xml: <clinical_study>
    <!-- This xml conforms to an XML Schema at:
      https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
    <required_header>
      <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
      <link_text>Link to the current ClinicalTrials.gov record.</link_text>
      <url>https://clinicaltrials.gov/ct2/show/NCT06012279</url>
    </required_header>
    <id_info>
      <org_study_id>MD-343-2021</org_study_id>
      <nct_id>NCT06012279</nct_id>
    </id_info>
    <brief_title>Clinical Outcomes of Dapagliflozin in Acute Heart Failure</brief_title>
    <official_title>Clinical Outcomes of Dapagliflozin in Acute Heart Failure, a Randomized Controlled Trial</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Cairo University</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>Aswan Heart Centre</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>Cairo University</source>
    <oversight_info>
      <has_dmc>No</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
      <is_us_export>No</is_us_export>
    </oversight_info>
    <brief_summary>
      <textblock>
        The goal of this clinical trial is to evaluate the short-term clinical outcomes of starting&#xD;
        Dapagliflozin on the same day of hospital admission in patients with acute decompensated&#xD;
        heart failure (ADHF).&#xD;
  &#xD;
        The main questions it aims to answer are:&#xD;
  &#xD;
          -  Does early initiation of Dapagliflozin improve the length of hospital stay and&#xD;
             in-hospital mortality in patients with ADHF?&#xD;
  &#xD;
          -  Does early initiation of Dapagliflozin enhance the diuretic response, weight reduction&#xD;
             and pro-BNP reduction in the acute stage of HF?&#xD;
  &#xD;
          -  Does early initiation of Dapagliflozin adversely affect the hemodynamic stability and&#xD;
             kidney functions in the acute stage of HF?&#xD;
  &#xD;
        Participants will be randomized with the ratio of 1:1 within 24 hours of admission to receive&#xD;
        Dapagliflozin 10 mg/day versus standard of care. Follow up will continue for 1 month after&#xD;
        hospital discharge.&#xD;
  &#xD;
        Researchers will compare the in-hospital and 30-day clinical outcomes in the Dapagliflozin&#xD;
        group versus the standard treatment group.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Background and Rationale:&#xD;
  &#xD;
        With growing interest in studying the pharmacodynamics of SGLT-2 inhibitors, several&#xD;
        cardio-protective mechanisms were defined beyond their diuretic effect. Those included&#xD;
        anti-inflammatory effect and attenuation of oxidative stress in myocardial cells,&#xD;
        renin-angiotensin aldosterone system blocking via activating AT-2 receptors, inhibition of&#xD;
        Na+-H+ exchanger within myocardial cells , improving cardiac metabolomics via supplying more&#xD;
        ketones , and weight reduction through lowering insulin secretion.&#xD;
  &#xD;
        These findings invited more research to evaluate their benefit in patients having heart&#xD;
        failure with reduced ejection fraction (HFrEF) regardless of diabetes mellitus (DM) status.&#xD;
        Two large trials (DAPA-HF and EMPEROR-Reduced) have shown a consistent mortality benefit for&#xD;
        SGLT-2 inhibitors in HFrEF patients in absence of DM.&#xD;
  &#xD;
        Having a wide safety margin and low risk of complications, the use of SGLT-2 inhibitors was&#xD;
        recently extended beyond the scope of cardiovascular disease to include patients with chronic&#xD;
        kidney disease after their renal protective role was validated in CREDENCE and DAPA-CKD&#xD;
        trials with significantly lower risk of albuminuria and disease progression.&#xD;
  &#xD;
        Since most of the forementioned studies included patients with chronic HF who are stable on&#xD;
        oral therapy, it has become urging to study the efficacy and safety of starting SGLT-2&#xD;
        inhibitors in patients with acute HF during the hospital phase. Ongoing trials have been&#xD;
        investigating this issue recently, with pending outcomes. However, patients with de-novo AHF&#xD;
        secondary to acute coronary syndrome have been excluded from these studies. Also, some of&#xD;
        those studies started SGLT2 inhibitors only after stabilization of acute heart failure&#xD;
        patients in-hospital.&#xD;
  &#xD;
        Objectives:&#xD;
  &#xD;
        The aim of this study is to evaluate the immediate and short-term clinical outcomes of&#xD;
        starting Dapagliflozin in patients with acute decompensated heart failure during&#xD;
        hospitalization.&#xD;
  &#xD;
        Study Methods&#xD;
  &#xD;
          -  Population of study: Patients admitted to hospital with acute heart failure, either&#xD;
             de-novo or acute decompensated on top of chronic.&#xD;
  &#xD;
          -  Study location: Kasr Al-Ainy Medical School, Cairo university.&#xD;
  &#xD;
          -  Recruitment location: Kasr Al-Ainy Medical School, Aswan Heart Centre.&#xD;
  &#xD;
          -  Methodology in details:&#xD;
  &#xD;
        A-Full medical history including:&#xD;
  &#xD;
        Age, gender, onset and duration of shortness of breath and NYHA functional class. Past&#xD;
        history of DM, HTN, CAD, VHD, HF, stroke, other comorbidities, and smoking status will be&#xD;
        obtained in all participants.&#xD;
  &#xD;
        B-Full clinical examination including:&#xD;
  &#xD;
        Assessment of body weight, height and calculation of BMI and BSA. Vital signs including blood&#xD;
        pressure measurement using standard technique, assessment of the pulse, respiratory rate and&#xD;
        temperature. Examination of all body systems.&#xD;
  &#xD;
        C- Blood sample and chemistry:&#xD;
  &#xD;
        Blood tests will be done to all participants. Lab workup will include CBC, liver and kidney&#xD;
        function tests, electrolytes, HBA1C and lipid profile. Estimated GFR will be calculated using&#xD;
        CKD-EPI equation.&#xD;
  &#xD;
        D- Serum NT-proBNP:&#xD;
  &#xD;
        On admission and on day 4.&#xD;
  &#xD;
        E- Electrocardiography (ECG):&#xD;
  &#xD;
        12-lead ECG will be done for all participants. Data will be recorded including rhythm, ST-T&#xD;
        changes, QRS width, and any form of conduction disturbance.&#xD;
  &#xD;
        F- Conventional Transthoracic echocardiography (TTE):&#xD;
  &#xD;
        TTE will be done for all patients on admission:&#xD;
  &#xD;
          -  Measure LV end-systolic and end-diastolic diameters.&#xD;
  &#xD;
          -  Measure LV systolic function by M-mode and Biplane Simpson's method.&#xD;
  &#xD;
          -  Measure LV diastolic function, E/A and E/e' ratio&#xD;
  &#xD;
          -  Calculate LA volume index.&#xD;
  &#xD;
          -  Calculate LV mass index.&#xD;
  &#xD;
          -  Assess cardiac valves (mitral, aortic and tricuspid valves).&#xD;
  &#xD;
          -  Estimate systolic pulmonary artery pressure.&#xD;
  &#xD;
          -  Measure RV dimensions and function.&#xD;
  &#xD;
          -  Measure RA area.&#xD;
  &#xD;
        G. 2D-Speckle tracking echocardiography:&#xD;
  &#xD;
        • Measure LV global longitudinal strain (GLS).&#xD;
  &#xD;
        H. Randomization:&#xD;
  &#xD;
          -  Patients will be randomized with the ratio of 1:1 within 24 hours of admission to&#xD;
             receive Dapagliflozin 10 mg/day versus standard of care (using online randomization&#xD;
             https://en.calc-site.com/randoms/grouping). Treatment will continue for 1 month after&#xD;
             discharge.&#xD;
  &#xD;
          -  Randomized treatment will be withheld in case of hypotension (SBP&lt;90 mmHg), development&#xD;
             of hypoglycemia &lt; 80 mg/dl, metabolic acidosis, or &gt;50% drop in eGFR for 2 consecutive&#xD;
             measures.&#xD;
  &#xD;
          -  Randomized treatment will be resumed after resolution of the previously mentioned&#xD;
             conditions.&#xD;
  &#xD;
        I. Hospital course:&#xD;
  &#xD;
          -  Daily vital signs and assessment of fluid status.&#xD;
  &#xD;
          -  Daily fluid balance.&#xD;
  &#xD;
          -  Body weight change after 4 days of hospital admission or less if discharged earlier.&#xD;
  &#xD;
          -  Response to diuretics defined as weight change per 40 mg of IV furosemide or equivalent&#xD;
             dose.&#xD;
  &#xD;
          -  Daily urea, creatinine and eGFR.&#xD;
  &#xD;
          -  Blood sugar monitoring.&#xD;
  &#xD;
        J. Follow-up visits:&#xD;
  &#xD;
        Patients will be followed in the outpatient clinic at 1 month after discharge, with the&#xD;
        following data to be obtained:&#xD;
  &#xD;
          1. NYHA class, and occurrence of any cardiac symptoms.&#xD;
  &#xD;
          2. Need and reason for re-hospitalization.&#xD;
  &#xD;
          3. History of dysuria, or genital discharge.&#xD;
  &#xD;
          4. Medication intake and compliance.&#xD;
  &#xD;
          5. Clinical examination including vital signs, body weight, and signs of left or right side&#xD;
             HF.&#xD;
  &#xD;
          6. Urea, creatinine and eGFR.&#xD;
  &#xD;
          7. Electrolytes including Na and K.&#xD;
  &#xD;
          8. HbA1C.&#xD;
  &#xD;
        K. Follow-up serum NT-proBNP:&#xD;
  &#xD;
          -  At 1 month after discharge.&#xD;
  &#xD;
          -  Data will be compared to baseline values.&#xD;
  &#xD;
        In case of mortality, data will be collected about the date and cause of mortality, and any&#xD;
        reported clinical events before mortality.&#xD;
  &#xD;
          -  Potential risks:&#xD;
  &#xD;
               1. Mild pain during blood sample withdrawal.&#xD;
  &#xD;
               2. Low incidence of occurrence of side effects for Dapagliflozin including urinary&#xD;
                  tract infection, hypotension, and in rare cases hypoglycemia or metabolic acidosis.&#xD;
  &#xD;
          -  Confidentiality of data:&#xD;
  &#xD;
        Data will be presented and used without inference to the name or personal data of the&#xD;
        patients. All patient records will be handelled in accordance to hospital and national&#xD;
        confidentiality protocols.&#xD;
  &#xD;
        - Sample size :&#xD;
  &#xD;
        Based on the results mentioned in a previously published similar study, where the frequency&#xD;
        of composite endpoint of worsening HF, rehospitalization for HF or death at 60 days was 10%&#xD;
        in the Empagliflozin group versus 33% in the placebo group, with a study power of 80% and a&#xD;
        significance level of 5%, and by using an online sample size calculator&#xD;
        (http://statulator.com/SampleSize/ss2P.html), the estimated sample size is 55 patients per&#xD;
        group.&#xD;
  &#xD;
        - Statistical analysis&#xD;
  &#xD;
        Descriptive statistics will be summarized as mean ± SD for normally distributed continuous&#xD;
        variables or otherwise as median and 25th to 75th percentile. Categorical variables will be&#xD;
        described by frequencies and percentages. Differences in paired samples will be tested using&#xD;
        the Wilcoxon signed-rank test or paired Student's t-test. Categorical variables will be&#xD;
        compared using the chi-square or Fisher's exact test. Statistical significance is defined at&#xD;
        a level of α ≤ 0.05.&#xD;
  &#xD;
        Kaplan-Meier survival curves will be drawn to assess differences between groups for the time&#xD;
        to an event. For the Cox model, univariate analysis of each of the possible predictors of the&#xD;
        outcome will be tested, and only those variables that are significant at P&lt;0.05 will be&#xD;
        included in a multivariable model. A stepwise option will be used to determine independent&#xD;
        predictors of the outcome variables.&#xD;
  &#xD;
        Analysis will be performed with SPSS, Version 24 (SPSS Inc., Chicago, IL, USA).&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Active, not recruiting</overall_status>
    <start_date type="Actual">August 1, 2023</start_date>
    <completion_date type="Anticipated">April 2024</completion_date>
    <primary_completion_date type="Anticipated">February 2024</primary_completion_date>
    <phase>Phase 4</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Randomized</allocation>
      <intervention_model>Parallel Assignment</intervention_model>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>All-cause mortality during hospitalization.</measure>
      <time_frame>From the date of admission until the date of discharge, average of 7 days</time_frame>
      <description>Death from any cause during the period of hospital stay.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Length of hospital stay</measure>
      <time_frame>From the date of admission until the date of discharge, average of 7 days</time_frame>
      <description>The number of days from hospital admission to discharge.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Diuretic response during the hospital phase.</measure>
      <time_frame>First 4 days of hospital admission</time_frame>
      <description>Defined as urine output per 40 mg of IV Furosemide or equivalent dose.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Change in NT-proBNP at day 4 (or at discharge if earlier).</measure>
      <time_frame>First 4 days of hospital admission</time_frame>
      <description>The difference between baseline NT-proBNP on admission and NT-proBNP at day 4.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Composite endpoint of cardiovascular death, re-admission for HF, or urgent clinic visit for decompensation at 1 month after hospital discharge.</measure>
      <time_frame>30 days after hospital discharge</time_frame>
      <description>Decompensation is defined as worsening symptoms +/- signs of HF requiring intensification of diuretic dose.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in serum NT-proBNP after 1 month.</measure>
      <time_frame>30 days after hospital discharge</time_frame>
      <description>The difference between baseline NT-proBNP and one month after discharge.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Worsening renal functions</measure>
      <time_frame>30 days after hospital discharge</time_frame>
      <description>Defined as &gt; 50% worsening of baseline eGFR, or absolute drop below 30 ml/min/1.73 m2.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Composite endpoint of genital infections, hypoglycemic events, hypotension events or diabetic ketoacidosis.</measure>
      <time_frame>30 days after hospital discharge</time_frame>
      <description>Reporting any side effects that could be due to Dapagliflozin after discharge</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">110</enrollment>
    <condition>Acute Heart Failure</condition>
    <arm_group>
      <arm_group_label>Dapagliflozin group</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>This group will receive oral Dapagliflozin 10 mg once daily within 24 hours from hospital admission, in addition to the standard treatment for acute heart failure.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Standard group</arm_group_label>
      <arm_group_type>No Intervention</arm_group_type>
      <description>This group will only receive the standard treatment for acute heart failure.</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Dapagliflozin 10mg Tab</intervention_name>
      <description>Dapagliflozin is a drug that works through inhibition of sodium glucose transporter-2 resulting in glucosuria.</description>
      <arm_group_label>Dapagliflozin group</arm_group_label>
      <other_name>Sodium-glucose cotransporter-2 inhibitors</other_name>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Adult patients above 18 years presenting with acute heart failure defined as rapid&#xD;
               development of dyspnea NYHA class III-IV associated with clinical signs of HF (e.g.&#xD;
               congested neck veins, pulmonary rales, lower limb swelling, radiological evidence of&#xD;
               pulmonary congestion) with LVEF ≤ 40%.&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            1. Cardiogenic shock on admission, defined as SBP &lt; 90 mmHg plus signs of peripheral&#xD;
               hypoperfusion or the need of vasopressor or inotropic support.&#xD;
  &#xD;
            2. Estimated GFR &lt; 30 mL/min/1.73 m2.&#xD;
  &#xD;
            3. Pregnancy or lactation.&#xD;
  &#xD;
            4. Type I DM or history of DKA.&#xD;
  &#xD;
            5. Treatment with any SGLT2 inhibitor in the last month.&#xD;
  &#xD;
            6. Known intolerance to any SGLT2 inhibitor.&#xD;
  &#xD;
            7. Severe anemia (Hemoglobin &lt; 7 g/dl).&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Magdy Abdelhamid, Professor</last_name>
      <role>Principal Investigator</role>
      <affiliation>Chairman of Cardiology Department, Cairo University</affiliation>
    </overall_official>
    <location>
      <facility>
        <name>Kasr Al-Ainy Medical School</name>
        <address>
          <city>Cairo</city>
          <zip>11562</zip>
          <country>Egypt</country>
        </address>
      </facility>
    </location>
    <location_countries>
      <country>Egypt</country>
    </location_countries>
    <reference>
      <citation>Damman K, Beusekamp JC, Boorsma EM, Swart HP, Smilde TDJ, Elvan A, van Eck JWM, Heerspink HJL, Voors AA. Randomized, double-blind, placebo-controlled, multicentre pilot study on the effects of empagliflozin on clinical outcomes in patients with acute decompensated heart failure (EMPA-RESPONSE-AHF). Eur J Heart Fail. 2020 Apr;22(4):713-722. doi: 10.1002/ejhf.1713. Epub 2020 Jan 7.</citation>
      <PMID>31912605</PMID>
    </reference>
    <reference>
      <citation>McMurray JJV, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Belohlavek J, Bohm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukat A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O'Meara E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O, Sjostrand M, Langkilde AM; DAPA-HF Trial Committees and Investigators. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019 Nov 21;381(21):1995-2008. doi: 10.1056/NEJMoa1911303. Epub 2019 Sep 19.</citation>
      <PMID>31535829</PMID>
    </reference>
    <reference>
      <citation>Ul Amin N, Sabir F, Amin T, Sarfraz Z, Sarfraz A, Robles-Velasco K, Cherrez-Ojeda I. SGLT2 Inhibitors in Acute Heart Failure: A Meta-Analysis of Randomized Controlled Trials. Healthcare (Basel). 2022 Nov 23;10(12):2356. doi: 10.3390/healthcare10122356.</citation>
      <PMID>36553880</PMID>
    </reference>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>August 10, 2023</study_first_submitted>
    <study_first_submitted_qc>August 24, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 25, 2023</study_first_posted>
    <last_update_submitted>August 24, 2023</last_update_submitted>
    <last_update_submitted_qc>August 24, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 25, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Cairo University</investigator_affiliation>
      <investigator_full_name>Hossameldin Elsayed Khalifa Hussein</investigator_full_name>
      <investigator_title>Assistant Lecturer of Cardiology</investigator_title>
    </responsible_party>
    <keyword>Dapagliflozin</keyword>
    <keyword>Acute heart failure</keyword>
    <keyword>Decompensated heart failure</keyword>
    <keyword>Hospitalization</keyword>
    <keyword>Sodium-glucose cotransporter-2 inhibitors</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Heart Failure</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Dapagliflozin</mesh_term>
      <mesh_term>Sodium-Glucose Transporter 2 Inhibitors</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>Yes</sharing_ipd>
      <ipd_description>Data obtained through this study may be provided to qualified researchers with academic interest. Data or samples shared will be coded, with no reference to participants' identity.</ipd_description>
      <ipd_info_type>Study Protocol</ipd_info_type>
      <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
      <ipd_time_frame>Data requests can be submitted starting 6 months after article publication and the data will be made accessible for up to 24 months. Extensions will be considered on a case-by-case basis</ipd_time_frame>
      <ipd_access_criteria>Access to trial IPD can be requested by qualified researchers engaging in independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan.</ipd_access_criteria>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: download date: ClinicalTrials.gov processed this data on September 20, 2023
  link text: Link to the current ClinicalTrials.gov record.
  url: https://clinicaltrials.gov/ct2/show/NCT06012279
  org study id: MD-343-2021
  nct id: NCT06012279
  lead sponsor: 
  collaborator: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  is us export: No
  The goal of this clinical trial is to evaluate the short-term clinical outcomes of starting
        Dapagliflozin on the same day of hospital admission in patients with acute decompensated
        heart failure (ADHF).
  
        The main questions it aims to answer are:
  
          -  Does early initiation of Dapagliflozin improve the length of hospital stay and
             in-hospital mortality in patients with ADHF?
  
          -  Does early initiation of Dapagliflozin enhance the diuretic response, weight reduction
             and pro-BNP reduction in the acute stage of HF?
  
          -  Does early initiation of Dapagliflozin adversely affect the hemodynamic stability and
             kidney functions in the acute stage of HF?
  
        Participants will be randomized with the ratio of 1:1 within 24 hours of admission to receive
        Dapagliflozin 10 mg/day versus standard of care. Follow up will continue for 1 month after
        hospital discharge.
  
        Researchers will compare the in-hospital and 30-day clinical outcomes in the Dapagliflozin
        group versus the standard treatment group.
  Background and Rationale:
  
        With growing interest in studying the pharmacodynamics of SGLT-2 inhibitors, several
        cardio-protective mechanisms were defined beyond their diuretic effect. Those included
        anti-inflammatory effect and attenuation of oxidative stress in myocardial cells,
        renin-angiotensin aldosterone system blocking via activating AT-2 receptors, inhibition of
        Na+-H+ exchanger within myocardial cells , improving cardiac metabolomics via supplying more
        ketones , and weight reduction through lowering insulin secretion.
  
        These findings invited more research to evaluate their benefit in patients having heart
        failure with reduced ejection fraction (HFrEF) regardless of diabetes mellitus (DM) status.
        Two large trials (DAPA-HF and EMPEROR-Reduced) have shown a consistent mortality benefit for
        SGLT-2 inhibitors in HFrEF patients in absence of DM.
  
        Having a wide safety margin and low risk of complications, the use of SGLT-2 inhibitors was
        recently extended beyond the scope of cardiovascular disease to include patients with chronic
        kidney disease after their renal protective role was validated in CREDENCE and DAPA-CKD
        trials with significantly lower risk of albuminuria and disease progression.
  
        Since most of the forementioned studies included patients with chronic HF who are stable on
        oral therapy, it has become urging to study the efficacy and safety of starting SGLT-2
        inhibitors in patients with acute HF during the hospital phase. Ongoing trials have been
        investigating this issue recently, with pending outcomes. However, patients with de-novo AHF
        secondary to acute coronary syndrome have been excluded from these studies. Also, some of
        those studies started SGLT2 inhibitors only after stabilization of acute heart failure
        patients in-hospital.
  
        Objectives:
  
        The aim of this study is to evaluate the immediate and short-term clinical outcomes of
        starting Dapagliflozin in patients with acute decompensated heart failure during
        hospitalization.
  
        Study Methods
  
          -  Population of study: Patients admitted to hospital with acute heart failure, either
             de-novo or acute decompensated on top of chronic.
  
          -  Study location: Kasr Al-Ainy Medical School, Cairo university.
  
          -  Recruitment location: Kasr Al-Ainy Medical School, Aswan Heart Centre.
  
          -  Methodology in details:
  
        A-Full medical history including:
  
        Age, gender, onset and duration of shortness of breath and NYHA functional class. Past
        history of DM, HTN, CAD, VHD, HF, stroke, other comorbidities, and smoking status will be
        obtained in all participants.
  
        B-Full clinical examination including:
  
        Assessment of body weight, height and calculation of BMI and BSA. Vital signs including blood
        pressure measurement using standard technique, assessment of the pulse, respiratory rate and
        temperature. Examination of all body systems.
  
        C- Blood sample and chemistry:
  
        Blood tests will be done to all participants. Lab workup will include CBC, liver and kidney
        function tests, electrolytes, HBA1C and lipid profile. Estimated GFR will be calculated using
        CKD-EPI equation.
  
        D- Serum NT-proBNP:
  
        On admission and on day 4.
  
        E- Electrocardiography (ECG):
  
        12-lead ECG will be done for all participants. Data will be recorded including rhythm, ST-T
        changes, QRS width, and any form of conduction disturbance.
  
        F- Conventional Transthoracic echocardiography (TTE):
  
        TTE will be done for all patients on admission:
  
          -  Measure LV end-systolic and end-diastolic diameters.
  
          -  Measure LV systolic function by M-mode and Biplane Simpson's method.
  
          -  Measure LV diastolic function, E/A and E/e' ratio
  
          -  Calculate LA volume index.
  
          -  Calculate LV mass index.
  
          -  Assess cardiac valves (mitral, aortic and tricuspid valves).
  
          -  Estimate systolic pulmonary artery pressure.
  
          -  Measure RV dimensions and function.
  
          -  Measure RA area.
  
        G. 2D-Speckle tracking echocardiography:
  
        • Measure LV global longitudinal strain (GLS).
  
        H. Randomization:
  
          -  Patients will be randomized with the ratio of 1:1 within 24 hours of admission to
             receive Dapagliflozin 10 mg/day versus standard of care (using online randomization
             https://en.calc-site.com/randoms/grouping). Treatment will continue for 1 month after
             discharge.
  
          -  Randomized treatment will be withheld in case of hypotension (SBP<90 mmHg), development
             of hypoglycemia < 80 mg/dl, metabolic acidosis, or >50% drop in eGFR for 2 consecutive
             measures.
  
          -  Randomized treatment will be resumed after resolution of the previously mentioned
             conditions.
  
        I. Hospital course:
  
          -  Daily vital signs and assessment of fluid status.
  
          -  Daily fluid balance.
  
          -  Body weight change after 4 days of hospital admission or less if discharged earlier.
  
          -  Response to diuretics defined as weight change per 40 mg of IV furosemide or equivalent
             dose.
  
          -  Daily urea, creatinine and eGFR.
  
          -  Blood sugar monitoring.
  
        J. Follow-up visits:
  
        Patients will be followed in the outpatient clinic at 1 month after discharge, with the
        following data to be obtained:
  
          1. NYHA class, and occurrence of any cardiac symptoms.
  
          2. Need and reason for re-hospitalization.
  
          3. History of dysuria, or genital discharge.
  
          4. Medication intake and compliance.
  
          5. Clinical examination including vital signs, body weight, and signs of left or right side
             HF.
  
          6. Urea, creatinine and eGFR.
  
          7. Electrolytes including Na and K.
  
          8. HbA1C.
  
        K. Follow-up serum NT-proBNP:
  
          -  At 1 month after discharge.
  
          -  Data will be compared to baseline values.
  
        In case of mortality, data will be collected about the date and cause of mortality, and any
        reported clinical events before mortality.
  
          -  Potential risks:
  
               1. Mild pain during blood sample withdrawal.
  
               2. Low incidence of occurrence of side effects for Dapagliflozin including urinary
                  tract infection, hypotension, and in rare cases hypoglycemia or metabolic acidosis.
  
          -  Confidentiality of data:
  
        Data will be presented and used without inference to the name or personal data of the
        patients. All patient records will be handelled in accordance to hospital and national
        confidentiality protocols.
  
        - Sample size :
  
        Based on the results mentioned in a previously published similar study, where the frequency
        of composite endpoint of worsening HF, rehospitalization for HF or death at 60 days was 10%
        in the Empagliflozin group versus 33% in the placebo group, with a study power of 80% and a
        significance level of 5%, and by using an online sample size calculator
        (http://statulator.com/SampleSize/ss2P.html), the estimated sample size is 55 patients per
        group.
  
        - Statistical analysis
  
        Descriptive statistics will be summarized as mean ± SD for normally distributed continuous
        variables or otherwise as median and 25th to 75th percentile. Categorical variables will be
        described by frequencies and percentages. Differences in paired samples will be tested using
        the Wilcoxon signed-rank test or paired Student's t-test. Categorical variables will be
        compared using the chi-square or Fisher's exact test. Statistical significance is defined at
        a level of α ≤ 0.05.
  
        Kaplan-Meier survival curves will be drawn to assess differences between groups for the time
        to an event. For the Cox model, univariate analysis of each of the possible predictors of the
        outcome will be tested, and only those variables that are significant at P<0.05 will be
        included in a multivariable model. A stepwise option will be used to determine independent
        predictors of the outcome variables.
  
        Analysis will be performed with SPSS, Version 24 (SPSS Inc., Chicago, IL, USA).
  allocation: Randomized
  intervention model: Parallel Assignment
  primary purpose: Treatment
  masking: None (Open Label)
  measure: All-cause mortality during hospitalization.
  time frame: From the date of admission until the date of discharge, average of 7 days
  description: Death from any cause during the period of hospital stay.
  measure: Length of hospital stay
  time frame: From the date of admission until the date of discharge, average of 7 days
  description: The number of days from hospital admission to discharge.
  measure: Diuretic response during the hospital phase.
  time frame: First 4 days of hospital admission
  description: Defined as urine output per 40 mg of IV Furosemide or equivalent dose.
  measure: Change in NT-proBNP at day 4 (or at discharge if earlier).
  time frame: First 4 days of hospital admission
  description: The difference between baseline NT-proBNP on admission and NT-proBNP at day 4.
  measure: Composite endpoint of cardiovascular death, re-admission for HF, or urgent clinic visit for decompensation at 1 month after hospital discharge.
  time frame: 30 days after hospital discharge
  description: Decompensation is defined as worsening symptoms +/- signs of HF requiring intensification of diuretic dose.
  measure: Change in serum NT-proBNP after 1 month.
  time frame: 30 days after hospital discharge
  description: The difference between baseline NT-proBNP and one month after discharge.
  measure: Worsening renal functions
  time frame: 30 days after hospital discharge
  description: Defined as > 50% worsening of baseline eGFR, or absolute drop below 30 ml/min/1.73 m2.
  measure: Composite endpoint of genital infections, hypoglycemic events, hypotension events or diabetic ketoacidosis.
  time frame: 30 days after hospital discharge
  description: Reporting any side effects that could be due to Dapagliflozin after discharge
  arm group label: Dapagliflozin group
  arm group type: Experimental
  description: This group will receive oral Dapagliflozin 10 mg once daily within 24 hours from hospital admission, in addition to the standard treatment for acute heart failure.
  arm group label: Standard group
  arm group type: No Intervention
  description: This group will only receive the standard treatment for acute heart failure.
  intervention type: Drug
  intervention name: Dapagliflozin 10mg Tab
  description: Dapagliflozin is a drug that works through inhibition of sodium glucose transporter-2 resulting in glucosuria.
  arm group label: Dapagliflozin group
  other name: Sodium-glucose cotransporter-2 inhibitors
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Magdy Abdelhamid, Professor
  role: Principal Investigator
  affiliation: Chairman of Cardiology Department, Cairo University
  facility: 
  country: Egypt
  citation: Damman K, Beusekamp JC, Boorsma EM, Swart HP, Smilde TDJ, Elvan A, van Eck JWM, Heerspink HJL, Voors AA. Randomized, double-blind, placebo-controlled, multicentre pilot study on the effects of empagliflozin on clinical outcomes in patients with acute decompensated heart failure (EMPA-RESPONSE-AHF). Eur J Heart Fail. 2020 Apr;22(4):713-722. doi: 10.1002/ejhf.1713. Epub 2020 Jan 7.
  PMID: 31912605
  citation: McMurray JJV, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Belohlavek J, Bohm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukat A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O'Meara E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O, Sjostrand M, Langkilde AM; DAPA-HF Trial Committees and Investigators. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019 Nov 21;381(21):1995-2008. doi: 10.1056/NEJMoa1911303. Epub 2019 Sep 19.
  PMID: 31535829
  citation: Ul Amin N, Sabir F, Amin T, Sarfraz Z, Sarfraz A, Robles-Velasco K, Cherrez-Ojeda I. SGLT2 Inhibitors in Acute Heart Failure: A Meta-Analysis of Randomized Controlled Trials. Healthcare (Basel). 2022 Nov 23;10(12):2356. doi: 10.3390/healthcare10122356.
  PMID: 36553880
  responsible party type: Principal Investigator
  investigator affiliation: Cairo University
  investigator full name: Hossameldin Elsayed Khalifa Hussein
  investigator title: Assistant Lecturer of Cardiology
  mesh term: Heart Failure
  mesh term: Dapagliflozin
  mesh term: Sodium-Glucose Transporter 2 Inhibitors
  sharing ipd: Yes
  ipd description: Data obtained through this study may be provided to qualified researchers with academic interest. Data or samples shared will be coded, with no reference to participants' identity.
  ipd info type: Study Protocol
  ipd info type: Statistical Analysis Plan (SAP)
  ipd time frame: Data requests can be submitted starting 6 months after article publication and the data will be made accessible for up to 24 months. Extensions will be considered on a case-by-case basis
  ipd access criteria: Access to trial IPD can be requested by qualified researchers engaging in independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan.