Isoniazid Dose Adjustment According to NAT2 Genotype (IDANAT2)

This study has been terminated.
(Enrolling participants has halted prematurely due to a low recruitment rate.)
Sponsor:
Information provided by:
University of Cologne
ClinicalTrials.gov Identifier:
NCT00571753
First received: December 11, 2007
Last updated: February 25, 2011
Last verified: February 2011
  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 3

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

Resource links provided by NLM:


Further study details as provided by University of Cologne:

Primary Outcome Measures:
  • 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: up to week 8 of therapy ] [ Designated as safety issue: Yes ]
  • Time course of sputum conversion [ Time Frame: up to week 8 of therapy ] [ Designated as safety issue: No ]
  • Duration of hospitalization [ Time Frame: up to week 8 of therapy ] [ Designated as safety issue: No ]

Estimated Enrollment: 900
Study Start Date: June 2008
Estimated Study Completion Date: February 2012
Estimated Primary Completion Date: December 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Test
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).
Active Comparator: Control
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

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

Locations
Bulgaria
Specialized Hospital for Active Treatment of Pulmonary Diseases "Sveta Sofia"
Sofia, Bulgaria, 1431
Germany
Zentralkrankenhaus Bad Berka GmbH
Bad Berka, Germany, 99437
Karl-Hansen-Klinik
Bad Lippspringe, Germany, 33175
Helios Klinikum Emil von Behring GmbH
Berlin, Germany, 14165
Medizinische Klinik I, Abteilung Pneumologie/Allergologie, Universitätsklinikum Frankfurt am Main
Frankfurt am Main, Germany, 60590
Abteilung Innere Medizin/ Pneumologie, Thoraxklinik am Universitätsklinikum Heidelberg
Heidelberg, Germany, 69126
Lungenfachklinik Immenhausen
Immenhausen, Germany, 34376
Department I of Internal Medicine, University Hospital, University of Cologne
Köln, Germany, 50931
Diakoniekrankenhaus Rotenburg
Rotenburg, Germany, 27356
Division of Infectious Diseases and Clinical Immunology, Department of Internal Medicine
Ulm, Germany, 89081
Poland
Specialized Hospital of Lung Diseases and Tuberculosis in Wielkopolska in Chodzież
Chodzież, Poland, 64-800
Department of Pulmonal Diseases, K. Marcinkowski University of Medical Sciences
Poznan, Poland, 60-569
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

No publications provided

Responsible Party: University of Cologne, Sponsor representative: Prof. Dr. med. Uwe Fuhr, Institute of Pharmacology, University Hospital, University of Cologne, Germany
ClinicalTrials.gov Identifier: NCT00571753     History of Changes
Other Study ID Numbers: IDANAT2, EUDRACT Number:2007-000224-41
Study First Received: December 11, 2007
Last Updated: February 25, 2011
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by University of Cologne:
pulmonary tuberculosis
NAT2 genotyping
hepatotoxicity of isoniazid

Additional relevant MeSH terms:
Tuberculosis
Tuberculosis, Pulmonary
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Isoniazid
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Fatty Acid Synthesis Inhibitors
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents

ClinicalTrials.gov processed this record on September 16, 2014