Tuberculosis Treatment Shortening Trial

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00130247
• Collaborator: (none)
• Enrollment: 394
• Locations: 3
• Arms: 2
• Actual Duration (Months): 79.7
• Patients Per Site: 131.3
• Patients Per Site Per Month: 1.6

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Tuberculosis	Drug: Ethambutol; Drug: Isoniazid; Drug: Pyrazinamide; Drug: Rifampin	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 394 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Apr 8, 2002
• Actual Primary Completion Date: Sep 2, 2008
• Actual Study Completion Date: Nov 28, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 2EHRZ/2HR arm 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.	Drug: Ethambutol; Mycobacteriostatic agent given to prevent emergence of drug resistance to other 1st line drugs; dosages are 15-25 milligram (mg)/ kilogram (kg)/day (d).; Drug: Isoniazid; Hydrazide of isonicotininc acid; antimicrobial activity is limited to mycobacteria where it inhibits the synthesis of mycolic acids.; Drug: Pyrazinamide; 1st line bactericidal agent; dosages are 15-30 mg/kg/d, up to 2 grams (gm)/d.; Drug: Rifampin; 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).
Active Comparator: 2EHRZ/4HR arm 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.	Drug: Ethambutol; Mycobacteriostatic agent given to prevent emergence of drug resistance to other 1st line drugs; dosages are 15-25 milligram (mg)/ kilogram (kg)/day (d).; Drug: Isoniazid; Hydrazide of isonicotininc acid; antimicrobial activity is limited to mycobacteria where it inhibits the synthesis of mycolic acids.; Drug: Pyrazinamide; 1st line bactericidal agent; dosages are 15-30 mg/kg/d, up to 2 grams (gm)/d.; Drug: Rifampin; 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).

Outcome Measures

Primary Outcome Measures

1. Bacteriologic or Clinical Relapse at 30 Months After Onset of Initial Anti-tuberculosis (TB) Treatment - Intention-to-treat [30 months]

   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.

2. Bacteriologic or Clinical Relapse at 30 Months After Onset of Initial Anti-TB Treatment - Per-protocol [30 months]

   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.

Secondary Outcome Measures

1. Treatment Failures or Relapses at 2 Years After Completion of TB Treatment: Intention to Treat [2 years]

   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.

2. Treatment Failures or Relapses at 2 Years After Completion of TB Treatment: Per Protocol [2 years]

   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.

3. Relapses at 1 and 2 Years [1 and 2 years after successful completion of initial anti-TB treatment]

4. Acquired Drug Resistance in Patients Who Relapsed [2 years]

5. Immunologic: Changes in Cytokine Levels in Mycobacterium Tubercolosis (MTB) Antigen-stimulated Whole Blood Culture Supernatants - Results Are Pending [After 2 and 6 months of anti-TB treatment and upon relapse]

6. Immunologic: Store Peripheral Blood Mononuclear Cells (PBMC) - Results Are Pending [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]

7. Immunologic: Changes in Sputum Cytokine Levels - Results Are Pending [After 1 and 2 months of anti-TB treatment]

8. Microbiologic: Changes in Sputum Mycobacterial mRNA - Results Are Pending [At 1 and 2 months of anti-TB treatment, and upon relapse]

9. Microbiologic: Time After Inoculation Until Culture Positive in BACTEC 460 or MGIT 960 Enriched Liquid Media After 2 Months in Treatment - Results Are Pending [Months 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 24, and 30]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Universidade Federal do Espirito Santo - Duke Hubert-Yeargan Center	Vitória	Espírito Santo	Brazil	29040-091
2	Makati Medical Center	Makati	National Capital Region	Philippines	1229
3	Mulago Hospital Complex	Kampala		Uganda	99999

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

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.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT00130247
• Other Study ID Numbers: 01-009
• First Posted: Aug 15, 2005
• Last Update Posted: Nov 8, 2018
• Last Verified: Apr 20, 2010

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID): Brazil; Philippines; Tuberculosis; Uganda
• Additional relevant MeSH terms: Tuberculosis; Rifampin; Isoniazid; Pyrazinamide; Ethambutol

Study Results

Participant Flow

Recruitment Details	HIV-uninfected 18 to 60 year old adults with suspected or newly diagnosed pulmonary tuberculosis were eligible for enrollment at participating sites in Kampala, Uganda; Vitória, Brazil; and Manila/Makati City, the Philippines. Screening began in April 2002 in Uganda, December 2002 in Brazil, and November 2003 in the Philippines.
Pre-assignment Detail	Subjects who met eligibility criteria were started on standard chemotherapy and routinely followed during anti-TB therapy. Patients with drug-susceptible TB who were sputum culture negative after 2 months of treatment were randomly assigned at 4 months to stop treatment or received an additional 2 months of daily isoniazid (INH) and rifampicin.

Arm/Group Title	4-Month Arm	6-Month Arm
Arm/Group Description	Daily treatment with 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.	Daily treatment with 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.
Period Title: Overall Study
STARTED	196	198
COMPLETED	194	194
NOT COMPLETED	2	4

Baseline Characteristics

Arm/Group Title	4-Month Arm	6-Month Arm	Total
Arm/Group Description	Daily treatment with 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.	Daily treatment with 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.	Total of all reporting groups
Overall Participants	196	198	394
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	196 100%	198 100%	394 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	31.2 (10)	30.3 (10)	30.8 (10)
Sex: Female, Male (Count of Participants)
Female	77 39.3%	78 39.4%	155 39.3%
Male	119 60.7%	120 60.6%	239 60.7%
Region of Enrollment (participants) [Number]
Philippines	47 24%	48 24.2%	95 24.1%
Brazil	81 41.3%	81 40.9%	162 41.1%
Uganda	68 34.7%	69 34.8%	137 34.8%

Outcome Measures

1. Primary Outcome

Title	Bacteriologic or Clinical Relapse at 30 Months After Onset of Initial Anti-tuberculosis (TB) Treatment - Intention-to-treat
Description	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.
Time Frame	30 months

Outcome Measure Data

Analysis Population Description

The intention to treat (ITT) analysis included all 394 fully eligible and randomized patients allocated to the shortened 4-month treatment group (N=196) or the standard 6-month treatment group (N=198). There were no allocated patients excluded in the ITT analysis dataset.

Arm/Group Title	4-Month Arm	6-Month Arm
Arm/Group Description	Daily treatment with 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.	Daily treatment with 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.
Measure Participants	196	198
Number [Participants]	13 6.6%	3 1.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	4-Month Arm, 6-Month Arm
	Comments	Comparison of binomial proportion of relapse: Intention-to-treat
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	This two-sided equivalence trial compared the efficacy of 4 and 6 months of treatment. We assumed that the risk of relapse for patients in the 6 month arm was 3.5% and that an absolute difference of 5% (i.e. relapse rate of 8.5%) was clinically meaningful. For a level of significance of 0.05 and 80% power (two sided), we estimated that 284 evaluable subjects per arm were required.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.051
	Confidence Interval	() 95%; 0.01 to 0.09
	Parameter Dispersion	Type: Value:
	Estimation Comments	Confidence interval for difference of binomial proportions adjusted with Hauck Anderson continuity correction.

2. Secondary Outcome

Title	Treatment Failures or Relapses at 2 Years After Completion of TB Treatment: Intention to Treat
Description	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.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

The intention to treat (ITT) analysis included all 394 fully eligible and randomized patients allocated to the shortened 4-month treatment group (N=196) or the standard 6-month treatment group (N=198). There were no allocated patients excluded in the ITT analysis dataset.

Arm/Group Title	4-Month Arm	6-Month Arm
Arm/Group Description	Daily treatment with 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.	Daily treatment with 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.
Measure Participants	196	198
Treatment Failures	0 0%	0 0%
Relapses	13 6.6%	3 1.5%

3. Secondary Outcome

Title	Treatment Failures or Relapses at 2 Years After Completion of TB Treatment: Per Protocol
Description	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.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

The per-protocol analysis included all 370 patients (185 per treatment arm) who received the intervention, completed treatment and full follow-up and did not have exogenous reinfection of TB. The 24 excluded subjects included 2 patients with exogenous reinfection of TB, 12 lost to follow-up, 4 deaths, and 6 who did not receive the intervention.

Arm/Group Title	4-Month Arm	6-Month Arm
Arm/Group Description	Daily treatment with 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.	Daily treatment with 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.
Measure Participants	185	185
Treatment Failures	0 0%	0 0%
Relapses	13 6.6%	3 1.5%

4. Secondary Outcome

Title	Relapses at 1 and 2 Years
Time Frame	1 and 2 years after successful completion of initial anti-TB treatment

Outcome Measure Data

Analysis Population Description

Analysis includes the 386 patients who received the intervention, completed treatment, and started post-treatment follow-up (193 patients in each treatment arm). Two subjects were lost after completing treatment and contributed no follow-up time, and 6 subjects did not receive the intervention so were not included in the analysis.

Arm/Group Title	4-Month Arm	6-Month Arm
Arm/Group Description	Daily treatment with 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.	Daily treatment with 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.
Measure Participants	193	193
Relapses at 1 year	10 5.1%	3 1.5%
Relapses at 2 years	13 6.6%	3 1.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	4-Month Arm, 6-Month Arm
	Comments	Rate of relapse at 1 year. All patients adherent with treatment and remaining in follow-up at 1 year were included in the calculation of the relapse incidence rate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Incidence rate ratio
	Estimated Value	3.43
	Confidence Interval	() 95%; 0.94 to 12.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	4-Month Arm, 6-Month Arm
	Comments	Rate of relapse at 2 years. All patients adherent with treatment and remaining in follow-up at 2 years were included in the calculation of the relapse incidence rate.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Incident rate ratio
	Estimated Value	4.52
	Confidence Interval	() 95%; 1.29 to 15.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Acquired Drug Resistance in Patients Who Relapsed
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

This analysis was per protocol and looked for acquired drug resistance among the 13 patients in the 4-Month Arm who relapsed and the 3 patients in the 6-Month Arm who relapsed.

Arm/Group Title	4-Month Arm	6-Month Arm
Arm/Group Description	Daily treatment with 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.	Daily treatment with 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.
Measure Participants	13	3
Number [Participants]	0 0%	0 0%

6. Secondary Outcome

Title	Immunologic: Changes in Cytokine Levels in Mycobacterium Tubercolosis (MTB) Antigen-stimulated Whole Blood Culture Supernatants - Results Are Pending
Time Frame	After 2 and 6 months of anti-TB treatment and upon relapse

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Immunologic: Store Peripheral Blood Mononuclear Cells (PBMC) - Results Are Pending
Time Frame	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	Immunologic: Changes in Sputum Cytokine Levels - Results Are Pending
Time Frame	After 1 and 2 months of anti-TB treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Secondary Outcome

Title	Microbiologic: Changes in Sputum Mycobacterial mRNA - Results Are Pending
Time Frame	At 1 and 2 months of anti-TB treatment, and upon relapse

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Primary Outcome

Title	Bacteriologic or Clinical Relapse at 30 Months After Onset of Initial Anti-TB Treatment - Per-protocol
Description	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.
Time Frame	30 months

Outcome Measure Data

Analysis Population Description

The per-protocol analysis included all 370 patients (185 per treatment arm) who received the intervention, completed treatment and full follow-up and did not have exogenous reinfection of TB. The 24 excluded subjects included 2 patients with exogenous reinfection of TB, 12 lost to follow-up, 4 deaths, and 6 who did not receive the intervention.

Arm/Group Title	4-Month Arm	6-Month Arm
Arm/Group Description	Daily treatment with 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.	Daily treatment with 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.
Measure Participants	185	185
Number [Participants]	13 6.6%	3 1.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	4-Month Arm, 6-Month Arm
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	This two-sided equivalence trial compared the efficacy of 4 and 6 months of treatment. We assumed that the risk of relapse for patients in the 6 month arm was 3.5% and that an absolute difference of 5% (i.e. relapse rate of 8.5%) was clinically meaningful. For a level of significance of 0.05 and 80% power (two sided), we estimated that 284 evaluable subjects per arm were required.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.054
	Confidence Interval	() 95%; 0.01 to 0.10
	Parameter Dispersion	Type: Value:
	Estimation Comments	Confidence interval for difference of binomial proportions adjusted with Hauck Anderson continuity correction.

11. Secondary Outcome

Title	Microbiologic: Time After Inoculation Until Culture Positive in BACTEC 460 or MGIT 960 Enriched Liquid Media After 2 Months in Treatment - Results Are Pending
Time Frame	Months 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 24, and 30

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	6 years
Adverse Event Reporting Description	Patients reported adverse events at scheduled or unscheduled visits. Adverse event forms were completed by medical officers on site
Arm/Group Title	4-Month Arm		6-Month Arm
Arm/Group Description	Daily treatment with 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.		Daily treatment with 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.
All Cause Mortality
	4-Month Arm		6-Month Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	4-Month Arm		6-Month Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/196 (9.7%)		22/198 (11.1%)
Cardiac disorders
Acute Myocardial Infarction (Death)	0/196 (0%)	0	1/198 (0.5%)	1
Coronary Arery Occlusion	0/196 (0%)	0	1/198 (0.5%)	1
Eye disorders
Glaucoma in Right Eye	1/196 (0.5%)	1	0/198 (0%)	0
Panuveitis	1/196 (0.5%)	1	0/198 (0%)	0
General disorders
Hyperhidrosis	1/196 (0.5%)	1	0/198 (0%)	0
Injury, poisoning and procedural complications
Gunshot Wound (Abdomen)	0/196 (0%)	0	1/198 (0.5%)	1
Gunshot Wound to Head (Death)	0/196 (0%)	0	1/198 (0.5%)	1
Suffocation (Death)	0/196 (0%)	0	1/198 (0.5%)	1
Investigations
Hospitalization (Unknown Cause of Abdominal Pain)	1/196 (0.5%)	1	0/198 (0%)	0
Musculoskeletal and connective tissue disorders
Other Acquired Calcaneus Deformity	0/196 (0%)	0	1/198 (0.5%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Vocal Cord Cyst	1/196 (0.5%)	1	0/198 (0%)	0
Nervous system disorders
Headache (Severe Post-operative)	1/196 (0.5%)	1	0/198 (0%)	0
Seizure	0/196 (0%)	0	1/198 (0.5%)	1
Pregnancy, puerperium and perinatal conditions
Pregnancy	10/77 (13%)	10	13/78 (16.7%)	14
Psychiatric disorders
Bipolar Affective Disorder	1/196 (0.5%)	1	0/198 (0%)	0
Reproductive system and breast disorders
Cystocele and Perineal Rupture	0/196 (0%)	0	1/198 (0.5%)	1
Endometrial Polyp	0/77 (0%)	0	1/78 (1.3%)	1
Fetal Death	1/77 (1.3%)	1	1/78 (1.3%)	1
Ovarian Cyst	1/196 (0.5%)	1	0/198 (0%)	0
Ovarian Teratoma (Benign)	1/77 (1.3%)	1	1/78 (1.3%)	1
Pelvic Abcess	1/196 (0.5%)	1	0/198 (0%)	0
Pre-eclampsia	0/77 (0%)	0	1/78 (1.3%)	1
Uterine Myoma	1/196 (0.5%)	1	0/198 (0%)	0
Respiratory, thoracic and mediastinal disorders
Bronchopneumonia	1/196 (0.5%)	1	0/198 (0%)	0
Hemoptysis	1/196 (0.5%)	2	0/198 (0%)	0
Pneumothorax	1/196 (0.5%)	1	0/198 (0%)	0
Skin and subcutaneous tissue disorders
Malignant Melanoma (Death)	0/196 (0%)	0	1/198 (0.5%)	1
Surgical and medical procedures
Surgical Intervention on Right Shoulder	0/196 (0%)	0	1/198 (0.5%)	1
Tracheal Plastic Repair	0/196 (0%)	0	1/198 (0.5%)	1
Other (Not Including Serious) Adverse Events
	4-Month Arm		6-Month Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	170/196 (86.7%)		164/198 (82.8%)
Blood and lymphatic system disorders
Hemoptysis	15/196 (7.7%)	19	15/198 (7.6%)	19
Gastrointestinal disorders
Abdominal Pain	48/196 (24.5%)	63	49/198 (24.7%)	59
Diarrhea	15/196 (7.7%)	20	10/198 (5.1%)	10
Nausea	20/196 (10.2%)	31	32/198 (16.2%)	41
Vomiting	15/196 (7.7%)	18	16/198 (8.1%)	19
General disorders
Fever	87/196 (44.4%)	148	67/198 (33.8%)	103
Malaise	17/196 (8.7%)	22	15/198 (7.6%)	18
Rigors	13/196 (6.6%)	15	12/198 (6.1%)	15
Sweating	13/196 (6.6%)	15	17/198 (8.6%)	22
Infections and infestations
Flu	40/196 (20.4%)	63	27/198 (13.6%)	46
Malaria	9/196 (4.6%)	12	2/198 (1%)	3
Tinea Infection	10/196 (5.1%)	12	6/198 (3%)	9
Metabolism and nutrition disorders
Appetite Lost	39/196 (19.9%)	49	30/198 (15.2%)	35
Weight Loss	24/196 (12.2%)	29	20/198 (10.1%)	26
Musculoskeletal and connective tissue disorders
Arthralgia	64/196 (32.7%)	92	64/198 (32.3%)	87
Back Pain	34/196 (17.3%)	46	31/198 (15.7%)	36
Myalgia	5/196 (2.6%)	5	15/198 (7.6%)	16
Pain in Limb	6/196 (3.1%)	8	11/198 (5.6%)	14
Nervous system disorders
Dizziness	18/196 (9.2%)	20	17/198 (8.6%)	18
Headache	64/196 (32.7%)	102	46/198 (23.2%)	66
Psychiatric disorders
Insomnia	8/196 (4.1%)	11	11/198 (5.6%)	15
Respiratory, thoracic and mediastinal disorders
Chest Pain	70/196 (35.7%)	115	52/198 (26.3%)	77
Coryza	11/196 (5.6%)	11	10/198 (5.1%)	11
Cough	104/196 (53.1%)	186	90/198 (45.5%)	162
Dyspnea	17/196 (8.7%)	18	9/198 (4.5%)	9
Produce Sputum	48/196 (24.5%)	57	39/198 (19.7%)	50
Purulent Sputum	34/196 (17.3%)	40	27/198 (13.6%)	33
Rhinorrhea	12/196 (6.1%)	17	17/198 (8.6%)	19
Sore Throat	14/196 (7.1%)	15	10/198 (5.1%)	10
Upper Respiratory Tract Infection	33/196 (16.8%)	50	27/198 (13.6%)	39
Skin and subcutaneous tissue disorders
Acne	14/196 (7.1%)	15	16/198 (8.1%)	17
Pruritis	46/196 (23.5%)	57	43/198 (21.7%)	52
Rash	18/196 (9.2%)	20	15/198 (7.6%)	15
Skin Lesion	15/196 (7.7%)	21	9/198 (4.5%)	22

Limitations/Caveats

Enrollment was stopped early and the number of patients enrolled was 1/2 of the original sample size. The study was completed.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.