TuberculosisPhase 3NCT00130247
Tuberculosis Treatment Shortening Trial
A Phase 3 study testing Ethambutol, Isoniazid and Pyrazinamide in people with Tuberculosis, run by National Institute of Allergy and Infectious Diseases (NIAID) at 3 sites in 3 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 60 years
- Conditions the study is for
- Tuberculosis
- What is being tested?
- Ethambutol, Isoniazid and Pyrazinamide
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 394 participants
- Where
- 3 sitesin 3 countries
- Study dates
- 8 Apr 2002to 28 Nov 2008
- Phase
- Phase 3
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- -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.
Who cannot join
- -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.
Trial locations and contacts
3 sites in 3 countries.
3 sites in 3 countries
Brazil1 site
Universidade Federal do Espirito Santo - Duke Hubert-Yeargan Center
Vitória, Espírito Santo, 29040-091
Philippines1 site
Makati Medical Center
Makati City, National Capital Region, 1229
About this study
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
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.
Read the 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.
- Conditions
- Tuberculosis
- Being tested
- Ethambutol, Isoniazid, Pyrazinamide, Rifampin
- Keywords
- Brazil, Philippines, Tuberculosis, Uganda
- Medical subject headings
- Tuberculosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EthambutolDrug
Mycobacteriostatic agent given to prevent emergence of drug resistance to other 1st line drugs; dosages are 15-25 milligram (mg)/ kilogram (kg)/day (d).
IsoniazidDrug
Hydrazide of isonicotininc acid; antimicrobial activity is limited to mycobacteria where it inhibits the synthesis of mycolic acids.
PyrazinamideDrug
1st line bactericidal agent; dosages are 15-30 mg/kg/d, up to 2 grams (gm)/d.
RifampinDrug
1st line bactericidal agent which inhibits deoxyribonucleic acid (DNA)-dependent ribonucleic acid (RNA) polymerase; dosages are 10 mg/kg/d (up to 600 mg/d).
| Study group | Role | What they receive |
|---|---|---|
| 2EHRZ/2HR arm | Experimental | Daily treatment with isoniazid (INH), rifampicin, ethambutol and pyrazinamide for 2 months followed by 2 months of daily INH plus rifampicin over a maximum time period of 18 weeks. Receives: Drug: Ethambutol; Drug: Isoniazid; Drug: Pyrazinamide; Drug: Rifampin |
| 2EHRZ/4HR arm | Active comparator | Daily treatment with Isoniazid (INH), rifampicin, ethambutol and pyrazinamide for 2 months followed by 4 months of daily INH plus rifampicin over a maximum time period of 28 weeks. Receives: Drug: Ethambutol; Drug: Isoniazid; Drug: Pyrazinamide; Drug: Rifampin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Bacteriologic or Clinical Relapse at 30 Months After Onset of Initial Anti-tuberculosis (TB) Treatment - Intention-to-treat
Patients who presented with TB after completion of study phase treatment but before the end of follow-up were classified as relapses. A bacteriologic relapse was defined as a patient who became consistently culture-positive [defined as at least 1 of the following]: (a) at least 1 sputum mycobacterial culture growing at least 10 colonies of MTB on solid medium; (b) 2 or more respiratory secretion cultures that are positive for MTB in liquid media; or (c) any culture from an extrapulmonary site that is positive for MTB during follow-up after successful completion of initial anti-TB treatment.
Measured: 30 months
Bacteriologic or Clinical Relapse at 30 Months After Onset of Initial Anti-TB Treatment - Per-protocol
Patients who presented with TB after completion of study phase treatment but before the end of follow-up were classified as relapses. A bacteriologic relapse was defined as a patient who became consistently culture-positive [defined as at least 1 of the following]: (a) at least 1 sputum mycobacterial culture growing at least 10 colonies of MTB on solid medium; (b) 2 or more respiratory secretion cultures that are positive for MTB in liquid media; or (c) any culture from an extrapulmonary site that is positive for MTB during follow-up after successful completion of initial anti-TB treatment.
Measured: 30 months
Secondary outcomes (9)
Treatment Failures or Relapses at 2 Years After Completion of TB Treatment: Intention to Treat
A culture-positive treatment failure was defined as initial culture conversion but subsequent reversion to culture positivity. A clinical treatment failure was defined as a patient with clinical and/or radiographic evidence of progressive tuberculosis not confirmed by a positive culture after 4 or more months of anti-TB treatment while still receiving treatment. Patients who defaulted before completing study treatment and returned later with culture-positive tuberculosis were termed failures after non-adherence.
Measured: 2 years
Treatment Failures or Relapses at 2 Years After Completion of TB Treatment: Per Protocol
A culture-positive treatment failure was defined as initial culture conversion but subsequent reversion to culture positivity. A clinical treatment failure was defined as a patient with clinical and/or radiographic evidence of progressive tuberculosis not confirmed by a positive culture after 4 or more months of anti-TB treatment while still receiving treatment. Patients who defaulted before completing study treatment and returned later with culture-positive tuberculosis were termed failures after non-adherence.
Measured: 2 years
Relapses at 1 and 2 Years
Measured: 1 and 2 years after successful completion of initial anti-TB treatment
Acquired Drug Resistance in Patients Who Relapsed
Measured: 2 years
Immunologic: Changes in Cytokine Levels in Mycobacterium Tuberculosis (MTB) Antigen-stimulated Whole Blood Culture Supernatants
Measured: After 2 and 6 months of anti-TB treatment and upon relapse
Immunologic: Store Peripheral Blood Mononuclear Cells (PBMC)
Measured: 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
Immunologic: Changes in Sputum Cytokine Levels
Measured: After 1 and 2 months of anti-TB treatment
Microbiologic: Changes in Sputum Mycobacterial mRNA
Measured: At 1 and 2 months of anti-TB treatment, and upon relapse
Microbiologic: Time After Inoculation Until Culture Positive in BACTEC 460 or MGIT 960 Enriched Liquid Media After 2 Months in Treatment
Measured: Months 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 24, and 30
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Aug 2005 (estimated)
- Study start8 Apr 2002
- Primary completion2 Sep 2008
- Study completion28 Nov 2008
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (7)Papers the sponsor has linked to this study.
- Other trials for TuberculosisStudies of the same condition, open and under way.
- More trials run by National Institute of Allergy and Infectious Diseases (NIAID)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 394 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00130247
- Sponsor's protocol ID
- 01-009
- Status last verified
- 20 Apr 2010
- First submitted
- 12 Aug 2005
- Last updated
- 15 Oct 2026
- Results posted
- Yes, on ClinicalTrials.gov
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Johnson JL, Thiel BA. Time until relapse in tuberculosis treatment trials: implication for phase 3 trial design. Am J Respir Crit Care Med. 2012 Sep 1;186(5):464. doi: 10.1164/ajrccm.186.5.464. No abstract available.
PubMed 22942350Palaci 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.
PubMed 17928422Bark CM, Dietze R, Okwera A, Quelapio MI, Thiel BA, Johnson JL. Clinical symptoms and microbiological outcomes in tuberculosis treatment trials. Tuberculosis (Edinb). 2011 Nov;91(6):601-4. doi: 10.1016/j.tube.2011.05.007. Epub 2011 Aug 2.
PubMed 21813327Colangeli 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.
PubMed 30157391Bark 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.
PubMed 22116143Johnson 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.
PubMed 19542476Maciel 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.
PubMed 23317958