PREVENT TB: Three Months of Weekly Rifapentine and Isoniazid for M. Tuberculosis Infection

• Sponsor: Centers for Disease Control and Prevention (U.S. Fed)
• Overall Status: Completed
• CT.gov ID: NCT00023452
• Collaborator: VA Office of Research and Development (U.S. Fed)
• Enrollment: 8,053
• Locations: 26
• Arms: 2
• Duration (Months): 147
• Patients Per Site: 309.7
• Patients Per Site Per Month: 2.1

Study Details

Study Description

Brief Summary

Open-label, multi-center, Phase III clinical trial to compare the effectiveness and tolerability of a three-month (12-dose) regimen of weekly rifapentine and isoniazid (3RPT/INH) to the effectiveness of a nine-month (270-dose)regimen of daily isoniazid (9INH) to prevent tuberculosis (TB) among high-risk tuberculin skin-test reactors, including children and HIV-infected persons, who require treatment of latent TB infection (LTBI).

Condition or Disease	Intervention/Treatment	Phase
Tuberculosis	Drug: RPT + INH once weekly for 3 months given by DOT; Drug: Isoniazid (INH) daily for 9 months	Phase 3

Detailed Description

The PRIMARY objective of this open-label Phase III clinical trial is to compare the effectiveness of a three-month (12-dose) regimen of weekly rifapentine and isoniazid (3RPT/INH) to the effectiveness of a nine-month (270-dose) regimen of daily isoniazid (9INH) to prevent tuberculosis (TB) among high-risk tuberculin skin-test reactors, including children and HIV-infected persons, who require treatment of latent TB infection (LTBI). The 3RPT/INH regimen will be given under direct observation and the 9INH regimen will be self-administered.

SECONDARY Objectives:

• Compare the rates of drug discontinuation due to adverse drug reactions associated with 3RPT/INH and 9INH.

• Compare the rates of drug discontinuation for any reason associated with 3RPT/INH and 9INH.

• Compare the rates of any grade 3, 4, or 5 drug toxicity associated with 3RPT/INH and 9INH.

• Compare treatment completion rates of 3RPT/INH and 9INH. Compare the efficacy (i.e., among persons who complete study-phase therapy) of 3RPT/INH and 9INH.

• Compare the effectiveness and tolerability of 3RPT/INH and 9INH in HIV-infected persons.

• Compare the effectiveness and tolerability of 3RPT/INH and 9INH in children < 18 years old.

• Compare the rates of methadone withdrawal associated with 3RPT/INH and 9INH among persons concomitantly receiving methadone.

• Describe patterns of antibiotic resistance among M. tuberculosis isolates in patients who develop TB despite treatment of latent infection.

Amendment of the study protocol to allow extension of enrollment to children < 12 years old and HIV-infected persons:

For assessment of the primary outcome, development of TB, a sample size of approximately 4,000 persons per arm will be required. To assess tolerability (one of the secondary outcomes) in sub-groups, children less than 12 years old and HIV-infected persons, a sample size of 644 per strata will be required. A sample size of 8,053 patients for the primary outcome was reached on February 15, 2008 (with expected follow-up completion time in 2010), leaving approximately 454 additional young children and 200 HIV-infected persons to be enrolled to achieve the targets of 644 for each group. The additional data on tolerability in those sub-groups will available for analysis in 2013.

Study Design

• Study Type: Interventional
• Actual Enrollment: 8053 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: TBTC Study 26: Effectiveness and Tolerability of Weekly Rifapentine/Isoniazid for 3 Months Versus Daily Isoniazid for 9 Months for the Treatment of Latent Tuberculosis Infection
• Study Start Date: Jun 1, 2001
• Actual Primary Completion Date: Oct 1, 2010
• Actual Study Completion Date: Sep 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Daily Isoniazid Isoniazid (INH) daily for 9 months (240 to 270 total doses).	Drug: Isoniazid (INH) daily for 9 months; Isoniazid (INH) 5 mg/kg (rounded up to nearest 50 or 100 mg; 300 mg max) daily x 270 doses (9 months) For children age 2 - 11, INH 10-15 mg/kg (round up to nearest 50 or 100 mg; 300 mg max) will be given.; Other Names: Isoniazid INH I 9INH
Experimental: Weekly Isoniazid / Rifapentine Isoniazid / Rifapentine (RPT/INH) weekly for 3 months (11 to 12 total doses) given by Directly Observed Therapy (DOT)	Drug: RPT + INH once weekly for 3 months given by DOT; Rifapentine (RPT) 900 mg once-weekly x 12 doses (3 months) for persons > 50.0 kg. For persons < 50.0 kg, the following doses will be given (Weight/Dose): 10.0-14.0 kg / 300 mg; 14.1-25.0 kg / 450 mg; 25.1-32.0 kg / 600 mg; 32.1-50.0 kg / 750 mg. PLUS Isoniazid (INH) 15 mg/kg (rounded up to nearest 50 or 100 mg; 900 mg max) once weekly x 12 doses if > 12 years old. INH 25 mg/kg (round up to nearest 50 or 100 mg; 900 mg max) if 2-11 years old. Therapy will be given by Directly Observed Therapy (DOT).; Other Names: INH isoniazid I Rifapentine RPT P Priftin 3HP 3INH/RPT

Outcome Measures

Primary Outcome Measures

1. Cumulative Rate of Culture-Confirmed TB Disease in Participants ≥18 Years of Age AND Culture-Confirmed or Probable (Clinical) TB Disease in Participants Less Than [<]18 Years of Age at 33 Months After Enrollment [Baseline up to Month 33]

   Cumulative TB disease rate defined as number of participants ≥18 years old with culture-confirmed TB disease (defined as positive culture for Mycobacterium tuberculosis [MTB]) and those <18 years old with probable (clinical) TB disease (defined as objective evidence of clinical TB disease [cough, fever, night sweats, weight loss, or hemoptysis] based on history or physical exam plus radiograph, computed tomography [CT] scan, other diagnostic tests PLUS response to antituberculosis therapy AND objective improvement of radiograph or other diagnostic tests; OR evidence of granuloma with organism positive for acid-fast bacilli [AFB], or caseating granulomata at autopsy or biopsy) between enrollment and the 990th Day of the Trial (33 months after enrollment, or end of the trial) per 100 participants with (w/)33 months of follow-up calculated using survival analysis methods (Kaplan-Meier approach).

Secondary Outcome Measures

1. Cumulative Rate of Culture-Confirmed TB Disease in Participants ≥18 Years of Age AND Culture-Confirmed or Probable (Clinical) TB Disease in Participants <18 Years of Age at 24 Months Following Completion of Study Therapy [Baseline up to Month 27 (3RPT/INH) or Month 33 (9INH)]

   Cumulative TB disease rate was defined as number of participants ≥18 years old with culture-confirmed TB disease (defined as positive culture for MTB) and those <18 years old with probable (clinical) TB disease (defined as objective evidence of clinical TB disease [cough, fever, night sweats, weight loss, or hemoptysis] based on history or physical exam plus radiograph, CT scan, other diagnostic tests PLUS response to antituberculosis therapy AND objective improvement of radiograph or other diagnostic tests; OR evidence of granuloma with organism positive for AFB], or caseating granulomata at autopsy or biopsy) between enrollment and 24 months after completion of study therapy per 100 participants with up to 33 months of follow-up and was calculated using survival analysis methods (Kaplan-Meier approach).

2. Cumulative Rate of Culture-Confirmed or Probable (Clinical) TB Disease (Regardless of Age) At 33 Months After Enrollment [Baseline up to 33 Months]

   Cumulative TB disease rate was defined as number of participants (regardless of age) with culture-confirmed TB disease (defined as positive culture for MTB]) or probable (clinical) TB disease (defined as objective evidence of clinical TB disease [cough, fever, night sweats, weight loss, or hemoptysis] based on history or physical exam plus radiograph, CT scan, other diagnostic tests PLUS response to antituberculosis therapy AND objective improvement of radiograph or other diagnostic tests; OR evidence of granuloma with organism positive for AFB, or caseating granulomata at autopsy or biopsy) between enrollment and the 990th Day of the Trial (33 months after enrollment, or end of the trial) per 100 participants w/33 months of follow-up and was calculated using survival analysis methods (Kaplan-Meier approach).

3. Percentage of Participants With Drug Discontinuation Due to Adverse Drug Reactions Associated With 3RPT/INH or 9INH [Baseline up to 60 days after the last dose of study drug (Month 5 [3RPT/INH] or Month 11 [9INH])]

   Discontinuation of study drug due to an adverse drug reaction associated with either 3RPT/INH or 9INH was defined as discontinuing treatment and/or study due to a treatment-related adverse event (AE) (considered either possibly, probably, or definitely related to the study drug by the investigator).

4. Percentage of Patients With Grade 3 or 4 Drug Toxicities Associated With 3RPT/INH or 9INH [Baseline up to 60 days after the last dose of study drug (Month 5 [3RPT/INH] or Month 11 [9INH])]

   Drug toxicities (or AEs) were graded using Common Toxicity Criteria (CTC version 2.0, Publish Date April 30, 1999, Cancer Therapy Evaluation Program). Grade 3 and 4 drug toxicities associated with 3RPT/INH or 9INH were defined as treatment-related Grade 3 or 4 AEs (considered either possibly, probably, or definitely related to the study drug by the investigator).

5. Percentage of Participants With Death Due to Any Cause [Baseline up to Month 35]

6. Percentage of Participants With Methadone Withdrawal Associated With 3RPT/INH and 9INH Among Participants Receiving Concomitant Methadone [Baseline to Month 33]

   Among participants concomitantly receiving methadone, the development of methadone withdrawal (defined as having >3 new symptoms for >7 days: nausea and vomiting, abdominal cramps, body aches, restlessness, irritability, dilated pupils, tremors, involuntary twitching, lacrimation, rhinorrhea, sneezing, yawning, excessive perspiration, goose flesh, or diarrhea).

7. Percentage of Participants With Drug Discontinuation for Any Reason Associated With 3RPT/INH or 9INH [Baseline up to Month 3 (3RPT/INH) or Month 9 (9INH)]

   Drug discontinuations for any reason associated with 3RPT/INH or 9INH included all reasons for discontinuation from study treatment, regardless of relationship to treatment.

8. Percentage of Participants Who Completed the Treatment Regimen [Baseline up to Month 3 (3RPT/INH) or Month 9 (9INH)]

   Completion in the 3RPT/INH arm was defined as: received 12 doses of RPT/INH within 16 weeks (12 weeks optimal). However, participants were considered to have completed therapy if at least 11 doses of RPT/INH had been received (~90%) during the 16-week time period. Completion in the 9INH arm was defined as: received 270 doses of INH within 52 weeks (39 weeks optimal). However, participants were considered to have completed therapy if at least 240 doses of INH were received (~90%) during the 52-week period.

9. Cumulative Rate of Culture-Confirmed TB Disease in Participants ≥18 Years of Age AND Culture Confirmed or Probable (Clinical) TB Disease Among Participants <18 Years of Age Who Completed Study Phase Therapy Within 33 Months of Enrollment [Baseline up to Month 33]

   Cumulative TB disease rate was defined as number of participants ≥18 years old with culture-confirmed TB disease (defined as positive culture for MTB) and <18 years old with probable (clinical) TB disease (defined as objective evidence of clinical TB disease [cough, fever, night sweats, weight loss, or hemoptysis] based on history or physical exam plus radiograph, CT scan, other diagnostic tests PLUS response to antituberculosis therapy AND objective improvement of radiograph or other diagnostic tests; OR evidence of granuloma with organism positive for AFB], or caseating granulomata at autopsy or biopsy) between enrollment and 33 months after enrollment (for those who completed therapy within 33 months) per 100 participants w/33 months of follow-up and was calculated using survival analysis methods (Kaplan-Meier approach).

10. Percentage of Participants With Resistance to Study Medications in Isolates of MTB From Participants Who Developed Active TB Disease Within 33 Months of Enrollment [Baseline up to Month 33]

    Drug-susceptibility testing (DST) was performed on isolates of MTB obtained from participants who developed signs and symptoms of active TB disease (including sputum specimens or specimens from appropriate body site for extrapulmonary TB disease). DST was performed at site's local laboratory and sent to Sponsor for confirmatory susceptibility testing. DST included all drugs currently used to treat TB disease, including pyrazinamide (PZA) and fluoroquinolones. Susceptibility was tested for other drugs at the Sponsor laboratory at the following concentrations: INH, 0.02, 1.0, and 5.0 micrograms per milliliter (µg/mL) and rifampin (RIF), 1.0 µg/mL. Isolates resistant to RIF were assumed to be resistant to RPT.

11. Cumulative Rate of Culture-Confirmed or Probable TB Disease in HIV-Infected Participants Within 33 Months After Enrollment [Baseline to Month 33]

    Cumulative TB disease rate was defined as number of HIV-infected participants ≥2 years old with culture-confirmed TB disease (defined as positive culture for MTB) or probable (clinical) TB disease (defined as objective evidence of clinical TB disease [cough, fever, night sweats, weight loss, or hemoptysis] based on history or physical exam plus radiograph, CT scan, other diagnostic tests PLUS response to antituberculosis therapy AND objective improvement of radiograph or other diagnostic tests; OR evidence of granuloma with organism positive for AFB], or caseating granulomata at autopsy or biopsy) between enrollment and the 990th day of the trial (33 months after enrollment, or end of the trial) per 100 participants w/33 months of follow-up and was calculated using survival analysis methods (Kaplan-Meier approach).

12. Cumulative Rate of HIV-Infected Participants With Culture-Confirmed or Probable TB Disease at 24 Months After Completion of Study Therapy [Baseline up to Month 27 (3RPT/INH) or Month 33 (9INH)]

    Cumulative TB disease rate was defined as number of HIV-infected participants with culture-confirmed TB (defined as positive culture for MTB) or probable (clinical) TB disease (defined as objective evidence of clinical TB disease [cough, fever, night sweats, weight loss, or hemoptysis] based on history or physical exam plus radiograph, CT scan, other diagnostic tests PLUS response to antituberculosis therapy AND objective improvement of radiograph or other diagnostic tests; OR evidence of granuloma with organism positive for AFB], or caseating granulomata at autopsy or biopsy) between enrollment and 24 months after completion of study therapy per 100 participants with up to 33 months of follow-up and was calculated using survival analysis methods (Kaplan-Meier approach).

13. Cumulative Rate of Participants <18 Years Old With Culture-Confirmed or Probable (Clinical) TB Disease Within 33 Months of Enrollment [Baseline up to Month 33]

    Cumulative TB disease rate was defined as number of participants <18 years old with culture-confirmed TB disease (defined as positive culture for MTB) or probable (clinical) TB disease (defined as objective evidence of clinical TB disease [cough, fever, night sweats, weight loss, or hemoptysis] based on history or physical exam plus radiograph, CT scan, other diagnostic tests PLUS response to antituberculosis therapy AND objective improvement of radiograph or other diagnostic tests; OR evidence of granuloma with organism positive for AFB], or caseating granulomata at autopsy or biopsy) between enrollment and the 990th day of the trial (33 months after enrollment, or end of the trial) per 100 participants w/33 months of follow-up and was calculated using survival analysis methods (Kaplan-Meier approach).

14. Cumulative Rate of Participants <12 Years Old With Culture-Confirmed or Probable (Clinical) TB Disease Within 33 Months of Enrollment [Baseline up to Month 33]

    Cumulative TB disease rate was defined as number of participants <12 years old with culture-confirmed TB disease (defined as positive culture for MTB) or probable (clinical) TB disease (defined as objective evidence of clinical TB disease [cough, fever, night sweats, weight loss, or hemoptysis] based on history or physical exam plus radiograph, CT scan, other diagnostic tests PLUS response to antituberculosis therapy AND objective improvement of radiograph or other diagnostic tests; OR evidence of granuloma with organism positive for AFB], or caseating granulomata at autopsy or biopsy) between enrollment and the 990th day of the trial (33 months after enrollment, or end of the trial) per 100 participants w/33 months of follow-up and was calculated using survival analysis methods (Kaplan-Meier approach).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

INCLUSION criteria:

• Males or nonpregnant, non-nursing females > 2 years old.

• Tuberculin (PPD) skin test reactors at high risk for developing TB but without evidence of active TB. High-risk reactors are defined as:

1. Household and other close contacts of persons with culture-confirmed TB who are TST-positive as part of a contact investigation conducted within two years of the date of enrollment. Close contact is defined as > 4 hours in a shared airspace during a one-week period. Among close contacts, a positive TST is defined as > 5 mm induration after 5 TU of PPD placed intradermally using the Mantoux technique.

2. TST converters--converting from a documented negative to positive TST within a two-year period. This is defined as persons with a tuberculin skin test of > 10 mm within two years of a nonreactive test or persons with an increase of > 10 mm within a two-year period.

3. HIV-seropositive, TST positive (> 5 mm induration) persons.

4. Persons with > 2 cm2 of pulmonary parenchymal fibrosis on chest X-ray, no prior history of TB treatment, > 5 mm induration on TST, and 3 sputum cultures negative for M. tuberculosis on final report.

• HIV-seropositive close contacts of persons with culture-confirmed TB, regardless of TST status. In addition, HIV-seropositive close contacts of persons with culture-confirmed TB who have a documented history of completing an adequate course of treatment for active TB or latent TB infection, are also eligible.

• Willing to provide signed informed consent, or parental consent and participant assent.

EXCLUSION criteria:

• Current confirmed culture-positive or clinical TB

• Suspected TB (as defined by the site investigator)

• Tuberculosis resistant to isoniazid or rifampin in the source case

• A history of treatment for > 14 consecutive days with a rifamycin or > 30 consecutive days with INH during the previous 2 years.

• A documented history of a completing an adequate course of treatment for active TB or latent TB infection in a person who is HIV-seronegative.

• History of sensitivity/intolerance to isoniazid or rifamycins

• Serum aminotransferase aspartate (AST, SGOT) > 5x upper limit of normal among persons in whom AST is determined

• Pregnant or nursing females

• Persons currently receiving or planning to receive HIV-1 protease inhibitors or nonnucleoside reverse transcriptase inhibitors in the first 90 days after enrollment.

• Weight < 10.0 kg

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Central Arkansas Veterans Health System	Little Rock	Arkansas	United States	72205
2	LA County/USC Medical Center	Los Angeles	California	United States	90033
3	UCSD Medical Center	San Diego	California	United States	92103
4	University of California, San Francisco	San Francisco	California	United States	94110
5	Denver Department of Public Health and Hospitals	Denver	Colorado	United States	80204
6	Washington, D.C. VAMC	Washington	District of Columbia	United States	20422
7	Emory University, Department of Medicine	Atlanta	Georgia	United States	30303
8	Chicago VA Medical Center (Lakeside)	Chicago	Illinois	United States	60611
9	Hines VA Medical Center	Hines	Illinois	United States	60141
10	Johns Hopkins University School of Medicine	Baltimore	Maryland	United States	21287-0003
11	Boston Medical Center	Boston	Massachusetts	United States	02118
12	New Jersey Medical School	Newark	New Jersey	United States	07107-3001
13	Columbia University/Presbyterian Medical Center	New York	New York	United States	10032
14	Harlem Hospital Center	New York	New York	United States	10037
15	Carolinas Medical Center	Charlotte	North Carolina	United States	28203
16	Duke University Medical Center	Durham	North Carolina	United States	34222
17	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232
18	University of North Texas Health Science Center	Fort Worth	Texas	United States	76107-2699
19	Michael Debakey Veterans Affairs Medical Center	Houston	Texas	United States	77009
20	Audi L. Murphy VA Hospital	San Antonio	Texas	United States	78284
21	Seattle King County Health Department	Seattle	Washington	United States	98104
22	Universidade Federal do Rio de Janeiro	Rio de Janeiro		Brazil	cep: 21941.590
23	University of British Columbia	Vancouver	British Columbia	Canada	Canada V5Z 4R4
24	University of Manitoba	Winnipeg	Manitoba	Canada	CANADA R3A 1R8
25	Montreal Chest Institute McGill University	Montreal	Quebec	Canada	H2X 2P4Pq Canada
26	Agencia de Salut Publica	Barcelona		Spain	08023

Sponsors and Collaborators

• Centers for Disease Control and Prevention
• VA Office of Research and Development

Investigators

• Study Director: Elsa M Villarino, MD, MPH, Centers for Disease Control and Prevention
• Study Chair: Timothy Sterling, MD, Vanderbilt University Medical Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• (Click here for more information about the Tuberculosis Trials Consortium(TBTC)

Publications

None provided.

• Responsible Party: Centers for Disease Control and Prevention
• ClinicalTrials.gov Identifier: NCT00023452
• Other Study ID Numbers: CDC-NCHSTP-3041; CDC TBTC Study 26
• First Posted: Sep 10, 2001
• Last Update Posted: Apr 10, 2018
• Last Verified: Jul 1, 2015

• Keywords provided by Centers for Disease Control and Prevention: Latent TB infection
• Additional relevant MeSH terms: Infections; Tuberculosis; Latent Tuberculosis; Isoniazid; Rifapentine

Study Results

Participant Flow

Pre-assignment Detail	The protocol design allowed enrollment of participants identified as members of the same household or group setting (such as group homes, settings) in clusters. The same treatment regimen to which a first participant was randomized could be assigned to other cluster members. All other participants enrolled were randomized individually.

Arm/Group Title	9INH	3RPT/INH
Arm/Group Description	Participants who were high-risk tuberculin skin test (TST) reactors (household and other close contacts of active tuberculosis [TB] cases, recent [within 2 years] tuberculin converters, participants with fibrotic lesions on chest x-ray [CXR], human immunodeficiency virus [HIV] infected participants) self-administered oral isoniazid (INH) tablets (aged greater than or equal to [≥12] years of age received 5 milligrams per kilogram [mg/kg] and participants 2-11 years of age received 10-15 mg/kg) once daily for 9 months (240 to 270 total doses).	Participants who were high-risk TST reactors (household and other close contacts of active TB cases, recent [within 2 years] tuberculin converters, participants with fibrotic lesions on CXR, HIV-infected participants) received oral INH tablets (≥12 years of age received 15 mg/kg and participants 2-11 years of age received 25 mg/kg) and oral rifapentine (RPT) tablets (between 300-900 mg based on weight) once per week for 3 months (11 to 12 total doses) administered by Directly Observed Therapy (DOT), defined as a healthcare worker observing ingestion of each dose of RPT and INH.
Period Title: Overall Study
STARTED	3908	4145
Randomized	3190	3174
Enrolled as Part of a Cluster	718	971
Completed Treatment	2585	3273
Not Treated	149	105
Completed Study	3174	3475
COMPLETED	2585	3273
NOT COMPLETED	1323	872

Baseline Characteristics

Arm/Group Title	9INH	3RPT/INH	Total
Arm/Group Description	Participants who were high-risk TST reactors (household and other close contacts of active TB cases, recent [within 2 years] tuberculin converters, participants with fibrotic lesions on CXR, HIV infected participants) self-administered oral INH tablets (≥12 years of age received 5 mg/kg and participants 2-11 years of age received 10-15 mg/kg) once daily for 9 months (240 to 270 total doses).	Participants who were high-risk TST reactors (household and other close contacts of active TB cases, recent [within 2 years] tuberculin converters, participants with fibrotic lesions on CXR, HIV infected participants) received oral INH tablets (≥12 years of age received 15 mg/kg and participants 2-11 years of age received 25 mg/kg) and oral RPT tablets (between 300-900 mg based on weight) once per week for 3 months (11 to 12 total doses) administered by DOT, defined as a healthcare worker observing ingestion of each dose of RPT and INH.	Total of all reporting groups
Overall Participants	3908	4145	8053
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	35	36	35
Sex/Gender, Customized (participants) [Number]
Female	1812 46.4%	1847 44.6%	3659 45.4%
Male	2096 53.6%	2297 55.4%	4393 54.6%
Missing	0 0%	1 0%	1 0%

Outcome Measures

1. Primary Outcome

Title	Cumulative Rate of Culture-Confirmed TB Disease in Participants ≥18 Years of Age AND Culture-Confirmed or Probable (Clinical) TB Disease in Participants Less Than [<]18 Years of Age at 33 Months After Enrollment
Description	Cumulative TB disease rate defined as number of participants ≥18 years old with culture-confirmed TB disease (defined as positive culture for Mycobacterium tuberculosis [MTB]) and those <18 years old with probable (clinical) TB disease (defined as objective evidence of clinical TB disease [cough, fever, night sweats, weight loss, or hemoptysis] based on history or physical exam plus radiograph, computed tomography [CT] scan, other diagnostic tests PLUS response to antituberculosis therapy AND objective improvement of radiograph or other diagnostic tests; OR evidence of granuloma with organism positive for acid-fast bacilli [AFB], or caseating granulomata at autopsy or biopsy) between enrollment and the 990th Day of the Trial (33 months after enrollment, or end of the trial) per 100 participants with (w/)33 months of follow-up calculated using survival analysis methods (Kaplan-Meier approach).
Time Frame	Baseline up to Month 33

Outcome Measure Data

Analysis Population Description

Modified Intention-to-Treat (MITT) Population: all participants who enrolled in study and were eligible (Ineligible=source TB case resistant to INH or rifampin; source TB case culture-negative for MTB; positive TST not confirmed; MTB drug susceptibility test results not available for source TB case; or TB disease at enrollment).

Arm/Group Title	9INH	3RPT/INH
Arm/Group Description	Participants who were high-risk TST reactors (household and other close contacts of active TB cases, recent [within 2 years] tuberculin converters, participants with fibrotic lesions on CXR, HIV infected participants) self-administered oral INH tablets (aged ≥12 years of age received 5 mg/kg and participants 2-11 years of age received 10-15 mg/kg) daily for 9 months (240 to 270 total doses).	Participants who were high-risk TST reactors (household and other close contacts of active TB cases, recent [within 2 years] tuberculin converters, participants with fibrotic lesions on CXR, HIV infected participants) received oral INH tablets (≥12 years of age received 15 mg/kg and participants 2-11 years of age received 25 mg/kg) and oral RPT tablets (between 300-900 mg based on weight) once per week for 3 months (11 to 12 total doses) administered by DOT, defined as a healthcare worker observing ingestion of each dose of RPT and INH.
Measure Participants	3745	3986
Number [TB cases per 100 participants w/followup]	0.43 0%	0.19 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	9INH, 3RPT/INH
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The noninferiority test statistic was based on the difference of the nonparametric Kaplan-Meier estimators. The asymptotic variance of the test statistic was obtained through Greenwood's formula and a two-sided 95% confidence interval (CI) was constructed for the difference. If the upper bound of the CI was smaller than the noninferiority margin 0.75%, then the null hypothesis would be rejected and noninferiority could be claimed.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Cumulative TB Disease Rate
	Estimated Value	-0.24
	Confidence Interval	(1-Sided) 95%; to 0.01
	Parameter Dispersion	Type: Value:
	Estimation Comments	The difference in cumulative TB disease rate is the rate in the 3RPT/INH arm minus the rate in the 9INH arm.

2. Secondary Outcome

Title	Cumulative Rate of Culture-Confirmed TB Disease in Participants ≥18 Years of Age AND Culture-Confirmed or Probable (Clinical) TB Disease in Participants <18 Years of Age at 24 Months Following Completion of Study Therapy
Description	Cumulative TB disease rate was defined as number of participants ≥18 years old with culture-confirmed TB disease (defined as positive culture for MTB) and those <18 years old with probable (clinical) TB disease (defined as objective evidence of clinical TB disease [cough, fever, night sweats, weight loss, or hemoptysis] based on history or physical exam plus radiograph, CT scan, other diagnostic tests PLUS response to antituberculosis therapy AND objective improvement of radiograph or other diagnostic tests; OR evidence of granuloma with organism positive for AFB], or caseating granulomata at autopsy or biopsy) between enrollment and 24 months after completion of study therapy per 100 participants with up to 33 months of follow-up and was calculated using survival analysis methods (Kaplan-Meier approach).
Time Frame	Baseline up to Month 27 (3RPT/INH) or Month 33 (9INH)

Outcome Measure Data

Analysis Population Description

MITT Population

Arm/Group Title	9INH	3RPT/INH
Arm/Group Description	Participants who were high-risk TST reactors (household and other close contacts of active TB cases, recent [within 2 years] tuberculin converters, participants with fibrotic lesions on CXR, HIV infected participants) self-administered oral INH tablets (aged ≥12 years of age received 5 mg/kg and participants 2-11 years of age received 10-15 mg/kg) once daily for 9 months (240 to 270 total doses).	Participants who were high-risk TST reactors (household and other close contacts of active TB cases, recent [within 2 years] tuberculin converters, participants with fibrotic lesions on CXR, HIV infected participants) received oral INH tablets (≥12 years of age received 15 mg/kg and participants 2-11 years of age received 25 mg/kg) and oral RPT tablets (between 300-900 mg based on weight) once per week for 3 months (11 to 12 total doses) administered by DOT, defined as a healthcare worker observing ingestion of each dose of RPT and INH.
Measure Participants	3651	3914
Number [TB cases per 100 participants w/followup]	0.37 0%	0.16 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	9INH, 3RPT/INH
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The noninferiority test statistic was based on the difference of the nonparametric Kaplan-Meier estimators. The asymptotic variance of the test statistic was obtained through Greenwood's formula and a two-sided 95% CI was constructed for the difference. If the upper bound of the CI was smaller than the noninferiority margin 0.75%, then the null hypothesis would be rejected and noninferiority could be claimed.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Cumulative TB Rate
	Estimated Value	-0.21
	Confidence Interval	(1-Sided) 95%; to 0.04
	Parameter Dispersion	Type: Value:
	Estimation Comments	The difference in cumulative TB disease rate is the percentage in the 3RPT/INH arm minus the percentage in the 9INH arm.

3. Secondary Outcome

Title	Cumulative Rate of Culture-Confirmed or Probable (Clinical) TB Disease (Regardless of Age) At 33 Months After Enrollment
Description	Cumulative TB disease rate was defined as number of participants (regardless of age) with culture-confirmed TB disease (defined as positive culture for MTB]) or probable (clinical) TB disease (defined as objective evidence of clinical TB disease [cough, fever, night sweats, weight loss, or hemoptysis] based on history or physical exam plus radiograph, CT scan, other diagnostic tests PLUS response to antituberculosis therapy AND objective improvement of radiograph or other diagnostic tests; OR evidence of granuloma with organism positive for AFB, or caseating granulomata at autopsy or biopsy) between enrollment and the 990th Day of the Trial (33 months after enrollment, or end of the trial) per 100 participants w/33 months of follow-up and was calculated using survival analysis methods (Kaplan-Meier approach).
Time Frame	Baseline up to 33 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	9INH	3RPT/INH
Arm/Group Description	Participants who were high-risk TST reactors (household and other close contacts of active TB cases, recent [within 2 years] tuberculin converters, participants with fibrotic lesions on CXR], HIV infected participants) self-administered oral INH tablets (aged ≥12 years of age received 5 mg/kg and participants 2-11 years of age received 10-15 mg/kg) once daily for 9 months (240 to 270 total doses).	Participants who were high-risk TST reactors (household and other close contacts of active TB cases, recent [within 2 years] tuberculin converters, participants with fibrotic lesions on CXR, HIV-infected participants) received oral INH tablets (≥12 years of age received 15 mg/kg and participants 2-11 years of age received 25 mg/kg) and oral RPT tablets (between 300-900 mg based on weight) once per week for 3 months (11 to 12 total doses) administered by DOT, defined as a healthcare worker observing ingestion of each dose of RPT and INH.
Measure Participants	3745	3986
Number [TB cases per 100 participants w/followup]	0.49 0%	0.24 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	9INH, 3RPT/INH
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The noninferiority test statistic was based on the difference of the nonparametric Kaplan-Meier estimators. The asymptotic variance of the test statistic was obtained through Greenwood's formula and a two-sided 95% CI was constructed for the difference. If the upper bound of the CI was smaller than the noninferiority margin 0.75%, then the null hypothesis would be rejected and noninferiority could be claimed.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Cumulative TB Disease Rate
	Estimated Value	-0.25
	Confidence Interval	(1-Sided) 95%; to 0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments	The difference in cumulative TB disease rate is the percentage in the 3RPT/INH arm minus the percentage in the 9INH arm.

4. Secondary Outcome

Title	Percentage of Participants With Drug Discontinuation Due to Adverse Drug Reactions Associated With 3RPT/INH or 9INH
Description	Discontinuation of study drug due to an adverse drug reaction associated with either 3RPT/INH or 9INH was defined as discontinuing treatment and/or study due to a treatment-related adverse event (AE) (considered either possibly, probably, or definitely related to the study drug by the investigator).
Time Frame	Baseline up to 60 days after the last dose of study drug (Month 5 [3RPT/INH] or Month 11 [9INH])

Outcome Measure Data

Analysis Population Description

Safety Population: all participants who enrolled in the study and took at least 1 dose of study drug.

Arm/Group Title	9INH	3RPT/INH
Arm/Group Description	Participants who were high-risk TST reactors (household and other close contacts of active TB cases, recent [within 2 years] tuberculin converters, participants with fibrotic lesions on CXR, HIV infected participants) self-administered oral INH tablets (aged ≥12 years of age received 5 mg/kg and participants 2-11 years of age received 10-15 mg/kg) once daily for 9 months (240 to 270 total doses).	Participants who were high-risk TST reactors (household and other close contacts of active TB cases, recent [within 2 years] tuberculin converters, participants with fibrotic lesions on CXR, HIV-infected participants) received oral INH tablets (≥12 years of age received 15 mg/kg and participants 2-11 years of age received 25 mg/kg) and oral RPT tablets (between 300-900 mg based on weight) once per week for 3 months (11 to 12 total doses) administered by DOT, defined as a healthcare worker observing ingestion of each dose of RPT and INH.
Measure Participants	3759	4040
Number [percentage of participants]	3.8 0.1%	4.9 0.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	9INH, 3RPT/INH
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.02
	Comments
	Method	Chi-squared
	Comments

5. Secondary Outcome

Title	Percentage of Patients With Grade 3 or 4 Drug Toxicities Associated With 3RPT/INH or 9INH
Description	Drug toxicities (or AEs) were graded using Common Toxicity Criteria (CTC version 2.0, Publish Date April 30, 1999, Cancer Therapy Evaluation Program). Grade 3 and 4 drug toxicities associated with 3RPT/INH or 9INH were defined as treatment-related Grade 3 or 4 AEs (considered either possibly, probably, or definitely related to the study drug by the investigator).
Time Frame	Baseline up to 60 days after the last dose of study drug (Month 5 [3RPT/INH] or Month 11 [9INH])

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	9INH	3RPT/INH
Arm/Group Description	Participants who were high-risk TST reactors (household and other close contacts of active TB cases, recent [within 2 years] tuberculin converters, participants with fibrotic lesions on CXR, HIV infected participants) self-administered oral INH tablets (aged ≥12 years of age received 5 mg/kg and participants 2-11 years of age received 10-15 mg/kg) once daily for 9 months (240 to 270 total doses).	Participants who were high-risk TST reactors (household and other close contacts of active TB cases, recent [within 2 years] tuberculin converters, participants with fibrotic lesions on CXR, HIV-infected participants) received oral INH tablets (≥12 years of age received 15 mg/kg and participants 2-11 years of age received 25 mg/kg) and oral RPT tablets (between 300-900 mg based on weight) once per week for 3 months (11 to 12 total doses) administered by DOT, defined as a healthcare worker observing ingestion of each dose of RPT and INH.
Measure Participants	3759	4040
Grade 3	2.2 0.1%	2.7 0.1%
Grade 4	0.4 0%	0.4 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	9INH, 3RPT/INH
	Comments	Grade 3 Drug Toxicity
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.24
	Comments
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	9INH, 3RPT/INH
	Comments	Grade 4 Drug Toxicity
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.59
	Comments
	Method	Chi-squared
	Comments

6. Secondary Outcome

Title	Percentage of Participants With Death Due to Any Cause
Time Frame	Baseline up to Month 35

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	9INH	3RPT/INH
Arm/Group Description	Participants who were high-risk TST reactors (household and other close contacts of active TB cases, recent [within 2 years] tuberculin converters, participants with fibrotic lesions on CXR, HIV infected participants) self-administered oral INH tablets (aged ≥12 years of age received 5 mg/kg and participants 2-11 years of age received 10-15 mg/kg) once daily for 9 months (240 to 270 total doses).	Participants who were high-risk TST reactors (household and other close contacts of active TB cases, recent [within 2 years] tuberculin converters, participants with fibrotic lesions on CXR, HIV-infected participants) received oral INH tablets (≥12 years of age received 15 mg/kg and participants 2-11 years of age received 25 mg/kg) and oral RPT tablets (between 300-900 mg based on weight) once per week for 3 months (11 to 12 total doses) administered by DOT, defined as a healthcare worker observing ingestion of each dose of RPT and INH.
Measure Participants	3759	4040
Number [percentage of participants]	1.0 0%	0.8 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	9INH, 3RPT/INH
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.22
	Comments
	Method	Chi-squared
	Comments

7. Secondary Outcome

Title	Percentage of Participants With Methadone Withdrawal Associated With 3RPT/INH and 9INH Among Participants Receiving Concomitant Methadone
Description	Among participants concomitantly receiving methadone, the development of methadone withdrawal (defined as having >3 new symptoms for >7 days: nausea and vomiting, abdominal cramps, body aches, restlessness, irritability, dilated pupils, tremors, involuntary twitching, lacrimation, rhinorrhea, sneezing, yawning, excessive perspiration, goose flesh, or diarrhea).
Time Frame	Baseline to Month 33

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	Percentage of Participants With Drug Discontinuation for Any Reason Associated With 3RPT/INH or 9INH
Description	Drug discontinuations for any reason associated with 3RPT/INH or 9INH included all reasons for discontinuation from study treatment, regardless of relationship to treatment.
Time Frame	Baseline up to Month 3 (3RPT/INH) or Month 9 (9INH)

Outcome Measure Data

Analysis Population Description

MITT Population

Arm/Group Title	9INH	3RPT/INH
Arm/Group Description	Participants who were high-risk TST reactors (household and other close contacts of active TB cases, recent [within 2 years] tuberculin converters, participants with fibrotic lesions on CXR, HIV infected participants) self-administered oral INH tablets (≥12 years of age received 5 mg/kg and participants 2-11 years of age received 10-15 mg/kg) once daily for 9 months (240 to 270 total doses).	Participants who were high-risk TST reactors (household and other close contacts of active TB cases, recent [within 2 years] tuberculin converters, participants with fibrotic lesions on CXR, HIV infected participants) received oral INH tablets (≥12 years of age received 15 mg/kg and participants 2-11 years of age received 25 mg/kg) and oral RPT tablets (between 300-900 mg based on weight) once per week for 3 months (11 to 12 total doses) administered by DOT, defined as a healthcare worker observing ingestion of each dose of RPT and INH.
Measure Participants	3745	3986
Number [percentage of participants]	31.0 0.8%	17.9 0.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	9INH, 3RPT/INH
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Chi-squared
	Comments

9. Secondary Outcome

Title	Percentage of Participants Who Completed the Treatment Regimen
Description	Completion in the 3RPT/INH arm was defined as: received 12 doses of RPT/INH within 16 weeks (12 weeks optimal). However, participants were considered to have completed therapy if at least 11 doses of RPT/INH had been received (~90%) during the 16-week time period. Completion in the 9INH arm was defined as: received 270 doses of INH within 52 weeks (39 weeks optimal). However, participants were considered to have completed therapy if at least 240 doses of INH were received (~90%) during the 52-week period.
Time Frame	Baseline up to Month 3 (3RPT/INH) or Month 9 (9INH)

Outcome Measure Data

Analysis Population Description

MITT Population

Arm/Group Title	9INH	3RPT/INH
Arm/Group Description	Participants who were high-risk TST reactors (household and other close contacts of active TB cases, recent [within 2 years] tuberculin converters, participants with fibrotic lesions on CXR, HIV infected participants) self-administered oral INH tablets (≥12 years of age received 5 mg/kg and participants 2-11 years of age received 10-15 mg/kg) once daily for 9 months (240 to 270 total doses).	Participants who were high-risk TST reactors (household and other close contacts of active TB cases, recent [within 2 years] tuberculin converters, participants with fibrotic lesions on CXR, HIV infected participants) received oral INH tablets (≥12 years of age received 15 mg/kg and participants 2-11 years of age received 25 mg/kg) and oral RPT tablets (between 300-900 mg based on weight) once per week for 3 months (11 to 12 total doses) administered by DOT, defined as a healthcare worker observing ingestion of each dose of RPT and INH.
Measure Participants	3745	3986
Number [percentage of participants]	69.0 1.8%	82.1 2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	9INH, 3RPT/INH
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Chi-squared
	Comments

10. Secondary Outcome

Title	Cumulative Rate of Culture-Confirmed TB Disease in Participants ≥18 Years of Age AND Culture Confirmed or Probable (Clinical) TB Disease Among Participants <18 Years of Age Who Completed Study Phase Therapy Within 33 Months of Enrollment
Description	Cumulative TB disease rate was defined as number of participants ≥18 years old with culture-confirmed TB disease (defined as positive culture for MTB) and <18 years old with probable (clinical) TB disease (defined as objective evidence of clinical TB disease [cough, fever, night sweats, weight loss, or hemoptysis] based on history or physical exam plus radiograph, CT scan, other diagnostic tests PLUS response to antituberculosis therapy AND objective improvement of radiograph or other diagnostic tests; OR evidence of granuloma with organism positive for AFB], or caseating granulomata at autopsy or biopsy) between enrollment and 33 months after enrollment (for those who completed therapy within 33 months) per 100 participants w/33 months of follow-up and was calculated using survival analysis methods (Kaplan-Meier approach).
Time Frame	Baseline up to Month 33

Outcome Measure Data

Analysis Population Description

Per Protocol Population: all enrolled and eligible participants (MITT Population) who completed study drug within targeted time period (11-12 3RPT/INH doses within 10-16 weeks; 240-270 INH doses within 35-52 weeks) or developed TB disease or died while on study therapy (or follow-up) but completed ≥75% of expected number of doses prior to event.

Arm/Group Title	9INH	3RPT/INH
Arm/Group Description	Participants who were high-risk TST reactors (household and other close contacts of active TB cases, recent [within 2 years] tuberculin converters, participants with fibrotic lesions on CXR, HIV infected participants) self-administered oral INH tablets (aged ≥12 years of age received 5 mg/kg and participants 2-11 years of age received 10-15 mg/kg) once daily for 9 months (240 to 270 total doses).	Participants who were high-risk TST reactors (household and other close contacts of active TB cases, recent [within 2 years] tuberculin converters, participants with fibrotic lesions on CXR, HIV-infected participants) received oral INH tablets (≥12 years of age received 15 mg/kg and participants 2-11 years of age received 25 mg/kg) and oral RPT tablets (between 300-900 mg based on weight) once per week for 3 months (11 to 12 total doses) administered by DOT, defined as a healthcare worker observing ingestion of each dose of RPT and INH.
Measure Participants	2585	3273
Number [TB cases per 100 participants w/followup]	0.11 0%	0.05 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	9INH, 3RPT/INH
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The noninferiority test statistic was based on the difference of the nonparametric Kaplan-Meier estimators. The asymptotic variance of the test statistic was obtained through Greenwood's formula and a two-sided 95% CI was constructed for the difference. If the upper bound of the CI was smaller than the noninferiority margin 0.75%, then the null hypothesis would be rejected and noninferiority could be claimed.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in Cumulative TB Disease Rate
	Estimated Value	-0.19
	Confidence Interval	(1-Sided) 95%; to 0.06
	Parameter Dispersion	Type: Value:
	Estimation Comments	The difference in cumulative TB disease rate is the percentage in the 3RPT/INH arm minus the percentage in the 9INH arm.

11. Secondary Outcome

Title	Percentage of Participants With Resistance to Study Medications in Isolates of MTB From Participants Who Developed Active TB Disease Within 33 Months of Enrollment
Description	Drug-susceptibility testing (DST) was performed on isolates of MTB obtained from participants who developed signs and symptoms of active TB disease (including sputum specimens or specimens from appropriate body site for extrapulmonary TB disease). DST was performed at site's local laboratory and sent to Sponsor for confirmatory susceptibility testing. DST included all drugs currently used to treat TB disease, including pyrazinamide (PZA) and fluoroquinolones. Susceptibility was tested for other drugs at the Sponsor laboratory at the following concentrations: INH, 0.02, 1.0, and 5.0 micrograms per milliliter (µg/mL) and rifampin (RIF), 1.0 µg/mL. Isolates resistant to RIF were assumed to be resistant to RPT.
Time Frame	Baseline up to Month 33

Outcome Measure Data

Analysis Population Description

N equals the number of participants who developed active TB disease during the study for which DST was performed.

Arm/Group Title	9INH	3RPT/INH
Arm/Group Description	Participants who were high-risk TST reactors (household and other close contacts of active TB cases, recent [within 2 years] tuberculin converters, participants with fibrotic lesions on CXR, HIV infected participants) self-administered oral INH tablets (≥12 years of age received 5 mg/kg and participants 2-11 years of age received 10-15 mg/kg) once daily for 9 months (240 to 270 total doses).	Participants who were high-risk TST reactors (household and other close contacts of active TB cases, recent [within 2 years] tuberculin converters, participants with fibrotic lesions on CXR, HIV infected participants) received oral INH tablets (≥12 years of age received 15 mg/kg and participants 2-11 years of age received 25 mg/kg) and oral RPT tablets (between 300-900 mg based on weight) once per week for 3 months (11 to 12 total doses) administered by DOT, defined as a healthcare worker observing ingestion of each dose of RPT and INH.
Measure Participants	13	7
INH monoresistance	15 0.4%	0 0%
RIF and PZA resistant	0 0%	14 0.3%

12. Secondary Outcome

Title	Cumulative Rate of Culture-Confirmed or Probable TB Disease in HIV-Infected Participants Within 33 Months After Enrollment
Description	Cumulative TB disease rate was defined as number of HIV-infected participants ≥2 years old with culture-confirmed TB disease (defined as positive culture for MTB) or probable (clinical) TB disease (defined as objective evidence of clinical TB disease [cough, fever, night sweats, weight loss, or hemoptysis] based on history or physical exam plus radiograph, CT scan, other diagnostic tests PLUS response to antituberculosis therapy AND objective improvement of radiograph or other diagnostic tests; OR evidence of granuloma with organism positive for AFB], or caseating granulomata at autopsy or biopsy) between enrollment and the 990th day of the trial (33 months after enrollment, or end of the trial) per 100 participants w/33 months of follow-up and was calculated using survival analysis methods (Kaplan-Meier approach).
Time Frame	Baseline to Month 33

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

13. Secondary Outcome

Title	Cumulative Rate of HIV-Infected Participants With Culture-Confirmed or Probable TB Disease at 24 Months After Completion of Study Therapy
Description	Cumulative TB disease rate was defined as number of HIV-infected participants with culture-confirmed TB (defined as positive culture for MTB) or probable (clinical) TB disease (defined as objective evidence of clinical TB disease [cough, fever, night sweats, weight loss, or hemoptysis] based on history or physical exam plus radiograph, CT scan, other diagnostic tests PLUS response to antituberculosis therapy AND objective improvement of radiograph or other diagnostic tests; OR evidence of granuloma with organism positive for AFB], or caseating granulomata at autopsy or biopsy) between enrollment and 24 months after completion of study therapy per 100 participants with up to 33 months of follow-up and was calculated using survival analysis methods (Kaplan-Meier approach).
Time Frame	Baseline up to Month 27 (3RPT/INH) or Month 33 (9INH)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

14. Secondary Outcome

Title	Cumulative Rate of Participants <18 Years Old With Culture-Confirmed or Probable (Clinical) TB Disease Within 33 Months of Enrollment
Description	Cumulative TB disease rate was defined as number of participants <18 years old with culture-confirmed TB disease (defined as positive culture for MTB) or probable (clinical) TB disease (defined as objective evidence of clinical TB disease [cough, fever, night sweats, weight loss, or hemoptysis] based on history or physical exam plus radiograph, CT scan, other diagnostic tests PLUS response to antituberculosis therapy AND objective improvement of radiograph or other diagnostic tests; OR evidence of granuloma with organism positive for AFB], or caseating granulomata at autopsy or biopsy) between enrollment and the 990th day of the trial (33 months after enrollment, or end of the trial) per 100 participants w/33 months of follow-up and was calculated using survival analysis methods (Kaplan-Meier approach).
Time Frame	Baseline up to Month 33

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

15. Secondary Outcome

Title	Cumulative Rate of Participants <12 Years Old With Culture-Confirmed or Probable (Clinical) TB Disease Within 33 Months of Enrollment
Description	Cumulative TB disease rate was defined as number of participants <12 years old with culture-confirmed TB disease (defined as positive culture for MTB) or probable (clinical) TB disease (defined as objective evidence of clinical TB disease [cough, fever, night sweats, weight loss, or hemoptysis] based on history or physical exam plus radiograph, CT scan, other diagnostic tests PLUS response to antituberculosis therapy AND objective improvement of radiograph or other diagnostic tests; OR evidence of granuloma with organism positive for AFB], or caseating granulomata at autopsy or biopsy) between enrollment and the 990th day of the trial (33 months after enrollment, or end of the trial) per 100 participants w/33 months of follow-up and was calculated using survival analysis methods (Kaplan-Meier approach).
Time Frame	Baseline up to Month 33

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Baseline until Month 35
Arm/Group Title	9INH		3RPT/INH
Arm/Group Description	Participants who were high-risk TST reactors (household and other close contacts of active TB cases, recent [within 2 years] tuberculin converters, participants with fibrotic lesions on CXR, HIV infected participants) self-administered oral INH tablets (≥12 years of age received 5 mg/kg and participants 2-11 years of age received 10-15 mg/kg) once daily for 9 months (240 to 270 total doses).		Participants who were high-risk TST reactors (household and other close contacts of active TB cases, recent [within 2 years] tuberculin converters, participants with fibrotic lesions on CXR, HIV infected participants) received oral INH tablets (≥12 years of age received 15 mg/kg and participants 2-11 years of age received 25 mg/kg) and oral RPT tablets (between 300-900 mg based on weight) once per week for 3 months (11 to 12 total doses) administered by DOT, defined as a healthcare worker observing ingestion of each dose of RPT and INH.
All Cause Mortality
	9INH		3RPT/INH
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	9INH		3RPT/INH
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	102/3759 (2.7%)		60/4040 (1.5%)
Blood and lymphatic system disorders
Anaemia	3/3759 (0.1%)		1/4040 (0%)
Cardiac disorders
Angina pectoris	0/3759 (0%)		2/4040 (0%)
Myocardial infarction	1/3759 (0%)		1/4040 (0%)
Acute myocardial infarction	0/3759 (0%)		1/4040 (0%)
Atrial fibrillation	1/3759 (0%)		0/4040 (0%)
Cardiac failure congestive	1/3759 (0%)		0/4040 (0%)
Left ventricular dysfunction	0/3759 (0%)		1/4040 (0%)
Ventricular extrasystoles	1/3759 (0%)		0/4040 (0%)
Gastrointestinal disorders
Abdominal pain	3/3759 (0.1%)		0/4040 (0%)
Pancreatitis	2/3759 (0.1%)		1/4040 (0%)
Vomiting	2/3759 (0.1%)		1/4040 (0%)
Gastrointestinal hemorrhage	0/3759 (0%)		2/4040 (0%)
Nausea	1/3759 (0%)		1/4040 (0%)
Abdominal pain upper	1/3759 (0%)		0/4040 (0%)
Colitis	1/3759 (0%)		0/4040 (0%)
Diverticulum	1/3759 (0%)		0/4040 (0%)
Oesophageal irritation	0/3759 (0%)		1/4040 (0%)
Pancreatitis acute	0/3759 (0%)		1/4040 (0%)
Periodontal disease	1/3759 (0%)		0/4040 (0%)
Rectal haemorrhage	1/3759 (0%)		0/4040 (0%)
General disorders
Chest pain	7/3759 (0.2%)		2/4040 (0%)
Chest discomfort	1/3759 (0%)		0/4040 (0%)
Local swelling	1/3759 (0%)		0/4040 (0%)
Pyrexia	0/3759 (0%)		1/4040 (0%)
Hepatobiliary disorders
Hepatitis	3/3759 (0.1%)		0/4040 (0%)
Cholelithiasis	0/3759 (0%)		2/4040 (0%)
Bile duct stone	0/3759 (0%)		1/4040 (0%)
Cholecystitis	1/3759 (0%)		0/4040 (0%)
Immune system disorders
Hypersensitivity	1/3759 (0%)		8/4040 (0.2%)
Infections and infestations
Cellulitis	3/3759 (0.1%)		2/4040 (0%)
Pneumonia	3/3759 (0.1%)		2/4040 (0%)
Bronchitis	2/3759 (0.1%)		1/4040 (0%)
Appendicitis perforated	2/3759 (0.1%)		0/4040 (0%)
Pyelonephritis	1/3759 (0%)		1/4040 (0%)
Abdominal wall abscess	1/3759 (0%)		0/4040 (0%)
Cholecystitis infective	1/3759 (0%)		0/4040 (0%)
Gastroenteritis	1/3759 (0%)		0/4040 (0%)
Helicobacter infection	1/3759 (0%)		0/4040 (0%)
Kidney infection	1/3759 (0%)		1/4040 (0%)
Lobar pneumonia	1/3759 (0%)		0/4040 (0%)
Meningitis viral	1/3759 (0%)		0/4040 (0%)
Pelvic inflammatory disease	0/3759 (0%)		1/4040 (0%)
Pharyngitis streptococcal	1/3759 (0%)		0/4040 (0%)
Sinusitis	1/3759 (0%)		0/4040 (0%)
Urinary tract infection	1/3759 (0%)		0/4040 (0%)
Wound infection	1/3759 (0%)		0/4040 (0%)
Injury, poisoning and procedural complications
Ankle fracture	2/3759 (0.1%)		0/4040 (0%)
Road traffic accident	1/3759 (0%)		1/4040 (0%)
Arthropod bite	1/3759 (0%)		0/4040 (0%)
Contusion	1/3759 (0%)		0/4040 (0%)
Laceration	1/3759 (0%)		0/4040 (0%)
Medication error	1/3759 (0%)		0/4040 (0%)
Overdose	1/3759 (0%)		0/4040 (0%)
Snake bite	0/3759 (0%)		1/4040 (0%)
Spinal compression fracture	1/3759 (0%)		0/4040 (0%)
Stab wound	0/3759 (0%)		1/4040 (0%)
Thermal burn	1/3759 (0%)		0/4040 (0%)
Tibia fracture	1/3759 (0%)		0/4040 (0%)
Wrist fracture	1/3759 (0%)		0/4040 (0%)
Metabolism and nutrition disorders
Diabetes mellitus	1/3759 (0%)		1/4040 (0%)
Hyperglycaemia	1/3759 (0%)		1/4040 (0%)
Gestational diabetes	1/3759 (0%)		0/4040 (0%)
Musculoskeletal and connective tissue disorders
Muscular weakness	1/3759 (0%)		1/4040 (0%)
Back pain	1/3759 (0%)		0/4040 (0%)
Flank pain	1/3759 (0%)		0/4040 (0%)
Pain in jaw	1/3759 (0%)		0/4040 (0%)
Pseudoarthrosis	0/3759 (0%)		1/4040 (0%)
Rhabdomyolysis	0/3759 (0%)		1/4040 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hepatic neoplasm malignant	1/3759 (0%)		0/4040 (0%)
Lung adenocarcinoma metastatic	1/3759 (0%)		0/4040 (0%)
Metastatic gastric cancer	1/3759 (0%)		0/4040 (0%)
Oesophageal carcinoma	0/3759 (0%)		1/4040 (0%)
Osteosarcoma recurrent	1/3759 (0%)		0/4040 (0%)
Nervous system disorders
Syncope	2/3759 (0.1%)		0/4040 (0%)
Cerebrovascular accident	1/3759 (0%)		0/4040 (0%)
Convulsion	0/3759 (0%)		1/4040 (0%)
Dizziness	1/3759 (0%)		0/4040 (0%)
Drug withdrawal convulsions	0/3759 (0%)		1/4040 (0%)
Dysarthria	1/3759 (0%)		0/4040 (0%)
Subarachnoid haemorrhage	0/3759 (0%)		1/4040 (0%)
Thalamic infarction	0/3759 (0%)		1/4040 (0%)
Toxic encephalopathy	0/3759 (0%)		1/4040 (0%)
VIIth nerve paralysis	0/3759 (0%)		1/4040 (0%)
Pregnancy, puerperium and perinatal conditions
Pregnancy	2/3759 (0.1%)		0/4040 (0%)
Psychiatric disorders
Depression	3/3759 (0.1%)		1/4040 (0%)
Depression suicidal	2/3759 (0.1%)		0/4040 (0%)
Drug dependence	1/3759 (0%)		1/4040 (0%)
Suicidal ideation	2/3759 (0.1%)		0/4040 (0%)
Suicide attempt	2/3759 (0.1%)		0/4040 (0%)
Disorientation	0/3759 (0%)		1/4040 (0%)
Major depression	1/3759 (0%)		0/4040 (0%)
Mental disorder	1/3759 (0%)		0/4040 (0%)
Mental status changes	1/3759 (0%)		0/4040 (0%)
Substance abuse	0/3759 (0%)		1/4040 (0%)
Suicidal behavior	1/3759 (0%)		0/4040 (0%)
Renal and urinary disorders
Urinary retention	1/3759 (0%)		0/4040 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	2/3759 (0.1%)		0/4040 (0%)
Chronic obstructive pulmonary disease	1/3759 (0%)		0/4040 (0%)
Emphysema	0/3759 (0%)		1/4040 (0%)
Pneumothorax	0/3759 (0%)		1/4040 (0%)
Pulmonary embolism	0/3759 (0%)		1/4040 (0%)
Skin and subcutaneous tissue disorders
Urticaria	0/3759 (0%)		1/4040 (0%)
Surgical and medical procedures
Hernia repair	3/3759 (0.1%)		0/4040 (0%)
Hysterectomy	1/3759 (0%)		2/4040 (0%)
Ankle operation	1/3759 (0%)		1/4040 (0%)
Cholecystectomy	1/3759 (0%)		1/4040 (0%)
Abdominal operation	1/3759 (0%)		1/4040 (0%)
Abscess drainage	0/3759 (0%)		1/4040 (0%)
Alcohol detoxification	1/3759 (0%)		0/4040 (0%)
Angioplasty	0/3759 (0%)		1/4040 (0%)
Arteriovenous graft	0/3759 (0%)		1/4040 (0%)
Cardiac operation	0/3759 (0%)		1/4040 (0%)
Endometriosis ablation	1/3759 (0%)		0/4040 (0%)
Craniotomy	0/3759 (0%)		1/4040 (0%)
Gallbladder operation	1/3759 (0%)		0/4040 (0%)
Inguinal hernia repair	1/3759 (0%)		0/4040 (0%)
Internal fixation of fracture	1/3759 (0%)		0/4040 (0%)
Knee arthroplasty	1/3759 (0%)		0/4040 (0%)
Open reduction of fracture	1/3759 (0%)		0/4040 (0%)
Salivary gland resection	1/3759 (0%)		0/4040 (0%)
Thyroidectomy	1/3759 (0%)		0/4040 (0%)
Transurethral prostatectomy	1/3759 (0%)		0/4040 (0%)
Varicose vein operation	0/3759 (0%)		1/4040 (0%)
Vascular disorders
Hypertension	3/3759 (0.1%)		1/4040 (0%)
Hypertensive crisis	2/3759 (0.1%)		0/4040 (0%)
Deep vein thrombosis	1/3759 (0%)		0/4040 (0%)
Other (Not Including Serious) Adverse Events
	9INH		3RPT/INH
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	226/3759 (6%)		248/4040 (6.1%)
Hepatobiliary disorders
Hepatitis	110/3759 (2.9%)		24/4040 (0.6%)
Immune system disorders
Hypersensitivity	17/3759 (0.5%)		153/4040 (3.8%)
Injury, poisoning and procedural complications
Medication error	36/3759 (1%)		27/4040 (0.7%)
Pregnancy, puerperium and perinatal conditions
Pregnancy	69/3759 (1.8%)		45/4040 (1.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.