Isoniazid Dose Adjustment According to NAT2 Genotype (IDANAT2)

A Double-blind, Multicentre, Parallel Group, Randomised, Controlled Trial to Evaluate the Possible Benefit of Isoniazid Dose Adjustment According to the Genotype for NAT2 (Arylamine N-acetyltransferase Type 2) in Patients With Pulmonary Tuberculosis

The study is conducted to compare safety and efficacy of isoniazid administered as an adjusted dose based on NAT2 (arylamine N-acetyltransferase type 2)genotype and as a standard dose.

The hypothesis is that the genotype-adjusted dose is superior to the standard dose with regard to hepatotoxicity and early treatment failure, respectively, in the group of slow and rapid acetylators of NAT2.

Inclusion Criteria:

• Patient is informed and given ample time and opportunity to think about her/his participation and has given her/his written informed consent
• Patient is willing and able to comply with all trial requirements, inclusive genotyping procedure
• Patient is between 18 and 75 years of age (inclusive) during the whole trial, male or female
• Patient has newly diagnosed pulmonary tuberculosis for whom daily antituberculosis therapy is indicated
• Patient has a smear-positive sputum
• Patient has radiological evidence of a pulmonary infiltrate.

Exclusion Criteria:

• Patients with known contraindications for isoniazid: acute hepatitis, macroscopic hematuria, allergy to isoniazid, peripheral neuritis, coagulopathy, severe haemorrhagic diathesis, seizure disorders, psychosis

• Patients with advanced or unstable chronic liver disease which is confirmed on results of biochemical or serological tests by eligibility assessment (relevant abnormalities of the following liver tests: ALT, AST, AP, total and conjugated bilirubin; positive serology for hepatitis), if the assessed risk-benefit ratio for the participation in the study is unfavourable (inclusion upon a decision of clinical investigator)

• Patients with a severe, life-threatening disease with a life expectancy of less than 2 years

• Patients known to have AIDS (CD4+ count <200/ml) or HIV-seropositive patients who are receiving HAART (highly active antiretroviral therapy). Note: HIV-positive patients may be included

• Patients with diabetes mellitus

• Patients with renal insufficiency (creatinine clearance < 30mL / min / 1.73m2) and patients on hemodialysis

• Patients with any other clinical conditions suggesting that he/she should not be included (decision of the clinical investigator)

• Patients with chronic infections requiring concomitant systemic antibacterial agents that are also active against M. tuberculosis (i.e. fluoroquinolones, aminoglycosides, macrolides)

• Patients with intake of systemic antibacterial agents that are also active against M. tuberculosis (i.e. fluoroquinolones, aminoglycosides, macrolides) within 4 weeks prior to antituberculosis treatment

• Patients who have ever received antituberculosis chemotherapy

• Patients who take any hepatotoxic agent on regular basis or have taken it within 3 month before study onset

• Patients with known drug / continuous severe alcohol abuse (drinking more than 60 g alcohol daily)

• Patients who participate in other interventional clinical studies;

• Female patients who are pregnant or lactating;

• Female patients not willing and capable to use two different contraceptive methods throughout the study, e.g. double barrier methods (e.g. diaphragm and condom by the partner, intrauterine devise and condom, sponge and condom, spermicide and condom). Acceptable alternatives of effective contraception are also sexual abstinence or vasectomized partner. In contrast, oral contraceptives are not recommended, since the effectiveness of them may be reduced due to a possible interaction with rifampicin

• Patients who are placed in a closed institution as a result of a court or any other authorities' decision

• Patients who are known or suspected not to comply with the study directives and/or known or suspected not to be reliable or trustworthy

• Patients who are known or suspected not to be capable of understanding and evaluating the information that is given to them as part of the formal information policy (informed consent), in particular regarding the foreseeable risks to which they will be exposed.

• Patients with any of followings will not be included into evaluation for efficacy:

  • Infection with Mycobacterium avium complex
  • Resistance of M. tuberculosis to isoniazid at the first screening test (initial culture).