Dapagliflozin in Respiratory Failure in Patients With COVID-19 (DARE-19)

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

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.

Study Overview

• Status: Completed
• Conditions: COVID-19
• Intervention / Treatment: Drug: Placebo; Drug: Dapagliflozin 10 milligram (mg)

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 Type: Interventional
• Enrollment (Actual): 1250
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • Sanatorio Güemes
  • Buenos Aires, Argentina
    • Fundacion Favaloro
  • Buenos Aires, Argentina
    • Hospital Español
  • Buenos Aires, Argentina
    • Hospital Fernandez
  • Buenos Aires, Argentina
    • Hospital Pirovano
  • Buenos Aires, Argentina
    • Hospital Santojanni
  • Buenos Aires, Argentina
    • Sanatorio Anchorena
  • Córdoba, Argentina
    • Clínica Vélez Sarsfield
  • Córdoba, Argentina
    • Hospital San Roque
  • Córdoba, Argentina
    • Sanatorio Privado Duarte Quiros de Clinica Colombo S.A.
  • Province Of Córdoba
    • Villa María, Province Of Córdoba, Argentina
      • Clínica de Especialidades Villa María
• Brazil
  • Barretos, Brazil, 14784-400
    • Fundação PIO XII
  • Rio de Janeiro, Brazil, 20725-090
    • Hospital Naval Marcílio Dias
  • São Paulo, Brazil, 04556-100
    • Hospital Santa Paula
  • São Paulo, Brazil, 04083-002
    • Hospital Moriah
  • São Paulo, Brazil, 05403-900
    • InCor - Instituto do Coração do Hospital das Clínicas FMUSP
  • Alagoas
    • Maceió, Alagoas, Brazil, 57051-160
      • Centro de Pesquisa Dr. Marco Mota
  • Bahia
    • Feira de Santana, Bahia, Brazil, 44035-010
      • Hospital EMEC e Hospital da Cidade
    • Ipiaú, Bahia, Brazil, 45570-000
      • Hospital e Clínica São Roque
    • Porto Seguro, Bahia, Brazil, 45810-000
      • Hospital Regional Deputado Luis Eduardo Magalhães
    • Salvador, Bahia, Brazil, 41950-275
      • Hospital Cardio Pulmonar
  • Ceará
    • Barbalha, Ceará, Brazil, 63180-000
      • Hospital Maternidade São Vicente de Paulo
    • Fortaleza, Ceará, Brazil, 60055-172
      • Unimed de Fortaleza
    • Fortaleza, Ceará, Brazil, 60840-285
      • Hospital de Messejana Dr Carlos Alberto Studart Gomes
  • Distrito Federal
    • Brasília, Distrito Federal, Brazil, 70390-700
      • Hospital Coração do Brasil
  • Espírito Santo
    • Serra, Espírito Santo, Brazil, 29166-828
      • Hospital Estadual Jayme dos Santos Neves
  • Goias
    • Goiania, Goias, Brazil, 74690-900
      • Liga de Hipertensão Arterial
  • Minas Gerais
    • Passos, Minas Gerais, Brazil, 37904-020
      • Santa Casa de Misericórdia de Passos
    • Uberaba, Minas Gerais, Brazil, 38025-440
      • Hospital São Domingos - Unimed Uberaba
  • Pernambuco
    • Recife, Pernambuco, Brazil, 50100-060
      • Procape
  • Rio Grande Do Norte
    • Natal, Rio Grande Do Norte, Brazil, 59037-170
      • Hospital Giselda Trigueiro
  • Rio Grande Do Sul
    • Bento Gonçalves, Rio Grande Do Sul, Brazil, 95700-084
      • Associação Dr. Bartholomeu Tacchini
    • Passo Fundo, Rio Grande Do Sul, Brazil, 99010-080
      • Hospital Sao Vicente de Paulo
    • Porto Alegre, Rio Grande Do Sul, Brazil, 90110-270
      • Hospital Mãe de Deus
    • Porto Alegre, Rio Grande Do Sul, Brazil, 90020-090
      • Irmandade da Santa Casa de Misericordia de Porto Alegre
  • Santa Catarina
    • Criciuma, Santa Catarina, Brazil, 88811-250
      • Hospital São José - Criciúma
    • Itajai, Santa Catarina, Brazil, 88301-303
      • IPEMI- Instituto de Pesquisas Médicas de Itajaí
    • Joinville, Santa Catarina, Brazil, 74605-050
      • Hospital Municipal Sao Jose
    • Joinville, Santa Catarina, Brazil, 89228-025
      • Hospital Regional Hans Dieter Schmidt
  • Sergipe
    • Aracaju, Sergipe, Brazil, 49055-530
      • Centro de Pesquisa Clinica do Coracao
  • São Paulo
    • Botucatu, São Paulo, Brazil, 18618-687
      • Faculdade de Medicina de Botucatu, Unesp
    • Campinas, São Paulo, Brazil, 13060-904
      • Instituto de Pesquisa Clínica de Campinas
    • Ribeirão Preto, São Paulo, Brazil, 14110-000
      • Unimed Ribeirão Preto
    • Santo André, São Paulo, Brazil, 09090-790
      • Fundação do ABC (Hospital Estadual Mário Covas)
    • São José do Rio Preto, São Paulo, Brazil, 15090-000
      • Centro Integrado de Pesquisas
    • Votuporanga, São Paulo, Brazil, 15500-003
      • Santa Casa de Votuporanga
• Canada
  • Ontario
    • Oakville, Ontario, Canada
      • Halton Healthcare Services
    • Oshawa, Ontario, Canada
      • Lakeridge Health
• India
  • Ahmedabad
    • Sola, Ahmedabad, India, 400022
      • CIMS Hospital Pvt. Ltd
  • Chennai-89
    • Manapakkam, Chennai-89, India
      • MIOT International Hospitals
  • Delhi
    • New Delhi, Delhi, India, 110029
      • All India Institute of Medical Science
  • Gujarat
    • Ahmedabad, Gujarat, India, 380015
      • Sanjivani Super Speciality Hospital Pvt Ltd
  • Maharashtra
    • Mumbai, Maharashtra, India, 400022
      • Lokmanya Tilak General Hospital
  • New Delhi
    • Saket, New Delhi, India, 110017
      • Max Smart Super Speciality Hospital
    • Saket, New Delhi, India, 110017
      • Max Super Speciality Hospital (A unit of Devki Devi Foundation)
  • Punjab
    • Ludhiāna, Punjab, India, 141001
      • Dayanand Medical College & Hospital
• Mexico
  • Acapulco, Mexico
    • Hospital Del Prado
  • Chihuahua, Mexico
    • Icaro Investigaciones en Medicina
  • Cuernavaca, Mexico
    • HG de Cuernavaca Dr. Jose G Parres
  • Cuernavaca, Mexico
    • JM Research
  • Durango, Mexico
    • Instituto de Investigaciones Aplicadas a la Neurosciencias
  • Guadalajara, Mexico
    • Antiguo Hospital Civil de Guadalajara "Fray Antonio Alcade"
  • Guadalajara, Mexico
    • Hospital San Javier
  • Guanajuato, Mexico
    • Invesclinic Mx
  • Jalisco, Mexico
    • CIMEZAP
  • Mexico City, Mexico
    • Hospital Medica Sur
  • Monterrey, Mexico
    • Hospital Clinica Nova
  • Monterrey, Mexico
    • Hospital San Jose TEC Salud
  • Puebla, Mexico
    • ECI Estudios Clinicos Internacionales
  • Queretaro, Mexico
    • Hospital SMIQ
  • Sonora, Mexico
    • Investigacion Medica Sonora
  • Toluca, Mexico
    • Sanatorio Santa Cruz de Toluca
• United Kingdom
  • Cb2 0qq
    • Cambridge, Cb2 0qq, United Kingdom
      • Addenbrooke's Hospital
• United States
  • Alabama
    • Fairhope, Alabama, United States, 36532
      • Heart Group of the Eastern Shore
  • Florida
    • Miami, Florida, United States, 33176
      • Baptist Hospital of Miami
  • Illinois
    • Evanston, Illinois, United States, 60201
      • NorthShore University HealthSystem
    • Maywood, Illinois, United States, 60153
      • Loyola University
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • Ascension - St. Vincent
  • Massachusetts
    • Burlington, Massachusetts, United States, 01805
      • Lahey Health
  • Michigan
    • Auburn Hills, Michigan, United States, 48326
      • McLaren Health Care
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Saint Luke's Mid America Heart Institute
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • Bronx, New York, United States, 10461
      • Jacobi Medical Center
    • Brooklyn, New York, United States, 11219
      • Maimonides Medical Center
    • Brooklyn, New York, United States, 11203
      • SUNY Downstate Medical Center
    • Roslyn, New York, United States, 11576
      • St. Francis Hospital
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina at Chapel Hill
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest Baptist Health
  • Pennsylvania
    • Lancaster, Pennsylvania, United States, 17604
      • Lancaster General Hospital
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
  • Tennessee
    • Memphis, Tennessee, United States, 38103
      • Clinical Trials Network of Tennessee
  • Texas
    • Edinburg, Texas, United States, 78539
      • DHR Health Institute for Research and Development
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
  • Virginia
    • Norfolk, Virginia, United States, 23507
      • Sentara Healthcare

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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:

   1. hypertension
   2. type 2 diabetes
   3. atherosclerotic cardiovascular disease
   4. heart failure (with either reduced or preserved left ventricular ejection fraction (LVEF))
   5. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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	Randomization through Day 30
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.	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	Randomization through Day 30

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Hospital Discharge	Time to hospital discharge (refers to index hospitalization only). Median time to hospital discharge is presented in days.	Randomization through Day 30
Total Number of Days Alive and Free From Respiratory Decompensation Requiring Initiation of Mechanical Ventilation (Includes Invasive or Non-invasive Ventilation, CPAP, or BiPAP)	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.	Randomization through Day 30
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)	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.	Randomization through Day 30
Time to Composite of Acute Kidney Injury or 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. 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.	Randomization through Day 30
Time to Death From Any Cause	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.	Randomization through Day 30

Collaborators and Investigators

• Sponsor: Saint Luke's Health System
• Collaborators: AstraZeneca; George Clinical Pty Ltd; Saint Luke's Hospital of Kansas City
• Investigators: Study Chair: Mikhail Kosiborod, MD, Saint Luke's Mid America Heart Institute

Publications and helpful links

General Publications

• Gasparyan SB, Buenconsejo J, Kowalewski EK, Oscarsson J, Bengtsson OF, Esterline R, Koch GG, Berwanger O, Kosiborod MN. Design and Analysis of Studies Based on Hierarchical Composite Endpoints: Insights from the DARE-19 Trial. Ther Innov Regul Sci. 2022 Sep;56(5):785-794. doi: 10.1007/s43441-022-00420-1. Epub 2022 Jun 14.
• Kosiborod MN, Esterline R, Furtado RHM, Oscarsson J, Gasparyan SB, Koch GG, Martinez F, Mukhtar O, Verma S, Chopra V, Buenconsejo J, Langkilde AM, Ambery P, Tang F, Gosch K, Windsor SL, Akin EE, Soares RVP, Moia DDF, Aboudara M, Hoffmann Filho CR, Feitosa ADM, Fonseca A, Garla V, Gordon RA, Javaheri A, Jaeger CP, Leaes PE, Nassif M, Pursley M, Silveira FS, Barroso WKS, Lazcano Soto JR, Nigro Maia L, Berwanger O. Dapagliflozin in patients with cardiometabolic risk factors hospitalised with COVID-19 (DARE-19): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol. 2021 Sep;9(9):586-594. doi: 10.1016/S2213-8587(21)00180-7. Epub 2021 Jul 21.

Study record dates

Study Major Dates

• Study Start (Actual): April 22, 2020
• Primary Completion (Actual): March 31, 2021
• Study Completion (Actual): June 11, 2021

Study Registration Dates

• First Submitted: April 14, 2020
• First Submitted That Met QC Criteria: April 14, 2020
• First Posted (Actual): April 17, 2020

Study Record Updates

• Last Update Posted (Actual): June 10, 2022
• Last Update Submitted That Met QC Criteria: May 13, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: COVID-19; dapagliflozin; sodium-glucose cotransporter-2 inhibitor (SGLT2i)
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Respiration Disorders; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Respiratory Insufficiency; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: D1690C00081; ESR-20-20653 (Other Grant/Funding Number: Astra Zeneca)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No