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

Sponsor

Centers for Disease Control and Prevention (U.S. Fed)

Overall Status

Completed

CT.gov ID

NCT00023374

Collaborator

US Department of Veterans Affairs (U.S. Fed)

Enrollment

Locations

Arm

124

Duration (Months)

4.3

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Tuberculosis	Drug: Rifampin Drug: Pyrazinamide Drug: Ethambutol Drug: REZ	N/A

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

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

Study Design

Study Type:

Interventional

Actual Enrollment :

98 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Study Start Date :

Aug 1, 2000

Actual Primary Completion Date :

Dec 1, 2006

Actual Study Completion Date :

Dec 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Rifampin+PZA+Ethambutol 6 mos of intermittent (2 or 3 times weekly) therapy with REZ	Drug: Rifampin 6mos REZ intermittent Drug: Pyrazinamide 6mos REZ intermittent Drug: Ethambutol 6mos REZ intermittent Drug: REZ Rif+PZA+EMB given 2 or 3 times weekly for 6 months

Arm

Intervention/Treatment

Experimental: Rifampin+PZA+Ethambutol

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

Drug: Rifampin

6mos REZ intermittent

Drug: Pyrazinamide

6mos REZ intermittent

Drug: Ethambutol

6mos REZ intermittent

Drug: REZ

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

Outcome Measures

Primary Outcome Measures

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]

Secondary Outcome Measures

Occurrence and timing of toxicities and drug intolerances [6 mos]
Time to completion and the frequency of successful completion [6 mos]
Occurrence of acquired resistance [30 mos]
Proportion with documented conversion of 8-week sputum cultures [8 wks]
Bacteriologic failure or relapse in patients with resistance to streptomycin [30 mos]
Bacteriologic failure or relapse among patient with history of prior treatment [30 mos]
Bacteriologic failure or relapse by duration of isoniazid received [30 mos]
Bacteriologic failure or relapse among patients with positive 8-week sputum cultures [30 mos]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion criteria:

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.
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)

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)

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.

Age: 18 years or older
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.
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:
. Amino aspartate transferase (AST) activity less than 3 times upper limit of normal;
. Total bilirubin level less than 2.5 times upper limit of normal;
. Creatinine level less than 2 times upper limit of normal;
. Hemoglobin level of at least 7.0 g/dL;
. Platelet count of at least 50,000 mm3
Karnofsky score of at least 60. See Appendix 6 for Karnofsky scoring system.
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.
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

Patients with known treatment-limiting reaction to rifamycins, pyrazinamide, or ethambutol.
Diagnosis of silicotuberculosis or tuberculosis of the central nervous system
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.
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.
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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Central Arkansas Veterans Health System	Little Rock	Arkansas	United States	72205
2	LA County/USC Medical Center	Los Angeles	California	United States	90033
3	University of California, San Francisco	San Francisco	California	United States	94110
4	Denver Department of Public Health and Hospitals	Denver	Colorado	United States	80204
5	Washington, D.C. VAMC	Washington	District of Columbia	United States	20422
6	Chicago VA Medical Center (Lakeside)	Chicago	Illinois	United States	60611
7	Hines VA Medical Center	Hines	Illinois	United States	60141
8	Johns Hopkins University School of Medicine	Baltimore	Maryland	United States	21287-0003
9	Boston Medical Center	Boston	Massachusetts	United States	02118
10	New Jersey Medical School	Newark	New Jersey	United States	07107-3001
11	New York University School of Medicine	New York	New York	United States	10016
12	Columbia University/Presbyterian Medical Center	New York	New York	United States	10032
13	Harlem Hospital Center	New York	New York	United States	10037
14	Carolinas Medical Center	Charlotte	North Carolina	United States	28203
15	Duke University Medical Center	Durham	North Carolina	United States	34222
16	Nashville VA Medical Center	Nashville	Tennessee	United States	37212-2637
17	University of North Texas Health Science Center	Fort Worth	Texas	United States	76107-2699
18	Thomas Street Clinic	Houston	Texas	United States	77009
19	Audi L. Murphy VA Hospital	San Antonio	Texas	United States	78284
20	Seattle King County Health Department	Seattle	Washington	United States	98104
21	University of British Columbia	Vancouver	British Columbia	Canada	Canada V5Z 4R4
22	University of Manitoba	Winnipeg	Manitoba	Canada	CANADA R3A 1R8
23	Montreal Chest Institute McGill University	Montreal	Quebec	Canada	H2X 2P4Pq Canada