Dapagliflozin in Respiratory Failure in Patients With COVID-19

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

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04350593

Acronym

DARE-19

Enrollment

1250

Registered

2020-04-17

Start date

2020-04-22

Completion date

2021-06-11

Last updated

2022-06-10

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

COVID-19

Keywords

sodium-glucose cotransporter-2 inhibitor (SGLT2i), dapagliflozin, 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.

Interventions

DRUGDapagliflozin 10 milligram (mg)

Active Comparator: Dapagliflozin 10 mg

DRUGPlacebo

Placebo Comparator

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
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
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

Secondary

Measure	Time frame	Description
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 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 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.
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 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.

Countries

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

Participant flow

Participants by arm

Arm	Count
Dapagliflozin 10mg Dapagliflozin 10 mg daily Dapagliflozin 10 MG: Active Comparator: Dapagliflozin 10mg	625
Placebo Dapagliflozin matching placebo 10 mg daily Placebo: Placebo Comparator	625
Total	1,250

Baseline characteristics

Characteristic	Dapagliflozin 10mg	Total	Placebo
Age >/= 60 years	339 Participants	699 Participants	360 Participants
Age, Continuous	61.0 years STANDARD_DEVIATION 13.4	61.4 years STANDARD_DEVIATION 13.5	61.8 years STANDARD_DEVIATION 13.5
Angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB)	225 Participants	444 Participants	219 Participants
Anti-coagulant	527 Participants	1054 Participants	527 Participants
Atherosclerotic cardiovascular disease	93 Participants	199 Participants	106 Participants
Beta-blocker	93 Participants	191 Participants	98 Participants
Biguanide	82 Participants	157 Participants	75 Participants
Blood pressure - diastolic	76.6 mm Hg STANDARD_DEVIATION 10.9	76.4 mm Hg STANDARD_DEVIATION 10.7	76.2 mm Hg STANDARD_DEVIATION 10.6
Blood pressure - systolic	126.6 mm Hg STANDARD_DEVIATION 16	126.8 mm Hg STANDARD_DEVIATION 16.1	127.0 mm Hg STANDARD_DEVIATION 16.3
Body Mass Index >/= 30	296 Participants	601 Participants	305 Participants
Calcium blocker	84 Participants	172 Participants	88 Participants
Chronic kidney disease, estimated glomerular filtration rate (eGFR) 25-60 mL/min per 1.73 m^2	38 Participants	82 Participants	44 Participants
Chronic obstructive pulmonary disease	25 Participants	57 Participants	32 Participants
Current smoker	29 Participants	49 Participants	20 Participants
Dexamethasone	133 Participants	269 Participants	136 Participants
Dipeptidyl peptidase 4 (DPP-4) inhibitor	17 Participants	28 Participants	11 Participants
eGFR	84.1 mL/min per 1.73 m^2 STANDARD_DEVIATION 25	83.8 mL/min per 1.73 m^2 STANDARD_DEVIATION 24.8	83.4 mL/min per 1.73 m^2 STANDARD_DEVIATION 24.6
Ethnicity (NIH/OMB) Hispanic or Latino	394 Participants	756 Participants	362 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	166 Participants	343 Participants	177 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	61 Participants	141 Participants	80 Participants
Glucagon-like peptide 1 (GLP-1) receptor agonist	6 Participants	14 Participants	8 Participants
Heart failure	44 Participants	90 Participants	46 Participants
Heart rate	79.3 beats per minute STANDARD_DEVIATION 13.7	79.5 beats per minute STANDARD_DEVIATION 13.7	79.7 beats per minute STANDARD_DEVIATION 13.7
Hypertension	526 Participants	1060 Participants	534 Participants
Insulin	223 Participants	444 Participants	221 Participants
Loop-diuretic	49 Participants	112 Participants	63 Participants
Other systemic glucocorticoid	50 Participants	105 Participants	55 Participants
Oxygen saturation	95.5 % (measured on supplemental oxygen) STANDARD_DEVIATION 1.7	95.3 % (measured on supplemental oxygen) STANDARD_DEVIATION 1.8	95.2 % (measured on supplemental oxygen) STANDARD_DEVIATION 1.8
Patients with two or more inclusion risk factors	292 Participants	611 Participants	319 Participants
Race (NIH/OMB) American Indian or Alaska Native	7 Participants	17 Participants	10 Participants
Race (NIH/OMB) Asian	35 Participants	64 Participants	29 Participants
Race (NIH/OMB) Black or African American	85 Participants	169 Participants	84 Participants
Race (NIH/OMB) More than one race	43 Participants	79 Participants	36 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants	1 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	452 Participants	911 Participants	459 Participants
Region of Enrollment Argentina	13 participants	27 participants	14 participants
Region of Enrollment Brazil	382 participants	762 participants	380 participants
Region of Enrollment Canada	2 participants	4 participants	2 participants
Region of Enrollment India	26 participants	50 participants	24 participants
Region of Enrollment Mexico	59 participants	118 participants	59 participants
Region of Enrollment United Kingdom	0 participants	2 participants	2 participants
Region of Enrollment United States	143 participants	287 participants	144 participants
Remdesivir	114 Participants	225 Participants	111 Participants
SARS-CoV-2 test result at baseline Negative	30 Participants	65 Participants	35 Participants
SARS-CoV-2 test result at baseline Positive	584 Participants	1159 Participants	575 Participants
SARS-CoV-2 test result at baseline Test results not known	11 Participants	26 Participants	15 Participants
Sex: Female, Male Female	260 Participants	533 Participants	273 Participants
Sex: Female, Male Male	365 Participants	717 Participants	352 Participants
Statin	122 Participants	266 Participants	144 Participants
Sulfonylurea	24 Participants	46 Participants	22 Participants
Systemic corticosteroids	176 Participants	355 Participants	179 Participants
Temperature	36.4 degrees Celcius STANDARD_DEVIATION 0.6	36.4 degrees Celcius STANDARD_DEVIATION 0.6	36.4 degrees Celcius STANDARD_DEVIATION 0.7
Type 2 diabetes	312 Participants	636 Participants	324 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	41 / 625	54 / 625
other Total, other adverse events	2 / 613	2 / 616
serious Total, serious adverse events	70 / 613	87 / 616

Outcome results

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