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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04350593
Recruitment Status : Recruiting
First Posted : April 17, 2020
Last Update Posted : April 17, 2020
Sponsor:
Collaborators:
AstraZeneca
George Clinical Pty Ltd
Information provided by (Responsible Party):
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 COVID-19 in the US and other countries with high prevalence of COVID-19. The study is evaluating the effect of dapagliflozin 10 mg versus placebo, given once daily for 30 days in addition to background local standard of care therapy, in reducing disease progression, complications, and all-cause mortality.

Condition or disease Intervention/treatment Phase
COVID-19 Drug: Dapagliflozin 10 MG Drug: Placebo Phase 3

Detailed Description:

Recent information on patients at risk for developing serious complications, including death, in the setting of COVID-19, indicate that those with cardiometabolic disease (hypertension, type 2 diabetes, atherosclerotic cardiovascular disease, heart failure, and/or kidney disease at baseline) are at much greater risk (Arentz et al 2020, Grasselli et al 2020). Moreover, a large proportion of these patients develop cardiovascular complications; many have markedly elevated NT-proBNP levels, and a substantial proportion have evidence of acute myocardial injury and/or acute kidney injury. SGLT2i have previously been demonstrated to have potent heart and kidney-protective effects in patients with type 2 diabetes, heart failure and/or chronic kidney disease, and may afford protection of these vital organ systems in the setting of COVID-19. (Kosiborod et al 2017, McMurray et al 2019, Neal et al 2017, Perkovic et al 2019, Wiviott et al 2019, Zinman et al 2015).

Furthermore, both pre-clinical and clinical studies suggest that SGLT2i may favorably impact the underlying mechanistic processes dysregulated in the setting of acute major illness (such as COVID-19) and include favorable effects on energy metabolism, autophagy, oxidative stress, tissue hypoxia and inflammation (Ferrannini 2017, Aragón-Herrera 2019, Tanaka et al 2018, Packer 2020, Esterline et al 2018). These mechanisms have been shown to be important in the setting of respiratory failure, sepsis and multi-organ failure/cytokine storm.

The study population will include hospitalized patients with mild-moderate manifestations of COVID-19 of any duration, but without the need for mechanical ventilation at the time of screening. The eligible patients should have risk-factors for developing serious complications of COVID-19.

It will include patients with a history of at least one of the following: hypertension, T2DM, atherosclerotic cardiovascular disease, HF and/or CKD stage 3 to 4 (eGFR ≥25 mL/min/1.73m2).

Patients will be treated for 30 days, with either dapagliflozin 10 mg 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 SARS CoV-2.

The primary efficacy endpoint of the study is time to first event of all-cause death or morbid disease complications (respiratory, cardiovascular and kidney) through 30 days of follow-up.

The safety data will be monitored by an Independent Data and Safety Monitoring Committee.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 900 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Estimated Study Start Date : April 15, 2020
Estimated Primary Completion Date : October 2020
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Dapagliflozin 10mg
Dapagliflozin 10 mg daily
Drug: Dapagliflozin 10 MG
Active Comparator: Dapagliflozin 10mg
Other Name: Farxiga

Placebo Comparator: Placebo
Dapagliflozin matching placebo 10 mg daily
Drug: Placebo
Placebo Comparator




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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

  2. Time to hospital discharge [ Time Frame: Randomization through Day 30 ]
    Time to hospital discharge

  3. 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

  4. 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)

  5. Time to death from any cause [ Time Frame: Randomization through Day 30 ]
    Time to death from any cause

  6. Time to new/worsened organ dysfunction [ Time Frame: Randomization through Day 30 ]
    Time to new/worsened organ dysfunction

  7. 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)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Provision of informed consent
  2. Male or female patients aged ≥18 years
  3. Currently hospitalized
  4. Confirmed SARS-CoV-2 infection by laboratory testing <72h prior to randomization or strongly suspected on presentation
  5. Chest radiography or CT findings consistent with COVID-19
  6. Mild-moderate disease: SpO2≥94% with low-flow supplemental oxygen (3 liters or less)
  7. Medical history of at least one of the following:

    1. hypertension
    2. T2DM
    3. atherosclerotic cardiovascular disease
    4. heart failure (with either reduced or preserved LVEF)
    5. CKD stage 3 to 4 (eGFR between 25 to 60 mL/min/1.73 m2)

Key Exclusion Criteria:

  1. Severe COVID-19: requiring mechanical ventilation via endotracheal intubation, and/or non-invasive ventilation
  2. Expected need for mechanical ventilation within the next 24 hours
  3. Expected survival of less than 24 hours at the time of presentation
  4. eGFR <25 mL/min/1.73 m2 or receiving renal replacement therapy/dialysis
  5. Systolic BP <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. Currently receiving or has received in the last 14 days, experimental immune modulators and/or monoclonal antibody therapies for COVID-19
  8. History of diabetic ketoacidosis within last 6 months
  9. Current treatment with any 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04350593


Contacts
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Contact: Sheryl Windsor 816-932-9858 swindsor@saint-lukes.org

Locations
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United States, Missouri
Saint Luke's Mid America Heart Institute Recruiting
Kansas City, Missouri, United States, 64111
Contact: Study Coordinator    816-932-5989      
Sponsors and Collaborators
Saint Luke's Health System
AstraZeneca
George Clinical Pty Ltd
Investigators
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Study Chair: Mikhail Kosiborod, MD Saint Luke's Mid America Heart Institute
Publications:
Grasselli G, Zangrillo A, Zanella A, Antonelli M, Cabrini L, Castelli A, Cereda D, Coluccello A, Foti G, Fumagalli R, Iotti G, Latronico N, Lorini L, Merler S, Natalini G, Piatti A, Ranieri MV, Scandroglio AM, Storti E, Cecconi M, Pesenti A; COVID-19 Lombardy ICU Network, Nailescu A, Corona A, Zangrillo A, Protti A, Albertin A, Forastieri Molinari A, Lombardo A, Pezzi A, Benini A, Scandroglio AM, Malara A, Castelli A, Coluccello A, Micucci A, Pesenti A, Sala A, Alborghetti A, Antonini B, Capra C, Troiano C, Roscitano C, Radrizzani D, Chiumello D, Coppini D, Guzzon D, Costantini E, Malpetti E, Zoia E, Catena E, Agosteo E, Barbara E, Beretta E, Boselli E, Storti E, Harizay F, Della Mura F, Lorini FL, Donato Sigurtà F, Marino F, Mojoli F, Rasulo F, Grasselli G, Casella G, De Filippi G, Castelli G, Aldegheri G, Gallioli G, Lotti G, Albano G, Landoni G, Marino G, Vitale G, Battista Perego G, Evasi G, Citerio G, Foti G, Natalini G, Merli G, Sforzini I, Bianciardi L, Carnevale L, Grazioli L, Cabrini L, Guatteri L, Salvi L, Dei Poli M, Galletti M, Gemma M, Ranucci M, Riccio M, Borelli M, Zambon M, Subert M, Cecconi M, Mazzoni MG, Raimondi M, Panigada M, Belliato M, Bronzini N, Latronico N, Petrucci N, Belgiorno N, Tagliabue P, Cortellazzi P, Gnesin P, Grosso P, Gritti P, Perazzo P, Severgnini P, Ruggeri P, Sebastiano P, Covello RD, Fernandez-Olmos R, Fumagalli R, Keim R, Rona R, Valsecchi R, Cattaneo S, Colombo S, Cirri S, Bonazzi S, Greco S, Muttini S, Langer T, Alaimo V, Viola U. Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy. JAMA. 2020 Apr 6. doi: 10.1001/jama.2020.5394. [Epub ahead of print]

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Responsible Party: Saint Luke's Health System
ClinicalTrials.gov Identifier: NCT04350593    
Other Study ID Numbers: D1690C00081
ESR-20-20653 ( Other Grant/Funding Number: Astra Zeneca )
First Posted: April 17, 2020    Key Record Dates
Last Update Posted: April 17, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Saint Luke's Health System:
SGLT2i
dapagliflozin
COVID-19
Additional relevant MeSH terms:
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Respiratory Insufficiency
Respiration Disorders
Respiratory Tract Diseases
2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents
Physiological Effects of Drugs