Tuberculosis Treatment Shortening Trial
Tuberculosis Treatment Shortening Trial
Tuberculosis (TB) is a serious infection that can affect the lungs and other parts of the
 body. The usual way to treat TB is to take 4 medicines by mouth every day for 2 months, then
 take 2 of the same medicines for 4 more months, for a total of 6 months. The purpose of this
 study is to see if taking 4 months of TB medicines is as effective in curing some TB patients
 as taking 6 months of TB medicines. Study participants will include 758 human
 immunodeficiency virus (HIV)-non-infected individuals, ages 18-60. Participants will be
 treated with 4 standard drugs called isoniazid, rifampicin, pyrazinamide and ethambutol. All
 individuals will take TB medicines for at least 4 months. After 4 months of treatment, if no
 TB germs are growing in sputum samples, participants will be assigned to either stop taking
 TB medicine (4 months of treatment) or to continue taking TB drugs for 2 more months (6
 months of treatment). Participants will be involved in study procedures for up to 30 months.
Tuberculosis (TB) is a major global health problem. TB is the current leading cause of death
 due to an identifiable infectious agent worldwide. One of the highest priorities for
 tuberculosis control programs is to shorten anti-TB treatment while maintaining its
 effectiveness. Current 6-month short course chemotherapy regimens are over 95% effective for
 the treatment of tuberculosis when fully administered. Six months is a long time, however,
 and patients frequently discontinue anti-TB treatment once their symptoms have improved. The
 duration of standard short course chemotherapy is one of the major obstacles to its
 successful application and poses substantial challenges to programs with respect to patient
 adherence, program resource needs, and logistical requirements for directly observed therapy.
 The primary objective of this study is to assess the efficacy of shortening anti-TB treatment
 to 4 months in human immunodeficiency virus (HIV)-non-infected adults with drug-susceptible,
 non-cavitary pulmonary tuberculosis who convert their sputum culture to negative after 2
 months of treatment. Secondary objectives of this study include: comparing pre-treatment
 sputum bacillary load in patients with and without cavitary disease; compare time after
 inoculation of BACTEC or Mycobacteria growth indicator tube (MGIT) liquid culture media until
 positive with semi-quantitative sputum acid fast bacteria (AFB) smear and culture on solid
 media as measures of pre-treatment sputum bacillary load; and determining the influence of
 immunologic characteristics of subjects pre-treatment, during treatment and at the end of
 therapy on rate of bacillary clearance and risk for relapse. A total of 758 HIV-non-infected
 adults, male or female, 18-60 years of age, with newly diagnosed initial episodes of sputum
 AFB smear-positive or -negative, culture-positive, non-cavitary, drug-susceptible pulmonary
 TB who are sputum culture negative after 2 months of anti-TB treatment will be randomly
 assigned to complete a total of 4 or 6 months of anti-TB therapy. The experimental regimen
 will include a total of 4 months of anti-TB treatment [2 months of daily isoniazid (INH),
 rifampicin, pyrazinamide and ethambutol followed by 2 months of daily INH and rifampicin].
 The comparative regimen will include a total of 6 months standard short course anti-TB
 chemotherapy (2 months of daily INH, rifampicin, pyrazinamide and ethambutol followed by 4
 months of daily INH and rifampicin). Subjects will be involved in study related procedures
 for approximately 30 months after beginning the initial anti-TB treatment.
Inclusion Criteria:

 -Adults, male or female, aged 18-60. -Newly diagnosed initial episodes of pulmonary
 tuberculosis. Sputum smear-positive and -negative patients are eligible for enrollment. The
 diagnosis of tuberculosis must be confirmed by culture. Acid fast bacteria (AFB) smear
 positive patients found later not to have tuberculosis (TB) (i.e. those with
 non-tuberculous mycobacterial disease) and those without culture confirmation [at least one
 culture on solid media growing > 10 colonies of Mycobacterium tuberculosis (MTB) or a
 positive BACTEC or Mycobacteria growth indicator tube (MGIT) enriched liquid culture
 growing MTB] will be removed from the study. -Chest X-ray and clinical findings consistent
 with tuberculosis. -Hemoglobin greater than or equal to 8 gm/dL (greater than or equal to
 5.0 mmol/L). -Serum creatinine < 2 mg/dL (< 177 micro mol/L). -Serum aspartate
 aminotransferase (AST) < 1.5 times the upper limit of normal for the testing laboratory,
 and serum total bilirubin < 1.3 mg/dL (22.2 micro mol/L). -Random serum glucose less than
 or equal to 150 mg/dl (8.3 mmol/L). -Ambulatory. -Willing to provide informed consent for
 study participation, provide required specimens for examination, and to undergo and receive
 results of human immunodeficiency virus (HIV) testing. -Willing to receive supervised
 anti-TB treatment. -Completion of the required 112 doses of chemotherapy within 18 weeks of
 starting treatment.

 Exclusion Criteria:

 -Human immunodeficiency virus (HIV)-infected. -History of prior tuberculosis or history of
 previous tuberculosis treatment. -Pregnant or breastfeeding. -Cavitary tuberculosis on
 initial chest X-ray (taken within 14 days of study entry). -Exposure to person(s) with
 known drug resistant tuberculosis. -Patients receiving chronic steroids or other
 immunosuppressive medications. -Extra-pulmonary tuberculosis. -Patients with drug resistant
 tuberculosis (resistance to isoniazid (INH), rifampicin, pyrazinamide or ethambutol).
 -Professional sex worker, alcoholic and/or intravenous (IV) drug abuser. -Silicosis or
 other serious chronic medical problems including diabetes mellitus or chronic renal
 failure. Final determination of eligibility will be made after review of drug
 susceptibility testing results on an initial sputum isolate and results of all sputum
 cultures. Pregnant patients may not be enrolled in the study. Patients in the 4 month arm
 who become pregnant during months 5 and 6 of study participation will be dropped from the
 study and receive an additional 2 months of treatment with INH and rifampicin.