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

NCT ID: NCT06484530

Last Updated: 2024-07-03

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 116 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-03-12
• Study Completion Date: 2024-09-18

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.

Detailed Description

Tuberculosis (TB) is a significant public health problem in Thailand and globally, especially in hot climates. TB infection is commonly found in the lungs, but it can also affect other important organs such as lymph nodes, pleura, abdomen, musculoskeletal system, urinary tract, and nervous system. The current standard treatment regimen for TB consists of a combination of drugs (isoniazid, rifampicin, pyrazinamide, and ethambutol), used for new TB patients who have not been treated before or have received less than 1 month of treatment. A major challenge in TB treatment is that patients must take multiple drugs continuously for at least 6 months, with common side effects including skin rash, dizziness, hepatitis, nausea, vomiting, and abdominal pain, often occurring within the first 2 months of treatment. Hepatotoxicity from anti-TB drugs is a common side effect, occurring in 20-60% of patients, mostly within the first 2 weeks to 2 months of starting treatment. Isoniazid, rifampicin, and pyrazinamide are the drugs most commonly associated with hepatotoxicity, typically causing hepatocellular injury of varying severity. NAT2 slow acetylator phenotype individuals are at higher risk. Studies in Thailand have found a high prevalence (25-30%) of NAT2 slow acetylators among Thai people. Preventing hepatotoxicity from anti-TB drugs is crucial, especially for high-risk patients, although clear guidelines are lacking. Previous studies have shown that administering N-acetylcysteine (NAC), an antioxidant, can reduce hepatotoxicity, particularly in slow acetylators. A recent controlled study by Kittichai Samaithongcharoen and colleagues demonstrated the significant efficacy of NAC in preventing hepatotoxicity in slow acetylators receiving standard TB treatment, with no cases of hepatotoxicity compared to a 50% incidence in the control group. Further research is needed to explore the effectiveness of NAC administration for preventing hepatotoxicity from anti-TB drugs, based on NAT2 genotype testing, compared to current standard TB 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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

NAT2 gene testing group

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.

Group Type: EXPERIMENTAL

N acetyl cysteine

Intervention Type: DRUG

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

Non NAT2 gene testing

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

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

N acetyl cysteine

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

Intervention Type: DRUG

Other Intervention Names

Standard anti TB drug regimen

Eligibility Criteria

Inclusion Criteria

• 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

Exclusion Criteria

• 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).

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Mahidol University

OTHER

Sponsor Role: lead

Responsible Party

Watcharasak Chotiyaputta

Associate professor, Faculty of Medicine, Siriraj

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Supot Nimanong

Role: PRINCIPAL_INVESTIGATOR

Mahidol University

Locations

Faculty of Medicine Siriraj Hospital, Mahidol University

Bangkok Noi, Bangkok, Thailand

Site Status: RECRUITING

Countries

Thailand

Central Contacts

Pongpot Namasae

Role: CONTACT

shy.pongpot@gmail.com

66954408520

Supot Nimanong

Role: CONTACT

supotgi@gmail.com

66819134336

Facility Contacts

Pongpot Namasae, MD

Role: primary

shy.pongpot@gmail.com

+66954408520

Supot Nimanong, MD

Role: backup

supotgi@gmail.com

+66819134336

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Other Identifiers

Si 708/2023

Identifier Type: -

Identifier Source: org_study_id