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

July 1, 2024 updated by: Watcharasak Chotiyaputta, Mahidol University

Gene-guided N-acetyl Cysteine for Prophylaxis of Anti-tuberculous Drug- Induced Hepatitis: A Randomized Controlled Trial

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Estimated)

116

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Thailand
    • Bangkok
      • Bangkok Noi, Bangkok, Thailand, 10700
        • Recruiting
        • Faculty of Medicine Siriraj Hospital, Mahidol University
        • Contact:
        • Contact:
        • Sub-Investigator:
          • Pongpot Namasae, MD
        • Principal Investigator:
          • Supot Nimanong, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

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).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 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.
Drug: N acetyl cysteine
1,200 mg/day for 8 weeks in NAT2 gene testing group and NAT2 gene phenotype is identified as slow acetylator.
Other Names:
  • Standard anti TB drug regimen
No Intervention: Non NAT2 gene testing
Tuberculosis patients will receive standard anti-tuberculosis medication without NAT2 gene testing.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Prevalence of hepatitis at 8 weeks
Time Frame: 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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Prevalence of hepatitis at 2 weeks
Time Frame: 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)
2 weeks

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Prevalence of hepatitis at 24 weeks
Time Frame: 24 weeks

To study the efficacy of administering N-acetylcysteine (NAC) to prevent drug-induced hepatitis at 24 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)
24 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Mahidol University

Investigators

  • Principal Investigator: Supot Nimanong, Mahidol University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 12, 2024

Primary Completion (Estimated)

September 18, 2024

Study Completion (Estimated)

September 18, 2024

Study Registration Dates

First Submitted

April 3, 2024

First Submitted That Met QC Criteria

July 1, 2024

First Posted (Actual)

July 3, 2024

Study Record Updates

Last Update Posted (Actual)

July 3, 2024

Last Update Submitted That Met QC Criteria

July 1, 2024

Last Verified

July 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Si 708/2023

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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