Dapagliflozin in Respiratory Failure in Patients With COVID-19

COVID-19 Clinical Trial

— DARE-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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04350593
• Other study ID #: D1690C00081
• Secondary ID: ESR-20-20653
• Status: Completed
• Phase: Phase 3
• Start date: April 22, 2020
• Est. completion date: June 11, 2021

Study information

• Verified date: May 2022
• Source: Saint Luke's Health System
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1250
• Est. completion date: June 11, 2021
• Est. primary completion date: March 31, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• COVID-19
• Respiratory Insufficiency

Intervention

Drug:
• Dapagliflozin 10 milligram (mg)
Active Comparator: Dapagliflozin 10 mg
• Placebo
Placebo Comparator

Locations

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

Sponsors (4)

Lead Sponsor	Collaborator
Saint Luke's Health System	AstraZeneca, George Clinical Pty Ltd, Saint Luke's Hospital of Kansas City

Countries where clinical trial is conducted

United States,  Argentina,  Brazil,  Canada,  India,  Mexico,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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