Isoniazid Dose Adjustment According to NAT2 Genotype (IDANAT2)

Pulmonary Tuberculosis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00571753
• Other study ID #: IDANAT2
• Secondary ID: EUDRACT Number:2
• Status: Terminated
• Phase: Phase 3
• First received: December 11, 2007
• Last updated: February 25, 2011
• Start date: June 2008
• Est. completion date: February 2012

Study information

• Verified date: February 2011
• Source: University of Cologne
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Federal Institute for Drugs and Medical Devices
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 900
• Est. completion date: February 2012
• Est. primary completion date: December 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

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).

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Pulmonary Tuberculosis
• Tuberculosis
• Tuberculosis, Pulmonary

Intervention

Drug:
• isoniazid
modified daily isoniazid dose according to NAT2 genotype (appr. 2.5 mg/kg, 5 mg/kg and 7.5 mg/kg for slow, intermediate and rapid acetylators, respectively).
• isoniazid
Treatment with a standard isoniazid dose of isoniazid (appr. 5 mg/kg b.w.)

Locations

Country	Name	City	State
Bulgaria	Specialized Hospital for Active Treatment of Pulmonary Diseases "Sveta Sofia"	Sofia
Germany	Zentralkrankenhaus Bad Berka GmbH	Bad Berka
Germany	Karl-Hansen-Klinik	Bad Lippspringe
Germany	Helios Klinikum Emil von Behring GmbH	Berlin
Germany	Medizinische Klinik I, Abteilung Pneumologie/Allergologie, Universitätsklinikum Frankfurt am Main	Frankfurt am Main
Germany	Abteilung Innere Medizin/ Pneumologie, Thoraxklinik am Universitätsklinikum Heidelberg	Heidelberg
Germany	Lungenfachklinik Immenhausen	Immenhausen
Germany	Department I of Internal Medicine, University Hospital, University of Cologne	Köln
Germany	Diakoniekrankenhaus Rotenburg	Rotenburg
Germany	Division of Infectious Diseases and Clinical Immunology, Department of Internal Medicine	Ulm
Poland	Specialized Hospital of Lung Diseases and Tuberculosis in Wielkopolska in Chodziez	Chodziez
Poland	Department of Pulmonal Diseases, K. Marcinkowski University of Medical Sciences	Poznan

Sponsors (1)

Lead Sponsor	Collaborator
University of Cologne

Countries where clinical trial is conducted

Bulgaria,  Germany,  Poland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of early treatment failure, defined as continuous or recurrently positive sputum cultures		occurring up to week 8 of therapy	No
Secondary	Further adverse events of isoniazid		up to week 8 of therapy	Yes
Secondary	Time course of sputum conversion		up to week 8 of therapy	No
Secondary	Duration of hospitalization		up to week 8 of therapy	No