Clinical trial NCT04350593: Dapagliflozin in Respiratory Failure in Patients With COVID-19
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: COVID-19
Keywords: sodium-glucose cotransporter-2 inhibitor (SGLT2i)
dapagliflozin
COVID-19
Lead sponsor: Saint Luke's Health System
Sponsor class: OTHER
Collaborators: name: St. Luke's Hospital, Kansas City, Missouri
name: AstraZeneca
name: George Clinical Pty Ltd
First posted: 2020-04-17
Enrollment: 1250
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: 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.
timeFrame: Randomization through Day 30
measure: 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.
timeFrame: Randomization through Day 30
Secondary outcomes:
measure: Time to Hospital Discharge
timeFrame: Randomization through Day 30
measure: Total Number of Days Alive and Free From Respiratory Decompensation Requiring Initiation of Mechanical Ventilation (Includes Invasive or Non-invasive Ventilation, CPAP, or BiPAP)
timeFrame: Randomization through Day 30
measure: 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)
timeFrame: Randomization through Day 30
measure: Time to Composite of Acute Kidney Injury or Initiation of Renal Replacement Therapy, or Death From Any Cause
timeFrame: Randomization through Day 30
measure: Time to Death From Any Cause
timeFrame: Randomization through Day 30
Other outcomes:
Locations:
city: Fairhope
country: United States
facility: Heart Group of the Eastern Shore
state: Alabama
city: Miami
country: United States
facility: Baptist Hospital of Miami
state: Florida
city: Evanston
country: United States
facility: NorthShore University HealthSystem
state: Illinois
city: Maywood
country: United States
facility: Loyola University
state: Illinois
city: Indianapolis
country: United States
facility: Ascension - St. Vincent
state: Indiana
city: Burlington
country: United States
facility: Lahey Health
state: Massachusetts
city: Auburn Hills
country: United States
facility: McLaren Health Care
state: Michigan
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Kansas City
country: United States
facility: Saint Luke's Mid America Heart Institute
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Bronx
country: United States
facility: Jacobi Medical Center
state: New York
city: Brooklyn
country: United States
facility: SUNY Downstate Medical Center
state: New York
city: Brooklyn
country: United States
facility: Maimonides Medical Center
state: New York
city: Roslyn
country: United States
facility: St. Francis Hospital
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Health
state: North Carolina
city: Lancaster
country: United States
facility: Lancaster General Hospital
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Memphis
country: United States
facility: Clinical Trials Network of Tennessee
state: Tennessee
city: Edinburg
country: United States
facility: DHR Health Institute for Research and Development
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Norfolk
country: United States
facility: Sentara Healthcare
state: Virginia
city: Villa María
country: Argentina
facility: Clínica de Especialidades Villa María
state: Province Of Córdoba
city: Buenos Aires
country: Argentina
facility: Fundación Favaloro
city: Buenos Aires
country: Argentina
facility: Hospital Español
city: Buenos Aires
country: Argentina
facility: Hospital Fernández
city: Buenos Aires
country: Argentina
facility: Hospital Pirovano
city: Buenos Aires
country: Argentina
facility: Hospital Santojanni
city: Buenos Aires
country: Argentina
facility: Sanatorio Anchorena
city: Buenos Aires
country: Argentina
facility: Sanatorio Güemes
city: Córdoba
country: Argentina
facility: Clínica Vélez Sarsfield
city: Córdoba
country: Argentina
facility: Hospital San Roque
city: Córdoba
country: Argentina
facility: Sanatorio Privado Duarte Quiros de Clinica Colombo S.A.
city: Maceió
country: Brazil
facility: Centro de Pesquisa Dr. Marco Mota
state: Alagoas
city: Feira de Santana
country: Brazil
facility: Hospital EMEC e Hospital da Cidade
state: Bahia
city: Ipiaú
country: Brazil
facility: Hospital e Clínica São Roque
state: Bahia
city: Porto Seguro
country: Brazil
facility: Hospital Regional Deputado Luis Eduardo Magalhães
state: Bahia
city: Salvador
country: Brazil
facility: Hospital Cárdio Pulmonar
state: Bahia
city: Barbalha
country: Brazil
facility: Hospital Maternidade São Vicente de Paulo
state: Ceará
city: Fortaleza
country: Brazil
facility: Unimed de Fortaleza
state: Ceará
city: Fortaleza
country: Brazil
facility: Hospital de Messejana Dr Carlos Alberto Studart Gomes
state: Ceará
city: Brasília
country: Brazil
facility: Hospital Coração do Brasil
state: Distrito Federal
city: Serra
country: Brazil
facility: Hospital Estadual Jayme dos Santos Neves
state: Espírito Santo
city: Goiania
country: Brazil
facility: Liga de Hipertensão Arterial
state: Goias
city: Passos
country: Brazil
facility: Santa Casa de Misericórdia de Passos
state: Minas Gerais
city: Uberaba
country: Brazil
facility: Hospital São Domingos - Unimed Uberaba
state: Minas Gerais
city: Recife
country: Brazil
facility: PROCAPE
state: Pernambuco
city: Natal
country: Brazil
facility: Hospital Giselda Trigueiro
state: Rio Grande Do Norte
city: Bento Gonçalves
country: Brazil
facility: Associação Dr. Bartholomeu Tacchini
state: Rio Grande Do Sul
city: Passo Fundo
country: Brazil
facility: Hospital São Vicente de Paulo
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: Irmandade da Santa Casa de Misericórdia de Porto Alegre
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: Hospital Mãe de Deus
state: Rio Grande Do Sul
city: Criciuma
country: Brazil
facility: Hospital São José - Criciúma
state: Santa Catarina
city: Itajai
country: Brazil
facility: IPEMI- Instituto de Pesquisas Médicas de Itajaí
state: Santa Catarina
city: Joinville
country: Brazil
facility: Hospital Municipal São José
state: Santa Catarina
city: Joinville
country: Brazil
facility: Hospital Regional Hans Dieter Schmidt
state: Santa Catarina
city: Aracaju
country: Brazil
facility: Centro de Pesquisa Clínica do Coração
state: Sergipe
city: Botucatu
country: Brazil
facility: Faculdade de Medicina de Botucatu, UNESP
state: São Paulo
city: Campinas
country: Brazil
facility: Instituto de Pesquisa Clínica de Campinas
state: São Paulo
city: Ribeirão Preto
country: Brazil
facility: Unimed Ribeirao Preto
state: São Paulo
city: Santo André
country: Brazil
facility: Fundação do ABC (Hospital Estadual Mário Covas)
state: São Paulo
city: São José do Rio Preto
country: Brazil
facility: Centro Integrado de Pesquisas
state: São Paulo
city: Votuporanga
country: Brazil
facility: Santa Casa de Votuporanga
state: São Paulo
city: Barretos
country: Brazil
facility: Fundação Pio XII
city: Rio de Janeiro
country: Brazil
facility: Hospital Naval Marcílio Dias
city: São Paulo
country: Brazil
facility: Hospital Moriah
city: São Paulo
country: Brazil
facility: Hospital Santa Paula
city: São Paulo
country: Brazil
facility: InCor - Instituto do Coração do Hospital das Clínicas FMUSP
city: Oakville
country: Canada
facility: Halton Healthcare Services
state: Ontario
city: Oshawa
country: Canada
facility: Lakeridge Health
state: Ontario
city: Sola
country: India
facility: CIMS Hospital Pvt. Ltd
state: Ahmedabad
city: Manapakkam
country: India
facility: MIOT International Hospitals
state: Chennai-89
city: New Delhi
country: India
facility: All India Institute of Medical Science
state: Delhi
city: Ahmedabad
country: India
facility: Sanjivani Super Speciality Hospital Pvt Ltd
state: Gujarat
city: Mumbai
country: India
facility: Lokmanya Tilak General Hospital
state: Maharashtra
city: Saket
country: India
facility: Max Smart Super Speciality Hospital
state: New Delhi
city: Saket
country: India
facility: Max Super Speciality Hospital (A unit of Devki Devi Foundation)
state: New Delhi
city: Ludhiāna
country: India
facility: Dayanand Medical College & Hospital
state: Punjab
city: Acapulco
country: Mexico
facility: Hospital del Prado
city: Chihuahua
country: Mexico
facility: Icaro Investigaciones en Medicina
city: Cuernavaca
country: Mexico
facility: HG de Cuernavaca Dr. Jose G Parres
city: Cuernavaca
country: Mexico
facility: JM Research
city: Durango
country: Mexico
facility: Instituto de Investigaciones Aplicadas a la Neurosciencias
city: Guadalajara
country: Mexico
facility: Antiguo Hospital Civil de Guadalajara "Fray Antonio Alcade"
city: Guadalajara
country: Mexico
facility: Hospital San Javier
city: Guanajuato
country: Mexico
facility: Invesclinic MX
city: Jalisco
country: Mexico
facility: CIMEZAP
city: Mexico City
country: Mexico
facility: Hospital Medica Sur
city: Monterrey
country: Mexico
facility: Hospital Clinica Nova
city: Monterrey
country: Mexico
facility: Hospital San Jose TEC Salud
city: Puebla
country: Mexico
facility: ECI Estudios Clinicos Internacionales
city: Queretaro
country: Mexico
facility: Hospital SMIQ
city: Sonora
country: Mexico
facility: Investigacion Medica Sonora
city: Toluca
country: Mexico
facility: Sanatorio Santa Cruz de Toluca
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
state: Cb2 0qq
Study officials:
affiliation: Saint Luke's Mid America Heart Institute
name: Mikhail Kosiborod, MD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.