N-Acetylcysteine Protection Against Radiation Induced Cellular Damage

Cardiac Arrhythmia Clinical Trial

— CARAPACE  

Official title:

Cardiac Arrhythmia Catheter Ablation Procedures Guided by x-Ray Imaging: N-Acetylcysteine Protection Against Radiation Induced Cellular damagE (CARAPACE Study)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04154982
• Other study ID #: CCM1006
• Status: Recruiting
• Phase: Phase 2
• Start date: September 2, 2020
• Est. completion date: December 1, 2024

Study information

• Verified date: August 2023
• Source: Centro Cardiologico Monzino
• Contact: Claudio Tondo
• Phone: +39025800
• Email: claudio.tondo[@]ccfm.it
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Catheter ablation procedures (CAPs) are first line treatment for a great variety of cardiac arrhythmias. CAPs require X-Ray imaging; consequently, CAPs cause ionizing radiation (IR) exposure for patients. Exposure to IR, even at low-doses, increases individual risk of developing cancer. IR cause DNA damage directly and, mostly, indirectly by formation of cellular free radicals. Furthermore different response to IR results from inherited variants in genes involved in DNA damage repair. N-acetylcysteine (NAC) is an aminoacid that can directly neutralize free radicals and increase antioxidant systems. Our preliminary data suggest that IR exposure in patients undergoing CAP deranges the oxidative stress status and the pre-procedure intravenous administration of NAC could decrease such abnormality.

Description:

CARAPACE is a prospective, randomized, single-blinded, parallel-arm monocenter study. Eligible patients undergoing CAP at the Arrhythmology Unit of Centro Cardiologico Monzino will be enrolled. The hypothesis driving our study, based on published literature and our preliminary data, is that administration of antioxidant agents, before cardiac procedures involving IR exposure, might prevent IR harmful effects on human tissues in terms of reduction of systemic oxidative stress status and, in parallel, of oxidative DNA damage. The antioxidant agent tested in our study is NAC. NAC is a well-tolerated and safe medication and it has antioxidant properties is based on three main mechanisms: 1) direct antioxidant effect, 2) glutathione (GSH) precursor action, and 3) its activity in breaking thiolated proteins. Another hypothesis to be tested is whether genes involved in DNA damage repair could explain the great variability in patient radiosensitivity to IR exposure and whether these genes could affect NAC protective/healing effects.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 550
• Est. completion date: December 1, 2024
• Est. primary completion date: December 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patient's age >18 years.
• Negative hCG pregnancy test (if appropriate).
• Indication to perform CAP guided by fluoroscopy (IR imaging).
• Ability and willingness to give informed consent and to comply with protocol.

Exclusion Criteria:

• Any contraindication to CAP (such as, pregnancy and breastfeeding).
• Hypersensitivity to the active substance or to any of the excipients.
• Enrollment in another study that may interfere with CARAPACE study.
• Administration of an experimental drug within 30 days or 5 half-lives of the investigational drug.
• Chronic kidney disease (serum creatinine >1.5 mg/dl).
• Acute/Chronic inflammatory disease.
• Antioxidant drugs intake over the previous 2 weeks.
• History of radiotherapy or chemotherapy in the last year.
• Any documented condition that, in PI's motivated judgement, makes the patient a poor candidate for the study.
• Computed tomography and/or coronary angiography within 5 days prior to baseline analysis.

Related Conditions & MeSH terms

• Arrhythmias, Cardiac
• Cardiac Arrhythmia

Intervention

Drug:
• Acetyl cysteine
1200 mg of NAC are intravenously administrated 1 hour prior to carrying out CAP.

Locations

Country	Name	City	State
Italy	Centro Cardiologico Monzino	Milano	MI

Sponsors (2)

Lead Sponsor	Collaborator
Centro Cardiologico Monzino	Ministry of Health, Italy

Country where clinical trial is conducted

Italy, 

References & Publications (15)

Aldini G, Altomare A, Baron G, Vistoli G, Carini M, Borsani L, Sergio F. N-Acetylcysteine as an antioxidant and disulphide breaking agent: the reasons why. Free Radic Res. 2018 Jul;52(7):751-762. doi: 10.1080/10715762.2018.1468564. Epub 2018 May 9. — View Citation

Amadio P, Colombo GI, Tarantino E, Gianellini S, Ieraci A, Brioschi M, Banfi C, Werba JP, Parolari A, Lee FS, Tremoli E, Barbieri SS. BDNFVal66met polymorphism: a potential bridge between depression and thrombosis. Eur Heart J. 2017 May 7;38(18):1426-1435. doi: 10.1093/eurheartj/ehv655. — View Citation

Andreassi MG, Foffa I, Manfredi S, Botto N, Cioppa A, Picano E. Genetic polymorphisms in XRCC1, OGG1, APE1 and XRCC3 DNA repair genes, ionizing radiation exposure and chromosomal DNA damage in interventional cardiologists. Mutat Res. 2009 Jun 18;666(1-2):57-63. doi: 10.1016/j.mrfmmm.2009.04.003. Epub 2009 Apr 22. — View Citation

Casella M, Dello Russo A, Russo E, Catto V, Pizzamiglio F, Zucchetti M, Majocchi B, Riva S, Vettor G, Dessanai MA, Fassini G, Moltrasio M, Tundo F, Vignati C, Conti S, Bonomi A, Carbucicchio C, Di Biase L, Natale A, Tondo C. X-Ray Exposure in Cardiac Electrophysiology: A Retrospective Analysis in 8150 Patients Over 7 Years of Activity in a Modern, Large-Volume Laboratory. J Am Heart Assoc. 2018 May 22;7(11):e008233. doi: 10.1161/JAHA.117.008233. — View Citation

Catto V, Stronati G, Porro B, Fiorelli S, Ricci V, Vavassori C, Russo E, Guerra F, Gasperetti A, Ribatti V, Sicuso R, Dello Russo A, Veglia F, Tondo C, Cavalca V, Colombo GI, Tremoli E, Casella M. Cardiac arrhythmia catheter ablation procedures guided by x-ray imaging: N-acetylcysteine protection against radiation-induced cellular damage (CARAPACE study): study design. J Interv Card Electrophysiol. 2021 Sep;61(3):577-582. doi: 10.1007/s10840-020-00853-4. Epub 2020 Aug 24. — View Citation

Cavalca V, Minardi F, Scurati S, Guidugli F, Squellerio I, Veglia F, Dainese L, Guarino A, Tremoli E, Caruso D. Simultaneous quantification of 8-iso-prostaglandin-F(2alpha) and 11-dehydro thromboxane B(2) in human urine by liquid chromatography-tandem mass spectrometry. Anal Biochem. 2010 Feb 15;397(2):168-74. doi: 10.1016/j.ab.2009.10.014. Epub 2009 Oct 13. — View Citation

Cervelli T, Panetta D, Navarra T, Gadhiri S, Salvadori P, Galli A, Caramella D, Basta G, Picano E, Del Turco S. A New Natural Antioxidant Mixture Protects against Oxidative and DNA Damage in Endothelial Cell Exposed to Low-Dose Irradiation. Oxid Med Cell Longev. 2017;2017:9085947. doi: 10.1155/2017/9085947. Epub 2017 Aug 9. — View Citation

Evans MD, Dizdaroglu M, Cooke MS. Oxidative DNA damage and disease: induction, repair and significance. Mutat Res. 2004 Sep;567(1):1-61. doi: 10.1016/j.mrrev.2003.11.001. — View Citation

Heidbuchel H, Wittkampf FH, Vano E, Ernst S, Schilling R, Picano E, Mont L, Jais P, de Bono J, Piorkowski C, Saad E, Femenia F. Practical ways to reduce radiation dose for patients and staff during device implantations and electrophysiological procedures. Europace. 2014 Jul;16(7):946-64. doi: 10.1093/europace/eut409. Epub 2014 May 2. — View Citation

Huang A, Glick SA. Genetic susceptibility to cutaneous radiation injury. Arch Dermatol Res. 2017 Jan;309(1):1-10. doi: 10.1007/s00403-016-1702-3. Epub 2016 Nov 22. — View Citation

Mu H, Sun J, Li L, Yin J, Hu N, Zhao W, Ding D, Yi L. Ionizing radiation exposure: hazards, prevention, and biomarker screening. Environ Sci Pollut Res Int. 2018 Jun;25(16):15294-15306. doi: 10.1007/s11356-018-2097-9. Epub 2018 Apr 29. — View Citation

Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007 Sep;81(3):559-75. doi: 10.1086/519795. Epub 2007 Jul 25. — View Citation

Squellerio I, Caruso D, Porro B, Veglia F, Tremoli E, Cavalca V. Direct glutathione quantification in human blood by LC-MS/MS: comparison with HPLC with electrochemical detection. J Pharm Biomed Anal. 2012 Dec;71:111-8. doi: 10.1016/j.jpba.2012.08.013. Epub 2012 Aug 23. — View Citation

Turnu L, Di Minno A, Porro B, Squellerio I, Bonomi A, Manega CM, Werba JP, Parolari A, Tremoli E, Cavalca V. Assessing Free-Radical-Mediated DNA Damage during Cardiac Surgery: 8-Oxo-7,8-dihydro-2'-deoxyguanosine as a Putative Biomarker. Oxid Med Cell Longev. 2017;2017:9715898. doi: 10.1155/2017/9715898. Epub 2017 Jun 4. — View Citation

Turnu L, Porro B, Alfieri V, Di Minno A, Russo E, Barbieri S, Bonomi A, Dello Russo A, Tondo C, D'Alessandra Y, Cavalca V, Tremoli E, Colombo GI, Casella M. Does Fluoroscopy Induce DNA Oxidative Damage in Patients Undergoing Catheter Ablation? Antioxid Redox Signal. 2018 Apr 20;28(12):1137-1143. doi: 10.1089/ars.2017.7334. Epub 2017 Nov 27. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Measurement of change in systemic oxidative stress (ratio between GSH oxidized form (GSSG) and GSH, 8-iso-prostaglandinF2a (8-iso-PGF2a) and 8-hydroxy-2-deoxyguanosine (8-OHdG)) and genomic DNA oxidative damage (percentage of DNA present in the tails).	Measurement of change in systemic oxidative stress (GSSG/GSH, 8-iso-PGF2a and 8-OHdG) and genomic DNA oxidative damage (% DNA present in the tails of the comet assay) between the two groups (NAC versus no NAC) at the different time-points (T0 = before CAP, T1 = 3h after CAP, T2 = 24h after CAP, T3 = 48h after CAP).	48 hours
Secondary	Measurement of change in systemic oxidative stress (GSSG/GSH, 8-iso-PGF2a and 8-OHdG) and genomic DNA oxidative damage (% DNA present in the tails) related to IR dose (fluoroscopy time (FT), Dose Area Product (DAP) and effective dose (ED)).	Measurement of change in systemic oxidative stress (GSSG/GSH, 8-iso-PGF2a and 8-OHdG) and genomic DNA oxidative damage (% DNA present in the tails) related to IR dose (FT, DAP and ED) between the two groups (NAC versus no NAC).	48 hours
Secondary	Measurement of change in genomic DNA oxidative damage (% DNA present in the tails) related to IR dose (FT, DAP and ED) and inherited variants in genes involved in DNA damage repair.	Measurement of change in genomic DNA oxidative damage (% DNA present in the tails) related to IR dose (FT, DAP and ED) and inherited variants in genes involved in DNA damage repair between the two groups (NAC versus no NAC).	48 hours
Secondary	Measurement of change in the response to NAC administration related to inherited variants in genes involved in DNA damage repair.		48 hours

External Links

•   Expert Consensus Document on Optimal Use of Ionizing Radiation in Cardiovascular Imaging
•   National Research Council. 2006. Health Risks from Exposure to Low Levels of Ionizing Radiation: BEIR VII Phase 2. Washington, DC: The National Academies Press.