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/NCT05964738</url>
    </required_header>
    <id_info>
      <org_study_id>REDICAE</org_study_id>
      <nct_id>NCT05964738</nct_id>
    </id_info>
    <brief_title>Effect of Diuretics Withdrawal in Chronic Heart Failure With Reduced Ejection Fraction</brief_title>
    <acronym>REDICAE</acronym>
    <official_title>Safety and Tolerability of Diuretics Withdrawal in Heart Failure With Reduced Ejection Fraction. REDICAE Trial.</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Maimónides Biomedical Research Institute of Córdoba</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>Sociedad Andaluza de Cardiología</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>Maimónides Biomedical Research Institute of Córdoba</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>
    </oversight_info>
    <brief_summary>
      <textblock>
        REDICAE trial was designed to evaluate the safety and tolerability of diuretics withdrawal in&#xD;
        stable, euvolemic chronic outpatients with heart failure with reduced ejection fraction. It&#xD;
        is a single-center, randomized, open-label, phase II clinical trial.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Treatment of heart failure with reduced ejection fraction (HFrEF) has improved patient&#xD;
        survival in recent decades. Diuretics are essentials in acute decompensated heart failure,&#xD;
        specially furosemide. However, when patients are stable and euvolemic diuretics (loop&#xD;
        diuretics, thiazide diuretics or acetazolamide) might increase adverse effects:&#xD;
        renin-angiotensin-aldosterone system activation, renal function impairment or electrolyte&#xD;
        disturbances.&#xD;
  &#xD;
        The 2021 European Society of Cardiology (ESC) Guidelines for the diagnosis and treatment of&#xD;
        acute and chronic heart failure recommend angiotensin-converting enzyme inhibitors (ACEI) or&#xD;
        angiotensin receptor-neprilysin inhibitor (ARNI), beta-blockers (BB), mineralocorticoid&#xD;
        receptor antagonists (MRA) and sodium-glucose co-transporter 2 inhibitors (iSTLT2) as&#xD;
        first-line therapy for HFrEF. A significant proportion of patients take a maintenance&#xD;
        diuretics dose despite the clinical benefits and prognosis are controversial.&#xD;
  &#xD;
        Current clinical guidelines suggest that diuretic use can be reduced or discontinued in&#xD;
        selected euvolemic or hypovolemic patients. This statement is based on the results of the&#xD;
        ReBIC-1 trial published in 2019, which showed a neutral effect of furosemide discontinuation&#xD;
        in stable chronic outpatients with HFrEF treated according to the 2016 ESC heart failure&#xD;
        guidelines standards of care.&#xD;
  &#xD;
        REDICAE trial was designed to evaluate the safety and tolerability of diuretics withdrawal,&#xD;
        not just furosemide, in stable euvolemic chronic outpatients with HFrEF. It is a&#xD;
        single-center, randomized, open-label phase II clinical trial.&#xD;
  &#xD;
        The pathophysiology of congestion in heart failure is complex and multifactorial. In the&#xD;
        REDICAE trial, volume status will be determined by biomarkers, echocardiography and&#xD;
        bioelectrical impedance analysis. The patients enrolled in the study will be under&#xD;
        contemporary guideline-directed medical therapy, including SGLT2 inhibitors. This trial is&#xD;
        the largest prospective trial evaluating the clinical effects of diuretic discontinuation in&#xD;
        HFrEF patients under contemporary pharmacological therapy for heart failure.&#xD;
  &#xD;
        REDICAE trial develops in Hospital Universitario Reina Sofía in Cordoba (Spain)&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Recruiting</overall_status>
    <start_date type="Actual">December 19, 2022</start_date>
    <completion_date type="Anticipated">June 30, 2024</completion_date>
    <primary_completion_date type="Anticipated">June 30, 2024</primary_completion_date>
    <phase>Phase 2</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>Change From Baseline in Dyspnea assessed by a visual analogue scale (VAS)</measure>
      <time_frame>baseline - 30 days - 90 days - 180 days</time_frame>
      <description>VAS scores are scaled from 0 to 100 millimeters (mm). Higher scores mean a worse outcome.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Acute decompensated heart failure events</measure>
      <time_frame>180 days</time_frame>
      <description>Number of Hospital admissions, emergency department visits or unscheduled medical appointments requiring intravenous diuretic treatment, and increase in diuretic dose or reintroduction of an oral diuretic.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Variation of plasmatic levels of natriuretic peptides</measure>
      <time_frame>baseline - 30 days - 90 days - 180 days</time_frame>
      <description>Levels of the N-terminal pro b-type natriuretic peptide (NT-proBNP)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Tissue fluid overload</measure>
      <time_frame>baseline - 30 days - 90 days - 180 days</time_frame>
      <description>Variation of plasmatic levels of antigen carbohydrate 125 (CA-125)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Body Composition Monitor (BCM) of Fresenius Medical Care</measure>
      <time_frame>baseline - 30 days - 90 days - 180 days</time_frame>
      <description>Variation of fluid overload assessed by bioelectrical impedance analysis</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Inferior vena cava (IVC) diameter</measure>
      <time_frame>baseline - 30 days - 90 days - 180 days</time_frame>
      <description>IVC diameter measured in its intra-hepatic portion at 2 cm of the junction with the hepatic veins using a longitudinal view from a sub-xiphoid position. IVC is dilated when its diameter is more than 20 mm.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Hepatic vein Doppler</measure>
      <time_frame>baseline - 30 days - 90 days - 180 days</time_frame>
      <description>Pulsed wave Doppler shows a systolic (S) and diastolic (D) components. Normal pattern (S &gt; D), mildly abnormal pattern (S &lt; D) and severely abnormal pattern (S reverses)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Portal vein Doppler</measure>
      <time_frame>baseline - 30 days - 90 days - 180 days</time_frame>
      <description>Pulsed wave Doppler shows a continuous nonpulsatile flow. Using the pulsatility fraction (PF=100*[(Vmax - Vmin)/Vmax)]) are three patterns: normal PF &lt; 30%, mildly abnormal PF 30-50% and severely abnormal PF &gt;50%.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Intra-renal venous Doppler</measure>
      <time_frame>baseline - 30 days - 90 days - 180 days</time_frame>
      <description>Pulsed wave Doppler shows a normal pattern when flow is continuous. Mildly abnormal pattern shows a biphasic flow (S and D). Severely abnormal pattern shows a monophasic flow (D)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Ultrasound congestion parameters by Venous Excess Ultrasound (VExUS) protocol</measure>
      <time_frame>baseline - 30 days - 90 days - 180 days</time_frame>
      <description>IVC diameter, hepatic vein Doppler, portal vein Doppler and intra-renal venous Doppler patterns are combined to report VExUS grades:&#xD;
  Grade 0 (no congestion): IVC &lt; 20 mm&#xD;
  Grade 1 (mild congestion): IVC ≥ 20 mm and any combination of normal or mildly abnormal pattern&#xD;
  Grade 2 (moderate congestion): IVC ≥ 20 mm + ≥ 1 severely abnormal pattern&#xD;
  Grado 4 (severe congestion): IVC ≥ 20 mm + ≥ 2 severely abnormal pattern</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Congestion assessed by lung ultrasound</measure>
      <time_frame>baseline - 30 days - 90 days - 180 days</time_frame>
      <description>Pleural effusion or pathological B lines. More than two B lines are considered as pathological.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Quality of life status</measure>
      <time_frame>baseline - 30 days - 90 days - 180 days</time_frame>
      <description>Change From Baseline in the Kansas City Cardiomyopathy Questionnaire 12 (KCCQ-12) score. KCCQ-12 scores are scaled from 0 to 100. Higher scores mean a better outcome.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>6 minute walk test</measure>
      <time_frame>baseline - 30 days - 90 days - 180 days</time_frame>
      <description>Change From Baseline in meters walked, as assessed by the 6 minute walk test</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">90</enrollment>
    <condition>Heart Failure</condition>
    <condition>Electric Impedance</condition>
    <condition>Dyspnea</condition>
    <condition>Safety</condition>
    <condition>Withdrawal</condition>
    <arm_group>
      <arm_group_label>Diuretics withdrawal</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
    </arm_group>
    <arm_group>
      <arm_group_label>Diuretics maintenance</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Diuretics withdrawal</intervention_name>
      <description>Diuretics that not have been demonstrated improve survival in chronic HFrEF are withdrawn</description>
      <arm_group_label>Diuretics withdrawal</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Diuretics maintenance</intervention_name>
      <description>Any diuretic could be used</description>
      <arm_group_label>Diuretics maintenance</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          INCLUSION CRITERIA:&#xD;
  &#xD;
            -  Outpatients diagnosed of chronic HFrEF by criteria of ESC Guidelines of 2021&#xD;
  &#xD;
            -  Age equal or greater than 18 year-old&#xD;
  &#xD;
            -  Stable and euvolemic outpatients determined by clinical criteria, biomarkers (CA-125 &lt;&#xD;
               23 U/mL) and bioelectrical impedance analysis&#xD;
  &#xD;
            -  Left Ventricular Ejection Fraction less than 50% by echocardiography or cardiovascular&#xD;
               magnetic resonance performed within 6 months before the screening visit&#xD;
  &#xD;
            -  New York Heart Association functional class I or II&#xD;
  &#xD;
            -  No episodes of acute decompensated heart failure within 2 months before the screening&#xD;
               visit&#xD;
  &#xD;
            -  Treatment with a stable dose of diuretic for at least 1 month before the screening&#xD;
               visit&#xD;
  &#xD;
            -  Optimal medical therapy with ACEI/ARNI, BB, MRA and iSGLT2 must be started to&#xD;
               titration unless any of them were contraindicated or not tolerated&#xD;
  &#xD;
            -  Plasma potassium &lt; 5 mg/dl in the screening visit&#xD;
  &#xD;
          EXCLUSION CRITERIA:&#xD;
  &#xD;
            -  Acute coronary syndrome within 3 months before screening visit&#xD;
  &#xD;
            -  Awaiting cardiac resynchronization therapy&#xD;
  &#xD;
            -  Any severe valve heart disease not yet treated&#xD;
  &#xD;
            -  Pulmonary hypertension or any severe pulmonary disease&#xD;
  &#xD;
            -  End-stage chronic kidney disease (on hemodialysis). Acute kidney injury&#xD;
  &#xD;
            -  Severe hepatic failure or cirrhosis&#xD;
  &#xD;
            -  Malignancy on active treatment&#xD;
  &#xD;
            -  Congenital heart disease&#xD;
  &#xD;
            -  Awaiting cardiac transplantation&#xD;
  &#xD;
            -  Inability to understand and sign the informed consent&#xD;
  &#xD;
            -  Participation in any other interventional clinical research&#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>Alberto Torres Zamudio, MD</last_name>
      <role>Principal Investigator</role>
      <affiliation>Hospital Universitario Reina Sofía de Córdoba</affiliation>
    </overall_official>
    <overall_official>
      <last_name>Juan Carlos Castillo Domínguez, MD, PhD</last_name>
      <role>Study Director</role>
      <affiliation>Maimónides Biomedical Research Institute of Córdoba</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Alberto Torres, MD</last_name>
      <phone>+34620650405</phone>
      <email>atorzam.29@gmail.com</email>
    </overall_contact>
    <location>
      <facility>
        <name>Hospital Universitario Reina Sofía</name>
        <address>
          <city>Córdoba</city>
          <state>Córdoba (Andalucía)</state>
          <zip>14004</zip>
          <country>Spain</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Alberto Torres Zamudio, MD</last_name>
        <email>atorzam.29@gmail.com</email>
      </contact>
      <investigator>
        <last_name>Juan Carlos Castillo Domínguez, MD, PhD</last_name>
        <role>Principal Investigator</role>
      </investigator>
      <investigator>
        <last_name>Rafael González Manzanares, MD, PhD</last_name>
        <role>Principal Investigator</role>
      </investigator>
      <investigator>
        <last_name>José López Aguilera, MD, PhD</last_name>
        <role>Principal Investigator</role>
      </investigator>
      <investigator>
        <last_name>Manuel Anguita Sánchez, MD, PhD</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location_countries>
      <country>Spain</country>
    </location_countries>
    <results_reference>
      <citation>McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Bohm M, Burri H, Butler J, Celutkiene J, Chioncel O, Cleland JGF, Coats AJS, Crespo-Leiro MG, Farmakis D, Gilard M, Heymans S, Hoes AW, Jaarsma T, Jankowska EA, Lainscak M, Lam CSP, Lyon AR, McMurray JJV, Mebazaa A, Mindham R, Muneretto C, Francesco Piepoli M, Price S, Rosano GMC, Ruschitzka F, Kathrine Skibelund A; ESC Scientific Document Group. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021 Sep 21;42(36):3599-3726. doi: 10.1093/eurheartj/ehab368. No abstract available. Erratum In: Eur Heart J. 2021 Oct 14;:</citation>
      <PMID>34447992</PMID>
    </results_reference>
    <results_reference>
      <citation>McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014 Sep 11;371(11):993-1004. doi: 10.1056/NEJMoa1409077. Epub 2014 Aug 30.</citation>
      <PMID>25176015</PMID>
    </results_reference>
    <results_reference>
      <citation>Vardeny O, Claggett B, Kachadourian J, Desai AS, Packer M, Rouleau J, Zile MR, Swedberg K, Lefkowitz M, Shi V, McMurray JJV, Solomon SD. Reduced loop diuretic use in patients taking sacubitril/valsartan compared with enalapril: the PARADIGM-HF trial. Eur J Heart Fail. 2019 Mar;21(3):337-341. doi: 10.1002/ejhf.1402. Epub 2019 Feb 11.</citation>
      <PMID>30741494</PMID>
    </results_reference>
    <results_reference>
      <citation>Jackson AM, Dewan P, Anand IS, Belohlavek J, Bengtsson O, de Boer RA, Bohm M, Boulton DW, Chopra VK, DeMets DL, Docherty KF, Dukat A, Greasley PJ, Howlett JG, Inzucchi SE, Katova T, Kober L, Kosiborod MN, Langkilde AM, Lindholm D, Ljungman CEA, Martinez FA, O'Meara E, Sabatine MS, Sjostrand M, Solomon SD, Tereshchenko S, Verma S, Jhund PS, McMurray JJV. Dapagliflozin and Diuretic Use in Patients With Heart Failure and Reduced Ejection Fraction in DAPA-HF. Circulation. 2020 Sep 15;142(11):1040-1054. doi: 10.1161/CIRCULATIONAHA.120.047077. Epub 2020 Jul 16. Erratum In: Circulation. 2020 Nov 17;142(20):e369.</citation>
      <PMID>32673497</PMID>
    </results_reference>
    <results_reference>
      <citation>Packer M, Anker SD, Butler J, Filippatos G, Ferreira JP, Pocock SJ, Sattar N, Brueckmann M, Jamal W, Cotton D, Iwata T, Zannad F; EMPEROR-Reduced Trial Committees and Investigators. Empagliflozin in Patients With Heart Failure, Reduced Ejection Fraction, and Volume Overload: EMPEROR-Reduced Trial. J Am Coll Cardiol. 2021 Mar 23;77(11):1381-1392. doi: 10.1016/j.jacc.2021.01.033.</citation>
      <PMID>33736819</PMID>
    </results_reference>
    <results_reference>
      <citation>Rohde LE, Rover MM, Figueiredo Neto JA, Danzmann LC, Bertoldi EG, Simoes MV, Silvestre OM, Ribeiro ALP, Moura LZ, Beck-da-Silva L, Prado D, Sant'Anna RT, Bridi LH, Zimerman A, Raupp da Rosa P, Biolo A. Short-term diuretic withdrawal in stable outpatients with mild heart failure and no fluid retention receiving optimal therapy: a double-blind, multicentre, randomized trial. Eur Heart J. 2019 Nov 21;40(44):3605-3612. doi: 10.1093/eurheartj/ehz554.</citation>
      <PMID>31424503</PMID>
    </results_reference>
    <results_reference>
      <citation>Romano G, Vitale G, Bellavia D, Agnese V, Clemenza F. Is diuretic withdrawal safe in patients with heart failure and reduced ejection fraction? A retrospective analysis of our outpatient cohort. Eur J Intern Med. 2017 Jul;42:e11-e13. doi: 10.1016/j.ejim.2017.03.025. Epub 2017 Apr 6. No abstract available.</citation>
      <PMID>28390780</PMID>
    </results_reference>
    <results_reference>
      <citation>Nunez J, Bayes-Genis A, Revuelta-Lopez E, Ter Maaten JM, Minana G, Barallat J, Cserkoova A, Bodi V, Fernandez-Cisnal A, Nunez E, Sanchis J, Lang C, Ng LL, Metra M, Voors AA. Clinical Role of CA125 in Worsening Heart Failure: A BIOSTAT-CHF Study Subanalysis. JACC Heart Fail. 2020 May;8(5):386-397. doi: 10.1016/j.jchf.2019.12.005. Epub 2020 Mar 11.</citation>
      <PMID>32171764</PMID>
    </results_reference>
    <results_reference>
      <citation>Ekman I, Granger B, Swedberg K, Stenlund H, Boman K. Measuring shortness of breath in heart failure (SOB-HF): development and validation of a new dyspnoea assessment tool. Eur J Heart Fail. 2011 Aug;13(8):838-45. doi: 10.1093/eurjhf/hfr062.</citation>
      <PMID>21791539</PMID>
    </results_reference>
    <verification_date>July 2023</verification_date>
    <study_first_submitted>June 28, 2023</study_first_submitted>
    <study_first_submitted_qc>July 25, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">July 28, 2023</study_first_posted>
    <last_update_submitted>July 25, 2023</last_update_submitted>
    <last_update_submitted_qc>July 25, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">July 28, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Maimónides Biomedical Research Institute of Córdoba</investigator_affiliation>
      <investigator_full_name>Alberto Torres Zamudio</investigator_full_name>
      <investigator_title>Physician. Cardiologist</investigator_title>
    </responsible_party>
    <keyword>Heart Failure</keyword>
    <keyword>Diuretics</keyword>
    <keyword>Dyspnea</keyword>
    <keyword>Safety</keyword>
    <keyword>Fluid overload</keyword>
    <keyword>Withdraw</keyword>
    <keyword>Electric Impedance</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Dyspnea</mesh_term>
      <mesh_term>Heart Failure</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Diuretics</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>Yes</sharing_ipd>
      <ipd_description>Contact by email with Central Contact Person</ipd_description>
      <ipd_info_type>Study Protocol</ipd_info_type>
      <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
      <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
      <ipd_time_frame>From October 2024</ipd_time_frame>
      <ipd_access_criteria>Contact by email with Central Contact Person</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/NCT05964738
  org study id: REDICAE
  nct id: NCT05964738
  lead sponsor: 
  collaborator: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  REDICAE trial was designed to evaluate the safety and tolerability of diuretics withdrawal in
        stable, euvolemic chronic outpatients with heart failure with reduced ejection fraction. It
        is a single-center, randomized, open-label, phase II clinical trial.
  Treatment of heart failure with reduced ejection fraction (HFrEF) has improved patient
        survival in recent decades. Diuretics are essentials in acute decompensated heart failure,
        specially furosemide. However, when patients are stable and euvolemic diuretics (loop
        diuretics, thiazide diuretics or acetazolamide) might increase adverse effects:
        renin-angiotensin-aldosterone system activation, renal function impairment or electrolyte
        disturbances.
  
        The 2021 European Society of Cardiology (ESC) Guidelines for the diagnosis and treatment of
        acute and chronic heart failure recommend angiotensin-converting enzyme inhibitors (ACEI) or
        angiotensin receptor-neprilysin inhibitor (ARNI), beta-blockers (BB), mineralocorticoid
        receptor antagonists (MRA) and sodium-glucose co-transporter 2 inhibitors (iSTLT2) as
        first-line therapy for HFrEF. A significant proportion of patients take a maintenance
        diuretics dose despite the clinical benefits and prognosis are controversial.
  
        Current clinical guidelines suggest that diuretic use can be reduced or discontinued in
        selected euvolemic or hypovolemic patients. This statement is based on the results of the
        ReBIC-1 trial published in 2019, which showed a neutral effect of furosemide discontinuation
        in stable chronic outpatients with HFrEF treated according to the 2016 ESC heart failure
        guidelines standards of care.
  
        REDICAE trial was designed to evaluate the safety and tolerability of diuretics withdrawal,
        not just furosemide, in stable euvolemic chronic outpatients with HFrEF. It is a
        single-center, randomized, open-label phase II clinical trial.
  
        The pathophysiology of congestion in heart failure is complex and multifactorial. In the
        REDICAE trial, volume status will be determined by biomarkers, echocardiography and
        bioelectrical impedance analysis. The patients enrolled in the study will be under
        contemporary guideline-directed medical therapy, including SGLT2 inhibitors. This trial is
        the largest prospective trial evaluating the clinical effects of diuretic discontinuation in
        HFrEF patients under contemporary pharmacological therapy for heart failure.
  
        REDICAE trial develops in Hospital Universitario Reina Sofía in Cordoba (Spain)
  allocation: Randomized
  intervention model: Parallel Assignment
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Change From Baseline in Dyspnea assessed by a visual analogue scale (VAS)
  time frame: baseline - 30 days - 90 days - 180 days
  description: VAS scores are scaled from 0 to 100 millimeters (mm). Higher scores mean a worse outcome.
  measure: Acute decompensated heart failure events
  time frame: 180 days
  description: Number of Hospital admissions, emergency department visits or unscheduled medical appointments requiring intravenous diuretic treatment, and increase in diuretic dose or reintroduction of an oral diuretic.
  measure: Variation of plasmatic levels of natriuretic peptides
  time frame: baseline - 30 days - 90 days - 180 days
  description: Levels of the N-terminal pro b-type natriuretic peptide (NT-proBNP)
  measure: Tissue fluid overload
  time frame: baseline - 30 days - 90 days - 180 days
  description: Variation of plasmatic levels of antigen carbohydrate 125 (CA-125)
  measure: Body Composition Monitor (BCM) of Fresenius Medical Care
  time frame: baseline - 30 days - 90 days - 180 days
  description: Variation of fluid overload assessed by bioelectrical impedance analysis
  measure: Inferior vena cava (IVC) diameter
  time frame: baseline - 30 days - 90 days - 180 days
  description: IVC diameter measured in its intra-hepatic portion at 2 cm of the junction with the hepatic veins using a longitudinal view from a sub-xiphoid position. IVC is dilated when its diameter is more than 20 mm.
  measure: Hepatic vein Doppler
  time frame: baseline - 30 days - 90 days - 180 days
  description: Pulsed wave Doppler shows a systolic (S) and diastolic (D) components. Normal pattern (S > D), mildly abnormal pattern (S < D) and severely abnormal pattern (S reverses)
  measure: Portal vein Doppler
  time frame: baseline - 30 days - 90 days - 180 days
  description: Pulsed wave Doppler shows a continuous nonpulsatile flow. Using the pulsatility fraction (PF=100*[(Vmax - Vmin)/Vmax)]) are three patterns: normal PF < 30%, mildly abnormal PF 30-50% and severely abnormal PF >50%.
  measure: Intra-renal venous Doppler
  time frame: baseline - 30 days - 90 days - 180 days
  description: Pulsed wave Doppler shows a normal pattern when flow is continuous. Mildly abnormal pattern shows a biphasic flow (S and D). Severely abnormal pattern shows a monophasic flow (D)
  measure: Ultrasound congestion parameters by Venous Excess Ultrasound (VExUS) protocol
  time frame: baseline - 30 days - 90 days - 180 days
  description: IVC diameter, hepatic vein Doppler, portal vein Doppler and intra-renal venous Doppler patterns are combined to report VExUS grades:
  Grade 0 (no congestion): IVC < 20 mm
  Grade 1 (mild congestion): IVC ≥ 20 mm and any combination of normal or mildly abnormal pattern
  Grade 2 (moderate congestion): IVC ≥ 20 mm + ≥ 1 severely abnormal pattern
  Grado 4 (severe congestion): IVC ≥ 20 mm + ≥ 2 severely abnormal pattern
  measure: Congestion assessed by lung ultrasound
  time frame: baseline - 30 days - 90 days - 180 days
  description: Pleural effusion or pathological B lines. More than two B lines are considered as pathological.
  measure: Quality of life status
  time frame: baseline - 30 days - 90 days - 180 days
  description: Change From Baseline in the Kansas City Cardiomyopathy Questionnaire 12 (KCCQ-12) score. KCCQ-12 scores are scaled from 0 to 100. Higher scores mean a better outcome.
  measure: 6 minute walk test
  time frame: baseline - 30 days - 90 days - 180 days
  description: Change From Baseline in meters walked, as assessed by the 6 minute walk test
  arm group label: Diuretics withdrawal
  arm group type: Experimental
  arm group label: Diuretics maintenance
  arm group type: Active Comparator
  intervention type: Drug
  intervention name: Diuretics withdrawal
  description: Diuretics that not have been demonstrated improve survival in chronic HFrEF are withdrawn
  arm group label: Diuretics withdrawal
  intervention type: Drug
  intervention name: Diuretics maintenance
  description: Any diuretic could be used
  arm group label: Diuretics maintenance
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Alberto Torres Zamudio, MD
  role: Principal Investigator
  affiliation: Hospital Universitario Reina Sofía de Córdoba
  last name: Juan Carlos Castillo Domínguez, MD, PhD
  role: Study Director
  affiliation: Maimónides Biomedical Research Institute of Córdoba
  last name: Alberto Torres, MD
  phone: +34620650405
  email: atorzam.29@gmail.com
  facility: 
  status: Recruiting
  contact: 
  investigator: 
  investigator: 
  investigator: 
  investigator: 
  country: Spain
  citation: McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Bohm M, Burri H, Butler J, Celutkiene J, Chioncel O, Cleland JGF, Coats AJS, Crespo-Leiro MG, Farmakis D, Gilard M, Heymans S, Hoes AW, Jaarsma T, Jankowska EA, Lainscak M, Lam CSP, Lyon AR, McMurray JJV, Mebazaa A, Mindham R, Muneretto C, Francesco Piepoli M, Price S, Rosano GMC, Ruschitzka F, Kathrine Skibelund A; ESC Scientific Document Group. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021 Sep 21;42(36):3599-3726. doi: 10.1093/eurheartj/ehab368. No abstract available. Erratum In: Eur Heart J. 2021 Oct 14;:
  PMID: 34447992
  citation: McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014 Sep 11;371(11):993-1004. doi: 10.1056/NEJMoa1409077. Epub 2014 Aug 30.
  PMID: 25176015
  citation: Vardeny O, Claggett B, Kachadourian J, Desai AS, Packer M, Rouleau J, Zile MR, Swedberg K, Lefkowitz M, Shi V, McMurray JJV, Solomon SD. Reduced loop diuretic use in patients taking sacubitril/valsartan compared with enalapril: the PARADIGM-HF trial. Eur J Heart Fail. 2019 Mar;21(3):337-341. doi: 10.1002/ejhf.1402. Epub 2019 Feb 11.
  PMID: 30741494
  citation: Jackson AM, Dewan P, Anand IS, Belohlavek J, Bengtsson O, de Boer RA, Bohm M, Boulton DW, Chopra VK, DeMets DL, Docherty KF, Dukat A, Greasley PJ, Howlett JG, Inzucchi SE, Katova T, Kober L, Kosiborod MN, Langkilde AM, Lindholm D, Ljungman CEA, Martinez FA, O'Meara E, Sabatine MS, Sjostrand M, Solomon SD, Tereshchenko S, Verma S, Jhund PS, McMurray JJV. Dapagliflozin and Diuretic Use in Patients With Heart Failure and Reduced Ejection Fraction in DAPA-HF. Circulation. 2020 Sep 15;142(11):1040-1054. doi: 10.1161/CIRCULATIONAHA.120.047077. Epub 2020 Jul 16. Erratum In: Circulation. 2020 Nov 17;142(20):e369.
  PMID: 32673497
  citation: Packer M, Anker SD, Butler J, Filippatos G, Ferreira JP, Pocock SJ, Sattar N, Brueckmann M, Jamal W, Cotton D, Iwata T, Zannad F; EMPEROR-Reduced Trial Committees and Investigators. Empagliflozin in Patients With Heart Failure, Reduced Ejection Fraction, and Volume Overload: EMPEROR-Reduced Trial. J Am Coll Cardiol. 2021 Mar 23;77(11):1381-1392. doi: 10.1016/j.jacc.2021.01.033.
  PMID: 33736819
  citation: Rohde LE, Rover MM, Figueiredo Neto JA, Danzmann LC, Bertoldi EG, Simoes MV, Silvestre OM, Ribeiro ALP, Moura LZ, Beck-da-Silva L, Prado D, Sant'Anna RT, Bridi LH, Zimerman A, Raupp da Rosa P, Biolo A. Short-term diuretic withdrawal in stable outpatients with mild heart failure and no fluid retention receiving optimal therapy: a double-blind, multicentre, randomized trial. Eur Heart J. 2019 Nov 21;40(44):3605-3612. doi: 10.1093/eurheartj/ehz554.
  PMID: 31424503
  citation: Romano G, Vitale G, Bellavia D, Agnese V, Clemenza F. Is diuretic withdrawal safe in patients with heart failure and reduced ejection fraction? A retrospective analysis of our outpatient cohort. Eur J Intern Med. 2017 Jul;42:e11-e13. doi: 10.1016/j.ejim.2017.03.025. Epub 2017 Apr 6. No abstract available.
  PMID: 28390780
  citation: Nunez J, Bayes-Genis A, Revuelta-Lopez E, Ter Maaten JM, Minana G, Barallat J, Cserkoova A, Bodi V, Fernandez-Cisnal A, Nunez E, Sanchis J, Lang C, Ng LL, Metra M, Voors AA. Clinical Role of CA125 in Worsening Heart Failure: A BIOSTAT-CHF Study Subanalysis. JACC Heart Fail. 2020 May;8(5):386-397. doi: 10.1016/j.jchf.2019.12.005. Epub 2020 Mar 11.
  PMID: 32171764
  citation: Ekman I, Granger B, Swedberg K, Stenlund H, Boman K. Measuring shortness of breath in heart failure (SOB-HF): development and validation of a new dyspnoea assessment tool. Eur J Heart Fail. 2011 Aug;13(8):838-45. doi: 10.1093/eurjhf/hfr062.
  PMID: 21791539
  responsible party type: Principal Investigator
  investigator affiliation: Maimónides Biomedical Research Institute of Córdoba
  investigator full name: Alberto Torres Zamudio
  investigator title: Physician. Cardiologist
  mesh term: Dyspnea
  mesh term: Heart Failure
  mesh term: Diuretics
  sharing ipd: Yes
  ipd description: Contact by email with Central Contact Person
  ipd info type: Study Protocol
  ipd info type: Informed Consent Form (ICF)
  ipd info type: Clinical Study Report (CSR)
  ipd time frame: From October 2024
  ipd access criteria: Contact by email with Central Contact Person