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

Phase 4

Recruiting

• Conditions: Tuberculosis (TB); Isoniazid Toxicity; Rifampicin Toxicity; Pyrazinamide Adverse Reaction; Ethambutol Toxicity; NAT2 Slow Acetylator Status; NAT2 Rapid Acetylator Status; NAT2 Polymorphism; N-Acetylcysteine
• Interventions: Drug: N acetyl cysteine

• Registration Number: NCT06484530
• Lead Sponsor: Mahidol University

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.

Study Timeline

• Study Start: 2024-03-12
• Study First Submitted: 2024-04-03
• Status Verified: 2024-07
• Study First Submitted QC: 2024-07-01
• Last Update Submitted: 2024-07-01
• Study First Posted: 2024-07-03
• Last Update Posted: 2024-07-03
• Primary Completion: 2024-09-18
• Study Completion: 2024-09-18

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 116

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

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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).

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
NAT2 gene testing group	N acetyl cysteine	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.

Primary Outcome Measures

Name	Time	Method
Prevalence of hepatitis at 8 weeks	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)

Secondary Outcome Measures

Name	Time	Method
Prevalence of hepatitis at 2 weeks	2 weeks	To study the efficacy of administering N-acetylcysteine (NAC) to prevent drug-induced hepatitis at 2 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)

Trial Locations

Locations (1)

Faculty of Medicine Siriraj Hospital, Mahidol University; 🇹🇭 Bangkok Noi, Bangkok, Thailand