Clinical trial NCT00130247: Tuberculosis Treatment Shortening Trial
Official title: A Prospective Study of Shortening the Duration of Standard Short Course Chemotherapy From 6 Months to 4 Months in HIV-non-infected Patients With Fully Drug-Susceptible, Non-cavitary Pulmonary Tuberculosis With Negative Sputum Cultures After 2 Months of Anti-TB Treatment
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Tuberculosis
Keywords: Brazil
Philippines
Tuberculosis
Uganda
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2005-08-15
Enrollment: 394
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Bacteriologic or Clinical Relapse at 30 Months After Onset of Initial Anti-tuberculosis (TB) Treatment - Intention-to-treat
timeFrame: 30 months
measure: Bacteriologic or Clinical Relapse at 30 Months After Onset of Initial Anti-TB Treatment - Per-protocol
timeFrame: 30 months
Secondary outcomes:
measure: Treatment Failures or Relapses at 2 Years After Completion of TB Treatment: Intention to Treat
timeFrame: 2 years
measure: Treatment Failures or Relapses at 2 Years After Completion of TB Treatment: Per Protocol
timeFrame: 2 years
measure: Relapses at 1 and 2 Years
timeFrame: 1 and 2 years after successful completion of initial anti-TB treatment
measure: Acquired Drug Resistance in Patients Who Relapsed
timeFrame: 2 years
measure: Immunologic: Changes in Cytokine Levels in Mycobacterium Tubercolosis (MTB) Antigen-stimulated Whole Blood Culture Supernatants - Results Are Pending
timeFrame: After 2 and 6 months of anti-TB treatment and upon relapse
measure: Immunologic: Store Peripheral Blood Mononuclear Cells (PBMC) - Results Are Pending
timeFrame: Pre-treatment and serum pre-treatment after 2 and 6 months of anti-TB treatment, and at the time of relapse for future immunologic analysis
measure: Immunologic: Changes in Sputum Cytokine Levels - Results Are Pending
timeFrame: After 1 and 2 months of anti-TB treatment
measure: Microbiologic: Changes in Sputum Mycobacterial mRNA - Results Are Pending
timeFrame: At 1 and 2 months of anti-TB treatment, and upon relapse
measure: Microbiologic: Time After Inoculation Until Culture Positive in BACTEC 460 or MGIT 960 Enriched Liquid Media After 2 Months in Treatment - Results Are Pending
timeFrame: Months 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 24, and 30
Other outcomes:
Locations:
city: Vitória
country: Brazil
facility: Universidade Federal do Espirito Santo - Duke Hubert-Yeargan Center
state: Espírito Santo
city: Makati
country: Philippines
facility: Makati Medical Center
state: National Capital Region
city: Kampala
country: Uganda
facility: Mulago Hospital Complex
Study officials:
References:
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citation: Palaci M, Dietze R, Hadad DJ, Ribeiro FK, Peres RL, Vinhas SA, Maciel EL, do Valle Dettoni V, Horter L, Boom WH, Johnson JL, Eisenach KD. Cavitary disease and quantitative sputum bacillary load in cases of pulmonary tuberculosis. J Clin Microbiol. 2007 Dec;45(12):4064-6. doi: 10.1128/JCM.01780-07. Epub 2007 Oct 10.
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citation: Colangeli R, Jedrey H, Kim S, Connell R, Ma S, Chippada Venkata UD, Chakravorty S, Gupta A, Sizemore EE, Diem L, Sherman DR, Okwera A, Dietze R, Boom WH, Johnson JL, Mac Kenzie WR, Alland D; DMID 01-009/Tuberculosis Trials Consortium Study 22 Teams. Bacterial Factors That Predict Relapse after Tuberculosis Therapy. N Engl J Med. 2018 Aug 30;379(9):823-833. doi: 10.1056/NEJMoa1715849.
citation: Bark CM, Thiel BA, Johnson JL. Pretreatment time to detection of Mycobacterium tuberculosis in liquid culture is associated with relapse after therapy. J Clin Microbiol. 2012 Feb;50(2):538. doi: 10.1128/JCM.06193-11. Epub 2011 Nov 23. No abstract available.
citation: Johnson JL, Hadad DJ, Dietze R, Maciel EL, Sewali B, Gitta P, Okwera A, Mugerwa RD, Alcaneses MR, Quelapio MI, Tupasi TE, Horter L, Debanne SM, Eisenach KD, Boom WH. Shortening treatment in adults with noncavitary tuberculosis and 2-month culture conversion. Am J Respir Crit Care Med. 2009 Sep 15;180(6):558-63. doi: 10.1164/rccm.200904-0536OC. Epub 2009 Jun 19.
citation: Maciel EL, Brioschi AP, Peres RL, Guidoni LM, Ribeiro FK, Hadad DJ, Vinhas SA, Zandonade E, Palaci M, Dietze R, Johnson JL. Smoking and 2-month culture conversion during anti-tuberculosis treatment. Int J Tuberc Lung Dis. 2013 Feb;17(2):225-8. doi: 10.5588/ijtld.12.0426.