key: cord-1028821-ljkvmttz
authors: Kosiborod, Mikhail; Berwanger, Otavio; Koch, Gary G.; Martinez, Felipe; Mukhtar, Omar; Verma, Subodh; Chopra, Vijay; Javaheri, Ali; Ambery, Philip; Gasparyan, Samvel B.; Buenconsejo, Joan; Sjöström, C. David; Langkilde, Anna Maria; Oscarsson, Jan; Esterline, Russell
title: Effects of dapagliflozin on prevention of major clinical events and recovery in patients with respiratory failure because of COVID‐19: Design and rationale for the DARE‐19 study
date: 2021-01-19
journal: Diabetes Obes Metab
DOI: 10.1111/dom.14296
sha: 0299b7074df5012e611b00a39c9198a9c35e078a
doc_id: 1028821
cord_uid: ljkvmttz

AIMS: Coronavirus disease 2019 (COVID‐19) is caused by a novel severe acute respiratory syndrome coronavirus 2. It can lead to multiorgan failure, including respiratory and cardiovascular decompensation, and kidney injury, with significant associated morbidity and mortality, particularly in patients with underlying metabolic, cardiovascular, respiratory or kidney disease. Dapagliflozin, a sodium‐glucose cotransporter‐2 inhibitor, has shown significant cardio‐ and renoprotective benefits in patients with type 2 diabetes (with and without atherosclerotic cardiovascular disease), heart failure and chronic kidney disease, and may provide similar organ protection in high‐risk patients with COVID‐19. MATERIALS AND METHODS: DARE‐19 (NCT04350593) is an investigator‐initiated, collaborative, international, multicentre, randomized, double‐blind, placebo‐controlled study testing the dual hypotheses that dapagliflozin can reduce the incidence of cardiovascular, kidney and/or respiratory complications or all‐cause mortality, or improve clinical recovery, in adult patients hospitalized with COVID‐19 but not critically ill on admission. Eligible patients will have ≥1 cardiometabolic risk factor for COVID‐19 complications. Patients will be randomized 1:1 to dapagliflozin 10 mg or placebo. Primary efficacy endpoints are time to development of new or worsened organ dysfunction during index hospitalization, or all‐cause mortality, and the hierarchical composite endpoint of change in clinical status through day 30 of treatment. Safety of dapagliflozin in individuals with COVID‐19 will be assessed. CONCLUSIONS: DARE‐19 will evaluate whether dapagliflozin can prevent COVID‐19‐related complications and all‐cause mortality, or improve clinical recovery, and assess the safety profile of dapagliflozin in this patient population. Currently, DARE‐19 is the first large randomized controlled trial investigating use of sodium‐glucose cotransporter 2 inhibitors in patients with COVID‐19.

nucleotide identity with human SARS-CoV. 1 Early epidemiological data indicate that 12% of SARS-CoV-2-positive patients develop symptoms that are significant enough to require hospitalization, and of these, nearly 24% may need to be treated in the intensive care unit. 2, 3 Hospital admission occurs at a median time of day 7 from the onset of symptoms, and many recover with supportive care. 4 In others, progressive deterioration is seen. Although respiratory failure is a key manifestation in most patients with COVID-19, it is increasingly being recognized that COVID-19 is a systemic disease, in which cardiovascular and kidney complications are common, and may be key drivers of poor outcomes, including death. [5] [6] [7] [8] [9] Risk factors associated with COVID-19 disease progression include older age and presence of cardiometabolic comorbidities such as type 2 diabetes (T2D), atherosclerotic cardiovascular disease (ASCVD), hypertension, heart failure (HF) and chronic kidney disease (CKD). 2, 9, 10 Observational studies have shown that age, male sex, obesity, ethnicity, chronic heart disease and reduced kidney function are independent risk predictors for COVID-related death, 11 whereas the data on prognostic importance of hypertension have been less clear, with different studies producing mixed results. 12 Individuals that have a combination of such underlying health conditions, and with evidence of acute myocardial injury, kidney injury and/or HF specifically, have a high risk of death because of COVID- 19. 5,13-16 The underlying mechanisms behind this greater risk are not yet fully understood, but compromised baseline organ function and metabolism combined with greater susceptibility to endothelial injury, inflammatory insults and tissue hypoxia probably play a role. 6, 7, 17, 18 Over the past several months, the unpredictable nature of the evolving global pandemic and the change in available standard of care (including medications) for treatment of COVID-19 have resulted in substantially lower rates of complications and death than what was observed early on, and studies suggest that mortality from COVID-19 is decreasing even after accounting for secular change in patient characteristics. 19 Consequently, faster and more complete recovery has now become an important treatment goal, on par with prevention of complications and death in patients hospitalized with COVID-19.

Although the primary action of sodium-glucose cotransporter-2 (SGLT2) inhibitors is on glucose and sodium reabsorption in the proximal convoluted tubule of the kidney, they have been shown to provide substantial cardiorenal protection in patient populations similar to those at risk for COVID-19 complications, namely, individuals with T2D, ASCVD, HF and CKD. SGLT2 inhibitors reduced the risk of cardiovascular and kidney events in patients with T2D in four large outcome trials investigating empagliflozin, canagliflozin and dapagliflozin. [20] [21] [22] [23] In the DAPA-HF trial, dapagliflozin reduced the risk of death and worsening of HF by 26% in patients with HF with reduced ejection fraction, with identical effects in patients with and without T2D 24, 25 ; these benefits were observed within days of randomization and were significant by day 28 of treatment. 26 SGLT2 inhibitors also consistently reduce the risk of kidney disease progression and acute kidney injury (AKI). [20] [21] [22] [23] Recently, the DAPA-CKD trial showed statistically significant and clinically meaningful effects of SGLT2 inhibitors on the primary endpoint of a composite of worsening of renal function or risk of death in adult patients with CKD; the study also met all its secondary endpoints in patients with CKD, with and without T2D. 27, 28 An important, and somewhat unexpected finding in the DAPA-CKD trial was a large, 31% relative reduction in allcause mortality in patients treated with dapagliflozin versus placebo, which was an effect driven largely by lower risk of death from noncardiovascular causes (including death from infectious disease and other aetiologies). These findings suggest that SGLT2 inhibitors may even have protective properties in clinical scenarios beyond chronic conditions such as T2D, cardiovascular and kidney disease. 28 The mechanisms that could explain the various protective effects of SGLT2 inhibitors overlap substantially with those triggered in COVID-19 ( Figure 1 ). SGLT2 inhibitors decrease glucose and insulin levels, and shift energy metabolism to an increased reliance on lipid oxidation, with a reduced reliance on glucose, and inhibition of glycolysis. 29 This mechanism may be particularly important in COVID-19, as SARS-CoV-2 may depend on the glycolytic pathway for its replication, stimulating lipogenesis, which appears to be one of the key drivers of cellular damage. 30 18 including in patients hospitalized with COVID-19 but not yet critically ill. Importantly, SGLT2 inhibitors may be most effective in patients who are at the highest risk of COVID-19 complications, that is, those with cardiometabolic comorbidities ( Figure 1 ). Early data from observational studies, although limited by potential residual confounding and small numbers, also suggests that background SGLT inhibitor therapy in patients with T2D that are hospitalized with COVID-19 is associated with a lower risk of in-hospital death and complications, as compared with other glucose-lowering drugs. 46 Thus, we hypothesize that dapagliflozin, a potent, highly-selective and orally-active SGLT2 inhibitor, has the potential to impart end-organ protection against SARS-CoV-2 by lowering the risks of cardiovascular and kidney complications, and possibly by preventing worsening of respiratory failure, thus reducing the risk of disease progression and death and improving clinical recovery in patients with COVID-19.

The dapagliflozin in respiratory failure in patients with COVID-19 study (DARE-19; NCT04350593) is a randomized, multicentre, double-blind, placebo-controlled, parallel-group, international Phase III trial in countries with a high prevalence of COVID-19. It includes patients with history of the following cardiometabolic risk factors; hypertension, T2D, ASCVD, HF (regardless of ejection fraction) and/or CKD (stages 3-4, defined as estimated glomerular filtration rate (eGFR) between 25 and 60 mL/min/1.73 m 2 ); these conditions are known to increase the risk of COVID-19 complications, and occur in large proportions of patients hospitalized with COVID-19. 9, 10, 15, 47 Notably, SGLT2 inhibitors have already shown benefits in these patient populations. [20] [21] [22] [23] [24] 48, 49 Therefore, while patients in the DARE-19 study will all be hospitalized with COVID-19, it is not expected that the risk factor profile of the DARE-19 study population will differ substantially from those already studied with SGLT2 inhibitors in general, and dapagliflozin specifically.

The study plans to enrol approximately 1200 adult patients hospitalized with COVID-19 across several countries in North America (United States, Canada, Mexico), Europe (United Kingdom), Latin America (Brazil and Argentina) and Asia (India) with a high prevalence F I G U R E 1 Primary action of dapagliflozin is on the SGLT2s expressed on the proximal tubules of the nephrons of the kidney. SGLT2 inhibition results in an immediate adaptive response to minimize loss of water and sodium. Loss of glucose is balanced by increased endogenous glucose production. 41, 45 The new homeostasis may be responsible for the favourable effects of dapagliflozin on the cardiovascular, renal and immune functions. The effects on glucose control, including insulin demand, endothelial function, oxidative stress, oxygen delivery capacity, congestion and inflammation [32] [33] [34] [35] [36] 42, 43 are probably most important to protect from worsening of organ function in hospitalized patients with COVID-19 and medical history with risk factors, including hypertension, T2D, HF, CKD and obesity. CKD, chronic kidney disease; HF, heart failure; SGLT2i, sodium-glucose cotransporter 2 inhibitor; T2D, type 2 diabetes of COVID-19. Study inclusion and exclusion criteria are detailed in Table 1 . Eligible individuals will include adults hospitalized with COVID-19 (oxygen saturation ≥94% on ≤5 L of supplemental oxy- Eligible individuals providing informed consent will enter a screening period of no more than 2 days. Randomization will be stratified by country. Individuals will be randomized 1:1 to dapagliflozin 10 mg or matched placebo once daily for 30 days; under most circumstances patients will be starting investigational product on the day of randomization. After the last dose of investigational product on day 30, patients will be followed for an observational period of an additional 60 days ( Figure 2 ). Treatment with dapagliflozin or matching placebo will be continued even if mechanical ventilation becomes necessary during T A B L E 1 Eligibility criteria Inclusion criteria

• Provision of informed consent before any study-specific procedures • Male or female patients aged ≥18 years on the day consent given • Currently hospitalized • Hospital admission no more than 4 days before screening • Confirmed SARS-CoV-2 infection by laboratory testing within 10 days before screening, or strongly suspected SARS-CoV-2 infection on presentation a • Chest radiography or CT findings that, in the opinion of the investigator, are consistent with COVID-19 • SpO 2 ≥94% while receiving low-flow supplemental oxygen (≤5 L) • Medical history of at least one of the following:

Hypertension T2D Atherosclerotic cardiovascular disease Heart failure (with either reduced or preserved LVEF) CKD stage 3-4 (eGFR between 25 and 60 mL/min/1.73 m 2 )

Exclusion criteria

• Respiratory decompensation requiring mechanical ventilation (includes invasive or non-invasive ventilation, CPAP, or BiPAP) • Expected need for mechanical ventilation (includes invasive or non-invasive ventilation, CPAP, or BiPAP) within the next 24 h • Anticipated transfer to another hospital facility, which is not another study site, within 72 h • Expected survival of less than 24 h at the time of presentation, in the judgement of the investigator • eGFR <25 mL/min/1.73 m 2 or receiving renal replacement therapy/dialysis • Evidence of oliguria (urine output <500 mL in 24 h or <0.5 mL/kg/h) or serum creatinine ≥1.5× baseline pre-hospitalization value, if available at the time of screening • Systolic BP <95 mmHg and/or requirement for vasopressor treatment and/or inotropic or mechanical circulatory support at screening • History of type 1 diabetes • Currently receiving or has received in the last 14 days, experimental immune modulators and/or monoclonal antibody therapies for COVID-19 b • History of diabetic ketoacidosis • Current treatment with any SGLT2i or having received treatment with any SGLT2i within 4 weeks before screening • History of hypersensitivity to dapagliflozin • Any other condition that in the judgement of the investigator would jeopardize the patient's participation in the study or that may interfere with the interpretation of study data or if the patient is considered unlikely to comply with study procedures, restrictions and requirements • Women of childbearing potential: current or planned pregnancy or currently lactating Women of childbearing potential are defined as any female who has experienced menarche and who is NOT permanently sterile or postmenopausal Post-menopausal is defined as 12 consecutive months with no menses without an alternative medical cause Women of childbearing potential, who are sexually active, must agree to use a medically accepted method of birth control for the duration of the study • Involvement in the planning and/or conduct of the study (applies to both investigator staff and/or staff at the study site) • Previous enrolment in the present study c • Current participation in another interventional clinical trial (with an investigational drug) that is not an observational registry Abbreviations: BiPAP, Bilevel positive airway pressure; BP, blood pressure; CKD, chronic kidney disease; COVID-19, coronavirus disease 2019; CPAP, Continuous positive airway pressure; CT, computed tomography; eGFR, estimated glomerular ejection fraction; LVEF, left ventricular ejection fraction; SARS-CoV-2, severe acute respiratory syndrome-related coronavirus 2; SGLT2i, sodium-glucose cotransporter 2 inhibitor; T2D, type 2 diabetes. a Proportion of patients randomized without a confirmed SARS-CoV-2-positive test will be closely monitored, and may be capped if it becomes greater than anticipated. b 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 programmes or in accordance with the local standard of care is permitted during the study. c Study design allows two attempts to meet the randomization criteria after enrolment.

COVID-19 treatment. In this case, the tablets will be crushed and administered via the gastric tube. All individuals will be treated according to local guidelines and standard of care treatment for patients hospitalized with COVID-19 (including open-label rescue therapies) at the participating hospitals.

DARE-19 is an investigator-initiated collaborative study, with the study design and protocol developed, and study procedures operationalized through close collaboration between Saint Luke's Mid America Heart Institute (Global Sponsor) and AstraZeneca (Funding Source). As a key collaborator, AstraZeneca participates in the conduct of the study and statistical analyses, which will be independently verified by the statistical group at Saint Luke's Mid America Heart

Institute. This study is being directed by the Executive Committee, comprising academic leaders and non-voting representatives from AstraZeneca. The Executive Committee will plan and direct trial-related academic publications. Safety is being closely monitored by an Independent Data and Safety Monitoring Committee (IDSMC). The trial will be reviewed by the regulatory authorities and ethics committees in each country/institution, as applicable. Informed consent will be obtained from all participating individuals before initiation of study procedures.

The goals of this study are to prevent COVID-19-related organ dysfunction during the index hospitalization (which is the most acute setting in individuals with COVID-19) or mortality through day 30, and to improve clinical recovery. During this study, if an individual is discharged from the index hospitalization without an event of organ dysfunction ( Figure 1, Table 2 ), then the individual will be assumed to have made a partial or full recovery from COVID-19 and therefore no longer be at high risk for developing COVID-19-related organ dysfunction. Therefore, for the assessment of primary efficacy endpoints only vital status information will be used after hospital discharge (for example, in the time-to-event analysis patients discharged from hospital without an event and alive on day 30 will be censored at day 30).

After all individuals complete the 30-day treatment period, and collection of the required data for this treatment period is completed, the study database will be locked, and the efficacy and safety report will be generated. An observational follow-up will continue for an additional 60 days, during which vital status and serious adverse events will continue to be assessed.

The primary objective of the study is to determine whether dapagliflozin 10 mg is superior to placebo in reducing the incidence of Figure 3B ). Exploratory analyses are listed in Table S1 and will include assessment of various biomarkers and laboratory parameters of disease severity (all collected at local laboratories at each site), and composite scores of clinical status.

Outcome events are reported by the local investigators and will not be adjudicated.

In addition to evaluating the efficacy endpoints, one of the key objectives of the DARE-19 trial is to assess the safety profile of dapagliflozin in patients hospitalized with COVID-19. Several measures have been incorporated in the protocol to minimize potential risks to participants. Patients with type 1 diabetes and those with any history of DKA are excluded from the study. Careful monitoring of acid-base balance and kidney function during hospitalization is mandated; in the absence of monitoring, dapagliflozin treatment will be temporarily interrupted. In the event of an abnormal increase in anion gap and/or reduction in bicarbonate levels, measurement of blood ketones, lactate levels and pH analysis will be performed to rule out the possibility of DKA (the diagnosis of which is based on strict protocol-defined criteria, see Table S2 ). The IDSMC will continuously review the safety data.

It is estimated that a sample size of approximately 1200 patients will provide adequate power to detect the treatment effect on prevention or recovery, when the dual endpoints are tested with alpha split between these endpoints. Since the original protocol was designed, the change in standard of care for treatment of COVID-19 resulted in lower event rates. Consequently, faster and more complete recovery has now become an important treatment goal on par with the prevention of complications and death in patients hospitalized with COVID- 19 , prompting the addition of 'recovery' to the primary objectives.

It is now estimated that about 10%-20% of patients will develop COVID-19-related complications during the index hospitalization or will experience death during the 30-day treatment period, while 80%-90% of patients will recover without experiencing death or early complications. Therefore, the sample size of approximately 1200 patients will provide approximately 100-250 events for the first dual primary endpoint (prevention).

To control the type I error for the dual primary endpoints, the allocated alpha of 5% will be split between them. For example, in the case of an even split, 100 events of the prevention endpoint will detect a hazard ratio of 0.54 with about 80% power at the type I con- 

A strong control of the type 1 error rate will be applied in testing the dual primary and secondary efficacy endpoints. For the dual primary endpoints, alpha will be allocated to each test of hypothesis, such that success on one of the endpoints will be sufficient to support a conclusion of effectiveness. 50 No interim efficacy analysis is planned.

All primary and secondary efficacy endpoints will be analysed based on the intent-to-treat principle. The time-to-event endpoints (i.e. the first primary endpoint, time to hospital discharge, time to death) will be analysed using the Cox proportional hazards regression, stratified by country, including a factor for treatment group, and will be adjusted for age and sex. Analysis for time to composite kidney endpoint will be done in the same way but will be adjusted only for baseline eGFR value. The HCE evaluating the clinical status change will be analysed using Win Ratio analysis based on the order (ranking) described in Table 2 . [51] [52] [53] Full details of all analyses, including the multiple testing strategy, will be provided in a statistical analysis plan completed before the end of the trial and unblinding of the results.

For the dual primary endpoints, subgroup analyses have been preplanned based on population demographics and clinical characteristics. Subgroups include age (≥60 versus <60 years), sex, race, country, the five cardiometabolic risk factors of the inclusion criteria (hypertension, ASCVD, HF, T2D and baseline eGFR with categories ≥60 versus <60 mL/min/1.73 m 2 ), 54 as well as subgroups defined by baseline laboratory measurements above or below median; including N-terminal pro B-type natriuretic peptide, high-sensitivity troponin,

high-sensitivity C-reactive protein and D-dimer.

The disease progression, associated complications and death. 2, 9, 10 Although the reasons behind this remain unclear, presence of cardiometabolic comorbidities and its underlying milieu of obesity, insulin resistance, inflammation and endothelial dysfunction at baseline, combined with already impaired target organ function, could increase susceptibility to further impairments in endothelial function, oxidative stress, inflammation and metabolic derangements, all seen in this patient population ( Figure 1) . Impaired T-cell responses, including to viral pathogens are also well described in obese, insulin-resistant individuals. 61 Against this proinflammatory and pro-thrombotic setting, SGLT2

inhibitors have the potential to affect many of these imbalances inhibitors, these events are rare. [20] [21] [22] 24 Another study investigating the effects of SGLT2 inhibitors in acutely hospitalized patients found no events of DKA in patients treated with empagliflozin, with one occurrence of DKA in the placebo group; there was no imbalance in volume depletion events between the two treatment groups. 64 Outcome trials have also showed consistent and robust benefits of SGLT2

inhibitors on kidney outcomes with no increase in the risk of AKI, 22, 69 and experimental studies suggest that the effect of dapagliflozin on fluid status may also be favourable, thereby reducing the risk of precipitating acute renal impairment. 38 

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