Back to results

Effect of Spironolactone in the Prevention of Anthracycline-induced Cardiotoxicity (SPIROTOX) (SPIROTOX)

Primary Purpose

Cardiotoxicity, Neoplasms, Chemotherapy Effect

Status

Not yet recruiting

Phase

Phase 4

Locations

Brazil

Study Type

Interventional

Intervention

Spironolactone

Placebo

About this trial

This is an interventional prevention trial for Cardiotoxicity focused on measuring Cardiotoxicity, Anthracyclines, Spironolactone

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Patients diagnosed with cancer indicated for anthracycline chemotherapy treatment Age 18 and above Signed informed consent form Exclusion Criteria: Previous use of anthracycline. Hypersensitivity to any mineralocorticoid receptor antagonists Symptoms of heart failure (exertional dyspnea, orthopnea, nocturnal paroxysmal dyspnea, and pulmonary or systemic congestion) Left ventricular ejection fraction (LVEF) < 45% Previous diagnosis of cardiomyopathy, coronary artery disease, or moderate to severe mitral or aortic disease Renal insufficiency defined as an estimated glomerular filtration rate < 30 ml/min/m2 Hyperkalemia, defined as serum potassium ≥ 5.0 mmol/L Chronic liver disease, defined aspartate aminotransferase (AST) or alanine aminotransferase (ALT) values more than 3 times the upper limit of normal Current participation in another study

Sites / Locations

Instituto do Coração

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Intervention

Control

Arm Description

Participants will be administered 25 mg of spironolactone daily for 12 months, beginning 5 to 15 days prior to chemotherapy.

Participants will be given placebo daily for 12 months, beginning 5 to 15 days prior to chemotherapy.

Outcomes

Primary Outcome Measures

Cardiotoxicity

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).

Secondary Outcome Measures

Left ventricular dysfunction

Decrease in ejection fraction (LVEF) ≥ 10% to LVEF < 50% seen on transthoracic echocardiogram and cardiac magnetic resonance imaging

Ventricular function

Relative reduction in global longitudinal strain ≥ 15%, observed on transthoracic echocardiogram and cardiac magnetic resonance imaging

Incidence of myocardial injury

Elevation of biomarkers (troponin T > 99th percentile and/or NT-proBNP > 125 pg/mL).

Oxygen consumption

Measurement of oxygen consumption (VO2), ventilatory equivalents for oxygen (VE/VO2) and for carbon dioxide (VE/VCO2) by cardiopulmonary exercise test

Ventricular diameters

Ventricular diameters measured by transthoracic echocardiogram

Myocardial work

Global work index (GWI) and global constructive work (GCW) measured by transthoracic echocardiogram

Diastolic dysfunction

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.

Composite endpoint of mortality or major cardiovascular outcomes

Composite endpoint of mortality or major cardiovascular outcomes (defined as acute myocardial infarction, symptomatic heart failure or complex arrhythmia).

Full Information

NCT ID

NCT06005259

First Posted

August 7, 2023

Last Updated

August 16, 2023

Sponsor

University of Sao Paulo

1. Study Identification

Unique Protocol Identification Number

NCT06005259

Brief Title

Effect of Spironolactone in the Prevention of Anthracycline-induced Cardiotoxicity (SPIROTOX)

Acronym

SPIROTOX

Official Title

Effect of Spironolactone in the Prevention of Anthracycline-induced Cardiotoxicity: a Randomized Clinical Trial (SPIROTOX Trial)

Study Type

Interventional

2. Study Status

Record Verification Date

August 2023

Overall Recruitment Status

Not yet recruiting

Study Start Date

October 1, 2023 (Anticipated)

Primary Completion Date

October 1, 2025 (Anticipated)

Study Completion Date

December 1, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of Sao Paulo

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

Detailed Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Cardiotoxicity, Neoplasms, Chemotherapy Effect, Heart Failure

Keywords

Cardiotoxicity, Anthracyclines, Spironolactone

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

264 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Intervention

Arm Type

Experimental

Arm Description

Participants will be administered 25 mg of spironolactone daily for 12 months, beginning 5 to 15 days prior to chemotherapy.

Arm Title

Control

Arm Type

Placebo Comparator

Arm Description

Participants will be given placebo daily for 12 months, beginning 5 to 15 days prior to chemotherapy.

Intervention Type

Drug

Intervention Name(s)

Spironolactone

Intervention Description

Spironolactone 25 mg capsule

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Placebo capsule

Primary Outcome Measure Information:

Title

Cardiotoxicity

Description

Time Frame

12 months

Secondary Outcome Measure Information:

Title

Left ventricular dysfunction

Description

Decrease in ejection fraction (LVEF) ≥ 10% to LVEF < 50% seen on transthoracic echocardiogram and cardiac magnetic resonance imaging

Time Frame

3, 6 and 12 months

Title

Ventricular function

Description

Relative reduction in global longitudinal strain ≥ 15%, observed on transthoracic echocardiogram and cardiac magnetic resonance imaging

Time Frame

3, 6 and 12 months

Title

Incidence of myocardial injury

Description

Elevation of biomarkers (troponin T > 99th percentile and/or NT-proBNP > 125 pg/mL).

Time Frame

6 and 12 months

Title

Oxygen consumption

Description

Measurement of oxygen consumption (VO2), ventilatory equivalents for oxygen (VE/VO2) and for carbon dioxide (VE/VCO2) by cardiopulmonary exercise test

Time Frame

6 and 12 months

Title

Ventricular diameters

Description

Ventricular diameters measured by transthoracic echocardiogram

Time Frame

3, 6 and 12 months

Title

Myocardial work

Description

Global work index (GWI) and global constructive work (GCW) measured by transthoracic echocardiogram

Time Frame

3, 6 and 12 months

Title

Diastolic dysfunction

Description

Time Frame

3, 6 and 12 months

Title

Composite endpoint of mortality or major cardiovascular outcomes

Description

Composite endpoint of mortality or major cardiovascular outcomes (defined as acute myocardial infarction, symptomatic heart failure or complex arrhythmia).

Time Frame

3, 6 and 12 months

Other Pre-specified Outcome Measures:

Title

Quality of life measured by EQ-5D-3L (EuroQol 5 Dimension 3 Level) questionnaire

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.

Time Frame

3, 6 and 12 months

Title

Medication adherence

Description

Medication adherence rate measured by the Morisky-Green index

Time Frame

3, 6 and 12 months

Title

Oncological Treatment Discontinuation Rate

Time Frame

12 months

Title

Tumor Recurrence

Time Frame

12 months

Title

Hospitalization Rate

Time Frame

12 months

Title

Mortality Rate

Time Frame

12 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Lucas T Kawahara

Phone

+5511980791999

lucas.kawahara10@gmail.com

First Name & Middle Initial & Last Name or Official Title & Degree

Ludhmila A Hajjar, MD, PhD

Phone

+551138932000

Ext

3272

ludhmila@terra.com.br

Facility Information:

Facility Name

Instituto do Coração

City

São Paulo

ZIP/Postal Code

05403-000

Country

Brazil

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

30844214

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/

Results Reference

background

PubMed Identifier

30673046

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.

Results Reference

background

PubMed Identifier

34243633

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.

Results Reference

background

PubMed Identifier

32258060

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.

Results Reference

background

PubMed Identifier

34904661

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.

Results Reference

background

PubMed Identifier

17161256

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.

Results Reference

background

PubMed Identifier

22727976

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.

Results Reference

background

PubMed Identifier

29540327

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.

Results Reference

background

PubMed Identifier

17101852

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.

Results Reference

background

PubMed Identifier

34436523

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.

Results Reference

background

PubMed Identifier

35492815

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.

Results Reference

background

PubMed Identifier

34384247

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.

Results Reference

background

PubMed Identifier

25410653

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.

Results Reference

background

PubMed Identifier

34396193

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.

Results Reference

background

PubMed Identifier

25948538

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.

Results Reference

background

PubMed Identifier

36017568

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.

Results Reference

background

PubMed Identifier

35207578

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.

Results Reference

background

Learn more about this trial

Effect of Spironolactone in the Prevention of Anthracycline-induced Cardiotoxicity (SPIROTOX)

We'll reach out to this number within 24 hrs