Clinical trial NCT06484530: Gene-guided N-acetyl Cysteine for Prophylaxis of Anti-tuberculous Drug- Induced Hepatitis
Official title: Gene-guided N-acetyl Cysteine for Prophylaxis of Anti-tuberculous Drug- Induced Hepatitis: A Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
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
Lead sponsor: Mahidol University
Sponsor class: OTHER
First posted: 2024-07-03
Enrollment: 116
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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.
Primary purpose: PREVENTION

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.

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).

Primary outcomes:
measure: Prevalence of hepatitis at 8 weeks
timeFrame: 8 weeks
Secondary outcomes:
measure: Prevalence of hepatitis at 2 weeks
timeFrame: 2 weeks
Other outcomes:
measure: Prevalence of hepatitis at 24 weeks
timeFrame: 24 weeks
Locations:
city: Bangkok Noi
country: Thailand
facility: Faculty of Medicine Siriraj Hospital, Mahidol University
state: Bangkok
Study officials:
affiliation: Mahidol University
name: Supot Nimanong
role: PRINCIPAL_INVESTIGATOR
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