Empagliflozin in improving exercise tolerance in HFpEF: Study Protocol for an open-label, randomized controlled study

Empagliflozin in improving exercise tolerance in HFpEF: Study Protocol for an open-label, randomized controlled study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Empagliflozin in improving exercise tolerance in HFpEF: Study Protocol for an open-label, randomized controlled study Rufeng Huang, Yecheng Deng, Mengshuang Li, Linghua Chen, Meifen Lv, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5038751/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 Apr, 2026 Read the published version in Trials → Version 1 posted 5 You are reading this latest preprint version Abstract Introduction Heart failure with preserved ejection fraction（HFpEF） constitutes nearly half of patients with heart failure, but there is still a lack of treatment options to improve prognosis. Empagliflozin is one of the novel hypoglycemic agent sodium glucose cotransporter 2 inhibitors（SGLT2i），however, its impact on exercise tolerance in HFpEF remains unclear. Further clinical investigations are warranted to elucidate the role of SGLT2i in HFpEF. This study aims to evaluate the efficacy and safety of empagliflozin on the exercise tolerance in patients with HFpEF through cardiopulmonary exercise test. Methods and Analysis: This study is a single-center, open-label, randomized controlled trial. We will randomly (1:1) assign 96 patients with an ejection fraction of more than 40% and class II–III heart failure to receive empagliflozin (10 mg once daily) or continue with the original treatment plan. The treatment duration will be 12 weeks. The primary endpoint is the evaluation of changes in peak oxygen uptake (peak VO2) after a 12-week period using cardiopulmonary exercise testing (CPET). The secondary endpoints included other parameters of CPET and ultrasound cardiogram, N-terminal pro-B-type natriuretic peptide level, alanine aminotransferase level, Aspartate Transaminase level，Estimated glomerular filtration rate level, New York Heart Association functional classification, and scores from the Minnesota Living with Heart Failure Questionnaire. Safety events associated with empagliflozin and CPET will be monitored. Discussion We used peak oxygen uptake, the gold standard for assessing exercise tolerance, to evaluate the efficacy and safety of empagliflozin in treating non-diabetic patients with HFpEF. The improvement in quality of life of heart failure patients by SGLT2i will be objectively assessed. Trial Registration : www.chictr.org.cn (ChiCTR2300072908). Registered on 04 July 2023. SGLT2i HFpEF CPET exercise tolerance Study Protocol Figures Figure 1 BACKGROUND Heart failure (HF) is a group of complex clinical syndromes characterized by abnormal structural and/or function of the heart due to a variety of causes, leading to impaired ventricular contraction and/or diastolic function. In patients with heart failure, those with heart failure with preserved ejection fraction(HFpEF) make up a large proportion. Community Data on the prevalence and incidence of HFpEF indicate that approximately 50% of patients with the clinical syndrome of heart failure have a preserved ejection fraction. [ 1 ] HFpEF is a highly prevalent, complex, and heterogeneous disease. The universally accepted pathophysiology of HFpEF includes left ventricular diastolic dysfunction, pulmonary vascular dysfunction and right ventricular dysfunction. [ 2 ] Currently, HFpEF lacks effective therapies, and clinical treatment primarily focuses on symptom alleviation. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) is a rising star among antidiabetic drugs. Increasing research has confirmed that SGLT2i have effects beyond glucose lowering, providing benefits to multiple organs such as the heart and kidneys, particularly in cardiovascular events, with a predominant focus on heart failure. SGLT2i exert therapeutic effects in heart failure through multiple mechanisms, including the inhibition of cardiac inflammation and fibrosis, antagonism of sodium retention, and enhancement of glomerular function. [ 3 ] SGLT2i can improve myocardial energy metabolism, promote ketone production and utilization, and decelerate the progression of heart failure. [ 4 ] Consequently, SGLT2i are gradually becoming first-line medications for the treatment of heart failure. However, due to the significant differences in the pathogenesis of HFpEF, clinical studies have failed to confirm that ACEI /ARB and beta-blockers can improve the prognosis or reduce the mortality rate of HFpEF patients. Consequently, there is a lack of evidence-based medical evidence for the treatment of HFpEF. But increasing clinical studies have found that SGLT2i can confer cardiovascular benefits to patients with HFpEF. The renowned randomized trials, EMPEROR-Preserved trial and DELIVER trial, have demonstrated that SGLT2i empagliflozin and dapagliflozin can reduce the composite risk of cardiovascular death or heart failure hospitalization in patients with HFrEF and HFpEF. [ 5 , 6 ] A meta-analysis revealed that the concurrent use of ARNI, MRA, and SGLT2i exerts potent anti-heart failure effects. [ 7 ] SGLT2i in the growing role of HfpEF. Further clinical studies are still needed to confirm the role of SGLT2i in HFpEF. Exercise intolerance is a symptom of HF ,which is in connection with an increasing risk of death. Cardiopulmonary exercise testing (CPET) a diagnostic examination that assesses cardiopulmonary function. It involves a series of assessments conducted by measuring changes in cardiopulmonary function and related parameters during exercise. In individuals with heart disease, CPET can quantify the extent to which exercise limitations are attributable to cardiac factors. Peak oxygen uptake (peak VO2) is considered the foremost standard for evaluating exercise intolerance in individuals with HF. [ 8 ] Peak VO2 is also an important predictor of mortality in patients with HFpEF. [ 9 ] The parameters of peak VO2, percent predicted peak VO2,and exercise duration in CPET had the strongest ability to predict mortality [ 9 ] . We designed the study to evaluate the efficacy of empagliflozin in exercise tolerance in patients with HFpEF. METHODS AND DESIGN Design This study is designed as a single-center, open-label, randomized controlled trial. After the screening period, eligible patients are randomly assigned (1:1 randomization) to receive either empagliflozin, 10 mg per day, or to continue with the original treatment plan. Figure 1 illustrates the design and procedures through the trial. Study Hypothesis Empagliflozin can improve exercise tolerance of patients with HFpEF. Study Population, Eligibility Criteria, and Recruitment Participants are men or women aged 18 to 75 years, who have New York Heart Association (NYHA)functional class II–III chronic heart failure and a left ventricular ejection fraction of more than 40%. The protocol requires patients to have an N-terminal pro–B-type natriuretic peptide (NT-proBNP) level of more than 300 pg per milliliter and estimated glomerular filtration rate ( eGFR ) more than 30 ml/min/1.73m^2. The study primarily excludes patients with diabetes, severe liver or kidney dysfunction, as well as those with other conditions deemed unsuitable for inclusion. The key inclusion and exclusion criteria are listed in Table 1 . The study will be conducted at The Third Affiliated Hospital of Guangzhou Medical University. Patients will be recruited by researchers describing this study in the outpatient service and inpatient departments. Posters containing study information will also be used within the hospital. Every patient will sign informed consent prior to enrollment. Table 1 Inclusion and exclusion criteria Inclusion criteria (1) Aged 18 to 75 years, male or female; (2) Patients with chronic HF (NYHA class II and III) diagnosed for at least 3 months and currently in HF NYHA class II-III; (3) LVEF > 40%; (4) NT-proBNP > 300 pg/mL; (5) eGFR ≥ 30ml/min/1.73m^2; (6) Able to understand and voluntarily sign the informed consent form; Exclusion criteria (1) Diabetes; (2) Acute coronary syndrome whihin the last 2 months or planned coronary revascularization during the trial; (3) Atrial fibrillation, cardiovascular and cerebrovascular events related to atrial fibrillation in the last 3 months; (4) Hypohepatia, defined by serum levels of transaminases more than three times the upper limit of normal at screening; (5) Using SGLT2i within 4 weeks prior to randomization; (6) Diseases that affect the results of CPET include arthropathy, peripheral vascular disease, lung disease and other diseases ; (7) The subject's resting ECG has the following abnormalities: (a) ventricular pre-excitation syndrome; (b) ventricular pacing rhythm; (c) resting ST segment depression of more than 2mm; (d) left bundle branch block or any intraventricular conduction delay with QRS duration greater than 120 ms; (8) Congenital heart defects, progressive decompensated congestive heart failure, severe valvular disease, hypertrophic obstructive cardiomyopathy, severe uncontrolled hypertension (sitting systolic blood pressure > 180mmHg or diastolic blood pressure > 110mmHg), severe anemia, suspected or known arterial dissection, acute myocarditis or pericardial effusion, active endocarditis, thrombophlebitis, or pulmonary embolism. (9) History of bleeding tendency, cerebral hemorrhage, or epilepsy requiring anticonvulsant medication. (10) Pregnant woman or breastfeeding woman. (11) Participated in any other trials or use of any investigational drugs within the 30 days prior to enrollment. (12) Drug abuse. The patient has a history of alcohol abuse or known drug dependence in the past 2 years. Withdrawal Criteria (1) Any suspected drug-related serious adverse events (e.g., allergic reactions). (2) Recurrence of acute heart failure or sudden severe dysfunction of organs such as the liver or kidneys. (3) Pregnancy. (4) Major protocol deviations. After randomization, it is found that the subject does not meet the inclusion criteria of the study protocol or does not follow the requirements of the study protocol, and continuing to participate in the study may pose unacceptable risks to the subject's health. (5) Loss to follow-up. The subject does not return to the clinic and cannot be successfully contacted. Information on attempts to contact the subject must be documented. (6) Voluntary withdrawal. The subject (or the subject's legal representative) wishes to withdraw from the study. The reason for withdrawal should be recorded in the case report form. (7) Study termination. The study is terminated by the sponsor, ethics committee, or regulatory authority. CPET, cardiopulmonary exercise testing; ECG, electrocardiogram. Randomization and Allocation Randomization sequences are generated using SAS 9.4 system programming, and subjects are randomly assigned in 1:1 into two groups. This trial is not blinded. Blinding This trial is not blinded. We currently lack the conditions to produce placebos. Intervention Patients in the empagliflozin group will receive empagliflozin (Boehringer Ingelheim Pharma GmbH & Co. KG) 10 mg once daily in addition to the standard medication regimen. The control group will continue with the original treatment regimen. All patients will be treated for 12 weeks. Concomitant Medication All patients will receive treatment for HFpEF according to the authoritative guidelines on heart failure therapy released by the ESC in 2021 . [ 10 ] At the same time, patients will feel the need to take other medications, which will be recorded and analyzed. Outcomes Primary Outcome The primary outcome is the variation in peak VO 2 during the study period. Secondary Outcomes Secondary outcomes include: (a)Changes in peak VO2/HR, anaerobic threshold (AT), and VE/VCO2 evaluated by cardiopulmonary exercise testing (CPET). (b)Variations in left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume (LVEDV), left atrial volume (LAV), E/E’, and pulmonary artery pressure (PAP) as evaluated by echocardiography. (c)Changes from baseline in levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), estimated glomerular filtration rate (eGFR), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) at week 12. (d)Changes from baseline in New York Heart Association (NYHA) functional class and Minnesota Heart Failure Quality of Life Questionnaire (MLHFQ) scores at week 12. (see Table 2 ) Table 2 Primary and Secondary endpoints Primary endpoint The variation in peak VO 2 during the study period. Secondary endpoint The changes of the following parameters from baseline to week 121. Other CPET parameters - peak VO 2 /HR - AT - VE/VCO 2 2. Ultrasound cardiogram - LVEF - LVE DV -LAV - E /E ’ - PAP 3. New York Hrart Association functional class 4. Minnesota Heart Failure Quality of Life Scale. 5. NT-proBNP. 6.ALT/AST/eGFR Safety endpoints Hypoglycemia,hypotension, deterioration of kidney function, urinary tract infection, elevated LDL cholesterol. CPET, cardiopulmonary exercise testing; Study Timelines Screening Visit (Day − 14 ± 3) The timeline and inspection items are listed in Table 3. At the screening visit, participants will receive ECG, eligibility laboratory tests, vital signs measurement, and drug history registration. Laboratory data will include urine pregnancy testing, complete blood count, biochemical indexes, NT-proBNP. Baseline Visit (Day 0) After completion of baseline data collection, participants who meet the inclusion criteria and do no meet any exclusion criteria will be enrolled in the trial. Participants will be randomly assigned, in a 1:1 ratio, to either empagliflozin or continue with the original treatment plan. Subjects will complete all baseline examinations, including CPET, ultrasound cardiogram, New York Hrart Association functional class and MLHFQ scores. Following baseline data collection, participants assigned to the empagliflozin group will receive empagliflozin 10 mg once daily in addition to their original treatment, while those in the control group will continue with their original treatment regimen。 Follow-Up Visit(Day 84 ± 3) We will conduct repeat assessments of all examinations including CPET and echocardiography to evaluate efficacy and safety. Table 3 | Schedule of assessments. Timelines Screening Visit Baseline Visit Follow-Up Visit Week -2 0 12 Day -14 ± 3 0 84 ± 3 Informed consent √ Inclusion/exclusion criteria √ √ Concomitant medication √ √ √ Vital signs √ √ √ Physical examination √ √ √ urine pregnancy testing a √ 12-lead ECG √ √ CPET √ √ Cardiac ultrasound √ √ Laboratory tests b √ √ New York Hrart Association functional class √ √ Minnesota Heart Failure Quality of Life Scale √ √ Medical history √ √ Adverse events c √ √ √ A Urine pregnancy testing for women of reproductive age. b Laboratory tests include: complete blood count,eGFR,ALT,AST,NT-proBNP. c Adverse events include:urinary system,hypoglycemia,renal function damage.,el. Data Collection and Analysis Sample Collection and Laboratory Measurements Blood samples will be collected during the screening visit and follow-up and follow-up visits by professional nurses in The Third Affiliated Hospital of Guangzhou Medical University and measure blood routine examination, biochemical indices, NT-proBNP in clinical lab. Women of reproductive age will be asked to providde urine samples for a pregnancy test during the screening visit. Cardiopulmonary Exercise Testing CPET will be conducted by professional physicians in the cardiac function department. Prior to the test, physicians will thoroughly review the patient's medical history and medication history exclude any contraindications, and obtain signed informed consent for the trial. CPET consists of two parts, static pulmonary function testing and the ramp protocol. Static pulmonary function testing will obtain respiratory parameters such as forced vital capacity and maximal flow-volume loops. The ramp protocol includes several stages: a rest period, an unloaded warm-up period, a power load period, and a recovery period. The power increment for the ramp protocol is calculated using the following formula: Predicted unloaded VO 2 (ml·min-1) = 150 + [6 × weight (kg)]; Predicted peak VO 2 (ml·min-1) = [height (cm) - age (years)] × 20 (males) or × 14 (females). [ 11 ] Finally, parameters such as peak VO 2 , AT, and VE/VCO 2 are obtained. CPET reports will be issued by professional physicians and reviewed by senior physicians. Cardiac ultrasound Echocardiography is performed by professional physicians. It primarily measures indices reflecting left ventricular systolic and diastolic function, including LVEF, LVEDV, LAV, E/E', and PAP. The modified Simpson’s method is utilized for LVEF measurement, tissue Doppler imaging is employed to measure E and e' values to derive E/e', and PAP is assessed. Three-dimensional color Doppler echocardiography is used for LAV measurement. Adverse Events and Safety Adverse events are categorized into two aspects: CPET-related adverse events and empagliflozin-related adverse events. Empagliflozin-related most common adverse reactions include hypoglycemia, hypotension, deterioration of kidney function, urinary tract infection, elevated LDL cholesterol levels will be monitored. According to the results from Phase III clinical trials, empagliflozin is generally well tolerated, with a low incidence of adverse events (2.2% in empagliflozin 10 mg). [ 12 ] Additionally, common adverse reactions are generally of mild intensity, rarely led to drug discontinuation, and tended not to recur. All adverse events will be documented in the case report form for evaluation and reporting to the Clinical Research and Applied Ethics Committee of The Third Affiliated Hospital of Guangzhou Medical University. Data Management and Monitoring After each follow-up visit, research data will be collected and documented in the case report form. All data will be kept by the investigators. Upon completion of the study, the data will be entered into the Clinical Trial Management Public Platform (medresman.org.cn) for data sharing. Compliance Evaluation Compliance evaluation will be assessed by the number of patient follow-up visits and bottles returned. Statistical Consideration Sample Size Assumptions This study adopted a one-to-one parallel design, evaluating the sample size based on the change in peak oxygen uptake before and after treatment as the primary efficacy endpoint. It was designed as a superiority trial to compare the means of two groups. Based on previous studies, the increase in peak oxygen uptake after six months of treatment was estimated to be 1.1 ± 2. 6ml/kg/min for the empagliflozin group and 0.5 ± 1.9ml/kg/min for the control group. It was assumed that a difference greater than 0 between the test and control groups would be clinically significant. The combined standard deviation of the change values for both groups was set at 2.4ml/kg/min. The sample size was calculated using the following formula: $$\:Nc=\frac{{{（Z}_{1-\alpha\:}+{Z}_{1-\beta\:}）}^{2}{\sigma\:}^{2}（1+\frac{1}{r}）}{{（{\mu\:}_{E}-{\mu\:}_{c}-\varDelta\:）}^{2}}$$ The average change values in peak oxygen uptake before and after treatment for the control group and the empagliflozin group are denoted by µ C and µ E respectively. σ represents the combined standard deviation, while α and β represent type I and type Il errors . The allocation ratio of sample size between the test group and the control group is denoted by r. In this study, α = 0.0 25, β = 0.2, µ E- µ C = 2.6, σ = 2.4, r = 1, Δ = 0. Calculations show that 38 subjects are required in each group. Consequently, a total of 96 subjects (48 individuals in each group) are included, accounting for an approximate dropout rate of 20%. Statistical analysis Statistical analysis will be conducted using SAS 9.4. All statistical tests will be two-tailed. For continuous data, statistical descriptions will include counts, means, standard deviations, medians, minimum and maximum values, and upper and lower quartiles. For categorical data, counts and percentages will be used for statistical descriptions. Between-group comparisons of continuous data will be conducted using t-tests or rank-sum tests, while categorical data will be compared using chi-square tests or Fisher's exact test. Non-parametric methods, such as the Wilcoxon rank-sum test, will be employed for ordinal data. Continuous data will be presented as mean ± standard deviation (‾x ± s). Normality tests will be conducted first, and if both groups meet the assumptions of normality and have equal variances, a t-test will be used for between-group comparisons. Otherwise, we will consider the non-parametric Wilcoxon rank-sum test. Primary efficacy endpoint analysis: The primary efficacy endpoint involves comparing the changes in peak oxygen uptake before and after treatment in both groups. Additionally, we will compute the one-sided 97.5% confidence interval for the difference in changes in peak oxygen uptake before and after treatment, comparing both the test and control groups. If the lower boundary of this one-sided 97.5% confidence interval exceed 0, we will conclude that the test group demonstrates superiority over the control group. DISCUSSION The characteristic of HFpEF is impaired diastolic function, especially in elderly heart failure patients who tend to adopt a sedentary lifestyle, leading to reduced cardiopulmonary exercise tolerance and diminished quality of life. Exercise intolerance is a hallmark symptom of heart failure. SGLT2i have been shown to provide significant benefits for heart failure patients, as evidenced by the Emperor-Preserved study. While the majority of previous studies on SGLT2i in heart failure have primarily focused on hospitalization and mortality rates, there has been limited research on patients' exercise tolerance. In response to the issue of decreased exercise tolerance in HFpEF, we conducted a more in-depth investigation. The efficacy of empagliflozin on exercise tolerance was assessed through cardiopulmonary exercise testing, evaluating improvements in both exercise tolerance and cardiac function. Exercise intolerance is a hallmark symptom of heart failure, associated with increased disability and mortality risk. Although previous studies have demonstrated that SGLT2i improves the outcome of the six-minute walk test in patients with HFpEF. [ 13 ] However, compared with the six-minute walk test, the results of the CPET are more accurate and objective. Our study selected peak oxygen uptake as the primary endpoint because it is considered the gold standard for assessing exercise tolerance. A study compared the results of CPET and tissue Doppler in 32 HFpEF patients, revealing a significant correlation between the impairment of peak VO 2 and the impairment of left ventricular filling pressure parameters, indirectly demonstrating an association between peak VO 2 with impaired left ventricular diastolic function. [ 14 ] Additionally, our research incorporated the MLHFQ and New York Heart Association functional classification to subjectively assess patients' quality of life, aiming to obtain the most authentic results through a comprehensive evaluation. Our goal is to demonstrate that empagliflozin improves exercise tolerance and living quality in patients with HFpEF. This could further support the therapeutic role of SGLT2i in HFpEF. Additionally, in previous studies, the intervention period for SGLT2i in HFpEF patients has typically been over six months. Short-term effects of empagliflozin have not been explored. Our study has an intervention period of 3 months to observe whether empagliflozin has short-term therapeutic effects on HfpEF. Currently, studies have confirmed the efficacy of SGLT2i in the treatment of HFpEF. Our research has observed the therapeutic response of non-diabetic patient populations to empagliflozin. However, several issues remain unresolved regarding the treatment of HFpEF with empagliflozin.Firstly, while there is some data on the efficacy of empagliflozin as a monotherapy, further research is needed to investigate its effects and potential interactions when used in combination with other HFpEF treatment medications. This is crucial for determining the optimal therapeutic regimen. A recent meta-study showed:, In patients with HF and LVEF > 40%, the quadruple combination of ARNI, BB, MRA, and SGLT2i provides the largest reduction in the risk of Cardiovascular death. [ 15 ] But there is a lack of real-world data. The clinical trial environment and real-world clinical practice settings differ significantly. More real-world data from everyday clinical practice is needed to assess the actual application, effectiveness, and safety of empagliflozin across different healthcare environments and patient populations. Trial Status The protocol version number is 2.0, with the version date being April 20, 2022. This study was registered at www.chictr.org.cn on July 4, 2023. However, due to a delay in receiving funding, the actual recruitment start date was pushed to January 2024. Considering the limited number of patients currently meeting the inclusion criteria, the study remains in the patient enrollment phase, with recruitment anticipated to be completed by the end of 2025. List of abbreviations CPET Cardiopulmonary exercise testing eGFR Estimated glomerular filtration rate HF Heart failure HFpEF Heart failure with preserved ejection fraction NYHA New York Heart Association NT-proBNP N-terminal pro–B-type natriuretic peptide peak VO2 Peak oxygen uptake SGLT2i Sodium-glucose cotransporter 2 inhibitors Declarations Funding The study was financed from Guangzhou Municipal Science and Techology Bureau (2023A03J0372). Authors’ contributions YD and RH conceptualised the study and participated in the initial study design, with assistance from ZH and LM. RH, MLi drafted the manuscript. MLv, LL, LC coordinated manuscript revisions. All other authors contributed to the study design and revisions of the manuscript. Conflict of Interest: We declare that we have no conflict of interest. Consent for publication ： Not applicable. Ethice statement and Dissemination The Clinical Research and Applied Ethics Committee of The Third Affiliated Hospital of Guangzhou Medical University reviewed and approved this study（ [2022] 037）. The study will proceed after obtaining informed consent from the patients and signing of the informed consent form.Study procedures are strictly observe the ethical standards of the Helsinki Declaration. After completion, we will publish the results in a peer reviewed journal. References Dunlay SM, Roger VL, Redfield MM. Epidemiology of heart failure with preserved ejection fraction[J]. Nat Rev Cardiol, 2017, 14(10):591-602. DOI: 10.1038/nrcardio.2017.65. Shah AM, Pfeffer MA. Heart failure with preserved ejection fraction: a forest of a variety of trees[J]. European Heart Journal, 2014, 35(48):3410-3412. DOI: 10.1093/eurheartj/ehu212. Anker SD, Butler J, Filippatos GS, et al. 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Myers J, Arena R, Cahalin LP, et al. Cardiopulmonary Exercise Testing in Heart Failure[J]. Current Problems in Cardiology, 2015, 40(8):322-372. DOI: 10.1016/j.cpcardiol.2015.01.009. Zafeiropoulos S, Farmakis IT, Milioglou I, et al. Pharmacological Treatments in Heart Failure With Mildly Reduced and Preserved Ejection Fraction: Systematic Review and Network Meta-Analysis[J]. JACC: Heart Failure, 2024, 12(4):616-627. DOI: 10.1016/j.jchf.2023.07.014. Supplementary Files SPIRITFillablechecklist..doc Cite Share Download PDF Status: Published Journal Publication published 07 Apr, 2026 Read the published version in Trials → Version 1 posted Reviewers agreed at journal 03 Oct, 2025 Reviewers invited by journal 28 Apr, 2025 Editor invited by journal 04 Mar, 2025 Editor assigned by journal 26 Jan, 2025 First submitted to journal 18 Jan, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5038751","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":448976223,"identity":"7a0566fc-8598-4183-a0c9-ed746ea5f0b9","order_by":0,"name":"Rufeng Huang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAy0lEQVRIiWNgGAWjYBAC9gYQaSDBw8/e2PjgAzFaeA6AyAILGcmew82GM4jX8qHCxuBGeps0B1Fa2HsPvwA5zODmwwZpBgY7Od0GQlp4zqVZgLRI3k5sMC5gSDY2O0BAi71EjpkBSAsfUEvyDIYDidsIaeGRfwPRwnDzYMNhHqK0SPAYPwBpEbjB2NhMnBaeHDNwvEj2JDYzzjAgwi887GeMPzD8qbPnZz/+/MeHCjs5glqAgE36D5xtQFg5CDATlUxGwSgYBaNgBAMAqlY9R/xna9kAAAAASUVORK5CYII=","orcid":"https://orcid.org/0009-0000-3177-2001","institution":"The Third Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":true,"prefix":"","firstName":"Rufeng","middleName":"","lastName":"Huang","suffix":""},{"id":448976224,"identity":"f05815fa-94bb-4166-9db6-bb46e7e3733f","order_by":1,"name":"Yecheng Deng","email":"","orcid":"","institution":"Guangzhou Military General Hospital: People's Liberation Army General Hospital of Southern Theatre Command","correspondingAuthor":false,"prefix":"","firstName":"Yecheng","middleName":"","lastName":"Deng","suffix":""},{"id":448976225,"identity":"3064c16d-846c-4657-9192-a007748a165d","order_by":2,"name":"Mengshuang Li","email":"","orcid":"","institution":"The Third Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Mengshuang","middleName":"","lastName":"Li","suffix":""},{"id":448976226,"identity":"bc29aa76-5d14-4ab7-86fc-bf2a6353db94","order_by":3,"name":"Linghua Chen","email":"","orcid":"","institution":"The Third Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Linghua","middleName":"","lastName":"Chen","suffix":""},{"id":448976227,"identity":"f3baca85-c6a5-4379-9e61-facbc967716e","order_by":4,"name":"Meifen Lv","email":"","orcid":"","institution":"The Third Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Meifen","middleName":"","lastName":"Lv","suffix":""},{"id":448976228,"identity":"53ca59fa-d6f4-4c97-88dd-5b1721fa5ce5","order_by":5,"name":"Lihua Liao","email":"","orcid":"","institution":"The Third Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Lihua","middleName":"","lastName":"Liao","suffix":""},{"id":448976229,"identity":"24cbe059-2ac4-4a37-b799-f93361f13448","order_by":6,"name":"Li Ma","email":"","orcid":"","institution":"The Third Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Ma","suffix":""},{"id":448976230,"identity":"b7113a30-6c4d-493c-85f5-8527e4f0c451","order_by":7,"name":"Zhaoqi Huang","email":"","orcid":"https://orcid.org/0000-0002-5873-5697","institution":"The Third Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Zhaoqi","middleName":"","lastName":"Huang","suffix":""}],"badges":[],"createdAt":"2024-09-05 14:03:46","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5038751/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5038751/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13063-026-09654-y","type":"published","date":"2026-04-07T15:58:24+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":82139931,"identity":"811d02e8-64c7-4bbb-84b6-6ff830f0c618","added_by":"auto","created_at":"2025-05-07 06:28:46","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":49770,"visible":true,"origin":"","legend":"\u003cp\u003eStudy design. ECG, electrocardiogram; UCG: ultrasound cardiogram;\u003c/p\u003e\n\u003cp\u003eCPET,cardiopulmonary exercise testing; Laboratory tests:complete blood count, serum lipids and biochemical tests. MLHFQ:Minnesota Heart Failure Quality of Life Scale.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-5038751/v1/0e8663b426c6e3f370367f72.jpg"},{"id":106808894,"identity":"ae849f96-ecb4-4c77-ad5a-c60c17672c91","added_by":"auto","created_at":"2026-04-13 16:04:41","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":800226,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5038751/v1/7a5be1ff-0349-4ecc-9346-ce2fd11ccae4.pdf"},{"id":82142129,"identity":"c77cc2ad-4454-44cc-a737-e3bfc778945d","added_by":"auto","created_at":"2025-05-07 06:36:46","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":131584,"visible":true,"origin":"","legend":"","description":"","filename":"SPIRITFillablechecklist..doc","url":"https://assets-eu.researchsquare.com/files/rs-5038751/v1/56189cc81706d3d62a29e138.doc"}],"financialInterests":"","formattedTitle":"Empagliflozin in improving exercise tolerance in HFpEF: Study Protocol for an open-label, randomized controlled study","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eHeart failure (HF) is a group of complex clinical syndromes characterized by abnormal structural and/or function of the heart due to a variety of causes, leading to impaired ventricular contraction and/or diastolic function. In patients with heart failure, those with heart failure with preserved ejection fraction(HFpEF) make up a large proportion. Community Data on the prevalence and incidence of HFpEF indicate that approximately 50% of patients with the clinical syndrome of heart failure have a preserved ejection fraction.\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e HFpEF is a highly prevalent, complex, and heterogeneous disease. The universally accepted pathophysiology of HFpEF includes left ventricular diastolic dysfunction, pulmonary vascular dysfunction and right ventricular dysfunction.\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e Currently, HFpEF lacks effective therapies, and clinical treatment primarily focuses on symptom alleviation.\u003c/p\u003e \u003cp\u003eSodium-glucose cotransporter 2 inhibitors (SGLT2i) is a rising star among antidiabetic drugs. Increasing research has confirmed that SGLT2i have effects beyond glucose lowering, providing benefits to multiple organs such as the heart and kidneys, particularly in cardiovascular events, with a predominant focus on heart failure. SGLT2i exert therapeutic effects in heart failure through multiple mechanisms, including the inhibition of cardiac inflammation and fibrosis, antagonism of sodium retention, and enhancement of glomerular function.\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e SGLT2i can improve myocardial energy metabolism, promote ketone production and utilization, and decelerate the progression of heart failure.\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e Consequently, SGLT2i are gradually becoming first-line medications for the treatment of heart failure.\u003c/p\u003e \u003cp\u003eHowever, due to the significant differences in the pathogenesis of HFpEF, clinical studies have failed to confirm that ACEI /ARB and beta-blockers can improve the prognosis or reduce the mortality rate of HFpEF patients. Consequently, there is a lack of evidence-based medical evidence for the treatment of HFpEF. But increasing clinical studies have found that SGLT2i can confer cardiovascular benefits to patients with HFpEF. The renowned randomized trials, EMPEROR-Preserved trial and DELIVER trial, have demonstrated that SGLT2i empagliflozin and dapagliflozin can reduce the composite risk of cardiovascular death or heart failure hospitalization in patients with HFrEF and HFpEF.\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e A meta-analysis revealed that the concurrent use of ARNI, MRA, and SGLT2i exerts potent anti-heart failure effects.\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e SGLT2i in the growing role of HfpEF. Further clinical studies are still needed to confirm the role of SGLT2i in HFpEF.\u003c/p\u003e \u003cp\u003eExercise intolerance is a symptom of HF ,which is in connection with an increasing risk of death. Cardiopulmonary exercise testing (CPET) a diagnostic examination that assesses cardiopulmonary function. It involves a series of assessments conducted by measuring changes in cardiopulmonary function and related parameters during exercise. In individuals with heart disease, CPET can quantify the extent to which exercise limitations are attributable to cardiac factors. Peak oxygen uptake (peak VO2) is considered the foremost standard for evaluating exercise intolerance in individuals with HF.\u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e Peak VO2 is also an important predictor of mortality in patients with HFpEF.\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e The parameters of peak VO2, percent predicted peak VO2,and exercise duration in CPET had the strongest ability to predict mortality \u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eWe designed the study to evaluate the efficacy of empagliflozin in exercise tolerance in patients with HFpEF.\u003c/p\u003e"},{"header":"METHODS AND DESIGN","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eDesign\u003c/h2\u003e \u003cp\u003eThis study is designed as a single-center, open-label, randomized controlled trial. After the screening period, eligible patients are randomly assigned (1:1 randomization) to receive either empagliflozin, 10 mg per day, or to continue with the original treatment plan. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e illustrates the design and procedures through the trial.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eStudy Hypothesis\u003c/h3\u003e\n\u003cp\u003eEmpagliflozin can improve exercise tolerance of patients with HFpEF.\u003c/p\u003e\n\u003ch3\u003eStudy Population, Eligibility Criteria, and Recruitment\u003c/h3\u003e\n\u003cp\u003eParticipants are men or women aged 18 to 75 years, who have New York Heart Association (NYHA)functional class II\u0026ndash;III chronic heart failure and a left ventricular ejection fraction of more than 40%. The protocol requires patients to have an N-terminal pro\u0026ndash;B-type natriuretic peptide (NT-proBNP) level of more than 300 pg per milliliter and estimated glomerular filtration rate ( eGFR ) more than 30 ml/min/1.73m^2.\u003c/p\u003e \u003cp\u003eThe study primarily excludes patients with diabetes, severe liver or kidney dysfunction, as well as those with other conditions deemed unsuitable for inclusion. The key inclusion and exclusion criteria are listed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eThe study will be conducted at The Third Affiliated Hospital of Guangzhou Medical University. Patients will be recruited by researchers describing this study in the outpatient service and inpatient departments. Posters containing study information will also be used within the hospital. Every patient will sign informed consent prior to enrollment.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eInclusion and exclusion criteria\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"1\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInclusion criteria\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e(1) Aged 18 to 75 years, male or female;\u003c/p\u003e \u003cp\u003e(2) Patients with chronic HF (NYHA class II and III) diagnosed for at least 3 months and currently in HF NYHA class II-III;\u003c/p\u003e \u003cp\u003e(3) LVEF\u0026thinsp;\u0026gt;\u0026thinsp;40%;\u003c/p\u003e \u003cp\u003e(4) NT-proBNP\u0026thinsp;\u0026gt;\u0026thinsp;300 pg/mL;\u003c/p\u003e \u003cp\u003e(5) eGFR\u0026thinsp;\u0026ge;\u0026thinsp;30ml/min/1.73m^2;\u003c/p\u003e \u003cp\u003e(6) Able to understand and voluntarily sign the informed consent form;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eExclusion criteria\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(1) Diabetes;\u003c/p\u003e \u003cp\u003e(2) Acute coronary syndrome whihin the last 2 months or planned coronary revascularization during the trial;\u003c/p\u003e \u003cp\u003e(3) Atrial fibrillation, cardiovascular and cerebrovascular events related to atrial fibrillation in the last 3 months;\u003c/p\u003e \u003cp\u003e(4) Hypohepatia, defined by serum levels of transaminases more than three times the upper limit of normal at screening;\u003c/p\u003e \u003cp\u003e(5) Using SGLT2i within 4 weeks prior to randomization;\u003c/p\u003e \u003cp\u003e(6) Diseases that affect the results of CPET include arthropathy, peripheral vascular disease, lung disease and other diseases ;\u003c/p\u003e \u003cp\u003e(7) The subject's resting ECG has the following abnormalities: (a) ventricular pre-excitation syndrome; (b) ventricular pacing rhythm; (c) resting ST segment depression of more than 2mm; (d) left bundle branch block or any intraventricular conduction delay with QRS duration greater than 120 ms;\u003c/p\u003e \u003cp\u003e(8) Congenital heart defects, progressive decompensated congestive heart failure, severe valvular disease, hypertrophic obstructive cardiomyopathy, severe uncontrolled hypertension (sitting systolic blood pressure\u0026thinsp;\u0026gt;\u0026thinsp;180mmHg or diastolic blood pressure\u0026thinsp;\u0026gt;\u0026thinsp;110mmHg), severe anemia, suspected or known arterial dissection, acute myocarditis or pericardial effusion, active endocarditis, thrombophlebitis, or pulmonary embolism.\u003c/p\u003e \u003cp\u003e(9) History of bleeding tendency, cerebral hemorrhage, or epilepsy requiring anticonvulsant medication.\u003c/p\u003e \u003cp\u003e(10) Pregnant woman or breastfeeding woman.\u003c/p\u003e \u003cp\u003e(11) Participated in any other trials or use of any investigational drugs within the 30 days prior to enrollment.\u003c/p\u003e \u003cp\u003e(12) Drug abuse. The patient has a history of alcohol abuse or known drug dependence in the past 2 years.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eWithdrawal Criteria\u003c/b\u003e\u003c/p\u003e \u003cp\u003e(1) Any suspected drug-related serious adverse events (e.g., allergic reactions).\u003c/p\u003e \u003cp\u003e(2) Recurrence of acute heart failure or sudden severe dysfunction of organs such as the liver or kidneys.\u003c/p\u003e \u003cp\u003e(3) Pregnancy.\u003c/p\u003e \u003cp\u003e(4) Major protocol deviations. After randomization, it is found that the subject does not meet the inclusion criteria of the study protocol or does not follow the requirements of the study protocol, and continuing to participate in the study may pose unacceptable risks to the subject's health.\u003c/p\u003e \u003cp\u003e(5) Loss to follow-up. The subject does not return to the clinic and cannot be successfully contacted. Information on attempts to contact the subject must be documented.\u003c/p\u003e \u003cp\u003e(6) Voluntary withdrawal. The subject (or the subject's legal representative) wishes to withdraw from the study. The reason for withdrawal should be recorded in the case report form.\u003c/p\u003e \u003cp\u003e(7) Study termination. The study is terminated by the sponsor, ethics committee, or regulatory authority.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eCPET, cardiopulmonary exercise testing; ECG, electrocardiogram.\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eRandomization and Allocation\u003c/h3\u003e\n\u003cp\u003eRandomization sequences are generated using SAS 9.4 system programming, and subjects are randomly assigned in 1:1 into two groups. This trial is not blinded.\u003c/p\u003e\n\u003ch3\u003eBlinding\u003c/h3\u003e\n\u003cp\u003eThis trial is not blinded. We currently lack the conditions to produce placebos.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eIntervention\u003c/h2\u003e \u003cp\u003ePatients in the empagliflozin group will receive empagliflozin (Boehringer Ingelheim Pharma GmbH \u0026amp; Co. KG) 10 mg once daily in addition to the standard medication regimen. The control group will continue with the original treatment regimen. All patients will be treated for 12 weeks.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eConcomitant Medication\u003c/h3\u003e\n\u003cp\u003e All patients will receive treatment for HFpEF according to the authoritative guidelines on heart failure therapy released by the ESC in 2021 .\u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e At the same time, patients will feel the need to take other medications, which will be recorded and analyzed.\u003c/p\u003e\n\u003ch3\u003eOutcomes\u003c/h3\u003e\n\u003cp\u003ePrimary Outcome\u003c/p\u003e \u003cp\u003eThe primary outcome is the variation in peak VO\u003csub\u003e2\u003c/sub\u003e during the study period.\u003c/p\u003e \u003cp\u003eSecondary Outcomes\u003c/p\u003e \u003cp\u003eSecondary outcomes include: (a)Changes in peak VO2/HR, anaerobic threshold (AT), and VE/VCO2 evaluated by cardiopulmonary exercise testing (CPET). (b)Variations in left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume (LVEDV), left atrial volume (LAV), E/E\u0026rsquo;, and pulmonary artery pressure (PAP) as evaluated by echocardiography. (c)Changes from baseline in levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), estimated glomerular filtration rate (eGFR), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) at week 12. (d)Changes from baseline in New York Heart Association (NYHA) functional class and Minnesota Heart Failure Quality of Life Questionnaire (MLHFQ) scores at week 12. (see Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePrimary and Secondary endpoints\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"1\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary endpoint\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThe variation in peak VO\u003csub\u003e2\u003c/sub\u003e during the study period.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSecondary endpoint\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThe changes of the following parameters from baseline to week 121. Other CPET parameters\u003c/p\u003e \u003cp\u003e- peak VO\u003csub\u003e2\u003c/sub\u003e/HR\u003c/p\u003e \u003cp\u003e- AT\u003c/p\u003e \u003cp\u003e- VE/VCO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e \u003cp\u003e2. Ultrasound cardiogram\u003c/p\u003e \u003cp\u003e- LVEF\u003c/p\u003e \u003cp\u003e- LVE DV\u003c/p\u003e\u003cp\u003e-LAV\u003c/p\u003e\u003cp\u003e- E /E \u0026rsquo;\u003c/p\u003e\u003cp\u003e- PAP\u003c/p\u003e\u003cp\u003e3. New York Hrart Association functional class\u003c/p\u003e\u003cp\u003e4. Minnesota Heart Failure Quality of Life Scale.\u003c/p\u003e\u003cp\u003e5. NT-proBNP.\u003c/p\u003e\u003cp\u003e6.ALT/AST/eGFR\u003c/p\u003e\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSafety endpoints\u003c/b\u003e\u003c/p\u003e \u003cp\u003eHypoglycemia,hypotension, deterioration of kidney function, urinary tract infection, elevated LDL cholesterol.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eCPET, cardiopulmonary exercise testing;\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eStudy Timelines\u003c/h2\u003e \u003cp\u003eScreening Visit (Day \u0026minus;\u0026thinsp;14\u0026thinsp;\u0026plusmn;\u0026thinsp;3)\u003c/p\u003e \u003cp\u003eThe timeline and inspection items are listed in Table\u0026nbsp;3. At the screening visit, participants will receive ECG, eligibility laboratory tests, vital signs measurement, and drug history registration. Laboratory data will include urine pregnancy testing, complete blood count, biochemical indexes, NT-proBNP.\u003c/p\u003e \u003cp\u003eBaseline Visit (Day 0)\u003c/p\u003e \u003cp\u003eAfter completion of baseline data collection, participants who meet the inclusion criteria and do no meet any exclusion criteria will be enrolled in the trial. Participants will be randomly assigned, in a 1:1 ratio, to either empagliflozin or continue with the original treatment plan. Subjects will complete all baseline examinations, including CPET, ultrasound cardiogram, New York Hrart Association functional class and MLHFQ scores. Following baseline data collection, participants assigned to the empagliflozin group will receive empagliflozin 10 mg once daily in addition to their original treatment, while those in the control group will continue with their original treatment regimen。\u003c/p\u003e \u003cp\u003eFollow-Up Visit(Day 84\u0026thinsp;\u0026plusmn;\u0026thinsp;3)\u003c/p\u003e \u003cp\u003eWe will conduct repeat assessments of all examinations including CPET and echocardiography to evaluate efficacy and safety.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003eTable\u0026nbsp;3 | Schedule of assessments.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTimelines\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eScreening Visit\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eBaseline Visit\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eFollow-Up Visit\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeek\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDay\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-14\u0026thinsp;\u0026plusmn;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e84\u0026thinsp;\u0026plusmn;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInformed consent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026radic;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInclusion/exclusion criteria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026radic;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026radic;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConcomitant medication\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026radic;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026radic;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026radic;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVital signs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026radic;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026radic;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026radic;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhysical examination\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026radic;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026radic;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026radic;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eurine pregnancy testing\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026radic;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12-lead ECG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026radic;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026radic;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCPET\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026radic;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026radic;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiac ultrasound\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026radic;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026radic;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLaboratory tests\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026radic;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026radic;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNew York Hrart Association functional class\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026radic;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026radic;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMinnesota Heart Failure Quality of Life Scale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026radic;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026radic;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eMedical history\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026radic;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026radic;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdverse events\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026radic;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026radic;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026radic;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003csup\u003e\u003cem\u003eA\u003c/em\u003e\u003c/sup\u003e \u003cem\u003eUrine pregnancy testing for women of reproductive age.\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003csup\u003e\u003cem\u003eb\u003c/em\u003e\u003c/sup\u003e\u003cem\u003eLaboratory tests include: complete blood count,eGFR,ALT,AST,NT-proBNP.\u003c/em\u003e\u003c/p\u003e \u003cp\u003e\u003csup\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sup\u003e\u003cem\u003eAdverse events include:urinary system,hypoglycemia,renal function damage.,el.\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"1\" nameend=\"c5\" namest=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eData Collection and Analysis\u003c/h2\u003e \u003cp\u003eSample Collection and Laboratory Measurements\u003c/p\u003e \u003cp\u003eBlood samples will be collected during the screening visit and follow-up and follow-up visits by professional nurses in The Third Affiliated Hospital of Guangzhou Medical University and measure blood routine examination, biochemical indices, NT-proBNP in clinical lab. Women of reproductive age will be asked to providde urine samples for a pregnancy test during the screening visit.\u003c/p\u003e \u003cp\u003eCardiopulmonary Exercise Testing\u003c/p\u003e \u003cp\u003eCPET will be conducted by professional physicians in the cardiac function department. Prior to the test, physicians will thoroughly review the patient's medical history and medication history exclude any contraindications, and obtain signed informed consent for the trial. CPET consists of two parts, static pulmonary function testing and the ramp protocol. Static pulmonary function testing will obtain respiratory parameters such as forced vital capacity and maximal flow-volume loops. The ramp protocol includes several stages: a rest period, an unloaded warm-up period, a power load period, and a recovery period. The power increment for the ramp protocol is calculated using the following formula: Predicted unloaded VO\u003csub\u003e2\u003c/sub\u003e (ml\u0026middot;min-1)\u0026thinsp;=\u0026thinsp;150 + [6 \u0026times; weight (kg)]; Predicted peak VO\u003csub\u003e2\u003c/sub\u003e (ml\u0026middot;min-1) = [height (cm) - age (years)] \u0026times; 20 (males) or \u0026times; 14 (females).\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e Finally, parameters such as peak VO\u003csub\u003e2\u003c/sub\u003e, AT, and VE/VCO\u003csub\u003e2\u003c/sub\u003e are obtained. CPET reports will be issued by professional physicians and reviewed by senior physicians.\u003c/p\u003e \u003cp\u003eCardiac ultrasound\u003c/p\u003e \u003cp\u003eEchocardiography is performed by professional physicians. It primarily measures indices reflecting left ventricular systolic and diastolic function, including LVEF, LVEDV, LAV, E/E', and PAP. The modified Simpson\u0026rsquo;s method is utilized for LVEF measurement, tissue Doppler imaging is employed to measure E and e' values to derive E/e', and PAP is assessed. Three-dimensional color Doppler echocardiography is used for LAV measurement.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eAdverse Events and Safety\u003c/h2\u003e \u003cp\u003eAdverse events are categorized into two aspects: CPET-related adverse events and empagliflozin-related adverse events. Empagliflozin-related most common adverse reactions include hypoglycemia, hypotension, deterioration of kidney function, urinary tract infection, elevated LDL cholesterol levels will be monitored. According to the results from Phase III clinical trials, empagliflozin is generally well tolerated, with a low incidence of adverse events (2.2% in empagliflozin 10 mg).\u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e Additionally, common adverse reactions are generally of mild intensity, rarely led to drug discontinuation, and tended not to recur. All adverse events will be documented in the case report form for evaluation and reporting to the Clinical Research and Applied Ethics Committee of The Third Affiliated Hospital of Guangzhou Medical University.\u003c/p\u003e \u003cp\u003e \u003cb\u003eData Management and Monitoring\u003c/b\u003e \u003c/p\u003e \u003cp\u003eAfter each follow-up visit, research data will be collected and documented in the case report form. All data will be kept by the investigators. Upon completion of the study, the data will be entered into the Clinical Trial Management Public Platform (medresman.org.cn) for data sharing.\u003c/p\u003e \u003cp\u003e \u003cb\u003eCompliance Evaluation\u003c/b\u003e \u003c/p\u003e \u003cp\u003eCompliance evaluation will be assessed by the number of patient follow-up visits and bottles returned.\u003c/p\u003e \u003cp\u003e \u003cb\u003eStatistical Consideration\u003c/b\u003e Sample Size Assumptions\u003c/p\u003e \u003cp\u003eThis study adopted a one-to-one parallel design, evaluating the sample size based on the change in peak oxygen uptake before and after treatment as the primary efficacy endpoint. It was designed as a superiority trial to compare the means of two groups. Based on previous studies, the increase in peak oxygen uptake after six months of treatment was estimated to be 1.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2. 6ml/kg/min for the empagliflozin group and 0.5\u0026thinsp;\u0026plusmn;\u0026thinsp;1.9ml/kg/min for the control group. It was assumed that a difference greater than 0 between the test and control groups would be clinically significant. The combined standard deviation of the change values for both groups was set at 2.4ml/kg/min. The sample size was calculated using the following formula:\u003cdiv id=\"Equa\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equa\" name=\"EquationSource\"\u003e\n$$\\:Nc=\\frac{{{（Z}_{1-\\alpha\\:}+{Z}_{1-\\beta\\:}）}^{2}{\\sigma\\:}^{2}（1+\\frac{1}{r}）}{{（{\\mu\\:}_{E}-{\\mu\\:}_{c}-\\varDelta\\:）}^{2}}$$\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eThe average change values in peak oxygen uptake before and after treatment for the control group and the empagliflozin group are denoted by \u0026micro; C and \u0026micro; E respectively. σ represents the combined standard deviation, while α and β represent type I and type Il errors .\u003c/p\u003e \u003cp\u003eThe allocation ratio of sample size between the test group and the control group is denoted by r. In this study, α\u0026thinsp;=\u0026thinsp;0.0 25, β\u0026thinsp;=\u0026thinsp;0.2, \u0026micro; E- \u0026micro; C\u0026thinsp;=\u0026thinsp;2.6, σ\u0026thinsp;=\u0026thinsp;2.4, r\u0026thinsp;=\u0026thinsp;1, Δ\u0026thinsp;=\u0026thinsp;0. Calculations show that 38 subjects are required in each group. Consequently, a total of 96 subjects (48 individuals in each group) are included, accounting for an approximate dropout rate of 20%.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eStatistical analysis will be conducted using SAS 9.4. All statistical tests will be two-tailed. For continuous data, statistical descriptions will include counts, means, standard deviations, medians, minimum and maximum values, and upper and lower quartiles. For categorical data, counts and percentages will be used for statistical descriptions. Between-group comparisons of continuous data will be conducted using t-tests or rank-sum tests, while categorical data will be compared using chi-square tests or Fisher's exact test. Non-parametric methods, such as the Wilcoxon rank-sum test, will be employed for ordinal data. Continuous data will be presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (\u0026oline;x\u0026thinsp;\u0026plusmn;\u0026thinsp;s). Normality tests will be conducted first, and if both groups meet the assumptions of normality and have equal variances, a t-test will be used for between-group comparisons. Otherwise, we will consider the non-parametric Wilcoxon rank-sum test. Primary efficacy endpoint analysis: The primary efficacy endpoint involves comparing the changes in peak oxygen uptake before and after treatment in both groups. Additionally, we will compute the one-sided 97.5% confidence interval for the difference in changes in peak oxygen uptake before and after treatment, comparing both the test and control groups. If the lower boundary of this one-sided 97.5% confidence interval exceed 0, we will conclude that the test group demonstrates superiority over the control group.\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe characteristic of HFpEF is impaired diastolic function, especially in elderly heart failure patients who tend to adopt a sedentary lifestyle, leading to reduced cardiopulmonary exercise tolerance and diminished quality of life. Exercise intolerance is a hallmark symptom of heart failure. SGLT2i have been shown to provide significant benefits for heart failure patients, as evidenced by the Emperor-Preserved study. While the majority of previous studies on SGLT2i in heart failure have primarily focused on hospitalization and mortality rates, there has been limited research on patients' exercise tolerance. In response to the issue of decreased exercise tolerance in HFpEF, we conducted a more in-depth investigation. The efficacy of empagliflozin on exercise tolerance was assessed through cardiopulmonary exercise testing, evaluating improvements in both exercise tolerance and cardiac function.\u003c/p\u003e \u003cp\u003eExercise intolerance is a hallmark symptom of heart failure, associated with increased disability and mortality risk. Although previous studies have demonstrated that SGLT2i improves the outcome of the six-minute walk test in patients with HFpEF. \u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003eHowever, compared with the six-minute walk test, the results of the CPET are more accurate and objective. Our study selected peak oxygen uptake as the primary endpoint because it is considered the gold standard for assessing exercise tolerance. A study compared the results of CPET and tissue Doppler in 32 HFpEF patients, revealing a significant correlation between the impairment of peak VO\u003csub\u003e2\u003c/sub\u003e and the impairment of left ventricular filling pressure parameters, indirectly demonstrating an association between peak VO\u003csub\u003e2\u003c/sub\u003e with impaired left ventricular diastolic function.\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e Additionally, our research incorporated the MLHFQ and New York Heart Association functional classification to subjectively assess patients' quality of life, aiming to obtain the most authentic results through a comprehensive evaluation. Our goal is to demonstrate that empagliflozin improves exercise tolerance and living quality in patients with HFpEF. This could further support the therapeutic role of SGLT2i in HFpEF.\u003c/p\u003e \u003cp\u003eAdditionally, in previous studies, the intervention period for SGLT2i in HFpEF patients has typically been over six months. Short-term effects of empagliflozin have not been explored. Our study has an intervention period of 3 months to observe whether empagliflozin has short-term therapeutic effects on HfpEF.\u003c/p\u003e \u003cp\u003eCurrently, studies have confirmed the efficacy of SGLT2i in the treatment of HFpEF. Our research has observed the therapeutic response of non-diabetic patient populations to empagliflozin. However, several issues remain unresolved regarding the treatment of HFpEF with empagliflozin.Firstly, while there is some data on the efficacy of empagliflozin as a monotherapy, further research is needed to investigate its effects and potential interactions when used in combination with other HFpEF treatment medications. This is crucial for determining the optimal therapeutic regimen. A recent meta-study showed:, In patients with HF and LVEF\u0026thinsp;\u0026gt;\u0026thinsp;40%, the quadruple combination of ARNI, BB, MRA, and SGLT2i provides the largest reduction in the risk of Cardiovascular death.\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e But there is a lack of real-world data. The clinical trial environment and real-world clinical practice settings differ significantly. More real-world data from everyday clinical practice is needed to assess the actual application, effectiveness, and safety of empagliflozin across different healthcare environments and patient populations.\u003c/p\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eTrial Status\u003c/h2\u003e \u003cp\u003eThe protocol version number is 2.0, with the version date being April 20, 2022. This study was registered at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ewww.chictr.org.cn\u003c/span\u003e\u003cspan address=\"http://www.chictr.org.cn\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e on July 4, 2023. However, due to a delay in receiving funding, the actual recruitment start date was pushed to January 2024. Considering the limited number of patients currently meeting the inclusion criteria, the study remains in the patient enrollment phase, with recruitment anticipated to be completed by the end of 2025.\u003c/p\u003e \u003c/div\u003e"},{"header":"List of abbreviations","content":"\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42.0408%;\"\u003e\n \u003cp\u003eCPET\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57.9592%;\"\u003e\n \u003cp\u003eCardiopulmonary exercise testing\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42.0408%;\"\u003e\n \u003cp\u003eeGFR\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57.9592%;\"\u003e\n \u003cp\u003eEstimated glomerular filtration rate\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42.0408%;\"\u003e\n \u003cp\u003eHF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57.9592%;\"\u003e\n \u003cp\u003eHeart failure\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42.0408%;\"\u003e\n \u003cp\u003eHFpEF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57.9592%;\"\u003e\n \u003cp\u003eHeart failure with preserved ejection fraction\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42.0408%;\"\u003e\n \u003cp\u003eNYHA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57.9592%;\"\u003e\n \u003cp\u003eNew York Heart Association\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42.0408%;\"\u003e\n \u003cp\u003eNT-proBNP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57.9592%;\"\u003e\n \u003cp\u003eN-terminal pro\u0026ndash;B-type natriuretic peptide\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42.0408%;\"\u003e\n \u003cp\u003epeak VO2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57.9592%;\"\u003e\n \u003cp\u003ePeak oxygen uptake\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 42.0408%;\"\u003e\n \u003cp\u003eSGLT2i\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 57.9592%;\"\u003e\n \u003cp\u003eSodium-glucose cotransporter 2 inhibitors\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was financed from Guangzhou Municipal Science and Techology Bureau (2023A03J0372).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYD and RH conceptualised the study and participated in the initial study design, with assistance from ZH and LM. RH, MLi drafted the manuscript. MLv, LL, LC coordinated manuscript revisions. All other authors contributed to the study design and revisions of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe declare that we have no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003cstrong\u003e：\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthice statement and Dissemination\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Clinical Research and Applied Ethics Committee of The Third Affiliated Hospital of Guangzhou Medical University reviewed and approved this study（ [2022] 037）. The study will proceed after obtaining informed consent from the patients and signing of the informed consent form.Study procedures are strictly observe the ethical standards of the Helsinki Declaration.\u003c/p\u003e\n\u003cp\u003eAfter completion, we will publish the results in a peer reviewed journal.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eDunlay SM, Roger VL, Redfield MM. Epidemiology of heart failure with preserved ejection fraction[J]. Nat Rev Cardiol, 2017, 14(10):591-602. DOI: 10.1038/nrcardio.2017.65.\u003c/li\u003e\n\u003cli\u003eShah AM, Pfeffer MA. Heart failure with preserved ejection fraction: a forest of a variety of trees[J]. European Heart Journal, 2014, 35(48):3410-3412. DOI: 10.1093/eurheartj/ehu212.\u003c/li\u003e\n\u003cli\u003eAnker SD, Butler J, Filippatos GS, et al. Evaluation of the effects of sodium\u0026ndash;glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR-Preserved Trial[J]. European Journal of Heart Failure, 2019, 21(10):1279-1287. DOI: 10.1002/ejhf.1596.\u003c/li\u003e\n\u003cli\u003eYurista SR, Sillj\u0026eacute; HHW, Oberdorf-Maass SU, et al. Sodium\u0026ndash;glucose co-transporter 2 inhibition with empagliflozin improves cardiac function in non-diabetic rats with left ventricular dysfunction after myocardial infarction[J]. European Journal of Heart Failure, 2019, 21(7):862-873. DOI: 10.1002/ejhf.1473.\u003c/li\u003e\n\u003cli\u003eAnker SD, Butler J, Filippatos G, et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction[J]. N Engl J Med, 2021, 385(16):1451-1461. DOI: 10.1056/NEJMoa2107038.\u003c/li\u003e\n\u003cli\u003eMcMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction[J]. N Engl J Med, 2019, 381(21):1995-2008. DOI: 10.1056/NEJMoa1911303.\u003c/li\u003e\n\u003cli\u003eZafeiropoulos S, Farmakis IT, Milioglou I, et al. Pharmacological Treatments in Heart Failure With Mildly Reduced and Preserved Ejection Fraction: Systematic Review and Network Meta-Analysis[J]. JACC: Heart Failure, 2024, 12(4):616-627. DOI: 10.1016/j.jchf.2023.07.014.\u003c/li\u003e\n\u003cli\u003eDhakal BP, Malhotra R, Murphy RM, et al. Mechanisms of Exercise Intolerance in Heart Failure With Preserved Ejection Fraction[J]. Circ Heart Fail, 2015, 8(2):286-294. DOI: 10.1161/CIRCHEARTFAILURE.114.001825.\u003c/li\u003e\n\u003cli\u003eKeteyian SJ, Patel M, Kraus WE, et al. Variables Measured during Cardiopulmonary Exercise Testing as Predictors of Mortality in Chronic Systolic Heart Failure[J]. J Am Coll Cardiol, 2016, 67(7):780-789. DOI: 10.1016/j.jacc.2015.11.050.\u003c/li\u003e\n\u003cli\u003eMcDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure[J]. Eur Heart J, 2021, 42(36):3599-3726. DOI: 10.1093/eurheartj/ehab368.\u003c/li\u003e\n\u003cli\u003eChinese Society of Cardiology, Chinese Medical Association, Professional Committee of Cardiopulmonary Prevention and Rehabilitation of Chinese Rehabilitation Medical Association, Editorial Board of Chinese Journal of Cardiology. Chinese expert consensus on standardized clinical application of cardiopulmonary exercise testing[J]. Chinese Journal of Cardiovascular Diseases, 2022, 50(10):973-986. DOI: 10.3760/cma.j.cn112148-20220316-00180.\u003c/li\u003e\n\u003cli\u003eNeeland IJ, Salahuddin U, McGuire DK. A Safety Evaluation of Empagliflozin for the Treatment of Type 2 Diabetes[J]. Expert Opin Drug Saf, 2016, 15(3):393-402. DOI: 10.1517/14740338.2016.1135900.\u003c/li\u003e\n\u003cli\u003eTanashat M, Manasrah A, Abouzid M. Effects of dapagliflozin and empagliflozin on 6-min walk distance in heart failure with preserved and reduced ejection fraction: A systematic review and meta-analysis of randomized controlled trials involving 2624 patients[J]. Eur J Clin Pharmacol, 2024, 80(7):951-963. DOI: 10.1007/s00228-024-03660-2.\u003c/li\u003e\n\u003cli\u003eMyers J, Arena R, Cahalin LP, et al. Cardiopulmonary Exercise Testing in Heart Failure[J]. Current Problems in Cardiology, 2015, 40(8):322-372. DOI: 10.1016/j.cpcardiol.2015.01.009.\u003c/li\u003e\n\u003cli\u003eZafeiropoulos S, Farmakis IT, Milioglou I, et al. Pharmacological Treatments in Heart Failure With Mildly Reduced and Preserved Ejection Fraction: Systematic Review and Network Meta-Analysis[J]. JACC: Heart Failure, 2024, 12(4):616-627. DOI: 10.1016/j.jchf.2023.07.014.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"SGLT2i, HFpEF, CPET, exercise tolerance, Study Protocol","lastPublishedDoi":"10.21203/rs.3.rs-5038751/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5038751/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHeart failure with preserved ejection fraction（HFpEF） constitutes nearly half of patients with heart failure, but there is still a lack of treatment options to improve prognosis. Empagliflozin is one of the novel hypoglycemic agent sodium glucose cotransporter 2 inhibitors（SGLT2i），however, its impact on exercise tolerance in HFpEF remains unclear. Further clinical investigations are warranted to elucidate the role of SGLT2i in HFpEF. This study aims to evaluate the efficacy and safety of empagliflozin on the exercise tolerance in patients with HFpEF through cardiopulmonary exercise test.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods and Analysis:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is a single-center, open-label, randomized controlled trial. We will randomly (1:1) assign 96 patients with an ejection fraction of more than 40% and class II–III heart failure to receive empagliflozin (10 mg once daily) or continue with the original treatment plan. The treatment duration will be 12 weeks. The primary endpoint is the evaluation of changes in peak oxygen uptake (peak VO2) after a 12-week period using cardiopulmonary exercise testing (CPET). The secondary endpoints included other parameters of CPET and ultrasound cardiogram, N-terminal pro-B-type natriuretic peptide level, alanine aminotransferase level, Aspartate Transaminase level，Estimated glomerular filtration rate level, New York Heart Association functional classification, and scores from the Minnesota Living with Heart Failure Questionnaire.\u003c/p\u003e\n\u003cp\u003eSafety events associated with empagliflozin and CPET will be monitored.\u003c/p\u003e\n\u003ch3\u003eDiscussion\u003c/h3\u003e\n\u003cp\u003eWe used peak oxygen uptake, the gold standard for assessing exercise tolerance, to evaluate the efficacy and safety of empagliflozin in treating non-diabetic patients with HFpEF. The improvement in quality of life of heart failure patients by SGLT2i will be objectively assessed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial Registration :\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ewww.chictr.org.cn (ChiCTR2300072908). Registered on 04 July 2023.\u003c/p\u003e","manuscriptTitle":"Empagliflozin in improving exercise tolerance in HFpEF: Study Protocol for an open-label, randomized controlled study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-07 06:28:42","doi":"10.21203/rs.3.rs-5038751/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-10-03T13:23:28+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-28T09:07:19+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"Trials","date":"2025-03-04T10:53:11+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-01-26T15:55:04+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2025-01-19T01:38:51+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"96adfcaa-c17b-40d7-bfdc-e9eb76643ff5","owner":[],"postedDate":"May 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-04-13T16:01:21+00:00","versionOfRecord":{"articleIdentity":"rs-5038751","link":"https://doi.org/10.1186/s13063-026-09654-y","journal":{"identity":"trials","isVorOnly":false,"title":"Trials"},"publishedOn":"2026-04-07 15:58:24","publishedOnDateReadable":"April 7th, 2026"},"versionCreatedAt":"2025-05-07 06:28:42","video":"","vorDoi":"10.1186/s13063-026-09654-y","vorDoiUrl":"https://doi.org/10.1186/s13063-026-09654-y","workflowStages":[]},"version":"v1","identity":"rs-5038751","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5038751","identity":"rs-5038751","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}