Dapagliflozin in Respiratory Failure in Patients With COVID-19

Phase 3

Completed

Conditions: COVID-19

Interventions: Drug: Dapagliflozin 10 milligram (mg)
Drug: Placebo

Registration Number: NCT04350593

Lead Sponsor: Saint Luke's Health System

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 1250

Inclusion Criteria

Provision of informed consent
Male or female patients aged ≥18 years
Currently hospitalized
Hospital admission no more than 4 days prior to screening
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
Chest radiography or computerized tomography (CT) findings that, in the opinion of the investigator, are consistent with coronavirus disease 2019 (COVID-19)
Blood oxygen saturation (SpO2) ≥ 94% while receiving low-flow supplemental oxygen (5 liters or less)
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

Respiratory decompensation requiring mechanical ventilation (includes invasive or non invasive ventilation, continuous positive airway pressure (CPAP), or bilevel positive airway pressure (BiPAP))
Expected need for mechanical ventilation (includes invasive or non-invasive ventilation, CPAP, or BiPAP) within the next 24 hours
Expected survival of less than 24 hours at the time of presentation, in the judgement of the investigator
eGFR <25 mL/min/1.73 m2 or receiving renal replacement therapy/dialysis
Systolic blood pressure <95 mmHg and/or requirement for vasopressor treatment and/or inotropic or mechanical circulatory support at Screening
History of type 1 diabetes mellitus
History of diabetic ketoacidosis
Currently receiving or has received in the last 14 days, experimental immune modulators and/or monoclonal antibody therapies for COVID-19
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
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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Dapagliflozin 10mg	Dapagliflozin 10 milligram (mg)	Dapagliflozin 10 mg daily
Placebo	Placebo	Dapagliflozin matching placebo 10 mg daily

Primary Outcome Measures

Name	Time	Method
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
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

Secondary Outcome Measures

Name	Time	Method
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.
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.
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.
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.
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.

Trial Locations

Locations (95): Hospital São Vicente de Paulo
🇧🇷
Passo Fundo, Rio Grande Do Sul, Brazil
Fundação do ABC (Hospital Estadual Mário Covas)
🇧🇷
Santo André, São Paulo, Brazil
NorthShore University HealthSystem
🇺🇸
Evanston, Illinois, United States
St. Francis Hospital
🇺🇸
Roslyn, New York, United States
Irmandade da Santa Casa de Misericórdia de Porto Alegre
🇧🇷
Porto Alegre, Rio Grande Do Sul, Brazil
Clínica Vélez Sarsfield
🇦🇷
Córdoba, Argentina
Lahey Health
🇺🇸
Burlington, Massachusetts, United States
Heart Group of the Eastern Shore
🇺🇸
Fairhope, Alabama, United States
DHR Health Institute for Research and Development
🇺🇸
Edinburg, Texas, United States
Halton Healthcare Services
🇨🇦
Oakville, Ontario, Canada
Fundación Favaloro
🇦🇷
Buenos Aires, Argentina
Hospital Fernández
🇦🇷
Buenos Aires, Argentina
Sentara Healthcare
🇺🇸
Norfolk, Virginia, United States
Hospital Mãe de Deus
🇧🇷
Porto Alegre, Rio Grande Do Sul, Brazil
Hospital Naval Marcílio Dias
🇧🇷
Rio de Janeiro, Brazil
Hospital Medica Sur
🇲🇽
Mexico City, Mexico
Max Super Speciality Hospital (A unit of Devki Devi Foundation)
🇮🇳
Saket, New Delhi, India
Hospital Clinica Nova
🇲🇽
Monterrey, Mexico
Baptist Hospital of Miami
🇺🇸
Miami, Florida, United States
Ascension - St. Vincent
🇺🇸
Indianapolis, Indiana, United States
Loyola University
🇺🇸
Maywood, Illinois, United States
McLaren Health Care
🇺🇸
Auburn Hills, Michigan, United States
SUNY Downstate Medical Center
🇺🇸
Brooklyn, New York, United States
Baylor College of Medicine
🇺🇸
Houston, Texas, United States
Liga de Hipertensão Arterial
🇧🇷
Goiania, Goias, Brazil
Lakeridge Health
🇨🇦
Oshawa, Ontario, Canada
Max Smart Super Speciality Hospital
🇮🇳
Saket, New Delhi, India
Addenbrooke's Hospital
🇬🇧
Cambridge, Cb2 0qq, United Kingdom
Hospital EMEC e Hospital da Cidade
🇧🇷
Feira de Santana, Bahia, Brazil
Hospital Coração do Brasil
🇧🇷
Brasília, Distrito Federal, Brazil
Santa Casa de Misericórdia de Passos
🇧🇷
Passos, Minas Gerais, Brazil
Hospital Cárdio Pulmonar
🇧🇷
Salvador, Bahia, Brazil
Centro de Pesquisa Dr. Marco Mota
🇧🇷
Maceió, Alagoas, Brazil
All India Institute of Medical Science
🇮🇳
New Delhi, Delhi, India
Hospital Estadual Jayme dos Santos Neves
🇧🇷
Serra, Espírito Santo, Brazil
Hospital e Clínica São Roque
🇧🇷
Ipiaú, Bahia, Brazil
Hospital São Domingos - Unimed Uberaba
🇧🇷
Uberaba, Minas Gerais, Brazil
Hospital Giselda Trigueiro
🇧🇷
Natal, Rio Grande Do Norte, Brazil
Associação Dr. Bartholomeu Tacchini
🇧🇷
Bento Gonçalves, Rio Grande Do Sul, Brazil
Maimonides Medical Center
🇺🇸
Brooklyn, New York, United States
Hospital Español
🇦🇷
Buenos Aires, Argentina
Lancaster General Hospital
🇺🇸
Lancaster, Pennsylvania, United States
Clinical Trials Network of Tennessee
🇺🇸
Memphis, Tennessee, United States
Jacobi Medical Center
🇺🇸
Bronx, New York, United States
University of Mississippi Medical Center
🇺🇸
Jackson, Mississippi, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
HG de Cuernavaca Dr. Jose G Parres
🇲🇽
Cuernavaca, Mexico
Lokmanya Tilak General Hospital
🇮🇳
Mumbai, Maharashtra, India
ECI Estudios Clinicos Internacionales
🇲🇽
Puebla, Mexico
Hospital SMIQ
🇲🇽
Queretaro, Mexico
Investigacion Medica Sonora
🇲🇽
Sonora, Mexico
Invesclinic MX
🇲🇽
Guanajuato, Mexico
Sanatorio Santa Cruz de Toluca
🇲🇽
Toluca, Mexico
Clínica de Especialidades Villa María
🇦🇷
Villa María, Province Of Córdoba, Argentina
Hospital del Prado
🇲🇽
Acapulco, Mexico
PROCAPE
🇧🇷
Recife, Pernambuco, Brazil
Hospital Pirovano
🇦🇷
Buenos Aires, Argentina
Hospital Santojanni
🇦🇷
Buenos Aires, Argentina
Sanatorio Privado Duarte Quiros de Clinica Colombo S.A.
🇦🇷
Córdoba, Argentina
IPEMI- Instituto de Pesquisas Médicas de Itajaí
🇧🇷
Itajai, Santa Catarina, Brazil
Unimed de Fortaleza
🇧🇷
Fortaleza, Ceará, Brazil
Faculdade de Medicina de Botucatu, UNESP
🇧🇷
Botucatu, São Paulo, Brazil
Centro Integrado de Pesquisas
🇧🇷
São José do Rio Preto, São Paulo, Brazil
Sanatorio Anchorena
🇦🇷
Buenos Aires, Argentina
Sanatorio Güemes
🇦🇷
Buenos Aires, Argentina
Hospital São José - Criciúma
🇧🇷
Criciuma, Santa Catarina, Brazil
MIOT International Hospitals
🇮🇳
Manapakkam, Chennai-89, India
Icaro Investigaciones en Medicina
🇲🇽
Chihuahua, Mexico
Antiguo Hospital Civil de Guadalajara "Fray Antonio Alcade"
🇲🇽
Guadalajara, Mexico
Hospital Municipal São José
🇧🇷
Joinville, Santa Catarina, Brazil
Hospital Regional Hans Dieter Schmidt
🇧🇷
Joinville, Santa Catarina, Brazil
Hospital San Roque
🇦🇷
Córdoba, Argentina
CIMS Hospital Pvt. Ltd
🇮🇳
Sola, Ahmedabad, India
Hospital San Jose TEC Salud
🇲🇽
Monterrey, Mexico
Unimed Ribeirao Preto
🇧🇷
Ribeirão Preto, São Paulo, Brazil
Dayanand Medical College & Hospital
🇮🇳
Ludhiāna, Punjab, India
JM Research
🇲🇽
Cuernavaca, Mexico
Instituto de Investigaciones Aplicadas a la Neurosciencias
🇲🇽
Durango, Mexico
Hospital San Javier
🇲🇽
Guadalajara, Mexico
CIMEZAP
🇲🇽
Jalisco, Mexico
Fundação Pio XII
🇧🇷
Barretos, Brazil
Hospital Moriah
🇧🇷
São Paulo, Brazil
Hospital Santa Paula
🇧🇷
São Paulo, Brazil
InCor - Instituto do Coração do Hospital das Clínicas FMUSP
🇧🇷
São Paulo, Brazil
Wake Forest Baptist Health
🇺🇸
Winston-Salem, North Carolina, United States
Saint Luke's Mid America Heart Institute
🇺🇸
Kansas City, Missouri, United States
University of North Carolina at Chapel Hill
🇺🇸
Chapel Hill, North Carolina, United States
Hospital Regional Deputado Luis Eduardo Magalhães
🇧🇷
Porto Seguro, Bahia, Brazil
Hospital Maternidade São Vicente de Paulo
🇧🇷
Barbalha, Ceará, Brazil
Hospital de Messejana Dr Carlos Alberto Studart Gomes
🇧🇷
Fortaleza, Ceará, Brazil
Centro de Pesquisa Clínica do Coração
🇧🇷
Aracaju, Sergipe, Brazil
Instituto de Pesquisa Clínica de Campinas
🇧🇷
Campinas, São Paulo, Brazil
Santa Casa de Votuporanga
🇧🇷
Votuporanga, São Paulo, Brazil
Sanjivani Super Speciality Hospital Pvt Ltd
🇮🇳
Ahmedabad, Gujarat, India
Rhode Island Hospital
🇺🇸
Providence, Rhode Island, United States