Tuberculosis
Conditions
Keywords
Latent TB infection
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).
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.
Interventions
DRUGRPT + 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).
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.
Sponsors
US Department of Veterans Affairs
Centers for Disease Control and Prevention
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| 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). |
| 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). |
| Percentage of Participants With Death Due to Any Cause | Baseline up to Month 35 | — |
| 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). |
| 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. |
| 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). |
| 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). |
| 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. |
| 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). |
| 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). |
| 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). |
| 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). |
| 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. |
Countries
Brazil, Canada, Spain, United States
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 9INH 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). | 3,908 |
| 3RPT/INH 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. | 4,145 |
| Total | 8,053 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 139 | 196 |
| Overall Study | Death | 2 | 0 |
| Overall Study | Ineligible for Study | 163 | 159 |
| Overall Study | Lost to Follow-up | 293 | 60 |
| Overall Study | Other | 204 | 69 |
| Overall Study | Out of Window | 129 | 69 |
| Overall Study | Physician Decision | 49 | 21 |
| Overall Study | Pregnant | 53 | 20 |
| Overall Study | Refused Treatment (continued follow-up) | 225 | 224 |
| Overall Study | Withdrawal by Subject | 66 | 54 |
Baseline characteristics
| Characteristic | 9INH | 3RPT/INH | Total |
|---|---|---|---|
| Age, Continuous | 35 years | 36 years | 35 years |
| Sex/Gender, Customized Female | 1812 participants | 1847 participants | 3659 participants |
| Sex/Gender, Customized Male | 2096 participants | 2297 participants | 4393 participants |
| Sex/Gender, Customized Missing | 0 participants | 1 participants | 1 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 226 / 3,759 | 248 / 4,040 |
| serious Total, serious adverse events | 102 / 3,759 | 60 / 4,040 |
Outcome results
Primary
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
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| 9INH | 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 | 0.43 TB cases per 100 participants w/followup |
| 3RPT/INH | 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 | 0.19 TB cases per 100 participants w/followup |
Secondary
Cumulative Rate of Culture-Confirmed or Probable (Clinical) TB Disease (Regardless of Age) At 33 Months After Enrollment
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 9INH | Cumulative Rate of Culture-Confirmed or Probable (Clinical) TB Disease (Regardless of Age) At 33 Months After Enrollment | 0.49 TB cases per 100 participants w/followup |
| 3RPT/INH | Cumulative Rate of Culture-Confirmed or Probable (Clinical) TB Disease (Regardless of Age) At 33 Months After Enrollment | 0.24 TB cases per 100 participants w/followup |
Secondary
Cumulative Rate of Culture-Confirmed or Probable TB Disease in HIV-Infected Participants Within 33 Months After Enrollment
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 9INH | Cumulative Rate of Culture-Confirmed or Probable TB Disease in HIV-Infected Participants Within 33 Months After Enrollment | 3.5 TB cases per 100 participants w/followup |
| 3RPT/INH | Cumulative Rate of Culture-Confirmed or Probable TB Disease in HIV-Infected Participants Within 33 Months After Enrollment | 1.01 TB cases per 100 participants w/followup |
Secondary
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
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| 9INH | 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 | 0.11 TB cases per 100 participants w/followup |
| 3RPT/INH | 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 | 0.05 TB cases per 100 participants w/followup |
Secondary
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
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)
Population: MITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 9INH | 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 | 0.37 TB cases per 100 participants w/followup |
| 3RPT/INH | 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 | 0.16 TB cases per 100 participants w/followup |
Secondary
Cumulative Rate of HIV-Infected Participants With Culture-Confirmed or Probable TB Disease at 24 Months After Completion of Study Therapy
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)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 9INH | Cumulative Rate of HIV-Infected Participants With Culture-Confirmed or Probable TB Disease at 24 Months After Completion of Study Therapy | 3.12 TB cases per 100 participants w/followup |
| 3RPT/INH | Cumulative Rate of HIV-Infected Participants With Culture-Confirmed or Probable TB Disease at 24 Months After Completion of Study Therapy | 1.07 TB cases per 100 participants w/followup |
Secondary
Cumulative Rate of Participants <12 Years Old With Culture-Confirmed or Probable (Clinical) TB Disease Within 33 Months of Enrollment
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 9INH | Cumulative Rate of Participants <12 Years Old With Culture-Confirmed or Probable (Clinical) TB Disease Within 33 Months of Enrollment | 1.35 TB cases per 100 participants w/followup |
| 3RPT/INH | Cumulative Rate of Participants <12 Years Old With Culture-Confirmed or Probable (Clinical) TB Disease Within 33 Months of Enrollment | 0.00 TB cases per 100 participants w/followup |
Secondary
Cumulative Rate of Participants <18 Years Old With Culture-Confirmed or Probable (Clinical) TB Disease Within 33 Months of Enrollment
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 9INH | Cumulative Rate of Participants <18 Years Old With Culture-Confirmed or Probable (Clinical) TB Disease Within 33 Months of Enrollment | 0.74 TB cases per 100 participants w/followup |
| 3RPT/INH | Cumulative Rate of Participants <18 Years Old With Culture-Confirmed or Probable (Clinical) TB Disease Within 33 Months of Enrollment | 0.00 TB cases per 100 participants w/followup |
Secondary
Percentage of Participants Who Completed the Treatment Regimen
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)
Population: MITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 9INH | Percentage of Participants Who Completed the Treatment Regimen | 69.0 percentage of participants |
| 3RPT/INH | Percentage of Participants Who Completed the Treatment Regimen | 82.1 percentage of participants |
p-value: <0.0001Chi-squared
Secondary
Percentage of Participants With Death Due to Any Cause
Time frame: Baseline up to Month 35
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 9INH | Percentage of Participants With Death Due to Any Cause | 1.0 percentage of participants |
| 3RPT/INH | Percentage of Participants With Death Due to Any Cause | 0.8 percentage of participants |
p-value: 0.22Chi-squared
Secondary
Percentage of Participants With Drug Discontinuation Due to Adverse Drug Reactions Associated With 3RPT/INH or 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).
Time frame: Baseline up to 60 days after the last dose of study drug (Month 5 [3RPT/INH] or Month 11 [9INH])
Population: Safety Population: all participants who enrolled in the study and took at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 9INH | Percentage of Participants With Drug Discontinuation Due to Adverse Drug Reactions Associated With 3RPT/INH or 9INH | 3.8 percentage of participants |
| 3RPT/INH | Percentage of Participants With Drug Discontinuation Due to Adverse Drug Reactions Associated With 3RPT/INH or 9INH | 4.9 percentage of participants |
p-value: 0.02Chi-squared
Secondary
Percentage of Participants With Drug Discontinuation for Any Reason Associated With 3RPT/INH or 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.
Time frame: Baseline up to Month 3 (3RPT/INH) or Month 9 (9INH)
Population: MITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 9INH | Percentage of Participants With Drug Discontinuation for Any Reason Associated With 3RPT/INH or 9INH | 31.0 percentage of participants |
| 3RPT/INH | Percentage of Participants With Drug Discontinuation for Any Reason Associated With 3RPT/INH or 9INH | 17.9 percentage of participants |
p-value: <0.001Chi-squared
Secondary
Percentage of Participants With Methadone Withdrawal Associated With 3RPT/INH and 9INH Among Participants Receiving Concomitant Methadone
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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 9INH | Percentage of Participants With Methadone Withdrawal Associated With 3RPT/INH and 9INH Among Participants Receiving Concomitant Methadone | 14 Participants |
| 3RPT/INH | Percentage of Participants With Methadone Withdrawal Associated With 3RPT/INH and 9INH Among Participants Receiving Concomitant Methadone | 15 Participants |
Secondary
Percentage of Participants With Resistance to Study Medications in Isolates of MTB From Participants Who Developed Active TB Disease Within 33 Months of Enrollment
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
Population: N equals the number of participants who developed active TB disease during the study for which DST was performed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 9INH | Percentage of Participants With Resistance to Study Medications in Isolates of MTB From Participants Who Developed Active TB Disease Within 33 Months of Enrollment | INH monoresistance | 15 percentage of participants |
| 9INH | Percentage of Participants With Resistance to Study Medications in Isolates of MTB From Participants Who Developed Active TB Disease Within 33 Months of Enrollment | RIF and PZA resistant | 0 percentage of participants |
| 3RPT/INH | Percentage of Participants With Resistance to Study Medications in Isolates of MTB From Participants Who Developed Active TB Disease Within 33 Months of Enrollment | INH monoresistance | 0 percentage of participants |
| 3RPT/INH | Percentage of Participants With Resistance to Study Medications in Isolates of MTB From Participants Who Developed Active TB Disease Within 33 Months of Enrollment | RIF and PZA resistant | 14 percentage of participants |
Secondary
Percentage of Patients With Grade 3 or 4 Drug Toxicities Associated With 3RPT/INH or 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).
Time frame: Baseline up to 60 days after the last dose of study drug (Month 5 [3RPT/INH] or Month 11 [9INH])
Population: Safety Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 9INH | Percentage of Patients With Grade 3 or 4 Drug Toxicities Associated With 3RPT/INH or 9INH | Grade 4 | 0.4 percentage of participants |
| 9INH | Percentage of Patients With Grade 3 or 4 Drug Toxicities Associated With 3RPT/INH or 9INH | Grade 3 | 2.2 percentage of participants |
| 3RPT/INH | Percentage of Patients With Grade 3 or 4 Drug Toxicities Associated With 3RPT/INH or 9INH | Grade 4 | 0.4 percentage of participants |
| 3RPT/INH | Percentage of Patients With Grade 3 or 4 Drug Toxicities Associated With 3RPT/INH or 9INH | Grade 3 | 2.7 percentage of participants |
Comparison: Grade 3 Drug Toxicityp-value: 0.24Chi-squared
Comparison: Grade 4 Drug Toxicityp-value: 0.59Chi-squared