Isoniazid Dose Adjustment According to NAT2 Genotype (IDANAT2)

NCT00571753 | Terminated Phase 3 DMC

• 2 other identifiers: IDANAT2EUDRACT Number:2007-000224-41
• Study Type: interventional
• Target: 900
• Locations: 3 countries
• Sites: 12

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.

Conditions

Pulmonary Tuberculosis

Keywords

pulmonary tuberculosis; NAT2 genotyping; hepatotoxicity of isoniazid

Outcome Measures

Primary Outcomes (1)

• Incidence of early treatment failure, defined as continuous or recurrently positive sputum cultures

  occurring up to week 8 of therapy

Secondary Outcomes (3)

• Further adverse events of isoniazid

  up to week 8 of therapy

• Time course of sputum conversion

  up to week 8 of therapy

• Duration of hospitalization

  up to week 8 of therapy

Study Arms (2)

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

Control

ACTIVE COMPARATOR

Treatment with standard isoniazid dose (appr. 5 mg/kg b.w.)

Drug: isoniazid

Interventions

isoniazid DRUG

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).

Test

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

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

Sponsors & Collaborators

• University of Cologne: lead

Study Sites (12)

Specialized Hospital for Active Treatment of Pulmonary Diseases "Sveta Sofia"

Sofia, 1431, Bulgaria

Location

Zentralkrankenhaus Bad Berka GmbH

Bad Berka, 99437, Germany

Location

Karl-Hansen-Klinik

Bad Lippspringe, 33175, Germany

Location

Helios Klinikum Emil von Behring GmbH

Berlin, 14165, Germany

Location

Department I of Internal Medicine, University Hospital, University of Cologne

Cologne, 50931, Germany

Location

Medizinische Klinik I, Abteilung Pneumologie/Allergologie, Universitätsklinikum Frankfurt am Main

Frankfurt am Main, 60590, Germany

Location

Abteilung Innere Medizin/ Pneumologie, Thoraxklinik am Universitätsklinikum Heidelberg

Heidelberg, 69126, Germany

Location

Lungenfachklinik Immenhausen

Immenhausen, 34376, Germany

Location

Diakoniekrankenhaus Rotenburg

Rotenburg (Wümme), 27356, Germany

Location

Division of Infectious Diseases and Clinical Immunology, Department of Internal Medicine

Ulm, 89081, Germany

Location

Specialized Hospital of Lung Diseases and Tuberculosis in Wielkopolska in Chodzież

Chodzież, 64-800, Poland

Location

Department of Pulmonal Diseases, K. Marcinkowski University of Medical Sciences

Poznan, 60-569, Poland

Location

MeSH Terms

Conditions

Tuberculosis, Pulmonary

Interventions

Isoniazid

Condition Hierarchy (Ancestors)

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring

Study Officials

• Gerd Fätkenheuer, Prof. Dr. med.

  Department I of Internal MedicineUniversity Hospital, University of Cologne

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: December 11, 2007
• First Posted: December 12, 2007
• Study Start: June 1, 2008
• Primary Completion: December 1, 2011
• Study Completion: February 1, 2012
• Last Updated: February 28, 2011

Record last verified: 2011-02

Locations

PL (2); DE (9); BU (1)