Isoniazid Dose Adjustment According to NAT2 Genotype (IDANAT2) - Full Text View

Sponsored by:	University of Cologne
Information provided by:	University of Cologne
ClinicalTrials.gov Identifier:	NCT00571753

Purpose

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.

Condition	Intervention	Phase
Pulmonary Tuberculosis	Drug: isoniazid	Phase III

MedlinePlus related topics: Tuberculosis

Drug Information available for: Isoniazid Ftivazide

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator), Active Control, Parallel Assignment, Safety/Efficacy Study
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

Further study details as provided by University of Cologne:

Primary Outcome Measures:

Incidence of hepatotoxicity defined by clinical chemistry parameters [ Time Frame: occurring up to week 8 of therapy ] [ Designated as safety issue: Yes ]
Incidence of early treatment failure, defined as continuous or recurrently positive sputum cultures [ Time Frame: occurring up to week 8 of therapy ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Further adverse events of isoniazid [ Time Frame: occurring up to week 24 of therapy ] [ Designated as safety issue: Yes ]
Late treatment failure, defined on the basis of radiological examination, i.e. lack of improvement in pulmonary radiograph [ Time Frame: after 24 weeks of therapy ] [ Designated as safety issue: No ]
Time course of sputum conversion [ Time Frame: up to week 24 of therapy ] [ Designated as safety issue: No ]

Estimated Enrollment:	900
Study Start Date:	June 2008
Estimated Study Completion Date:	January 2011
Estimated Primary Completion Date:	December 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Test: Experimental Isoniazid dose adapted according to NAT2 status i.e. appr. 2.5 mg/kg, 5 mg/kg and 7.5 mg/kg for slow, intermediate and rapid acetylators, respectively	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).
Control: Active Comparator Treatment with standard isoniazid dose (appr. 5 mg/kg b.w.)	Drug: isoniazid Treatment with a standard isoniazid dose of isoniazid (appr. 5 mg/kg b.w.)

Eligibility

Ages Eligible for Study:	18 Years to 75 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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).

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00571753

Sponsors and Collaborators

University of Cologne

Investigators

Principal Investigator:

Gerd Fätkenheuer, Prof. Dr. med.

Department I of Internal MedicineUniversity Hospital, University of Cologne

More Information

Responsible Party:	Institute of Pharmacology, University Hospital, University of Cologne, Germany ( University of Cologne, Sponsor representative: Prof. Dr. med. Uwe Fuhr )
Study ID Numbers:	IDANAT2, EUDRACT Number:2007-000224-41
Study First Received:	December 11, 2007
Last Updated:	June 2, 2008
ClinicalTrials.gov Identifier:	NCT00571753
Health Authority:	Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by University of Cologne:

pulmonary tuberculosis
NAT2 genotyping
hepatotoxicity of isoniazid

Study placed in the following topic categories:

Bacterial Infections
Gram-Positive Bacterial Infections
Respiratory Tract Infections
Respiratory Tract Diseases
Tuberculosis, pulmonary

Lung Diseases
Tuberculosis, Pulmonary
Mycobacterium Infections
Tuberculosis
Isoniazid

Additional relevant MeSH terms:

Antimetabolites
Anti-Infective Agents
Anti-Bacterial Agents
Molecular Mechanisms of Pharmacological Action
Therapeutic Uses

Antilipemic Agents
Antitubercular Agents
Pharmacologic Actions
Fatty Acid Synthesis Inhibitors
Actinomycetales Infections

ClinicalTrials.gov processed this record on January 13, 2009