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/NCT06005259</url>
    </required_header>
    <id_info>
      <org_study_id>SPIROTOX</org_study_id>
      <nct_id>NCT06005259</nct_id>
    </id_info>
    <brief_title>Effect of Spironolactone in the Prevention of Anthracycline-induced Cardiotoxicity (SPIROTOX)</brief_title>
    <acronym>SPIROTOX</acronym>
    <official_title>Effect of Spironolactone in the Prevention of Anthracycline-induced Cardiotoxicity: a Randomized Clinical Trial (SPIROTOX Trial)</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>University of Sao Paulo</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>University of Sao Paulo</source>
    <oversight_info>
      <has_dmc>Yes</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 effect of spironolactone in the primary&#xD;
        prevention of cardiotoxicity in cancer patients who are undergoing chemotherapy with&#xD;
        anthracycline within 12 months. The main question it aims to answer is:&#xD;
  &#xD;
        • Does spironolactone reduce the incidence of cardiotoxicity in patients undergoing&#xD;
        anthracycline chemotherapy?&#xD;
  &#xD;
        Participants will:&#xD;
  &#xD;
          -  Be cancer patients over 18 years starting treatment with anthracycline;&#xD;
  &#xD;
          -  Be randomized to receive either spironolactone or a placebo for 1 year;&#xD;
  &#xD;
          -  Undergo assessments of their left ventricular ejection fraction (LVEF), global&#xD;
             longitudinal strain, and cardiac biomarkers over the 12-month period.&#xD;
  &#xD;
        Researchers will compare the spironolactone group to the placebo group to see if&#xD;
        cardiotoxicity incidence differs between the two.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Objective:&#xD;
  &#xD;
        To assess the potential of spironolactone in preventing anthracycline-induced cardiotoxicity&#xD;
        among cancer patients.&#xD;
  &#xD;
        Background:&#xD;
  &#xD;
        There's ongoing debate and a dearth of evidence regarding the role of mineralocorticoid&#xD;
        receptor antagonists, such as spironolactone, in averting anthracycline-induced&#xD;
        cardiotoxicity.&#xD;
  &#xD;
        Study Design:&#xD;
  &#xD;
        A randomized, double-blind, placebo-controlled trial conducted at a single center.&#xD;
  &#xD;
        Sample Size:&#xD;
  &#xD;
        264 patients.&#xD;
  &#xD;
        Intervention:&#xD;
  &#xD;
        Eligible participants will be randomized on a 1:1 basis to either receive spironolactone or a&#xD;
        placebo over a 12-month period.&#xD;
  &#xD;
        Primary Outcome:&#xD;
  &#xD;
        Incidence of cardiotoxicity at the 12-month mark.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">October 1, 2023</start_date>
    <completion_date type="Anticipated">December 1, 2025</completion_date>
    <primary_completion_date type="Anticipated">October 1, 2025</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>Prevention</primary_purpose>
      <masking>Triple (Participant, Care Provider, Investigator)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Cardiotoxicity</measure>
      <time_frame>12 months</time_frame>
      <description>Incidence of cardiotoxicity, defined as:&#xD;
  A decrease in ejection fraction (LVEF) by 10% or more to LVEF &lt; 50%, as seen on transthoracic echocardiogram; OR&#xD;
  Relative drop in global longitudinal strain greater than 15% compared to baseline, observed on transthoracic echocardiogram; OR&#xD;
  New increase in cardiac biomarkers (troponin T &gt; 99th percentile and/or NT-proBNP &gt; 125 pg/mL).</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Left ventricular dysfunction</measure>
      <time_frame>3, 6 and 12 months</time_frame>
      <description>Decrease in ejection fraction (LVEF) ≥ 10% to LVEF &lt; 50% seen on transthoracic echocardiogram and cardiac magnetic resonance imaging</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Ventricular function</measure>
      <time_frame>3, 6 and 12 months</time_frame>
      <description>Relative reduction in global longitudinal strain ≥ 15%, observed on transthoracic echocardiogram and cardiac magnetic resonance imaging</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Incidence of myocardial injury</measure>
      <time_frame>6 and 12 months</time_frame>
      <description>Elevation of biomarkers (troponin T &gt; 99th percentile and/or NT-proBNP &gt; 125 pg/mL).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Oxygen consumption</measure>
      <time_frame>6 and 12 months</time_frame>
      <description>Measurement of oxygen consumption (VO2), ventilatory equivalents for oxygen (VE/VO2) and for carbon dioxide (VE/VCO2) by cardiopulmonary exercise test</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Ventricular diameters</measure>
      <time_frame>3, 6 and 12 months</time_frame>
      <description>Ventricular diameters measured by transthoracic echocardiogram</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Myocardial work</measure>
      <time_frame>3, 6 and 12 months</time_frame>
      <description>Global work index (GWI) and global constructive work (GCW) measured by transthoracic echocardiogram</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Diastolic dysfunction</measure>
      <time_frame>3, 6 and 12 months</time_frame>
      <description>Assessment by echocardiography the incidence of diastolic dysfunction using the following parameters: peak E-wave velocity, peak A-wave velocity, mitral valve (MV) E/A ratio, MV deceleration time, pulsed-wave tissue doppler imaging e' velocity, Mitral E/e', left atrium maximum volume index, pulmonary vein(PV) systole(S) wave, PV diastole (D) wave, continuous wave (CW) doppler: tricuspid regurgitation, systolic jet velocity; Color M- mode.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Composite endpoint of mortality or major cardiovascular outcomes</measure>
      <time_frame>3, 6 and 12 months</time_frame>
      <description>Composite endpoint of mortality or major cardiovascular outcomes (defined as acute myocardial infarction, symptomatic heart failure or complex arrhythmia).</description>
    </secondary_outcome>
    <other_outcome>
      <measure>Quality of life measured by EQ-5D-3L (EuroQol 5 Dimension 3 Level) questionnaire</measure>
      <time_frame>3, 6 and 12 months</time_frame>
      <description>The EQ-5D is a participant rated questionnaire to assess health-related quality of life in terms of a single utility score. Health State Profile component assesses level of current health for 5 dimensions: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression, using 3 levels; 1 indicates better health state (no problems); 3 indicate worst health state (&quot;confined to bed&quot;). Scoring formula developed by EuroQol Group assigns a utility value for each domain in the profile. Score is transformed and results in a total score range -0.594 to 1.000; higher score indicates a better health state.</description>
    </other_outcome>
    <other_outcome>
      <measure>Medication adherence</measure>
      <time_frame>3, 6 and 12 months</time_frame>
      <description>Medication adherence rate measured by the Morisky-Green index</description>
    </other_outcome>
    <other_outcome>
      <measure>Oncological Treatment Discontinuation Rate</measure>
      <time_frame>12 months</time_frame>
    </other_outcome>
    <other_outcome>
      <measure>Tumor Recurrence</measure>
      <time_frame>12 months</time_frame>
    </other_outcome>
    <other_outcome>
      <measure>Hospitalization Rate</measure>
      <time_frame>12 months</time_frame>
    </other_outcome>
    <other_outcome>
      <measure>Mortality Rate</measure>
      <time_frame>12 months</time_frame>
    </other_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">264</enrollment>
    <condition>Cardiotoxicity</condition>
    <condition>Neoplasms</condition>
    <condition>Chemotherapy Effect</condition>
    <condition>Heart Failure</condition>
    <arm_group>
      <arm_group_label>Intervention</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Participants will be administered 25 mg of spironolactone daily for 12 months, beginning 5 to 15 days prior to chemotherapy.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Control</arm_group_label>
      <arm_group_type>Placebo Comparator</arm_group_type>
      <description>Participants will be given placebo daily for 12 months, beginning 5 to 15 days prior to chemotherapy.</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Spironolactone</intervention_name>
      <description>Spironolactone 25 mg capsule</description>
      <arm_group_label>Intervention</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Placebo</intervention_name>
      <description>Placebo capsule</description>
      <arm_group_label>Control</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Patients diagnosed with cancer indicated for anthracycline chemotherapy treatment&#xD;
  &#xD;
            -  Age 18 and above&#xD;
  &#xD;
            -  Signed informed consent form&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Previous use of anthracycline.&#xD;
  &#xD;
            -  Hypersensitivity to any mineralocorticoid receptor antagonists&#xD;
  &#xD;
            -  Symptoms of heart failure (exertional dyspnea, orthopnea, nocturnal paroxysmal&#xD;
               dyspnea, and pulmonary or systemic congestion)&#xD;
  &#xD;
            -  Left ventricular ejection fraction (LVEF) &lt; 45%&#xD;
  &#xD;
            -  Previous diagnosis of cardiomyopathy, coronary artery disease, or moderate to severe&#xD;
               mitral or aortic disease&#xD;
  &#xD;
            -  Renal insufficiency defined as an estimated glomerular filtration rate &lt; 30 ml/min/m2&#xD;
  &#xD;
            -  Hyperkalemia, defined as serum potassium ≥ 5.0 mmol/L&#xD;
  &#xD;
            -  Chronic liver disease, defined aspartate aminotransferase (AST) or alanine&#xD;
               aminotransferase (ALT) values more than 3 times the upper limit of normal&#xD;
  &#xD;
            -  Current participation in another study&#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_contact>
      <last_name>Lucas T Kawahara</last_name>
      <phone>+5511980791999</phone>
      <email>lucas.kawahara10@gmail.com</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Ludhmila A Hajjar, MD, PhD</last_name>
      <phone>+551138932000</phone>
      <phone_ext>3272</phone_ext>
      <email>ludhmila@terra.com.br</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Instituto do Coração</name>
        <address>
          <city>São Paulo</city>
          <zip>05403-000</zip>
          <country>Brazil</country>
        </address>
      </facility>
    </location>
    <location_countries>
      <country>Brazil</country>
    </location_countries>
    <reference>
      <citation>Venkatesh P, Kasi A. Anthracyclines. 2023 Jan 30. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from http://www.ncbi.nlm.nih.gov/books/NBK538187/</citation>
      <PMID>30844214</PMID>
    </reference>
    <reference>
      <citation>Barbosa RR, Bourguignon TB, Torres LD, Arruda LS, Jacques TM, Serpa RG, Calil OA, Barbosa LFM. Anthracycline-associated cardiotoxicity in adults: systematic review on the cardioprotective role of beta-blockers. Rev Assoc Med Bras (1992). 2018 Aug;64(8):745-754. doi: 10.1590/1806-9282.64.08.745.</citation>
      <PMID>30673046</PMID>
    </reference>
    <reference>
      <citation>Rawat PS, Jaiswal A, Khurana A, Bhatti JS, Navik U. Doxorubicin-induced cardiotoxicity: An update on the molecular mechanism and novel therapeutic strategies for effective management. Biomed Pharmacother. 2021 Jul;139:111708. doi: 10.1016/j.biopha.2021.111708. Epub 2021 May 13.</citation>
      <PMID>34243633</PMID>
    </reference>
    <reference>
      <citation>Cardinale D, Iacopo F, Cipolla CM. Cardiotoxicity of Anthracyclines. Front Cardiovasc Med. 2020 Mar 18;7:26. doi: 10.3389/fcvm.2020.00026. eCollection 2020.</citation>
      <PMID>32258060</PMID>
    </reference>
    <reference>
      <citation>Herrmann J, Lenihan D, Armenian S, Barac A, Blaes A, Cardinale D, Carver J, Dent S, Ky B, Lyon AR, Lopez-Fernandez T, Fradley MG, Ganatra S, Curigliano G, Mitchell JD, Minotti G, Lang NN, Liu JE, Neilan TG, Nohria A, O'Quinn R, Pusic I, Porter C, Reynolds KL, Ruddy KJ, Thavendiranathan P, Valent P. Defining cardiovascular toxicities of cancer therapies: an International Cardio-Oncology Society (IC-OS) consensus statement. Eur Heart J. 2022 Jan 31;43(4):280-299. doi: 10.1093/eurheartj/ehab674.</citation>
      <PMID>34904661</PMID>
    </reference>
    <reference>
      <citation>Kalay N, Basar E, Ozdogru I, Er O, Cetinkaya Y, Dogan A, Inanc T, Oguzhan A, Eryol NK, Topsakal R, Ergin A. Protective effects of carvedilol against anthracycline-induced cardiomyopathy. J Am Coll Cardiol. 2006 Dec 5;48(11):2258-62. doi: 10.1016/j.jacc.2006.07.052. Epub 2006 Nov 9.</citation>
      <PMID>17161256</PMID>
    </reference>
    <reference>
      <citation>Kaya MG, Ozkan M, Gunebakmaz O, Akkaya H, Kaya EG, Akpek M, Kalay N, Dikilitas M, Yarlioglues M, Karaca H, Berk V, Ardic I, Ergin A, Lam YY. Protective effects of nebivolol against anthracycline-induced cardiomyopathy: a randomized control study. Int J Cardiol. 2013 Sep 1;167(5):2306-10. doi: 10.1016/j.ijcard.2012.06.023. Epub 2012 Jun 22.</citation>
      <PMID>22727976</PMID>
    </reference>
    <reference>
      <citation>Avila MS, Ayub-Ferreira SM, de Barros Wanderley MR Jr, das Dores Cruz F, Goncalves Brandao SM, Rigaud VOC, Higuchi-Dos-Santos MH, Hajjar LA, Kalil Filho R, Hoff PM, Sahade M, Ferrari MSM, de Paula Costa RL, Mano MS, Bittencourt Viana Cruz CB, Abduch MC, Lofrano Alves MS, Guimaraes GV, Issa VS, Bittencourt MS, Bocchi EA. Carvedilol for Prevention of Chemotherapy-Related Cardiotoxicity: The CECCY Trial. J Am Coll Cardiol. 2018 May 22;71(20):2281-2290. doi: 10.1016/j.jacc.2018.02.049. Epub 2018 Mar 11.</citation>
      <PMID>29540327</PMID>
    </reference>
    <reference>
      <citation>Cardinale D, Colombo A, Sandri MT, Lamantia G, Colombo N, Civelli M, Martinelli G, Veglia F, Fiorentini C, Cipolla CM. Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation. 2006 Dec 5;114(23):2474-81. doi: 10.1161/CIRCULATIONAHA.106.635144. Epub 2006 Nov 13.</citation>
      <PMID>17101852</PMID>
    </reference>
    <reference>
      <citation>Livi L, Barletta G, Martella F, Saieva C, Desideri I, Bacci C, Del Bene MR, Airoldi M, Amoroso D, Coltelli L, Scotti V, Becherini C, Visani L, Salvestrini V, Mariotti M, Pedani F, Bernini M, Sanchez L, Orzalesi L, Nori J, Bianchi S, Olivotto I, Meattini I. Cardioprotective Strategy for Patients With Nonmetastatic Breast Cancer Who Are Receiving an Anthracycline-Based Chemotherapy: A Randomized Clinical Trial. JAMA Oncol. 2021 Oct 1;7(10):1544-1549. doi: 10.1001/jamaoncol.2021.3395.</citation>
      <PMID>34436523</PMID>
    </reference>
    <reference>
      <citation>Omland T, Heck SL, Gulati G. The Role of Cardioprotection in Cancer Therapy Cardiotoxicity: JACC: CardioOncology State-of-the-Art Review. JACC CardioOncol. 2022 Mar 15;4(1):19-37. doi: 10.1016/j.jaccao.2022.01.101. eCollection 2022 Mar.</citation>
      <PMID>35492815</PMID>
    </reference>
    <reference>
      <citation>Wang Y, Lu X, Wang X, Qiu Q, Zhu P, Ma L, Ma X, Herrmann J, Lin X, Wang W, Xu X. atg7-Based Autophagy Activation Reverses Doxorubicin-Induced Cardiotoxicity. Circ Res. 2021 Oct;129(8):e166-e182. doi: 10.1161/CIRCRESAHA.121.319104. Epub 2021 Aug 13.</citation>
      <PMID>34384247</PMID>
    </reference>
    <reference>
      <citation>Akpek M, Ozdogru I, Sahin O, Inanc M, Dogan A, Yazici C, Berk V, Karaca H, Kalay N, Oguzhan A, Ergin A. Protective effects of spironolactone against anthracycline-induced cardiomyopathy. Eur J Heart Fail. 2015 Jan;17(1):81-9. doi: 10.1002/ejhf.196. Epub 2014 Nov 20.</citation>
      <PMID>25410653</PMID>
    </reference>
    <reference>
      <citation>Davis MK, Villa D, Tsang TSM, Starovoytov A, Gelmon K, Virani SA. Effect of Eplerenone on Diastolic Function in Women Receiving Anthracycline-Based Chemotherapy for Breast Cancer. JACC CardioOncol. 2019 Dec 17;1(2):295-298. doi: 10.1016/j.jaccao.2019.10.001. eCollection 2019 Dec. No abstract available.</citation>
      <PMID>34396193</PMID>
    </reference>
    <reference>
      <citation>Cardinale D, Colombo A, Bacchiani G, Tedeschi I, Meroni CA, Veglia F, Civelli M, Lamantia G, Colombo N, Curigliano G, Fiorentini C, Cipolla CM. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation. 2015 Jun 2;131(22):1981-8. doi: 10.1161/CIRCULATIONAHA.114.013777. Epub 2015 May 6.</citation>
      <PMID>25948538</PMID>
    </reference>
    <reference>
      <citation>Lyon AR, Lopez-Fernandez T, Couch LS, Asteggiano R, Aznar MC, Bergler-Klein J, Boriani G, Cardinale D, Cordoba R, Cosyns B, Cutter DJ, de Azambuja E, de Boer RA, Dent SF, Farmakis D, Gevaert SA, Gorog DA, Herrmann J, Lenihan D, Moslehi J, Moura B, Salinger SS, Stephens R, Suter TM, Szmit S, Tamargo J, Thavendiranathan P, Tocchetti CG, van der Meer P, van der Pal HJH; ESC Scientific Document Group. 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Eur Heart J. 2022 Nov 1;43(41):4229-4361. doi: 10.1093/eurheartj/ehac244. No abstract available. Erratum In: Eur Heart J. 2023 May 7;44(18):1621.</citation>
      <PMID>36017568</PMID>
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      <citation>Laufer-Perl M, Perelman-Gvili M, Sirota Dorfman S, Baruch G, Rothschild E, Beer G, Arbel Y, Arnold JH, Rozenbaum Z, Banai S, Topilsky Y, Kapusta L. Prevalence of Right Ventricle Strain Changes following Anthracycline Therapy. Life (Basel). 2022 Feb 15;12(2):291. doi: 10.3390/life12020291.</citation>
      <PMID>35207578</PMID>
    </reference>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>August 7, 2023</study_first_submitted>
    <study_first_submitted_qc>August 16, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 22, 2023</study_first_posted>
    <last_update_submitted>August 16, 2023</last_update_submitted>
    <last_update_submitted_qc>August 16, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 22, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>University of Sao Paulo</investigator_affiliation>
      <investigator_full_name>Ludhmila Abrahão Hajjar MD, PhD</investigator_full_name>
      <investigator_title>Full Professor</investigator_title>
    </responsible_party>
    <keyword>Cardiotoxicity</keyword>
    <keyword>Anthracyclines</keyword>
    <keyword>Spironolactone</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Cardiotoxicity</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Spironolactone</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </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/NCT06005259
  org study id: SPIROTOX
  nct id: NCT06005259
  lead sponsor: 
  has dmc: Yes
  is fda regulated drug: No
  is fda regulated device: No
  is us export: No
  The goal of this clinical trial is to evaluate the effect of spironolactone in the primary
        prevention of cardiotoxicity in cancer patients who are undergoing chemotherapy with
        anthracycline within 12 months. The main question it aims to answer is:
  
        • Does spironolactone reduce the incidence of cardiotoxicity in patients undergoing
        anthracycline chemotherapy?
  
        Participants will:
  
          -  Be cancer patients over 18 years starting treatment with anthracycline;
  
          -  Be randomized to receive either spironolactone or a placebo for 1 year;
  
          -  Undergo assessments of their left ventricular ejection fraction (LVEF), global
             longitudinal strain, and cardiac biomarkers over the 12-month period.
  
        Researchers will compare the spironolactone group to the placebo group to see if
        cardiotoxicity incidence differs between the two.
  Objective:
  
        To assess the potential of spironolactone in preventing anthracycline-induced cardiotoxicity
        among cancer patients.
  
        Background:
  
        There's ongoing debate and a dearth of evidence regarding the role of mineralocorticoid
        receptor antagonists, such as spironolactone, in averting anthracycline-induced
        cardiotoxicity.
  
        Study Design:
  
        A randomized, double-blind, placebo-controlled trial conducted at a single center.
  
        Sample Size:
  
        264 patients.
  
        Intervention:
  
        Eligible participants will be randomized on a 1:1 basis to either receive spironolactone or a
        placebo over a 12-month period.
  
        Primary Outcome:
  
        Incidence of cardiotoxicity at the 12-month mark.
  allocation: Randomized
  intervention model: Parallel Assignment
  primary purpose: Prevention
  masking: Triple (Participant, Care Provider, Investigator)
  measure: Cardiotoxicity
  time frame: 12 months
  description: Incidence of cardiotoxicity, defined as:
  A decrease in ejection fraction (LVEF) by 10% or more to LVEF < 50%, as seen on transthoracic echocardiogram; OR
  Relative drop in global longitudinal strain greater than 15% compared to baseline, observed on transthoracic echocardiogram; OR
  New increase in cardiac biomarkers (troponin T > 99th percentile and/or NT-proBNP > 125 pg/mL).
  measure: Left ventricular dysfunction
  time frame: 3, 6 and 12 months
  description: Decrease in ejection fraction (LVEF) ≥ 10% to LVEF < 50% seen on transthoracic echocardiogram and cardiac magnetic resonance imaging
  measure: Ventricular function
  time frame: 3, 6 and 12 months
  description: Relative reduction in global longitudinal strain ≥ 15%, observed on transthoracic echocardiogram and cardiac magnetic resonance imaging
  measure: Incidence of myocardial injury
  time frame: 6 and 12 months
  description: Elevation of biomarkers (troponin T > 99th percentile and/or NT-proBNP > 125 pg/mL).
  measure: Oxygen consumption
  time frame: 6 and 12 months
  description: Measurement of oxygen consumption (VO2), ventilatory equivalents for oxygen (VE/VO2) and for carbon dioxide (VE/VCO2) by cardiopulmonary exercise test
  measure: Ventricular diameters
  time frame: 3, 6 and 12 months
  description: Ventricular diameters measured by transthoracic echocardiogram
  measure: Myocardial work
  time frame: 3, 6 and 12 months
  description: Global work index (GWI) and global constructive work (GCW) measured by transthoracic echocardiogram
  measure: Diastolic dysfunction
  time frame: 3, 6 and 12 months
  description: Assessment by echocardiography the incidence of diastolic dysfunction using the following parameters: peak E-wave velocity, peak A-wave velocity, mitral valve (MV) E/A ratio, MV deceleration time, pulsed-wave tissue doppler imaging e' velocity, Mitral E/e', left atrium maximum volume index, pulmonary vein(PV) systole(S) wave, PV diastole (D) wave, continuous wave (CW) doppler: tricuspid regurgitation, systolic jet velocity; Color M- mode.
  measure: Composite endpoint of mortality or major cardiovascular outcomes
  time frame: 3, 6 and 12 months
  description: Composite endpoint of mortality or major cardiovascular outcomes (defined as acute myocardial infarction, symptomatic heart failure or complex arrhythmia).
  measure: Quality of life measured by EQ-5D-3L (EuroQol 5 Dimension 3 Level) questionnaire
  time frame: 3, 6 and 12 months
  description: The EQ-5D is a participant rated questionnaire to assess health-related quality of life in terms of a single utility score. Health State Profile component assesses level of current health for 5 dimensions: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression, using 3 levels; 1 indicates better health state (no problems); 3 indicate worst health state ("confined to bed"). Scoring formula developed by EuroQol Group assigns a utility value for each domain in the profile. Score is transformed and results in a total score range -0.594 to 1.000; higher score indicates a better health state.
  measure: Medication adherence
  time frame: 3, 6 and 12 months
  description: Medication adherence rate measured by the Morisky-Green index
  measure: Oncological Treatment Discontinuation Rate
  time frame: 12 months
  measure: Tumor Recurrence
  time frame: 12 months
  measure: Hospitalization Rate
  time frame: 12 months
  measure: Mortality Rate
  time frame: 12 months
  arm group label: Intervention
  arm group type: Experimental
  description: Participants will be administered 25 mg of spironolactone daily for 12 months, beginning 5 to 15 days prior to chemotherapy.
  arm group label: Control
  arm group type: Placebo Comparator
  description: Participants will be given placebo daily for 12 months, beginning 5 to 15 days prior to chemotherapy.
  intervention type: Drug
  intervention name: Spironolactone
  description: Spironolactone 25 mg capsule
  arm group label: Intervention
  intervention type: Drug
  intervention name: Placebo
  description: Placebo capsule
  arm group label: Control
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Lucas T Kawahara
  phone: +5511980791999
  email: lucas.kawahara10@gmail.com
  last name: Ludhmila A Hajjar, MD, PhD
  phone: +551138932000
  phone ext: 3272
  email: ludhmila@terra.com.br
  facility: 
  country: Brazil
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  PMID: 30844214
  citation: Barbosa RR, Bourguignon TB, Torres LD, Arruda LS, Jacques TM, Serpa RG, Calil OA, Barbosa LFM. Anthracycline-associated cardiotoxicity in adults: systematic review on the cardioprotective role of beta-blockers. Rev Assoc Med Bras (1992). 2018 Aug;64(8):745-754. doi: 10.1590/1806-9282.64.08.745.
  PMID: 30673046
  citation: Rawat PS, Jaiswal A, Khurana A, Bhatti JS, Navik U. Doxorubicin-induced cardiotoxicity: An update on the molecular mechanism and novel therapeutic strategies for effective management. Biomed Pharmacother. 2021 Jul;139:111708. doi: 10.1016/j.biopha.2021.111708. Epub 2021 May 13.
  PMID: 34243633
  citation: Cardinale D, Iacopo F, Cipolla CM. Cardiotoxicity of Anthracyclines. Front Cardiovasc Med. 2020 Mar 18;7:26. doi: 10.3389/fcvm.2020.00026. eCollection 2020.
  PMID: 32258060
  citation: Herrmann J, Lenihan D, Armenian S, Barac A, Blaes A, Cardinale D, Carver J, Dent S, Ky B, Lyon AR, Lopez-Fernandez T, Fradley MG, Ganatra S, Curigliano G, Mitchell JD, Minotti G, Lang NN, Liu JE, Neilan TG, Nohria A, O'Quinn R, Pusic I, Porter C, Reynolds KL, Ruddy KJ, Thavendiranathan P, Valent P. Defining cardiovascular toxicities of cancer therapies: an International Cardio-Oncology Society (IC-OS) consensus statement. Eur Heart J. 2022 Jan 31;43(4):280-299. doi: 10.1093/eurheartj/ehab674.
  PMID: 34904661
  citation: Kalay N, Basar E, Ozdogru I, Er O, Cetinkaya Y, Dogan A, Inanc T, Oguzhan A, Eryol NK, Topsakal R, Ergin A. Protective effects of carvedilol against anthracycline-induced cardiomyopathy. J Am Coll Cardiol. 2006 Dec 5;48(11):2258-62. doi: 10.1016/j.jacc.2006.07.052. Epub 2006 Nov 9.
  PMID: 17161256
  citation: Kaya MG, Ozkan M, Gunebakmaz O, Akkaya H, Kaya EG, Akpek M, Kalay N, Dikilitas M, Yarlioglues M, Karaca H, Berk V, Ardic I, Ergin A, Lam YY. Protective effects of nebivolol against anthracycline-induced cardiomyopathy: a randomized control study. Int J Cardiol. 2013 Sep 1;167(5):2306-10. doi: 10.1016/j.ijcard.2012.06.023. Epub 2012 Jun 22.
  PMID: 22727976
  citation: Avila MS, Ayub-Ferreira SM, de Barros Wanderley MR Jr, das Dores Cruz F, Goncalves Brandao SM, Rigaud VOC, Higuchi-Dos-Santos MH, Hajjar LA, Kalil Filho R, Hoff PM, Sahade M, Ferrari MSM, de Paula Costa RL, Mano MS, Bittencourt Viana Cruz CB, Abduch MC, Lofrano Alves MS, Guimaraes GV, Issa VS, Bittencourt MS, Bocchi EA. Carvedilol for Prevention of Chemotherapy-Related Cardiotoxicity: The CECCY Trial. J Am Coll Cardiol. 2018 May 22;71(20):2281-2290. doi: 10.1016/j.jacc.2018.02.049. Epub 2018 Mar 11.
  PMID: 29540327
  citation: Cardinale D, Colombo A, Sandri MT, Lamantia G, Colombo N, Civelli M, Martinelli G, Veglia F, Fiorentini C, Cipolla CM. Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation. 2006 Dec 5;114(23):2474-81. doi: 10.1161/CIRCULATIONAHA.106.635144. Epub 2006 Nov 13.
  PMID: 17101852
  citation: Livi L, Barletta G, Martella F, Saieva C, Desideri I, Bacci C, Del Bene MR, Airoldi M, Amoroso D, Coltelli L, Scotti V, Becherini C, Visani L, Salvestrini V, Mariotti M, Pedani F, Bernini M, Sanchez L, Orzalesi L, Nori J, Bianchi S, Olivotto I, Meattini I. Cardioprotective Strategy for Patients With Nonmetastatic Breast Cancer Who Are Receiving an Anthracycline-Based Chemotherapy: A Randomized Clinical Trial. JAMA Oncol. 2021 Oct 1;7(10):1544-1549. doi: 10.1001/jamaoncol.2021.3395.
  PMID: 34436523
  citation: Omland T, Heck SL, Gulati G. The Role of Cardioprotection in Cancer Therapy Cardiotoxicity: JACC: CardioOncology State-of-the-Art Review. JACC CardioOncol. 2022 Mar 15;4(1):19-37. doi: 10.1016/j.jaccao.2022.01.101. eCollection 2022 Mar.
  PMID: 35492815
  citation: Wang Y, Lu X, Wang X, Qiu Q, Zhu P, Ma L, Ma X, Herrmann J, Lin X, Wang W, Xu X. atg7-Based Autophagy Activation Reverses Doxorubicin-Induced Cardiotoxicity. Circ Res. 2021 Oct;129(8):e166-e182. doi: 10.1161/CIRCRESAHA.121.319104. Epub 2021 Aug 13.
  PMID: 34384247
  citation: Akpek M, Ozdogru I, Sahin O, Inanc M, Dogan A, Yazici C, Berk V, Karaca H, Kalay N, Oguzhan A, Ergin A. Protective effects of spironolactone against anthracycline-induced cardiomyopathy. Eur J Heart Fail. 2015 Jan;17(1):81-9. doi: 10.1002/ejhf.196. Epub 2014 Nov 20.
  PMID: 25410653
  citation: Davis MK, Villa D, Tsang TSM, Starovoytov A, Gelmon K, Virani SA. Effect of Eplerenone on Diastolic Function in Women Receiving Anthracycline-Based Chemotherapy for Breast Cancer. JACC CardioOncol. 2019 Dec 17;1(2):295-298. doi: 10.1016/j.jaccao.2019.10.001. eCollection 2019 Dec. No abstract available.
  PMID: 34396193
  citation: Cardinale D, Colombo A, Bacchiani G, Tedeschi I, Meroni CA, Veglia F, Civelli M, Lamantia G, Colombo N, Curigliano G, Fiorentini C, Cipolla CM. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation. 2015 Jun 2;131(22):1981-8. doi: 10.1161/CIRCULATIONAHA.114.013777. Epub 2015 May 6.
  PMID: 25948538
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  PMID: 36017568
  citation: Laufer-Perl M, Perelman-Gvili M, Sirota Dorfman S, Baruch G, Rothschild E, Beer G, Arbel Y, Arnold JH, Rozenbaum Z, Banai S, Topilsky Y, Kapusta L. Prevalence of Right Ventricle Strain Changes following Anthracycline Therapy. Life (Basel). 2022 Feb 15;12(2):291. doi: 10.3390/life12020291.
  PMID: 35207578
  responsible party type: Principal Investigator
  investigator affiliation: University of Sao Paulo
  investigator full name: Ludhmila Abrahão Hajjar MD, PhD
  investigator title: Full Professor
  mesh term: Cardiotoxicity
  mesh term: Spironolactone
  sharing ipd: No