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

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

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.

Study Overview

• Status: Completed
• Conditions: Tuberculosis
• Intervention / Treatment: Drug: Rifampin; Drug: Pyrazinamide; Drug: Ethambutol; Drug: REZ

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

• Study Type: Interventional
• Enrollment (Actual): 98
• Phase: Not Applicable

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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

Outcome Measure	Time Frame
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

Collaborators and Investigators

• Sponsor: Centers for Disease Control and Prevention
• Collaborators: US Department of Veterans Affairs
• Investigators: Principal Investigator: Randall Reves, MD, Denver Health and Hospitals, Denver CO

Publications and helpful links

General Publications

• 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.
• 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.

Helpful Links

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

Study record dates

Study Major Dates

• Study Start: August 1, 2000
• Primary Completion (Actual): December 1, 2006
• Study Completion (Actual): December 1, 2010

Study Registration Dates

• First Submitted: September 6, 2001
• First Submitted That Met QC Criteria: September 8, 2001
• First Posted (Estimate): September 10, 2001

Study Record Updates

• Last Update Posted (Estimate): August 3, 2011
• Last Update Submitted That Met QC Criteria: August 2, 2011
• Last Verified: June 1, 2011

More Information

Terms related to this study

• Keywords: treatment; efficacy; TB; tuberculosis; toxicity; isoniazid resistance; isoniazid intolerance
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Bacterial Agents; Leprostatic Agents; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Rifampin; Pyrazinamide; Ethambutol
• Other Study ID Numbers: CDC-NCHSTP-2340; 24