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

• ClinicalTrials.gov Identifier: NCT04350593
• Recruitment Status: Completed
• First Posted: April 17, 2020
• Results First Posted: April 13, 2022
• Last Update Posted: June 10, 2022
• Sponsor: Saint Luke's Health System
• Collaborators: Saint Luke's Hospital of Kansas City; AstraZeneca; George Clinical Pty Ltd
• Information provided by (Responsible Party): Saint Luke's Health System

Tracking Information

• First Submitted Date: April 14, 2020
• First Posted Date: April 17, 2020
• Results First Submitted Date: March 29, 2022
• Results First Posted Date: April 13, 2022
• Last Update Posted Date: June 10, 2022
• Actual Study Start Date: April 22, 2020
• Actual Primary Completion Date: March 31, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 13, 2022)

• 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 Frame: 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
• 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. [ Time Frame: 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

Original Primary Outcome Measures (submitted: April 14, 2020)

Time to first occurrence of either death from any cause or new/worsened organ dysfunction through 30 days of follow up, defined as at least one of the following: [ Time Frame: Randomization through Day 30 ]

• Respiratory decompensation
• New or worsening congestive HF
• 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
• Initiation of renal replacement therapy

Current Secondary Outcome Measures (submitted: May 13, 2022)

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

Original Secondary Outcome Measures (submitted: April 14, 2020)

• Hierarchical composite outcome measures: [ Time Frame: Randomization through Day 30 ]
  1. Time to death from any cause
  2. Time to new/worsened organ dysfunction (as defined in the primary outcome measure)
  3. Clinical status at Day 30 for patients still hospitalized and without any worsening organ dysfunction (using points 3 to 5 of a 7-point ordinal scale)
  4. Time to hospital discharge
• Time to hospital discharge [ Time Frame: Randomization through Day 30 ]
  Time to hospital discharge
• Total number of days alive, out of hospital, and/or free from mechanical ventilation [ Time Frame: Randomization through Day 30 ]
  Total number of days alive, out of hospital, and/or free from mechanical ventilation
• Total number of days alive, not in the ICU, and free from mechanical ventilation (as defined in the primary outcome measure) [ Time Frame: Randomization through Day 30 ]
  Total number of days alive, not in the ICU, and free from mechanical ventilation (as defined in the primary outcome measure)
• Time to death from any cause [ Time Frame: Randomization through Day 30 ]
  Time to death from any cause
• Time to new/worsened organ dysfunction [ Time Frame: Randomization through Day 30 ]
  Time to new/worsened organ dysfunction
• Time to acute kidney injury (defined as doubling of s-Creatinine compared to baseline) [ Time Frame: Randomization through Day 30 ]
  Time to acute kidney injury (defined as doubling of s-Creatinine compared to baseline)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: COVID-19

Intervention

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

Study Arms

• Active Comparator: Dapagliflozin 10mg
  Dapagliflozin 10 mg daily
  Intervention: Drug: Dapagliflozin 10 milligram (mg)
• Placebo Comparator: Placebo
  Dapagliflozin matching placebo 10 mg daily
  Intervention: Drug: Placebo

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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 25, 2021): 1250
• Original Estimated Enrollment (submitted: April 14, 2020): 900
• Actual Study Completion Date: June 11, 2021
• Actual Primary Completion Date: March 31, 2021 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Brazil, Canada, India, Mexico, United Kingdom, United States

Administrative Information

• NCT Number: NCT04350593
• Other Study ID Numbers: D1690C00081; ESR-20-20653 ( Other Grant/Funding Number: Astra Zeneca )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Saint Luke's Health System
• Original Responsible Party: Same as current
• Current Study Sponsor: Saint Luke's Health System
• Original Study Sponsor: Same as current

Collaborators

• 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

• PRS Account: Saint Luke's Health System
• Verification Date: May 2022