Clinical trial NCT00023374: TBTC Study 24: Intermittent Treatment of TB With Isoniazid Resistance or Intolerance
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Tuberculosis
Keywords: tuberculosis
TB
isoniazid resistance
isoniazid intolerance
treatment
efficacy
toxicity
Lead sponsor: Centers for Disease Control and Prevention
Sponsor class: FED
Collaborators: name: US Department of Veterans Affairs
First posted: 2001-09-10
Enrollment: 98
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

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.

Primary outcomes:
measure: 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
timeFrame: 30 mos
Secondary outcomes:
measure: Occurrence and timing of toxicities and drug intolerances
timeFrame: 6 mos
measure: Time to completion and the frequency of successful completion
timeFrame: 6 mos
measure: Occurrence of acquired resistance
timeFrame: 30 mos
measure: Proportion with documented conversion of 8-week sputum cultures
timeFrame: 8 wks
measure: Bacteriologic failure or relapse in patients with resistance to streptomycin
timeFrame: 30 mos
measure: Bacteriologic failure or relapse among patient with history of prior treatment
timeFrame: 30 mos
measure: Bacteriologic failure or relapse by duration of isoniazid received
timeFrame: 30 mos
measure: Bacteriologic failure or relapse among patients with positive 8-week sputum cultures
timeFrame: 30 mos
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Central Arkansas Veterans Health System
state: Arkansas
city: Los Angeles
country: United States
facility: LA County/USC Medical Center
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Denver
country: United States
facility: Denver Department of Public Health and Hospitals
state: Colorado
city: Washington
country: United States
facility: Washington, D.C. VAMC
state: District of Columbia
city: Chicago
country: United States
facility: Chicago VA Medical Center (Lakeside)
state: Illinois
city: Hines
country: United States
facility: Hines VA Medical Center
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins University School of Medicine
state: Maryland
city: Boston
country: United States
facility: Boston Medical Center
state: Massachusetts
city: Newark
country: United States
facility: New Jersey Medical School
state: New Jersey
city: New York
country: United States
facility: New York University School of Medicine
state: New York
city: New York
country: United States
facility: Columbia University/Presbyterian Medical Center
state: New York
city: New York
country: United States
facility: Harlem Hospital Center
state: New York
city: Charlotte
country: United States
facility: Carolinas Medical Center
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Nashville
country: United States
facility: Nashville VA Medical Center
state: Tennessee
city: Fort Worth
country: United States
facility: University of North Texas Health Science Center
state: Texas
city: Houston
country: United States
facility: Thomas Street Clinic
state: Texas
city: San Antonio
country: United States
facility: Audi L. Murphy VA Hospital
state: Texas
city: Seattle
country: United States
facility: Seattle King County Health Department
state: Washington
city: Vancouver
country: Canada
facility: University of British Columbia
state: British Columbia
city: Winnipeg
country: Canada
facility: University of Manitoba
state: Manitoba
city: Montreal
country: Canada
facility: Montreal Chest Institute McGill University
state: Quebec
Study officials:
affiliation: Denver Health and Hospitals, Denver CO
name: Randall Reves, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.