Isoniazid Dose Adjustment According to NAT2 Genotype (IDANAT2)
Primary Purpose
Pulmonary Tuberculosis
Status
Terminated
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
isoniazid
isoniazid
Sponsored by
About this trial
This is an interventional treatment trial for Pulmonary Tuberculosis focused on measuring pulmonary tuberculosis, NAT2 genotyping, hepatotoxicity of isoniazid
Eligibility 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).
Sites / Locations
- Specialized Hospital for Active Treatment of Pulmonary Diseases "Sveta Sofia"
- Zentralkrankenhaus Bad Berka GmbH
- Karl-Hansen-Klinik
- Helios Klinikum Emil von Behring GmbH
- Medizinische Klinik I, Abteilung Pneumologie/Allergologie, Universitätsklinikum Frankfurt am Main
- Abteilung Innere Medizin/ Pneumologie, Thoraxklinik am Universitätsklinikum Heidelberg
- Lungenfachklinik Immenhausen
- Department I of Internal Medicine, University Hospital, University of Cologne
- Diakoniekrankenhaus Rotenburg
- Division of Infectious Diseases and Clinical Immunology, Department of Internal Medicine
- Specialized Hospital of Lung Diseases and Tuberculosis in Wielkopolska in Chodzież
- Department of Pulmonal Diseases, K. Marcinkowski University of Medical Sciences
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Test
Control
Arm Description
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
Treatment with standard isoniazid dose (appr. 5 mg/kg b.w.)
Outcomes
Primary Outcome Measures
Incidence of early treatment failure, defined as continuous or recurrently positive sputum cultures
Secondary Outcome Measures
Further adverse events of isoniazid
Time course of sputum conversion
Duration of hospitalization
Full Information
NCT ID
NCT00571753
First Posted
December 11, 2007
Last Updated
February 25, 2011
Sponsor
University of Cologne
1. Study Identification
Unique Protocol Identification Number
NCT00571753
Brief Title
Isoniazid Dose Adjustment According to NAT2 Genotype (IDANAT2)
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
Study Type
Interventional
2. Study Status
Record Verification Date
February 2011
Overall Recruitment Status
Terminated
Why Stopped
Enrolling participants has halted prematurely due to a low recruitment rate.
Study Start Date
June 2008 (undefined)
Primary Completion Date
December 2011 (Anticipated)
Study Completion Date
February 2012 (Anticipated)
3. Sponsor/Collaborators
Name of the Sponsor
University of Cologne
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pulmonary Tuberculosis
Keywords
pulmonary tuberculosis, NAT2 genotyping, hepatotoxicity of isoniazid
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
900 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Test
Arm Type
Experimental
Arm Description
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
Arm Title
Control
Arm Type
Active Comparator
Arm Description
Treatment with standard isoniazid dose (appr. 5 mg/kg b.w.)
Intervention Type
Drug
Intervention Name(s)
isoniazid
Intervention Description
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).
Intervention Type
Drug
Intervention Name(s)
isoniazid
Intervention Description
Treatment with a standard isoniazid dose of isoniazid (appr. 5 mg/kg b.w.)
Primary Outcome Measure Information:
Title
Incidence of early treatment failure, defined as continuous or recurrently positive sputum cultures
Time Frame
occurring up to week 8 of therapy
Secondary Outcome Measure Information:
Title
Further adverse events of isoniazid
Time Frame
up to week 8 of therapy
Title
Time course of sputum conversion
Time Frame
up to week 8 of therapy
Title
Duration of hospitalization
Time Frame
up to week 8 of therapy
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility 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).
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Gerd Fätkenheuer, Prof. Dr. med.
Organizational Affiliation
Department I of Internal MedicineUniversity Hospital, University of Cologne
Official's Role
Principal Investigator
Facility Information:
Facility Name
Specialized Hospital for Active Treatment of Pulmonary Diseases "Sveta Sofia"
City
Sofia
ZIP/Postal Code
1431
Country
Bulgaria
Facility Name
Zentralkrankenhaus Bad Berka GmbH
City
Bad Berka
ZIP/Postal Code
99437
Country
Germany
Facility Name
Karl-Hansen-Klinik
City
Bad Lippspringe
ZIP/Postal Code
33175
Country
Germany
Facility Name
Helios Klinikum Emil von Behring GmbH
City
Berlin
ZIP/Postal Code
14165
Country
Germany
Facility Name
Medizinische Klinik I, Abteilung Pneumologie/Allergologie, Universitätsklinikum Frankfurt am Main
City
Frankfurt am Main
ZIP/Postal Code
60590
Country
Germany
Facility Name
Abteilung Innere Medizin/ Pneumologie, Thoraxklinik am Universitätsklinikum Heidelberg
City
Heidelberg
ZIP/Postal Code
69126
Country
Germany
Facility Name
Lungenfachklinik Immenhausen
City
Immenhausen
ZIP/Postal Code
34376
Country
Germany
Facility Name
Department I of Internal Medicine, University Hospital, University of Cologne
City
Köln
ZIP/Postal Code
50931
Country
Germany
Facility Name
Diakoniekrankenhaus Rotenburg
City
Rotenburg
ZIP/Postal Code
27356
Country
Germany
Facility Name
Division of Infectious Diseases and Clinical Immunology, Department of Internal Medicine
City
Ulm
ZIP/Postal Code
89081
Country
Germany
Facility Name
Specialized Hospital of Lung Diseases and Tuberculosis in Wielkopolska in Chodzież
City
Chodzież
ZIP/Postal Code
64-800
Country
Poland
Facility Name
Department of Pulmonal Diseases, K. Marcinkowski University of Medical Sciences
City
Poznan
ZIP/Postal Code
60-569
Country
Poland
12. IPD Sharing Statement
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Isoniazid Dose Adjustment According to NAT2 Genotype (IDANAT2)
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