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

This study has been completed.
Sponsor:
Collaborator:
Information provided by:
Centers for Disease Control and Prevention
ClinicalTrials.gov Identifier:
NCT00023374
First received: September 6, 2001
Last updated: August 2, 2011
Last verified: June 2011
  Purpose

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 Intervention
Tuberculosis
Drug: Rifampin
Drug: Pyrazinamide
Drug: Ethambutol
Drug: REZ

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Centers for Disease Control and Prevention:

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 [ Time Frame: 30 mos ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Occurrence and timing of toxicities and drug intolerances [ Time Frame: 6 mos ] [ Designated as safety issue: Yes ]
  • Time to completion and the frequency of successful completion [ Time Frame: 6 mos ] [ Designated as safety issue: No ]
  • Occurrence of acquired resistance [ Time Frame: 30 mos ] [ Designated as safety issue: No ]
  • Proportion with documented conversion of 8-week sputum cultures [ Time Frame: 8 wks ] [ Designated as safety issue: No ]
  • Bacteriologic failure or relapse in patients with resistance to streptomycin [ Time Frame: 30 mos ] [ Designated as safety issue: No ]
  • Bacteriologic failure or relapse among patient with history of prior treatment [ Time Frame: 30 mos ] [ Designated as safety issue: No ]
  • Bacteriologic failure or relapse by duration of isoniazid received [ Time Frame: 30 mos ] [ Designated as safety issue: No ]
  • Bacteriologic failure or relapse among patients with positive 8-week sputum cultures [ Time Frame: 30 mos ] [ Designated as safety issue: No ]

Enrollment: 98
Study Start Date: August 2000
Study Completion Date: December 2010
Primary Completion Date: December 2006 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00023374

  Show 23 Study Locations
Sponsors and Collaborators
Investigators
Principal Investigator: Randall Reves, MD Denver Health and Hospitals, Denver CO
  More Information

Additional Information:
No publications provided by Centers for Disease Control and Prevention

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Stefan Goldberg, CDC
ClinicalTrials.gov Identifier: NCT00023374     History of Changes
Other Study ID Numbers: CDC-NCHSTP-2340, 24
Study First Received: September 6, 2001
Last Updated: August 2, 2011
Health Authority: United States: Federal Government

Keywords provided by Centers for Disease Control and Prevention:
tuberculosis
TB
isoniazid resistance
isoniazid intolerance
treatment
efficacy
toxicity

Additional relevant MeSH terms:
Tuberculosis
Actinomycetales Infections
Bacterial Infections
Gram-Positive Bacterial Infections
Mycobacterium Infections
Ethambutol
Isoniazid
Pyrazinamide
Rifampin
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antitubercular
Antimetabolites
Antitubercular Agents
Enzyme Inhibitors
Fatty Acid Synthesis Inhibitors
Hypolipidemic Agents
Leprostatic Agents
Lipid Regulating Agents
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on November 23, 2014