Colchicine Versus Beta-blockers, Angiotensin-converting Enzyme Inhibitors, and Statins for Prevention of Chemotherapy-Induced Cardiomyopathy

Chemotherapy Induced Systolic Dysfunction Clinical Trial

— BASiC-CIC  

Official title:

Colchicine Versus Beta-blockers, Angiotensin-converting Enzyme Inhibitors, and Statins for Prevention of Chemotherapy-Induced Cardiomyopathy

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06304896
• Other study ID #: #18240343
• Status: Not yet recruiting
• Phase: Phase 1
• Start date: May 1, 2024
• Est. completion date: December 1, 2025

Study information

• Verified date: March 2024
• Source: Arab Contractors Medical Centre
• Contact: Eslam Abbas, MBChB, MSc
• Phone: 01023054574
• Email: islam.omr[@]med.au.edu.eg
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

BASiC-CIC Trial is a multicenter, double-blinded, randomized, placebo-controlled clinical trial to investigate whether repurposing colchicine or a combination of beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and statins will be effective as a prophylactic treatment for the prevention of chemotherapy-induced cardiomyopathy, reduction of major adverse cardiovascular events, and all-cause mortality.

Description:

The 2021 European Society of Cardiology (ESC) guidelines recommend that the treatment with angiotensin-converting enzyme inhibitors (ACEi) and a beta-blocker (preferably carvedilol) should be considered in cancer patients developing left ventricle systolic dysfunction, defined as a 10% or more decrease in left ventricular ejection fraction (LVEF) from baseline value or a value lower than 50%, during anthracycline chemotherapy. This statement has a class of recommendation of II with a level of evidence B, which means that the weight of evidence/opinion is in favor of the usefulness of these treatments. The statement recommends starting the dual treatment after echocardiographic evidence of cardiac affection. Therefore, whether pre-treatment with these dual cardio-protective agents will protect the patient's heart from the toxic effects of the chemotherapeutic intervention is unclear. Additionally, The 2022 ACC/AHA/HFSA American guidelines recommend that in asymptomatic patients with cancer therapy-related cardiomyopathy (ejection fraction<50%), angiotensin-receptor blocker (ARBs)and beta-blockers are reasonable to prevent progression to heart failure and improve cardiac function. The statement also recommends starting the dual treatment after echocardiographic evidence of cardiac affection. However, these guidelines state that in patients at risk of cancer therapy-related cardiomyopathy, initiation of beta blockers and ACEi/ARB for the primary prevention of drug-induced cardiomyopathy is of uncertain benefit and further clinical research is an unmet need. Accordingly, the effectiveness of preemptive use of ACEi-ARB and/or selected beta-blockers (such as carvedilol and nebivolol) in reducing the risk of cancer therapy-related cardiomyopathy has been investigated in a number of small clinical trials, with conflicting findings. Additionally, statins have pleiotropic therapeutic effects that range from endothelial stabilization to suppression of inflammation. However, its role in decreasing disease morbidity (repeated hospitalization) in established chronic heart failure is also uncertain. On the other hand, colchicine is an immunomodulator that accumulates in the white blood cells and affects them in a variety of ways including decreasing motility, mobilization, and adhesion. Generally, colchicine appears to inhibit multiple proinflammatory mechanisms, while enabling increased levels of anti-inflammatory mediators. In a randomized trial involving patients with chronic coronary disease, the risk of cardiovascular events was significantly lower among those who received 0.5 mg of colchicine once daily than among those who received a placebo. Accordingly, colchicine can reduce the risk of cardiovascular events in patients with chronic coronary artery disease, but its efficacy in improving the functional status in patients with established chronic heart failure is also uncertain. While the use of this immunomodulatory agent in established heart failure is uncertain, its effectiveness in the prophylactic reduction of chemotherapy-induced cardiomyopathy in patients with normal pre-treatment ejection fraction has not been investigated. Accordingly, 150 enrolled cancer patients who are candidates for guideline-directed anthracycline-based chemotherapy with or without the anti-HER2 trastuzumab at the time of presentation, will undergo the following: - General and Local cardiac examination. - CBC. - Chemistry Panel including KFTs, LFTs. - Serum electrolytes levels. - Baseline resting surface 12 leads ECG followed by serial recording (monthly for a total of 6 months). - Baseline Echocardiography followed by serial imaging every 2 months for a total of 6 months. - Baseline serum BNP test/NT-proBNP followed by serial testing every 2 months for a total of 6 months.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 150
• Est. completion date: December 1, 2025
• Est. primary completion date: May 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Willing and able to provide written informed consent prior to performing study procedures.
• A cancer patient who is a candidate for a guideline-directed, anthracycline-based chemotherapy with or without the anti-HER2 trastuzumab.
• Baseline LVEF = 50% without evident structural heart disease by pre-treatment echocardiographic examination.

Exclusion Criteria:

• Critically ill Cancer patients who are admitted to ICU.
• Ischemic cardiomyopathy with LVEF = 50%.
• Dilated cardiomyopathy with LVEF = 50%.
• Advanced valvular heart disease (severe valvular affection in the form of stenosis or regurgitation).
• Systolic BP < 90 mmHg or diastolic BP < 60 mmHg.
• Liver cell failure.
• End-stage chronic kidney disease on regular dialysis.
• Pregnancy.
• Lactation.
• Chronic muscle diseases such as dermatomyositis, polymyositis, or muscular dystrophy.
• Acute trauma or burns within 2 weeks.
• History of allergy to the implemented drugs.

Related Conditions & MeSH terms

• Cardiomyopathies
• Chemotherapy Induced Systolic Dysfunction

Intervention

Drug:
• Carvedilol
Carvedilol 6.25 mg oral tablets. Prescribed: Twice daily PO with 200 mL of water.
• Ramipril
Ramipril 2.5 mg oral capsules. Prescribed: Once daily PO with 200 mL of water.
• Rosuvastatin
Rosuvastatin 20 mg oral tablets. Prescribed: Once daily PO with 200 mL of water.
• Colchicine
Colchicine 0.6 mg oral tablets/capsules. Prescribed: Once daily PO with 200 mL of water.
• Placebo
Placebo oral capsules. Prescribed: Once daily PO with 200 mL of water.

Locations

Country	Name	City	State
Egypt	Arab Contractors Medical Centre	Cairo

Sponsors (1)

Lead Sponsor	Collaborator
Arab Contractors Medical Centre

Country where clinical trial is conducted

Egypt, 

References & Publications (20)

Authors/Task Force Members:; 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: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). With the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2022 Jan;24(1):4-131. doi: 10.1002/ejhf.2333. — View Citation

Bosch X, Rovira M, Sitges M, Domenech A, Ortiz-Perez JT, de Caralt TM, Morales-Ruiz M, Perea RJ, Monzo M, Esteve J. Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies: the OVERCOME trial (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies). J Am Coll Cardiol. 2013 Jun 11;61(23):2355-62. doi: 10.1016/j.jacc.2013.02.072. Epub 2013 Apr 10. — View Citation

Deftereos S, Giannopoulos G, Panagopoulou V, Bouras G, Raisakis K, Kossyvakis C, Karageorgiou S, Papadimitriou C, Vastaki M, Kaoukis A, Angelidis C, Pagoni S, Pyrgakis V, Alexopoulos D, Manolis AS, Stefanadis C, Cleman MW. Anti-inflammatory treatment with colchicine in stable chronic heart failure: a prospective, randomized study. JACC Heart Fail. 2014 Apr;2(2):131-7. doi: 10.1016/j.jchf.2013.11.006. — View Citation

Golwala H. Enalapril/carvedilol for prevention of chemotherapy-induced heart failure: an end to the problem. J Am Coll Cardiol. 2013 Dec 24;62(25):2450-2451. doi: 10.1016/j.jacc.2013.06.059. Epub 2013 Sep 4. No abstract available. — View Citation

Guglin M, Krischer J, Tamura R, Fink A, Bello-Matricaria L, McCaskill-Stevens W, Munster PN. Randomized Trial of Lisinopril Versus Carvedilol to Prevent Trastuzumab Cardiotoxicity in Patients With Breast Cancer. J Am Coll Cardiol. 2019 Jun 11;73(22):2859-2868. doi: 10.1016/j.jacc.2019.03.495. — View Citation

Gulati G, Heck SL, Ree AH, Hoffmann P, Schulz-Menger J, Fagerland MW, Gravdehaug B, von Knobelsdorff-Brenkenhoff F, Bratland A, Storas TH, Hagve TA, Rosjo H, Steine K, Geisler J, Omland T. Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 x 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol. Eur Heart J. 2016 Jun 1;37(21):1671-80. doi: 10.1093/eurheartj/ehw022. Epub 2016 Feb 21. — View Citation

Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, Deswal A, Drazner MH, Dunlay SM, Evers LR, Fang JC, Fedson SE, Fonarow GC, Hayek SS, Hernandez AF, Khazanie P, Kittleson MM, Lee CS, Link MS, Milano CA, Nnacheta LC, Sandhu AT, Stevenson LW, Vardeny O, Vest AR, Yancy CW. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022 May 3;145(18):e895-e1032. doi: 10.1161/CIR.0000000000001063. Epub 2022 Apr 1. Erratum In: Circulation. 2022 May 3;145(18):e1033. Circulation. 2022 Sep 27;146(13):e185. Circulation. 2023 Apr 4;147(14):e674. — View 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. — View Citation

Kuo MC, Chang SJ, Hsieh MC. Colchicine Significantly Reduces Incident Cancer in Gout Male Patients: A 12-Year Cohort Study. Medicine (Baltimore). 2015 Dec;94(50):e1570. doi: 10.1097/MD.0000000000001570. — View Citation

Nidorf SM, Fiolet ATL, Mosterd A, Eikelboom JW, Schut A, Opstal TSJ, The SHK, Xu XF, Ireland MA, Lenderink T, Latchem D, Hoogslag P, Jerzewski A, Nierop P, Whelan A, Hendriks R, Swart H, Schaap J, Kuijper AFM, van Hessen MWJ, Saklani P, Tan I, Thompson AG, Morton A, Judkins C, Bax WA, Dirksen M, Alings M, Hankey GJ, Budgeon CA, Tijssen JGP, Cornel JH, Thompson PL; LoDoCo2 Trial Investigators. Colchicine in Patients with Chronic Coronary Disease. N Engl J Med. 2020 Nov 5;383(19):1838-1847. doi: 10.1056/NEJMoa2021372. Epub 2020 Aug 31. — View Citation

Rogers JK, Jhund PS, Perez AC, Bohm M, Cleland JG, Gullestad L, Kjekshus J, van Veldhuisen DJ, Wikstrand J, Wedel H, McMurray JJ, Pocock SJ. Effect of rosuvastatin on repeat heart failure hospitalizations: the CORONA Trial (Controlled Rosuvastatin Multinational Trial in Heart Failure). JACC Heart Fail. 2014 Jun;2(3):289-97. doi: 10.1016/j.jchf.2013.12.007. Epub 2014 Apr 30. — View Citation

Shah P, Garris R, Abboud R, Vasudev R, Patel H, Doshi R, Shamoon F, Bikkina M. Meta-Analysis Comparing Usefulness of Beta Blockers to Preserve Left Ventricular Function During Anthracycline Therapy. Am J Cardiol. 2019 Sep 1;124(5):789-794. doi: 10.1016/j.amjcard.2019.05.046. Epub 2019 Jun 6. — View Citation

Smiseth OA, Edvardsen T, Skulstad H. Cardioprotection during chemotherapy: need for faster transfer of knowledge from cardiology to oncology and role for a cardio-oncologist. J Am Coll Cardiol. 2013 Jun 11;61(23):2363-4. doi: 10.1016/j.jacc.2013.02.073. Epub 2013 Apr 10. No abstract available. — View Citation

Spallarossa P, Guerrini M, Arboscello E, Sicbaldi V. Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction. J Am Coll Cardiol. 2013 Dec 24;62(25):2451-2452. doi: 10.1016/j.jacc.2013.07.077. Epub 2013 Sep 4. No abstract available. — View Citation

Sun X, Duan J, Gong C, Feng Y, Hu J, Gu R, Xu B. Colchicine Ameliorates Dilated Cardiomyopathy Via SIRT2-Mediated Suppression of NLRP3 Inflammasome Activation. J Am Heart Assoc. 2022 Jul 5;11(13):e025266. doi: 10.1161/JAHA.122.025266. Epub 2022 Jun 29. — View Citation

Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R, Lucci D, Nicolosi GL, Porcu M, Tognoni G; Gissi-HF Investigators. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet. 2008 Oct 4;372(9645):1231-9. doi: 10.1016/S0140-6736(08)61240-4. Epub 2008 Aug 29. — View Citation

van der Harst P, de Boer RA. Statins in the treatment of heart failure. Circ Heart Fail. 2010 May;3(3):462-4. doi: 10.1161/CIRCHEARTFAILURE.110.956342. No abstract available. — View Citation

Wittayanukorn S, Qian J, Westrick SC, Billor N, Johnson B, Hansen RA. Prevention of Trastuzumab and Anthracycline-induced Cardiotoxicity Using Angiotensin-converting Enzyme Inhibitors or beta-blockers in Older Adults With Breast Cancer. Am J Clin Oncol. 2018 Sep;41(9):909-918. doi: 10.1097/COC.0000000000000389. — View Citation

Zhang FS, He QZ, Qin CH, Little PJ, Weng JP, Xu SW. Therapeutic potential of colchicine in cardiovascular medicine: a pharmacological review. Acta Pharmacol Sin. 2022 Sep;43(9):2173-2190. doi: 10.1038/s41401-021-00835-w. Epub 2022 Jan 19. — View Citation

Zhang T, Chen W, Jiang X, Liu L, Wei K, Du H, Wang H, Li J. Anticancer effects and underlying mechanism of Colchicine on human gastric cancer cell lines in vitro and in vivo. Biosci Rep. 2019 Jan 15;39(1):BSR20181802. doi: 10.1042/BSR20181802. Print 2019 Jan 31. — View Citation

* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Chemotherapy-induced cardiomyopathy	An identification of a drop in the LVEF using echocardiography more than or equal to 10% from the baseline at the time of presentation and/or a decline of the LVEF less than 50%.	6 months
Primary	Chemotherapy-induced cardiomyopathy	An identification of at least one value of serum NT-proBNP over 125 pg/mL in patients less than 75 years of age, or 450pg/mL in patients more than 75 years of age.	6 months
Secondary	Major Adverse Cardiovascular Events	The non-fatal major cardiovascular adverse events include: Non-fatal myocardial infarction.; Non-fatal stroke.; Hospitalization due to unstable angina.; Hospitalization due to serious arrhythmias.; Hospitalization due to heart failure.	6 months
Secondary	All-Cause Mortality	Mortality	6 months