Gene-guided N-acetyl Cysteine for Prophylaxis of Anti-tuberculous Drug- Induced Hepatitis

NCT06484530 | Recruiting Phase 4 DMC

• 1 other identifier: Si 708/2023
• Study Type: interventional
• Target: 116
• Locations: 1 country
• Sites: 1

Brief Summary

Tuberculosis (TB) remains a significant public health concern in Thailand and globally, especially in tropical regions, with pulmonary TB being predominant. Besides affecting the lungs, TB can also impact extrapulmonary organs. Standard TB treatment involves a combination of drugs administered for at least 6 months, but it can cause adverse effects such as hepatitis. Hepatotoxicity, occurring in 20-60% of patients, is commonly linked to isoniazid, rifampicin, and pyrazinamide. Slow acetylators of the NAT2 gene are particularly susceptible. Previous research suggests N-acetylcysteine (NAC) may mitigate hepatotoxicity, especially among slow acetylators. A recent study by Kittichai Samaithongcharoen and team showed that NAC reduced hepatotoxicity incidence significantly among slow acetylators. This underscores the potential of NAC in preventing drug-induced hepatotoxicity in TB treatment, warranting further investigation against standard treatment protocols.

Conditions

Tuberculosis (TB); Isoniazid Toxicity; Rifampicin Toxicity; Pyrazinamide Adverse Reaction; Ethambutol Toxicity; NAT2 Slow Acetylator Status; NAT2 Rapid Acetylator Status; NAT2 Polymorphism; N-Acetylcysteine

Keywords

Tuberculosis (TB); Isoniazid Toxicity; Rifampicin Toxicity; Pyrazinamide Adverse Reaction; Ethambutol Toxicity; NAT2 Slow Acetylator Status; NAT2 Rapid Acetylator Status; NAT2 Polymorphism; N-Acetylcysteine

Outcome Measures

Primary Outcomes (1)

• Prevalence of hepatitis at 8 weeks

  To study the efficacy of administering N-acetylcysteine (NAC) to prevent drug-induced hepatitis at 8 weeks from anti-tuberculosis medication using gene-guided therapy compared to conventional therapy. Significant hepatitis was defined as elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) more than 5 times of baseline levels or Total bilirubin(TB) more than 2.5 milligrams per decilitre (mg/dL)

  8 weeks

Secondary Outcomes (1)

• Prevalence of hepatitis at 2 weeks

  2 weeks

Other Outcomes (1)

• Prevalence of hepatitis at 24 weeks

  24 weeks

Study Arms (2)

NAT2 gene testing group

EXPERIMENTAL

Tuberculosis patients will undergo NAT2 gene testing before starting anti-tuberculosis medication. If the NAT2 gene phenotype is identified as slow acetylator, the patient will receive NAC medication at a dose of 600 mg twice daily for 8 weeks in addition to anti-tuberculosis medication. If the NAT2 gene phenotype is identified as rapid or intermediate acetylator, the patient will receive only anti-tuberculosis medication.

Drug: N acetyl cysteine

Non NAT2 gene testing

NO INTERVENTION

Tuberculosis patients will receive standard anti-tuberculosis medication without NAT2 gene testing.

Interventions

N acetyl cysteine DRUG

1,200 mg/day for 8 weeks in NAT2 gene testing group and NAT2 gene phenotype is identified as slow acetylator.

Also known as: Standard anti TB drug regimen

NAT2 gene testing group

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients aged 18 - 80 years old.
• Newly diagnosed tuberculosis patients (both pulmonary and extrapulmonary).
• Received standard anti-tuberculosis medication according to standard regimens (2HRZE/4HR, 2HRE/7HR).
• Willing to participate in the research

You may not qualify if:

• Infected with HIV.
• Severe liver dysfunction classified as Child-Pugh B or C.
• Chronic untreated liver diseases such as hepatitis B or C, alcoholic liver disease.
• Abnormal liver function tests including AST \> 1.5 times the upper limit of normal (48 U/L), ALT \> 1.5 times the upper limit of normal (55 U/L), ALP \> upper limit of normal (110 U/L), Total bilirubin \> upper limit of normal (1.2 mg/dL).
• Diagnosed with cancer.
• History of allergy to N-acetylcysteine (NAC).
• Pregnant or breastfeeding.
• Severe comorbidities such as CKD stage 4-5, chronic heart failure, severe pulmonary diseases (COPD, bronchiectasis).

Sponsors & Collaborators

• Mahidol University: lead

Study Sites (1)

Faculty of Medicine Siriraj Hospital, Mahidol University

Bangkok Noi, Bangkok, 10700, Thailand

RECRUITING

Related Publications (15)

• Palwatwichai A. Tuberculosis in Thailand. Respirology. 2001 Mar;6(1):65-70. doi: 10.1046/j.1440-1843.2001.00299.x.

  PMID: 11264766 BACKGROUND

• Treatment of Tuberculosis: Guidelines. 4th edition. Geneva: World Health Organization; 2010. Available from http://www.ncbi.nlm.nih.gov/books/NBK138748/

  PMID: 23741786 BACKGROUND

• Wiwatworapan T, Anantasetagoon T. Extra-pulmonary tuberculosis at a regional hospital in Thailand. Southeast Asian J Trop Med Public Health. 2008 May;39(3):521-5.

  PMID: 18564694 BACKGROUND

• Bouazzi OE, Hammi S, Bourkadi JE, Tebaa A, Tanani DS, Soulaymani-Bencheikh R, Badrane N, Bengueddour R. First line anti-tuberculosis induced hepatotoxicity: incidence and risk factors. Pan Afr Med J. 2016 Nov 16;25:167. doi: 10.11604/pamj.2016.25.167.10060. eCollection 2016.

  PMID: 28292129 BACKGROUND

• Anand AC, Seth AK, Paul M, Puri P. Risk Factors of Hepatotoxicity During Anti-tuberculosis Treatment. Med J Armed Forces India. 2006 Jan;62(1):45-9. doi: 10.1016/S0377-1237(06)80155-3. Epub 2011 Jul 21.

  PMID: 27407844 BACKGROUND

• Gaude GS, Chaudhury A, Hattiholi J. Drug-induced hepatitis and the risk factors for liver injury in pulmonary tuberculosis patients. J Family Med Prim Care. 2015 Apr-Jun;4(2):238-43. doi: 10.4103/2249-4863.154661.

  PMID: 25949974 BACKGROUND

• Ramappa V, Aithal GP. Hepatotoxicity Related to Anti-tuberculosis Drugs: Mechanisms and Management. J Clin Exp Hepatol. 2013 Mar;3(1):37-49. doi: 10.1016/j.jceh.2012.12.001. Epub 2012 Dec 20.

  PMID: 25755470 BACKGROUND

• Ostapowicz G, Fontana RJ, Schiodt FV, Larson A, Davern TJ, Han SH, McCashland TM, Shakil AO, Hay JE, Hynan L, Crippin JS, Blei AT, Samuel G, Reisch J, Lee WM; U.S. Acute Liver Failure Study Group. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med. 2002 Dec 17;137(12):947-54. doi: 10.7326/0003-4819-137-12-200212170-00007.

  PMID: 12484709 BACKGROUND

• Fountain FF, Tolley E, Chrisman CR, Self TH. Isoniazid hepatotoxicity associated with treatment of latent tuberculosis infection: a 7-year evaluation from a public health tuberculosis clinic. Chest. 2005 Jul;128(1):116-23. doi: 10.1378/chest.128.1.116.

  PMID: 16002924 BACKGROUND

• Kopanoff DE, Snider DE Jr, Caras GJ. Isoniazid-related hepatitis: a U.S. Public Health Service cooperative surveillance study. Am Rev Respir Dis. 1978 Jun;117(6):991-1001. doi: 10.1164/arrd.1978.117.6.991.

  PMID: 666111 BACKGROUND

• International Union Against Tuberculosis Committee on Prophylaxis. Efficacy of various durations of isoniazid preventive therapy for tuberculosis: five years of follow-up in the IUAT trial. International Union Against Tuberculosis Committee on Prophylaxis. Bull World Health Organ. 1982;60(4):555-64.

  PMID: 6754120 BACKGROUND

• Steele MA, Burk RF, DesPrez RM. Toxic hepatitis with isoniazid and rifampin. A meta-analysis. Chest. 1991 Feb;99(2):465-71. doi: 10.1378/chest.99.2.465. No abstract available.

  PMID: 1824929 BACKGROUND

• Thongraung W, Sittidach M, Khwansuwan P, Sariyasuntorn K, Wongsampan S. Evaluation of the physicians' approach to the diagnosis and treatment of patients with antituberculosis drug-induced hepatotoxicity. J Eval Clin Pract. 2012 Dec;18(6):1119-25. doi: 10.1111/j.1365-2753.2011.01706.x. Epub 2011 Jun 22.

  PMID: 21696520 BACKGROUND

• Huang YS, Chern HD, Su WJ, Wu JC, Lai SL, Yang SY, Chang FY, Lee SD. Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatitis. Hepatology. 2002 Apr;35(4):883-9. doi: 10.1053/jhep.2002.32102.

  PMID: 11915035 BACKGROUND

• Yang S, Hwang SJ, Park JY, Chung EK, Lee JI. Association of genetic polymorphisms of CYP2E1, NAT2, GST and SLCO1B1 with the risk of anti-tuberculosis drug-induced liver injury: a systematic review and meta-analysis. BMJ Open. 2019 Aug 1;9(8):e027940. doi: 10.1136/bmjopen-2018-027940.

  PMID: 31375612 BACKGROUND

MeSH Terms

Conditions

Tuberculosis

Interventions

Acetylcysteine

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Cysteine; Amino Acids, Sulfur; Sulfur Compounds; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins

Study Officials

• Supot Nimanong

  Mahidol University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Pongpot Namasae

CONTACT

66954408520; shy.pongpot@gmail.com

Supot Nimanong

CONTACT

66819134336; supotgi@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate professor, Faculty of Medicine, Siriraj

Model Details: Patients with tuberculosis who meet the research criteria will be randomly assigned into 2 groups using a block of four method with a 1:1 ratio. Patients in group 1 will undergo NAT2 gene testing before starting anti-tuberculosis medication. If the NAT2 gene phenotype is identified as slow acetylator, the patient will receive NAC medication at a dose of 600 mg twice daily for 8 weeks in addition to anti-tuberculosis medication. If the NAT2 gene phenotype is identified as rapid or intermediate acetylator, the patient will receive only anti-tuberculosis medication. Patients in group 2 will receive standard anti-tuberculosis medication without NAT2 gene testing.All patients will undergo blood tests to monitor liver function, kidney function, and blood count at 2, 8 weeks, and 6 months after starting medication.

Study Record Dates

• First Submitted: April 3, 2024
• First Posted: July 3, 2024
• Study Start: March 12, 2024
• Primary Completion: September 18, 2024
• Study Completion: September 18, 2024
• Last Updated: July 3, 2024

Record last verified: 2024-07

Locations

TH (1)