CT) findings that, in the opinion of the investigator, are consistent with coronavirus disease 2019 (COVID-19)

7. Blood oxygen saturation (SpO2) ≥ 94% while receiving low-flow supplemental oxygen (5 liters or less)

8. Medical history of at least one of the following:

9. hypertension

10. type 2 diabetes

11. atherosclerotic cardiovascular disease

12. heart failure (with either reduced or preserved left ventricular ejection fraction (LVEF))

13. chronic kidney disease stage 3 to 4 (estimated glomerular filtration rate (eGFR) between 25 to 60 mL/min/1.73 m2)

Key Exclusion Criteria:

1. Respiratory decompensation requiring mechanical ventilation (includes invasive or non invasive ventilation, continuous positive airway pressure (CPAP), or bilevel positive airway pressure (BiPAP))

2. Expected need for mechanical ventilation (includes invasive or non-invasive ventilation, CPAP, or BiPAP) within the next 24 hours

3. Expected survival of less than 24 hours at the time of presentation, in the judgement of the investigator

4. eGFR <25 mL/min/1.73 m2 or receiving renal replacement therapy/dialysis

5. Systolic blood pressure <95 mmHg and/or requirement for vasopressor treatment and/or inotropic or mechanical circulatory support at Screening

6. History of type 1 diabetes mellitus

7. History of diabetic ketoacidosis

8. Currently receiving or has received in the last 14 days, experimental immune modulators and/or monoclonal antibody therapies for COVID-19

9. Current treatment with any sodium-glucose cotransporter-2 inhibitor (SGLT2i) (eg, dapagliflozin, canagliflozin, empagliflozin, ertugliflozin) or having received treatment with any SGLT2i within 4 weeks prior to screening

10. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Heart Group of the Eastern Shore	Fairhope	Alabama	United States	36532
2	Baptist Hospital of Miami	Miami	Florida	United States	33176
3	NorthShore University HealthSystem	Evanston	Illinois	United States	60201
4	Loyola University	Maywood	Illinois	United States	60153
5	Ascension - St. Vincent	Indianapolis	Indiana	United States	46260
6	Lahey Health	Burlington	Massachusetts	United States	01805
7	McLaren Health Care	Auburn Hills	Michigan	United States	48326
8	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
9	Saint Luke's Mid America Heart Institute	Kansas City	Missouri	United States	64111
10	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
11	Jacobi Medical Center	Bronx	New York	United States	10461
12	SUNY Downstate Medical Center	Brooklyn	New York	United States	11203
13	Maimonides Medical Center	Brooklyn	New York	United States	11219
14	St. Francis Hospital	Roslyn	New York	United States	11576
15	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina	United States	27599
16	Wake Forest Baptist Health	Winston-Salem	North Carolina	United States	27157
17	Lancaster General Hospital	Lancaster	Pennsylvania	United States	17604
18	Rhode Island Hospital	Providence	Rhode Island	United States	02903
19	Clinical Trials Network of Tennessee	Memphis	Tennessee	United States	38103
20	DHR Health Institute for Research and Development	Edinburg	Texas	United States	78539
21	Baylor College of Medicine	Houston	Texas	United States	77030
22	Sentara Healthcare	Norfolk	Virginia	United States	23507
23	Clínica de Especialidades Villa María	Villa María	Province Of Córdoba	Argentina
24	Fundación Favaloro	Buenos Aires		Argentina
25	Hospital Español	Buenos Aires		Argentina
26	Hospital Fernández	Buenos Aires		Argentina
27	Hospital Pirovano	Buenos Aires		Argentina
28	Hospital Santojanni	Buenos Aires		Argentina
29	Sanatorio Anchorena	Buenos Aires		Argentina
30	Sanatorio Güemes	Buenos Aires		Argentina
31	Clínica Vélez Sarsfield	Córdoba		Argentina
32	Hospital San Roque	Córdoba		Argentina
33	Sanatorio Privado Duarte Quiros de Clinica Colombo S.A.	Córdoba		Argentina
34	Centro de Pesquisa Dr. Marco Mota	Maceió	Alagoas	Brazil	57051-160
35	Hospital EMEC e Hospital da Cidade	Feira de Santana	Bahia	Brazil	44035-010
36	Hospital e Clínica São Roque	Ipiaú	Bahia	Brazil	45570-000
37	Hospital Regional Deputado Luis Eduardo Magalhães	Porto Seguro	Bahia	Brazil	45810-000
38	Hospital Cárdio Pulmonar	Salvador	Bahia	Brazil	41950-275
39	Hospital Maternidade São Vicente de Paulo	Barbalha	Ceará	Brazil	63180-000
40	Unimed de Fortaleza	Fortaleza	Ceará	Brazil	60055-172
41	Hospital de Messejana Dr Carlos Alberto Studart Gomes	Fortaleza	Ceará	Brazil	60840-285
42	Hospital Coração do Brasil	Brasília	Distrito Federal	Brazil	70390-700
43	Hospital Estadual Jayme dos Santos Neves	Serra	Espírito Santo	Brazil	29166-828
44	Liga de Hipertensão Arterial	Goiania	Goias	Brazil	74690-900
45	Santa Casa de Misericórdia de Passos	Passos	Minas Gerais	Brazil	37904-020
46	Hospital São Domingos - Unimed Uberaba	Uberaba	Minas Gerais	Brazil	38025-440
47	PROCAPE	Recife	Pernambuco	Brazil	50100-060
48	Hospital Giselda Trigueiro	Natal	Rio Grande Do Norte	Brazil	59037-170
49	Associação Dr. Bartholomeu Tacchini	Bento Gonçalves	Rio Grande Do Sul	Brazil	95700-084
50	Hospital São Vicente de Paulo	Passo Fundo	Rio Grande Do Sul	Brazil	99010-080
51	Irmandade da Santa Casa de Misericórdia de Porto Alegre	Porto Alegre	Rio Grande Do Sul	Brazil	90020-090
52	Hospital Mãe de Deus	Porto Alegre	Rio Grande Do Sul	Brazil	90110-270
53	Hospital São José - Criciúma	Criciuma	Santa Catarina	Brazil	88811-250
54	IPEMI- Instituto de Pesquisas Médicas de Itajaí	Itajai	Santa Catarina	Brazil	88301-303
55	Hospital Municipal São José	Joinville	Santa Catarina	Brazil	74605-050
56	Hospital Regional Hans Dieter Schmidt	Joinville	Santa Catarina	Brazil	89228-025
57	Centro de Pesquisa Clínica do Coração	Aracaju	Sergipe	Brazil	49055-530
58	Faculdade de Medicina de Botucatu, UNESP	Botucatu	São Paulo	Brazil	18618-687
59	Instituto de Pesquisa Clínica de Campinas	Campinas	São Paulo	Brazil	13060-904
60	Unimed Ribeirao Preto	Ribeirão Preto	São Paulo	Brazil	14110-000
61	Fundação do ABC (Hospital Estadual Mário Covas)	Santo André	São Paulo	Brazil	09090-790
62	Centro Integrado de Pesquisas	São José do Rio Preto	São Paulo	Brazil	15090-000
63	Santa Casa de Votuporanga	Votuporanga	São Paulo	Brazil	15500-003
64	Fundação Pio XII	Barretos		Brazil	14784-400
65	Hospital Naval Marcílio Dias	Rio de Janeiro		Brazil	20725-090
66	Hospital Moriah	São Paulo		Brazil	04083-002
67	Hospital Santa Paula	São Paulo		Brazil	04556-100
68	InCor - Instituto do Coração do Hospital das Clínicas FMUSP	São Paulo		Brazil	05403-900
69	Halton Healthcare Services	Oakville	Ontario	Canada
70	Lakeridge Health	Oshawa	Ontario	Canada
71	CIMS Hospital Pvt. Ltd	Sola	Ahmedabad	India	400022
72	MIOT International Hospitals	Manapakkam	Chennai-89	India
73	All India Institute of Medical Science	New Delhi	Delhi	India	110029
74	Sanjivani Super Speciality Hospital Pvt Ltd	Ahmedabad	Gujarat	India	380015
75	Lokmanya Tilak General Hospital	Mumbai	Maharashtra	India	400022
76	Max Smart Super Speciality Hospital	Saket	New Delhi	India	110017
77	Max Super Speciality Hospital (A unit of Devki Devi Foundation)	Saket	New Delhi	India	110017
78	Dayanand Medical College & Hospital	Ludhiāna	Punjab	India	141001
79	Hospital del Prado	Acapulco		Mexico
80	Icaro Investigaciones en Medicina	Chihuahua		Mexico
81	HG de Cuernavaca Dr. Jose G Parres	Cuernavaca		Mexico
82	JM Research	Cuernavaca		Mexico
83	Instituto de Investigaciones Aplicadas a la Neurosciencias	Durango		Mexico
84	Antiguo Hospital Civil de Guadalajara "Fray Antonio Alcade"	Guadalajara		Mexico
85	Hospital San Javier	Guadalajara		Mexico
86	Invesclinic MX	Guanajuato		Mexico
87	CIMEZAP	Jalisco		Mexico
88	Hospital Medica Sur	Mexico City		Mexico
89	Hospital Clinica Nova	Monterrey		Mexico
90	Hospital San Jose TEC Salud	Monterrey		Mexico
91	ECI Estudios Clinicos Internacionales	Puebla		Mexico
92	Hospital SMIQ	Queretaro		Mexico
93	Investigacion Medica Sonora	Sonora		Mexico
94	Sanatorio Santa Cruz de Toluca	Toluca		Mexico
95	Addenbrooke's Hospital	Cambridge	Cb2 0qq	United Kingdom

Sponsors and Collaborators

• Saint Luke's Health System
• Saint Luke's Hospital of Kansas City
• AstraZeneca
• George Clinical Pty Ltd

Investigators

• Study Chair: Mikhail Kosiborod, MD, Saint Luke's Mid America Heart Institute

Study Documents (Full-Text)

• Study Protocol - Nov 20, 2020
• Statistical Analysis Plan - Mar 3, 2021

More Information

Publications

None provided.

• Responsible Party: Saint Luke's Health System
• ClinicalTrials.gov Identifier: NCT04350593
• Other Study ID Numbers: D1690C00081; ESR-20-20653
• First Posted: Apr 17, 2020
• Last Update Posted: Jun 10, 2022
• Last Verified: May 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Saint Luke's Health System: sodium-glucose cotransporter-2 inhibitor (SGLT2i); dapagliflozin; COVID-19
• Additional relevant MeSH terms: COVID-19; Respiratory Insufficiency; Dapagliflozin

Study Results

Participant Flow

Arm/Group Title	Dapagliflozin 10mg	Placebo
Arm/Group Description	Dapagliflozin 10 mg daily Dapagliflozin 10 MG: Active Comparator: Dapagliflozin 10mg	Dapagliflozin matching placebo 10 mg daily Placebo: Placebo Comparator
Period Title: Overall Study
STARTED	625	625
COMPLETED	617	620
NOT COMPLETED	8	5

Baseline Characteristics

Arm/Group Title	Dapagliflozin 10mg	Placebo	Total
Arm/Group Description	Dapagliflozin 10 mg daily Dapagliflozin 10 MG: Active Comparator: Dapagliflozin 10mg	Dapagliflozin matching placebo 10 mg daily Placebo: Placebo Comparator	Total of all reporting groups
Overall Participants	625	625	1250
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.0 (13.4)	61.8 (13.5)	61.4 (13.5)
Sex: Female, Male (Count of Participants)
Female	260 41.6%	273 43.7%	533 42.6%
Male	365 58.4%	352 56.3%	717 57.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	394 63%	362 57.9%	756 60.5%
Not Hispanic or Latino	166 26.6%	177 28.3%	343 27.4%
Unknown or Not Reported	61 9.8%	80 12.8%	141 11.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	7 1.1%	10 1.6%	17 1.4%
Asian	35 5.6%	29 4.6%	64 5.1%
Native Hawaiian or Other Pacific Islander	1 0.2%	0 0%	1 0.1%
Black or African American	85 13.6%	84 13.4%	169 13.5%
White	452 72.3%	459 73.4%	911 72.9%
More than one race	43 6.9%	36 5.8%	79 6.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Canada	2 0.3%	2 0.3%	4 0.3%
Argentina	13 2.1%	14 2.2%	27 2.2%
United States	143 22.9%	144 23%	287 23%
Brazil	382 61.1%	380 60.8%	762 61%
United Kingdom	0 0%	2 0.3%	2 0.2%
Mexico	59 9.4%	59 9.4%	118 9.4%
India	26 4.2%	24 3.8%	50 4%
Type 2 diabetes (Count of Participants)
Count of Participants [Participants]	312 49.9%	324 51.8%	636 50.9%
Heart failure (Count of Participants)
Count of Participants [Participants]	44 7%	46 7.4%	90 7.2%
Hypertension (Count of Participants)
Count of Participants [Participants]	526 84.2%	534 85.4%	1060 84.8%
Atherosclerotic cardiovascular disease (Count of Participants)
Count of Participants [Participants]	93 14.9%	106 17%	199 15.9%
Chronic kidney disease, estimated glomerular filtration rate (eGFR) 25-60 mL/min per 1.73 m^2 (Count of Participants)
Count of Participants [Participants]	38 6.1%	44 7%	82 6.6%
Patients with two or more inclusion risk factors (Count of Participants)
Count of Participants [Participants]	292 46.7%	319 51%	611 48.9%
Age >/= 60 years (Count of Participants)
Count of Participants [Participants]	339 54.2%	360 57.6%	699 55.9%
Body Mass Index >/= 30 (Count of Participants)
Count of Participants [Participants]	296 47.4%	305 48.8%	601 48.1%
Chronic obstructive pulmonary disease (Count of Participants)
Count of Participants [Participants]	25 4%	32 5.1%	57 4.6%
Current smoker (Count of Participants)
Count of Participants [Participants]	29 4.6%	20 3.2%	49 3.9%
Heart rate (beats per minute) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [beats per minute]	79.3 (13.7)	79.7 (13.7)	79.5 (13.7)
Blood pressure - systolic (mm Hg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mm Hg]	126.6 (16.0)	127.0 (16.3)	126.8 (16.1)
Blood pressure - diastolic (mm Hg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mm Hg]	76.6 (10.9)	76.2 (10.6)	76.4 (10.7)
Temperature (degrees Celcius) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [degrees Celcius]	36.4 (0.6)	36.4 (0.7)	36.4 (0.6)
Oxygen saturation (% (measured on supplemental oxygen)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [% (measured on supplemental oxygen)]	95.5 (1.7)	95.2 (1.8)	95.3 (1.8)
eGFR (mL/min per 1.73 m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mL/min per 1.73 m^2]	84.1 (25.0)	83.4 (24.6)	83.8 (24.8)
SARS-CoV-2 test result at baseline (Count of Participants)
Positive	584 93.4%	575 92%	1159 92.7%
Negative	30 4.8%	35 5.6%	65 5.2%
Test results not known	11 1.8%	15 2.4%	26 2.1%
Angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) (Count of Participants)
Count of Participants [Participants]	225 36%	219 35%	444 35.5%
Beta-blocker (Count of Participants)
Count of Participants [Participants]	93 14.9%	98 15.7%	191 15.3%
Calcium blocker (Count of Participants)
Count of Participants [Participants]	84 13.4%	88 14.1%	172 13.8%
Loop-diuretic (Count of Participants)
Count of Participants [Participants]	49 7.8%	63 10.1%	112 9%
Statin (Count of Participants)
Count of Participants [Participants]	122 19.5%	144 23%	266 21.3%
Anti-coagulant (Count of Participants)
Count of Participants [Participants]	527 84.3%	527 84.3%	1054 84.3%
Biguanide (Count of Participants)
Count of Participants [Participants]	82 13.1%	75 12%	157 12.6%
Sulfonylurea (Count of Participants)
Count of Participants [Participants]	24 3.8%	22 3.5%	46 3.7%
Dipeptidyl peptidase 4 (DPP-4) inhibitor (Count of Participants)
Count of Participants [Participants]	17 2.7%	11 1.8%	28 2.2%
Glucagon-like peptide 1 (GLP-1) receptor agonist (Count of Participants)
Count of Participants [Participants]	6 1%	8 1.3%	14 1.1%
Insulin (Count of Participants)
Count of Participants [Participants]	223 35.7%	221 35.4%	444 35.5%
Remdesivir (Count of Participants)
Count of Participants [Participants]	114 18.2%	111 17.8%	225 18%
Systemic corticosteroids (Count of Participants)
Count of Participants [Participants]	176 28.2%	179 28.6%	355 28.4%
Dexamethasone (Count of Participants)
Count of Participants [Participants]	133 21.3%	136 21.8%	269 21.5%
Other systemic glucocorticoid (Count of Participants)
Count of Participants [Participants]	50 8%	55 8.8%	105 8.4%

Outcome Measures

1. Primary Outcome

Title	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.
Description	Time to first occurrence of new/worsened organ dysfunction during index hospitalization or death from any cause. Event rates are presented as the number of subjects with event per 100 patient month (30 days) of follow-up. Unit of Measure: Patients with events per 100 patient-months (pt-mos) at risk. 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 extracorporeal membrane oxygenation (ECMO) New or worsening congestive heart failure 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
Time Frame	Randomization through Day 30

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dapagliflozin 10mg	Placebo
Arm/Group Description	Dapagliflozin 10 mg daily Dapagliflozin 10 MG: Active Comparator: Dapagliflozin 10mg	Dapagliflozin matching placebo 10 mg daily Placebo: Placebo Comparator
Measure Participants	625	625
Number [Patients with events/100 pt-mos at risk]	12.4	15.6

2. Primary Outcome

Title	Improving Clinical Recovery: Hierarchical Composite Outcome Measure Including Death From Any Cause Through Day 30, New/Worsened Organ Dysfunction, Clinical Status at Day 30 and Hospital Discharge Before Day 30 and Alive at Day 30.
Description	The number of patients experiencing improvement by day 30 compared with baseline (discharged from hospital without a worsening event and alive, or still in hospital without a worsening event and without oxygen support) in the hierarchical composite endpoint analysis. Hierarchical composite outcome measure includes: Death from any cause through Day 30 New/worsened organ dysfunction Clinical status at Day 30 for patients still hospitalized and without any worsening organ dysfunction Hospital discharge before Day 30 and alive at Day 30
Time Frame	Randomization through Day 30

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dapagliflozin 10mg	Placebo
Arm/Group Description	Dapagliflozin 10 mg daily Dapagliflozin 10 MG: Active Comparator: Dapagliflozin 10mg	Dapagliflozin matching placebo 10 mg daily Placebo: Placebo Comparator
Measure Participants	625	625
Number [participants]	547 87.5%	532 85.1%

3. Secondary Outcome

Title	Time to Hospital Discharge
Description	Time to hospital discharge (refers to index hospitalization only). Median time to hospital discharge is presented in days.
Time Frame	Randomization through Day 30

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dapagliflozin 10mg	Placebo
Arm/Group Description	Dapagliflozin 10 mg daily Dapagliflozin 10 MG: Active Comparator: Dapagliflozin 10mg	Dapagliflozin matching placebo 10 mg daily Placebo: Placebo Comparator
Measure Participants	625	625
Median (95% Confidence Interval) [days]	5	6

4. Secondary Outcome

Title	Total Number of Days Alive and Free From Respiratory Decompensation Requiring Initiation of Mechanical Ventilation (Includes Invasive or Non-invasive Ventilation, CPAP, or BiPAP)
Description	Total number of days alive and free from mechanical ventilation (includes invasive or non-invasive ventilation, CPAP, or BiPAP) is calculated for each patient as total follow-up time (30 days) substracted days in hospital with mechanical ventilation and days dead.
Time Frame	Randomization through Day 30

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dapagliflozin 10mg	Placebo
Arm/Group Description	Dapagliflozin 10 mg daily Dapagliflozin 10 MG: Active Comparator: Dapagliflozin 10mg	Dapagliflozin matching placebo 10 mg daily Placebo: Placebo Comparator
Measure Participants	625	625
Mean (Standard Deviation) [days]	27.8 (6.8)	27.4 (7.4)

5. Secondary Outcome

Title	Total Number of Days Alive, Not in the ICU, and Free From Respiratory Decompensation Requiring Initiation of Mechanical Ventilation (Includes Invasive or Non-invasive Ventilation, CPAP, or BiPAP)
Description	Total number of days alive, not in the ICU and free from mechanical ventilation (includes invasive or non-invasive ventilation, CPAP, or BiPAP) is calculated for each patient as total follow-up time (30 days) substracted days in ICU and days dead.
Time Frame	Randomization through Day 30

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dapagliflozin 10mg	Placebo
Arm/Group Description	Dapagliflozin 10 mg daily Dapagliflozin 10 MG: Active Comparator: Dapagliflozin 10mg	Dapagliflozin matching placebo 10 mg daily Placebo: Placebo Comparator
Measure Participants	625	625
Mean (Standard Deviation) [days]	27.5 (7.2)	27.1 (7.7)

6. Secondary Outcome

Title	Time to Composite of Acute Kidney Injury or Initiation of Renal Replacement Therapy, or Death From Any Cause
Description	Acute kidney injury is defined as an episode of doubling s-creatinine compared to baseline during index hospitalization or SAE. Initiation of renal replacement therapy is defined as initiation of renal replacement therapy during index hospitalization or SAE. Event rates are presented as the number of subjects with event per 100 patient month (30 days) of follow-up. Unit of Measure: Patients with events per 100 patient-months (pt-mos) at risk.
Time Frame	Randomization through Day 30

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dapagliflozin 10mg	Placebo
Arm/Group Description	Dapagliflozin 10 mg daily Dapagliflozin 10 MG: Active Comparator: Dapagliflozin 10mg	Dapagliflozin matching placebo 10 mg daily Placebo: Placebo Comparator
Measure Participants	625	625
Number [Patients with events/100 pt-mos at risk]	8.2	11.2

7. Secondary Outcome

Title	Time to Death From Any Cause
Description	Time to death from any cause. Event rates are presented as the number of subjects with event per 100 patient month (30 days) of follow-up. Unit of Measure: Patients with events per 100 patient-months (pt-mos) at risk.
Time Frame	Randomization through Day 30

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dapagliflozin 10mg	Placebo
Arm/Group Description	Dapagliflozin 10 mg daily Dapagliflozin 10 MG: Active Comparator: Dapagliflozin 10mg	Dapagliflozin matching placebo 10 mg daily Placebo: Placebo Comparator
Measure Participants	625	625
Number [Patients with events/100 pt-mos at risk]	6.8	9.0

Adverse Events

Time Frame	Adverse events were collected from the time of signing informed consent through the end of the 30-day treatment period.
Adverse Event Reporting Description	All-cause mortality was monitored in the total started population of 1250 patients. Serious adverse events, adverse events resulting in the discontinuation of study drug, and safety events of acute kidney injury and diabetic ketoacidosis were monitored in the safety population defined as patients who received at least one dose of study medication. 613 patients in the dapagliflozin group and 616 patients in the placebo group received at least one dose of study medication.
Arm/Group Title	Dapagliflozin 10mg		Placebo
Arm/Group Description	Dapagliflozin 10 mg daily Dapagliflozin 10 MG: Active Comparator: Dapagliflozin 10mg		Dapagliflozin matching placebo 10 mg daily Placebo: Placebo Comparator
All Cause Mortality
	Dapagliflozin 10mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	41/625 (6.6%)		54/625 (8.6%)
Serious Adverse Events
	Dapagliflozin 10mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	70/613 (11.4%)		87/616 (14.1%)
Blood and lymphatic system disorders
Anemia	0/613 (0%)		1/616 (0.2%)
Cardiac disorders
Cardio-respiratory arrest	3/613 (0.5%)		2/616 (0.3%)
Atrial fibrillation	1/613 (0.2%)		2/616 (0.3%)
Cardiac failure	1/613 (0.2%)		1/616 (0.2%)
Cardiac failure acute	1/613 (0.2%)		0/616 (0%)
Acute myocardial infarction	1/613 (0.2%)		1/616 (0.2%)
Cardiac arrest	1/613 (0.2%)		1/616 (0.2%)
Cardiac failure congestive	0/613 (0%)		1/616 (0.2%)
Myocardial infarction	0/613 (0%)		1/616 (0.2%)
Cardiac Disorder	1/613 (0.2%)		0/616 (0%)
Arrhythmia	0/613 (0%)		1/616 (0.2%)
Gastrointestinal disorders
Abdominal pain	1/613 (0.2%)		0/616 (0%)
Gastrointestinal hemorrhage	1/613 (0.2%)		0/616 (0%)
Pancreatitis acute	0/613 (0%)		1/616 (0.2%)
Upper gastrointestinal hemorrhage	0/613 (0%)		1/616 (0.2%)
General disorders
Asthenia	1/613 (0.2%)		1/616 (0.2%)
Multiple organ dysfunction syndrome	3/613 (0.5%)		5/616 (0.8%)
General physical health deterioration	0/613 (0%)		1/616 (0.2%)
Infections and infestations
COVID-19	5/613 (0.8%)		3/616 (0.5%)
Septic Shock	5/613 (0.8%)		6/616 (1%)
Severe acute respiratory syndrome	3/613 (0.5%)		3/616 (0.5%)
COVID-19 pneumonia	1/613 (0.2%)		4/616 (0.6%)
Device related sepsis	1/613 (0.2%)		0/616 (0%)
Emphysematous pyelonephritis	1/613 (0.2%)		0/616 (0%)
Herpes virus infection	1/613 (0.2%)		0/616 (0%)
Infection	1/613 (0.2%)		1/616 (0.2%)
Meningoencephalitis herpetic	1/613 (0.2%)		0/616 (0%)
Sepsis	1/613 (0.2%)		3/616 (0.5%)
Labyrinthitis	0/613 (0%)		1/616 (0.2%)
Pneumonia	0/613 (0%)		8/616 (1.3%)
Pneumonia bacterial	0/613 (0%)		2/616 (0.3%)
Pulmonary sepsis	1/613 (0.2%)		1/616 (0.2%)
Urinary tract infection enterococcal	0/613 (0%)		1/616 (0.2%)
Injury, poisoning and procedural complications
Femur fracture	0/613 (0%)		1/616 (0.2%)
Rib fracture	0/613 (0%)		1/616 (0.2%)
Investigations
Blood electrolytes abnormal	1/613 (0.2%)		0/616 (0%)
Blood creatinine increased	0/613 (0%)		1/616 (0.2%)
Metabolism and nutrition disorders
Lactic acidosis	2/613 (0.3%)		0/616 (0%)
Diabetic ketoacidosis	1/613 (0.2%)		0/616 (0%)
Diabetic metabolic decompensation	1/613 (0.2%)		0/616 (0%)
Euglycemic diabetic ketoacidosis	1/613 (0.2%)		0/616 (0%)
Hyperkalemia	1/613 (0.2%)		0/616 (0%)
Metabolic acidosis	1/613 (0.2%)		0/616 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Transitional cell carcinoma	1/613 (0.2%)		0/616 (0%)
Prostate cancer	0/613 (0%)		1/616 (0.2%)
Nervous system disorders
Ischemic stroke	1/613 (0.2%)		0/616 (0%)
Myasthenia gravis	1/613 (0.2%)		0/616 (0%)
Cerebral disorder	0/613 (0%)		1/616 (0.2%)
Cerebrovascular accident	0/613 (0%)		1/616 (0.2%)
Presnycope	0/613 (0%)		1/616 (0.2%)
Syncope	0/613 (0%)		1/616 (0.2%)
Psychiatric disorders
Psychotic disorder	1/613 (0.2%)		0/616 (0%)
Renal and urinary disorders
Acute kidney injury	21/613 (3.4%)		32/616 (5.2%)
Renal impairment	1/613 (0.2%)		1/616 (0.2%)
Renal injury	0/613 (0%)		2/616 (0.3%)
Respiratory, thoracic and mediastinal disorders
Respiratory failure	11/613 (1.8%)		11/616 (1.8%)
Acute respiratory failure	4/613 (0.7%)		4/616 (0.6%)
Hypoxia	3/613 (0.5%)		2/616 (0.3%)
Pulmonary embolism	2/613 (0.3%)		2/616 (0.3%)
Respiration abnormal	1/613 (0.2%)		0/616 (0%)
Chronic obstructive pulmonary disease	0/613 (0%)		1/616 (0.2%)
Dyspnea	0/613 (0%)		2/616 (0.3%)
Pneumothorax	0/613 (0%)		1/616 (0.2%)
Pulmonary edema	0/613 (0%)		2/616 (0.3%)
Respiratory distress	0/613 (0%)		2/616 (0.3%)
Respiratory tract inflammation	0/613 (0%)		1/616 (0.2%)
Vascular disorders
Arterial thrombosis	1/613 (0.2%)		0/616 (0%)
Deep vein thrombosis	1/613 (0.2%)		0/616 (0%)
Hemorrhage	0/613 (0%)		1/616 (0.2%)
Hypovolemic shock	1/613 (0.2%)		1/616 (0.2%)
Shock	1/613 (0.2%)		2/616 (0.3%)
Other (Not Including Serious) Adverse Events
	Dapagliflozin 10mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/613 (0.3%)		2/616 (0.3%)
Renal and urinary disorders
Acute Kidney Injury	2/613 (0.3%)		2/616 (0.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The sponsor can review results communications prior to public release and can embargo communications regarding results for a period that is less than or equal to 45 days from the time submitted to the sponsor for review. The sponsor cannot require changes to the communication with the exception of requiring the removal of confidential information. The embargo can be extended to 90 days if there would be any patent applications to be filed by the sponsor related to the proposed publication.