TBTC Study 24: Intermittent Treatment of TB With Isoniazid Resistance or Intolerance

Tuberculosis Clinical Trial

Official title:

TBTC Study 24: A Non-Comparative Study of the Efficacy of a Largely-Intermittent, Six-Month Tuberculosis Treatment Regimen Among Patients Who Will Not Receive Isoniazid Due to Initial Isoniazid Resistance or Intolerance

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00023374
• Other study ID #: CDC-NCHSTP-2340
• Secondary ID: 24
• Status: Completed
• Phase: N/A
• First received: September 6, 2001
• Last updated: August 2, 2011
• Start date: August 2000
• Est. completion date: December 2010

Study information

• Verified date: June 2011
• Source: Centers for Disease Control and Prevention
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial Summary

This study is a prospective, open-label, nonrandomized trial using a largely-intermittent, six-month tuberculosis treatment regimen among patients who will not receive isoniazid due to the presence of initial isoniazid resistance or intolerance. Subjects are enrolled after resistance or intolerance to isoniazid has been documented, and are treated for a total of six months (nine months if baseline chest x-ray shows cavitation and 2-month sputum culture is positive) with twice weekly or thrice weekly rifampin, ethambutol, and pyrazinamide.

Description:

Primary Objective:

To evaluate the efficacy of a directly-observed, largely-intermittent, six-month regimen of rifampin, pyrazinamide, ethambutol among patients with culture confirmed isoniazid-resistant M. tuberculosis.

Secondary Objectives:

To describe the rate, severity and timing of toxicities and drug intolerances associated with this treatment regimen.

To describe the utility of this regimen among patients who are unable to continue the standard 4-drug regimen due to the development of intolerance to isoniazid

Recruitment information / eligibility

• Status: Completed
• Enrollment: 98
• Est. completion date: December 2010
• Est. primary completion date: December 2006
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion criteria:

1. Culture-confirmed pulmonary or extrapulmonary tuberculosis due to a strain of M tuberculosis sensitive to rifampin, ethambutol and pyrazinamide based upon specimens (sputum or other pulmonary or extrapulmonary disease site specimens) collected no more than 8 weeks before and no more than 2 weeks after the start of the initial therapy. Susceptibility testing results documenting susceptibility to rifampin and ethambutol must be available at the time of enrollment. Susceptibility results to pyrazinamide may be pending at enrollment as long as pyrazinamide resistance is not known to be present based on prior testing. If pyrazinamide resistance is detected and confirmed (see Study Definitions) the patient will be withdrawn from the study therapy, treatment continued as recommended by the treating physician, and follow-up continued as per the protocol.

2. Decision to discontinue or not use isoniazid for one or both of these following conditions within the first 70 days of therapy:

• Isoniazid resistant strain (growth in 0.2 mcg/ml or 0.1 mcg/ml of isoniazid on solid or liquid media, respectively)

• The discontinuation of isoniazid due to intolerance (as judged by the principal investigator - see Study Definitions)

3. For patients enrolled after the start of therapy, documentation of adequate initial regimen as recommended in the CDC/ATS Treatment Guidelines (Appendix 1) is required. There are two means by which this requirement can be met:

• The standard 4-drug regimen of isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin or both.

• The same regimen with isoniazid excluded for some or all doses in patients with known isoniazid intolerance or tuberculosis due to an isoniazid-resistant strain (i.e., the 3-drug regimen of rifampin, pyrazinamide and either ethambutol or streptomycin or both)

4. A minimum duration of daily treatment as defined by one of two methods:

• 14 daily doses within 17 days (with at least 10 of the 14 doses directly observed)

• 14 directly observed doses within 23 days

Following the minimum daily phase of therapy, adequate pre-enrollment treatment is defined as directly administered therapy given daily, twice weekly, or thrice weekly using CDC/ATS guidelines. Documenting pre-enrollment therapy is accomplished by hospital medical records and/or clinic entries of DOT.

5. Age: 18 years or older

6. Documentation of negative test for human immunodeficiency virus (HIV) infection. Documentation means written copies of HIV laboratory test results. A negative HIV test result within the 6 months prior to enrollment is acceptable.

7. Documentation of study baseline laboratory parameters. Baseline laboratory parameters obtained no more than 2 weeks prior to enrollment and must be within the following limits:

1. . Amino aspartate transferase (AST) activity less than 3 times upper limit of normal;

2. . Total bilirubin level less than 2.5 times upper limit of normal;

3. . Creatinine level less than 2 times upper limit of normal;

4. . Hemoglobin level of at least 7.0 g/dL;

5. . Platelet count of at least 50,000 mm3

8. Karnofsky score of at least 60. See Appendix 6 for Karnofsky scoring system.

9. A negative pregnancy test within the past 14 days for women with child-bearing potential, and a willingness to practice an adequate (preferably barrier) method of birth control. In addition, women with child-bearing potential should be offered information concerning sources of contraceptive counseling and services.

10. Informed consent signed by patient and investigator documenting the willingness to use the 3-drug, intermittent regimen is required, in accordance with state law and local IRB requirements. Patients who are unable to provide informed consent due to an inability to comprehend English may be enrolled by providing informed consent by either of two means:

• the use of a translator to provide a verbal translation of the IRB-approved English version of the consent form; the translator will sign the English form attesting the translation and the patient will sign the IRB-approved translation of the short form

• the use of a translated consent document, approved by the IRB, that is in the patient's native language.

Exclusion criteria

1. Patients with known treatment-limiting reaction to rifamycins, pyrazinamide, or ethambutol.

2. Diagnosis of silicotuberculosis or tuberculosis of the central nervous system

3. Patients who, during initial therapy with CDC/ATS recommended therapy with isoniazid, rifampin and pyrazinamide plus either ethambutol or streptomycin or both, have received greater than 21 days of treatment with additional drugs with known antituberculosis activity - see Concomitant Medications During Study Phase Therapy.

4. Patients with isoniazid intolerance or isoniazid-resistant tuberculosis who during pre-enrollment therapy have missed a total of two weeks of directly observed therapy doses due to non-compliance.

5. Patients enrolled due to isoniazid intolerance who during pre-enrollment therapy have missed a total of over 4 weeks of directly observed therapy doses for management of drug intolerance.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Tuberculosis

Intervention

Drug:
• Rifampin
6mos REZ intermittent
• Pyrazinamide
6mos REZ intermittent
• Ethambutol
6mos REZ intermittent
• REZ
Rif+PZA+EMB given 2 or 3 times weekly for 6 months

Locations

Country	Name	City	State
Canada	Montreal Chest Institute McGill University	Montreal	Quebec
Canada	University of British Columbia	Vancouver	British Columbia
Canada	University of Manitoba	Winnipeg	Manitoba
United States	Johns Hopkins University School of Medicine	Baltimore	Maryland
United States	Boston Medical Center	Boston	Massachusetts
United States	Carolinas Medical Center	Charlotte	North Carolina
United States	Chicago VA Medical Center (Lakeside)	Chicago	Illinois
United States	Denver Department of Public Health and Hospitals	Denver	Colorado
United States	Duke University Medical Center	Durham	North Carolina
United States	University of North Texas Health Science Center	Fort Worth	Texas
United States	Hines VA Medical Center	Hines	Illinois
United States	Thomas Street Clinic	Houston	Texas
United States	Central Arkansas Veterans Health System	Little Rock	Arkansas
United States	LA County/USC Medical Center	Los Angeles	California
United States	Nashville VA Medical Center	Nashville	Tennessee
United States	Columbia University/Presbyterian Medical Center	New York	New York
United States	Harlem Hospital Center	New York	New York
United States	New York University School of Medicine	New York	New York
United States	New Jersey Medical School	Newark	New Jersey
United States	Audi L. Murphy VA Hospital	San Antonio	Texas
United States	University of California, San Francisco	San Francisco	California
United States	Seattle King County Health Department	Seattle	Washington
United States	Washington, D.C. VAMC	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
Centers for Disease Control and Prevention	VA Office of Research and Development

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Combined endpoint of bacteriologic plus clinical failure and relapse within 2 years of completing treatment among patients with isoniazid-resistant tuberculosis and among patients enrolled with intolerance to isoniazid		30 mos	No
Secondary	Occurrence and timing of toxicities and drug intolerances		6 mos	Yes
Secondary	Time to completion and the frequency of successful completion		6 mos	No
Secondary	Occurrence of acquired resistance		30 mos	No
Secondary	Proportion with documented conversion of 8-week sputum cultures		8 wks	No
Secondary	Bacteriologic failure or relapse in patients with resistance to streptomycin		30 mos	No
Secondary	Bacteriologic failure or relapse among patient with history of prior treatment		30 mos	No
Secondary	Bacteriologic failure or relapse by duration of isoniazid received		30 mos	No
Secondary	Bacteriologic failure or relapse among patients with positive 8-week sputum cultures		30 mos	No

External Links

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