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Carvedilol, a \u03b2-blocker with unique antioxidant properties, emerged as a strategy to prevent AIC, but recent trials question its effectiveness. Some evidence suggests that the antioxidant, not the \u03b2-blocker effect, could prevent related cardiotoxicity. However, carvedilol\u2019s antioxidant effects are probably not enough to prevent cardiotoxicity manifestations in certain cases. We hypothesize that breast cancer patients taking carvedilol as well as a non-hypoxic myocardial preconditioning based on docosahexaenoic acid (DHA), an enhancer of cardiac endogenous antioxidant capacity, will develop less subclinical cardiotoxicity manifestations than patients randomized to double placebo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods\/design<\/jats:title><jats:p>We designed a pilot, randomized controlled, two-arm clinical trial with 32 patients to evaluate the effects of non-hypoxic cardiac preconditioning (DHA) plus carvedilol on subclinical cardiotoxicity in breast cancer patients undergoing anthracycline treatment. The trial includes four co-primary endpoints: changes in left ventricular ejection fraction (LVEF) determined by cardiac magnetic resonance (CMR); changes in global longitudinal strain (GLS) determined by two-dimensional echocardiography (ECHO); elevation in serum biomarkers (hs-cTnT and NT-ProBNP); and one electrocardiographic variable (QTc interval). Secondary endpoints include other imaging, biomarkers and the occurrence of major adverse cardiac events during follow-up. The enrollment and follow-up for clinical outcomes is ongoing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>We expect a group of anthracycline-treated breast cancer patients exposed to carvedilol and non-hypoxic myocardial preconditioning with DHA to show less subclinical cardiotoxicity manifestations than a comparable group exposed to placebo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Trial registration<\/jats:title><jats:p>ISRCTN registry, ID:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/www.isrctn.com\/ISRCTN69560410\">ISRCTN69560410<\/jats:ext-link>. Registered on 8 June 2016.<\/jats:p><\/jats:sec>","DOI":"10.1186\/s13063-019-3963-6","type":"journal-article","created":{"date-parts":[[2020,2,4]],"date-time":"2020-02-04T14:02:36Z","timestamp":1580824956000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Prevention of doxorubicin-induced Cardiotoxicity by pharmacological non-hypoxic myocardial preconditioning based on Docosahexaenoic Acid (DHA) and carvedilol direct antioxidant effects: study protocol for a pilot, randomized, double-blind, controlled trial (CarDHA trial)"],"prefix":"10.1186","volume":"21","author":[{"given":"Rodrigo","family":"Carrasco","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mar\u00eda Cristina","family":"Ramirez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kjersti","family":"Nes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andr\u00e9s","family":"Schuster","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rub\u00e9n","family":"Aguayo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcelo","family":"Morales","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristobal","family":"Ramos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Hasson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Camilo G.","family":"Sotomayor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pablo","family":"Henriquez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ignacio","family":"Cort\u00e9s","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcia","family":"Erazo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudio","family":"Salas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3424-4807","authenticated-orcid":false,"given":"Juan G.","family":"Gormaz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,2,4]]},"reference":[{"key":"3963_CR1","doi-asserted-by":"publisher","unstructured":"Jemal A, Ward EM, Johnson CJ, et al. 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Written informed consent was obtained from all patients prior to trial participation. In case of amendments to the protocol, approval will be requested to the aforementioned ethics committee. Subsequently, the investigators, trial participants and trial registries will be informed. A Data Monitoring Committee (DMC) was not implemented in this trial because of the small sample size, easily controlled interventions with a low incidence of side effects. However, the research team will collect, assess reports and manage the data monitoring and reported adverse events. Any data, forms, reports, results and other records will be identified only with a participant identification number to maintain confidentiality. All records will be kept in a locked file cabinet. All computer and networking entries will be done using identification number only, where possible. All computers that contain records are password-protected. 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