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

NCT ID: NCT00023374

Last Updated: 2011-08-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 98 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2000-08-31
• Study Completion Date: 2010-12-31

Brief 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.

Detailed 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

Conditions

Tuberculosis

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Rifampin+PZA+Ethambutol

6 mos of intermittent (2 or 3 times weekly) therapy with REZ

Group Type: EXPERIMENTAL

Rifampin

Intervention Type: DRUG

6mos REZ intermittent

Pyrazinamide

Intervention Type: DRUG

6mos REZ intermittent

Ethambutol

Intervention Type: DRUG

6mos REZ intermittent

REZ

Intervention Type: DRUG

Rif+PZA+EMB given 2 or 3 times weekly for 6 months

Interventions

Rifampin

6mos REZ intermittent

Intervention Type: DRUG

Pyrazinamide

6mos REZ intermittent

Intervention Type: DRUG

Ethambutol

6mos REZ intermittent

Intervention Type: DRUG

REZ

Rif+PZA+EMB given 2 or 3 times weekly for 6 months

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

US Department of Veterans Affairs

FED

Sponsor Role: collaborator

Centers for Disease Control and Prevention

FED

Sponsor Role: lead

Responsible Party

CDC

Principal Investigators

Randall Reves, MD

Role: PRINCIPAL_INVESTIGATOR

Denver Health and Hospitals, Denver CO

Locations

Central Arkansas Veterans Health System

Little Rock, Arkansas, United States

LA County/USC Medical Center

Los Angeles, California, United States

University of California, San Francisco

San Francisco, California, United States

Denver Department of Public Health and Hospitals

Denver, Colorado, United States

Washington, D.C. VAMC

Washington D.C., District of Columbia, United States

Chicago VA Medical Center (Lakeside)

Chicago, Illinois, United States

Hines VA Medical Center

Hines, Illinois, United States

Johns Hopkins University School of Medicine

Baltimore, Maryland, United States

Boston Medical Center

Boston, Massachusetts, United States

New Jersey Medical School

Newark, New Jersey, United States

New York University School of Medicine

New York, New York, United States

Columbia University/Presbyterian Medical Center

New York, New York, United States

Harlem Hospital Center

New York, New York, United States

Carolinas Medical Center

Charlotte, North Carolina, United States

Duke University Medical Center

Durham, North Carolina, United States

Nashville VA Medical Center

Nashville, Tennessee, United States

University of North Texas Health Science Center

Fort Worth, Texas, United States

Thomas Street Clinic

Houston, Texas, United States

Audi L. Murphy VA Hospital

San Antonio, Texas, United States

Seattle King County Health Department

Seattle, Washington, United States

University of British Columbia

Vancouver, British Columbia, Canada

University of Manitoba

Winnipeg, Manitoba, Canada

Montreal Chest Institute McGill University

Montreal, Quebec, Canada

Countries

United States; Canada

References

Reves R, Heilig CM, Tapy JM, Bozeman L, Kyle RP, Hamilton CD, Bock N, Narita M, Wing D, Hershfield E, Goldberg SV; Tuberculosis Trials Consortium. Intermittent tuberculosis treatment for patients with isoniazid intolerance or drug resistance. Int J Tuberc Lung Dis. 2014 May;18(5):571-80. doi: 10.5588/ijtld.13.0304.

Reference Type: DERIVED

PMID: 24903795 (View on PubMed)

Funck-Jensen KL, Dalsgaard J, Grove EL, Hvas AM, Kristensen SD. Increased platelet aggregation and turnover in the acute phase of ST-elevation myocardial infarction. Platelets. 2013;24(7):528-37. doi: 10.3109/09537104.2012.738838. Epub 2012 Dec 5.

Reference Type: DERIVED

PMID: 23216571 (View on PubMed)

Related Links

http://www.cdc.gov/nchstp/tb/tbtc/

(Click here for more information about the Tuberculosis Trials Consortium(TBTC

Other Identifiers

24

Identifier Type: -

Identifier Source: secondary_id

CDC-NCHSTP-2340

Identifier Type: -

Identifier Source: org_study_id