Tuberculosis, HIV Infections
Conditions
Brief summary
HIV-infected people have an increased risk of developing active tuberculosis (TB). At the time the study was designed, the standard course of treatment for TB was 6 to 9 months of isoniazid (INH).This study compared the safety and effectiveness of a 4-week regimen of rifapentine (RPT) plus INH versus a standard 9-month regimen of INH in HIV-infected people who are at risk of developing active TB.
Detailed description
The World Health Organization (WHO) estimated that in 2017 there were 10 million new cases of TB, and 1.6 million people died as a result of TB. Among new TB cases, it is estimated that 920,000 occurred in people who were HIV-coinfected, and 23% of TB deaths were among HIV-coinfected individuals. In Africa, TB is the leading AIDS-related opportunistic infection. Latent TB infection occurs when people are infected with the bacteria that cause TB, but they do not have any symptoms of TB infection. Latent TB can develop into active TB, and HIV-infected people have an increased risk of progressing from latent TB to active TB. INH is a medication that is prescribed for people with latent TB to help prevent active TB from developing. The standard INH treatment regimen is 6 to 9 months; a shorter treatment regimen of 3 months of once-weekly RPT plus INH has proven to be as effective and improved adherence. The purpose of this study was to compare the safety and effectiveness of a 4-week daily regimen of RPT plus INH to a standard 9-month daily INH regimen for TB prevention in HIV-infected individuals. This study enrolled HIV-infected people who did not have evidence of active TB but who were at high risk of developing active TB. Participants were randomly assigned to receive RPT and INH once a day for 4 weeks or INH once a day for 9 months. All participants received pyridoxine (vitamin B6) with each dose of INH to help prevent possible side effects. Study visits occurred at baseline and Weeks 2, 4, 8, 12, 16, 20, 24, and 36. At select study visits, participants had a physical exam, clinical assessment, blood collection, and a chest radiograph or chest computed tomography (CT) scan (if needed). Some participants had their blood stored for future testing. Follow-up study visits occurred every 12 weeks starting at Week 48 and continued for 3 years after the last participant enrolled.
Interventions
RPT dosing was be based on participants' weight: Participants who weighed 30 kg to less than 35 kg received 300 mg once daily (administered as two 150-mg tablets). Participants who weighed 35 kg to less than 45 kg received 450 mg once daily (administered as three 150-mg tablets). Participants who weighed greater than 45 kg received 600 mg once daily (administered as four 150-mg tablets).
DRUGIsoniazid (INH)
Participants received one 300-mg tablet or three 100-mg tablets of INH once daily.
DIETARY_SUPPLEMENTPyridoxine (Vitamin B6)
Participants received 25 mg or 50 mg of pyridoxine, based on the current local, national, or international dosing guidelines. Participants who received 25 mg of pyridoxine took one 25-mg tablet once daily with INH. Participants who received 50 mg of pyridoxine took two 25-mg tablets once daily with INH.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
13 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* HIV-1 infection * Tuberculin skin test (TST) reactivity greater than or equal to 5 mm or a positive interferon gamma release assay (IGRA) at any time prior to study entry, OR living in a high TB burden area. More information on this criterion can be found in the protocol. * Laboratory values obtained within 30 days prior to study entry: 1. Absolute neutrophil count (ANC) greater than 750 cells/mm\^3 2. Hemoglobin greater than or equal to 7.4 g/dL 3. Platelet count greater than or equal to 50,000/mm\^3 4. AST (SGOT) and ALT (SGPT) less than or equal to three times the upper limit of normal (ULN) 5. Total bilirubin less than or equal to 2.5 times the ULN * Chest radiograph or chest CT scan without evidence of active tuberculosis, unless one has been performed within 30 days prior to entry * Female participants of reproductive potential must have a negative serum or urine pregnancy test performed within 7 days prior to study entry. More information on this criterion can be found in the protocol. * All participants must agree not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, donate sperm, in vitro fertilization) while receiving RPT and for 6 weeks after stopping this drug * Female participants who are participating in sexual activity that could lead to pregnancy must agree to use one reliable non-hormonal form of contraceptive while receiving RPT and for 6 weeks after stopping this drug. More information on this criterion can be found in the protocol. * Weight of greater than or equal to 30 kg * Participant or legal guardian is able and willing to provide informed consent
Exclusion criteria
* Treatment for active or latent TB (pulmonary or extrapulmonary) within 2 years prior to study entry or, at screening, presence of any confirmed or probable TB based on criteria listed in the current ACTG Diagnosis Appendix * History of multi-drug resistant (MDR) or extensively-drug resistant (XDR) TB at any time prior to study entry * Known exposure to MDR or XDR TB (e.g., household member of a person with MDR or XDR TB) at any time prior to study entry * Treatment for more than 14 consecutive days with a rifamycin or more than 30 consecutive days with INH at any time during the 2 years prior to enrollment * For participants taking antiretroviral therapy (ART) at study entry, only approved nucleoside reverse transcriptase inhibitors (NRTIs) with efavirenz (EFV) or nevirapine (NVP) for at least 4 weeks were permitted * History of liver cirrhosis at any time prior to study entry. * Evidence of acute hepatitis, such as abdominal pain, jaundice, dark urine, and/or light stools within 90 days prior to study entry * Diagnosis of porphyria at any time prior to study entry * Peripheral neuropathy greater than or equal to Grade 2 according to the December 2004 (Clarification, August 2009) Division of AIDS (DAIDS) Toxicity Table, within 90 days prior to study entry * Known allergy/sensitivity or any hypersensitivity to components of study drugs or their formulation * Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements * Serious illness requiring systemic treatment and/or hospitalization within 30 days prior to study entry * Breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of First Diagnosis of Active Tuberculosis, Death Related to Tuberculosis, or Death From Unknown Cause | From entry to occurrence of event, up to end of follow-up 3 years after last participant enrolled (median follow-up time: 3.3 years) | Incidence rate (events per 100 person-years) was estimated, and 95.1% confidence interval used to account for interim analysis of primary efficacy outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Targeted Adverse Event | From entry to occurrence of event, up to end of follow-up 3 years after last participant enrolled (median follow-up time: 3.3 years) | Targeted adverse events include each new grade 3 or 4 laboratory value or sign or symptom that is at least one grade increase from baseline for the following: nausea and vomiting; cutaneous; drug-associated fever; elevated aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]), alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]), or bilirubin; and peripheral neuropathy |
| Number of Participants in Each Category of Ordered Categorical Variable Indicating Most Stringent Level of Study Drug Management Due to Toxicity That Was Required Over the Treatment Period | From entry to end of treatment (up to 8 weeks for Arm A; up to 54 weeks for Arm B) | Ordered categories include: 1. Premature permanent treatment discontinuation 2. Treatment hold for more than 7 consecutive days 3. None of the above |
| Cumulative Incidence of Death From Any Cause | From entry to occurrence of event, up to end of follow-up 3 years after last participant enrolled (median follow-up time: 3.3 years) | Data table estimates for percentage who died by each time point were estimated using Kaplan-Meier at 1, 2, 3, and 4 years post-entry. |
| Cumulative Incidence of Death Due to a Non-TB Event | From entry to occurrence of event, up to end of follow-up 3 years after last participant enrolled (median follow-up time: 3.3 years) | Cumulative incidence function estimated nonparametrically, treating TB-related deaths as competing risks. |
| Number of Participants With Occurrence of One or More Serious Adverse Events (SAEs) Versus no SAEs | From entry to occurrence of event, up to end of follow-up 3 years after last participant enrolled (median follow-up time: 3.3 years) | Occurrence of any SAE that meets the ICH definition of an SAE |
| Efavirenz (EFV) Plasma Concentrations in Arm A | Measured at Weeks 0, 2, 4, and 16 | Mean and standard deviation. Week 16 samples have not yet been analyzed because the metabolite assay is being validated, and requires submission for approval by the Clinical Pharmacology Quality Assurance Program. Analysis of week 16 samples are anticipated to be available in September 2019. |
| Nevirapine (NVP) Plasma Concentrations in Arm A | Measured at Weeks 0, 2, and 4 | Mean and standard deviation |
| EFV Plasma Concentrations in Arm B | Measured at weeks 0, 2 and 4 | For Version 2.0 of the protocol only, measured in the first 90 participants randomized to Arm B who enter the study taking EFV and who meet dose timing criteria. Outcome measure was not assessed because no participants enrolled under version 2.0 of the protocol were on Efavirenz at study entry. |
| Number of Participants With Antibiotic Resistance Among Mycobacterium Tuberculosis (MTB) Isolates in Participants Who Develop Active Tuberculosis | After TB diagnosis | Among MTB-diagnosed participants who underwent drug-susceptibility testing, the number who had any resistance to a particular drug. |
Countries
Botswana, Brazil, Haiti, Kenya, Malawi, Peru, South Africa, Thailand, United States, Zimbabwe
Participant flow
Recruitment details
Forty-five Clinical Research sites across 10 countries participated in the study. The first participant was randomized on May 23, 2012. Accrual closed on November 12, 2014 with 3,000 participants enrolled in the study.
Pre-assignment details
Randomization was 1:1, and stratified by CD4 count (\< 100, 100-250, and \> 250 cells/mm\^3), and antiretroviral therapy status (receiving antiretroviral therapy or not receiving antiretroviral therapy at enrollment).
Participants by arm
| Arm | Count |
|---|---|
| RPT Plus INH Regimen (Arm A) Participants received RPT (dosage based on their weight), 300 mg of INH, and 25 mg or 50 mg of pyridoxine (vitamin B6) each day during Weeks 1 to 4. During Weeks 5 to 36, participants did not receive any study medications.
Rifapentine (RPT): RPT dosing was based on participants' weight:
Participants who weighed 30 kg to less than 35 kg received 300 mg once daily (administered as two 150-mg tablets).
Participants who weighed 35 kg to less than 45 kg received 450 mg once daily (administered as three 150-mg tablets).
Participants who weighed greater than 45 kg will receive 600 mg once daily (administered as four 150-mg tablets).
Isoniazid (INH): Participants received one 300-mg tablet or three 100-mg tablets of INH once daily.
Pyridoxine (Vitamin B6): Participants received 25 mg or 50 mg of pyridoxine, based on the current local, national, or international dosing guidelines.
Participants receiving 25 mg of pyridoxine took one 25-mg tablet once daily | 1,496 |
| INH Regimen (Arm B) Participants received 300 mg of INH and 25 mg or 50 mg of pyridoxine (vitamin B6) each day during Weeks 1 to 36.
Isoniazid (INH): Participants received one 300-mg tablet or three 100-mg tablets of INH once daily.
Pyridoxine (Vitamin B6): Participants received 25 mg or 50 mg of pyridoxine, based on the current local, national, or international dosing guidelines.
Participants receiving 25 mg of pyridoxine took one 25-mg tablet once daily with INH.
Participants receiving 50 mg of pyridoxine took two 25-mg tablets once daily with INH. | 1,504 |
| Total | 3,000 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 21 | 27 |
| Overall Study | Lost to Follow-up | 115 | 111 |
| Overall Study | Participant not willing to adhere to req | 31 | 29 |
| Overall Study | Participant Unable to get to clinic | 93 | 103 |
| Overall Study | Severe debilitation, unable to continue | 1 | 2 |
| Overall Study | Site closed | 22 | 21 |
| Overall Study | Withdrawal by Subject | 15 | 18 |
Baseline characteristics
| Characteristic | RPT Plus INH Regimen (Arm A) | INH Regimen (Arm B) | Total |
|---|---|---|---|
| Age, Continuous | 35.7 years STANDARD_DEVIATION 10.3 | 35.6 years STANDARD_DEVIATION 10.3 | 35.7 years STANDARD_DEVIATION 10.3 |
| Age, Customized Age at Entry >20, <=30 years | 421 Participants | 455 Participants | 876 Participants |
| Age, Customized Age at Entry <=20 years | 77 Participants | 70 Participants | 147 Participants |
| Age, Customized Age at Entry >30, <=40 years | 523 Participants | 514 Participants | 1037 Participants |
| Age, Customized Age at Entry >40, <=50 years | 342 Participants | 331 Participants | 673 Participants |
| Age, Customized Age at Entry >50 years | 133 Participants | 134 Participants | 267 Participants |
| Antiretroviral Therapy (ART) at Entry Efavirenz-based | 650 Participants | 649 Participants | 1299 Participants |
| Antiretroviral Therapy (ART) at Entry Neither Efavirenz nor Nevirapine-based | 3 Participants | 6 Participants | 9 Participants |
| Antiretroviral Therapy (ART) at Entry Nevirapine-based | 97 Participants | 100 Participants | 197 Participants |
| Antiretroviral Therapy (ART) at Entry Not on ART | 746 Participants | 749 Participants | 1495 Participants |
| Body Mass Index (BMI) | 24.6 kg/m^2 STANDARD_DEVIATION 5.2 | 24.5 kg/m^2 STANDARD_DEVIATION 5.3 | 24.5 kg/m^2 STANDARD_DEVIATION 5.2 |
| HIV-1 RNA Viral load among participants on ART at entry Detectable | 154 Participants | 143 Participants | 297 Participants |
| HIV-1 RNA Viral load among participants on ART at entry Not Reported | 27 Participants | 26 Participants | 53 Participants |
| HIV-1 RNA Viral load among participants on ART at entry Undetectable | 569 Participants | 586 Participants | 1155 Participants |
| IV Drug Use Currently | 2 Participants | 1 Participants | 3 Participants |
| IV Drug Use Never | 1489 Participants | 1497 Participants | 2986 Participants |
| IV Drug Use Previously | 5 Participants | 6 Participants | 11 Participants |
| Prior Tuberculosis History No | 1414 Participants | 1415 Participants | 2829 Participants |
| Prior Tuberculosis History Yes | 82 Participants | 89 Participants | 171 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Asian, Pacific Islander | 122 Participants | 128 Participants | 250 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Black Non-Hispanic | 992 Participants | 991 Participants | 1983 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Hispanic (Regardless of Race) | 361 Participants | 369 Participants | 730 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Not Reported | 5 Participants | 4 Participants | 9 Participants |
| Race/Ethnicity, Customized Race/Ethnicity White Non-Hispanic | 16 Participants | 12 Participants | 28 Participants |
| Region of Enrollment Botswana | 210 participants | 212 participants | 422 participants |
| Region of Enrollment Brazil | 102 participants | 98 participants | 200 participants |
| Region of Enrollment Haiti | 198 participants | 198 participants | 396 participants |
| Region of Enrollment Kenya | 93 participants | 94 participants | 187 participants |
| Region of Enrollment Malawi | 106 participants | 108 participants | 214 participants |
| Region of Enrollment Peru | 258 participants | 257 participants | 515 participants |
| Region of Enrollment South Africa | 307 participants | 309 participants | 616 participants |
| Region of Enrollment Thailand | 121 participants | 124 participants | 245 participants |
| Region of Enrollment United States | 45 participants | 46 participants | 91 participants |
| Region of Enrollment Zimbabwe | 56 participants | 58 participants | 114 participants |
| Screening CD4 counts >=100,<=250 cells/mm^3 | 160 Participants | 165 Participants | 325 Participants |
| Screening CD4 counts <100 cells/mm^3 | 37 Participants | 37 Participants | 74 Participants |
| Screening CD4 counts >250 cells/mm^3 | 1299 Participants | 1302 Participants | 2601 Participants |
| Sex: Female, Male Female | 802 Participants | 812 Participants | 1614 Participants |
| Sex: Female, Male Male | 694 Participants | 692 Participants | 1386 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 21 / 1,496 | 27 / 1,504 |
| other Total, other adverse events | 1,051 / 1,496 | 1,042 / 1,504 |
| serious Total, serious adverse events | 40 / 1,496 | 68 / 1,504 |
Outcome results
Primary
Incidence of First Diagnosis of Active Tuberculosis, Death Related to Tuberculosis, or Death From Unknown Cause
Incidence rate (events per 100 person-years) was estimated, and 95.1% confidence interval used to account for interim analysis of primary efficacy outcome.
Time frame: From entry to occurrence of event, up to end of follow-up 3 years after last participant enrolled (median follow-up time: 3.3 years)
Population: All participants who started study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RPT Plus INH Regimen (Arm A) | Incidence of First Diagnosis of Active Tuberculosis, Death Related to Tuberculosis, or Death From Unknown Cause | 0.6506 Events per 100 person-years |
| INH Regimen (Arm B) | Incidence of First Diagnosis of Active Tuberculosis, Death Related to Tuberculosis, or Death From Unknown Cause | 0.6736 Events per 100 person-years |
Comparison: Mantel-Haenszel method used for estimating standardized incidence rate in each arm and incidence rate difference.95.1% CI: [-0.346, 0.3]
Secondary
Cumulative Incidence of Death Due to a Non-TB Event
Cumulative incidence function estimated nonparametrically, treating TB-related deaths as competing risks.
Time frame: From entry to occurrence of event, up to end of follow-up 3 years after last participant enrolled (median follow-up time: 3.3 years)
Population: All participants who started study treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| RPT Plus INH Regimen (Arm A) | Cumulative Incidence of Death Due to a Non-TB Event | Cumulative incidence by 1 year post-randomization | 0.3 events per 100 participants |
| RPT Plus INH Regimen (Arm A) | Cumulative Incidence of Death Due to a Non-TB Event | Cumulative incidence by 2 years post-randomization | 0.4 events per 100 participants |
| RPT Plus INH Regimen (Arm A) | Cumulative Incidence of Death Due to a Non-TB Event | Cumulative incidence by 3 years post-randomization | 0.9 events per 100 participants |
| RPT Plus INH Regimen (Arm A) | Cumulative Incidence of Death Due to a Non-TB Event | Cumulative incidence by 4 years post-randomization | 1.6 events per 100 participants |
| INH Regimen (Arm B) | Cumulative Incidence of Death Due to a Non-TB Event | Cumulative incidence by 4 years post-randomization | 2.0 events per 100 participants |
| INH Regimen (Arm B) | Cumulative Incidence of Death Due to a Non-TB Event | Cumulative incidence by 1 year post-randomization | 0.5 events per 100 participants |
| INH Regimen (Arm B) | Cumulative Incidence of Death Due to a Non-TB Event | Cumulative incidence by 3 years post-randomization | 1.5 events per 100 participants |
| INH Regimen (Arm B) | Cumulative Incidence of Death Due to a Non-TB Event | Cumulative incidence by 2 years post-randomization | 1.0 events per 100 participants |
Comparison: Competing risk analysis using the Fine-Gray model, treating TB-related deaths as competing risks, and other deaths including deaths of unknown cause as the event of interest.~H0: Hazard Ratio for Arm A vs Arm B = 1p-value: 0.280295% CI: [0.762, 2.559]Hazard Ratio
Secondary
Cumulative Incidence of Death From Any Cause
Data table estimates for percentage who died by each time point were estimated using Kaplan-Meier at 1, 2, 3, and 4 years post-entry.
Time frame: From entry to occurrence of event, up to end of follow-up 3 years after last participant enrolled (median follow-up time: 3.3 years)
Population: All Participants who started study treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| RPT Plus INH Regimen (Arm A) | Cumulative Incidence of Death From Any Cause | 1 year post-entry | 0.35 events per 100 participants |
| RPT Plus INH Regimen (Arm A) | Cumulative Incidence of Death From Any Cause | 2 years post-entry | 0.49 events per 100 participants |
| RPT Plus INH Regimen (Arm A) | Cumulative Incidence of Death From Any Cause | 3 years post-entry | 1.05 events per 100 participants |
| RPT Plus INH Regimen (Arm A) | Cumulative Incidence of Death From Any Cause | 4 years post-entry | 2.00 events per 100 participants |
| INH Regimen (Arm B) | Cumulative Incidence of Death From Any Cause | 4 years post-entry | 2.29 events per 100 participants |
| INH Regimen (Arm B) | Cumulative Incidence of Death From Any Cause | 1 year post-entry | 0.63 events per 100 participants |
| INH Regimen (Arm B) | Cumulative Incidence of Death From Any Cause | 3 years post-entry | 1.62 events per 100 participants |
| INH Regimen (Arm B) | Cumulative Incidence of Death From Any Cause | 2 years post-entry | 1.15 events per 100 participants |
Comparison: H0: Survival curve Arm A = Survival curve Arm Bp-value: 0.3078Log Rank
Secondary
Efavirenz (EFV) Plasma Concentrations in Arm A
Mean and standard deviation. Week 16 samples have not yet been analyzed because the metabolite assay is being validated, and requires submission for approval by the Clinical Pharmacology Quality Assurance Program. Analysis of week 16 samples are anticipated to be available in September 2019.
Time frame: Measured at Weeks 0, 2, 4, and 16
Population: Only measured in the first 90 participants randomized to Arm A who entered the study taking EFV and who meet dose timing criteria; and, under Version 2.0 of the protocol, at Weeks 0, 2, 4, and 16 in the first 30 participants randomized to Arm A who enter the study taking EFV and who meet dose timing criteria.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RPT Plus INH Regimen (Arm A) | Efavirenz (EFV) Plasma Concentrations in Arm A | Week 0 | 3787 nanograms per mL | Standard Deviation 4922 |
| RPT Plus INH Regimen (Arm A) | Efavirenz (EFV) Plasma Concentrations in Arm A | Week 2 | 3870 nanograms per mL | Standard Deviation 7011 |
| RPT Plus INH Regimen (Arm A) | Efavirenz (EFV) Plasma Concentrations in Arm A | Week 4 | 4082 nanograms per mL | Standard Deviation 4916 |
Secondary
EFV Plasma Concentrations in Arm B
For Version 2.0 of the protocol only, measured in the first 90 participants randomized to Arm B who enter the study taking EFV and who meet dose timing criteria. Outcome measure was not assessed because no participants enrolled under version 2.0 of the protocol were on Efavirenz at study entry.
Time frame: Measured at weeks 0, 2 and 4
Population: Outcome measure was not assessed because no participants enrolled under version 2.0 of the protocol were on Efavirenz at study entry.
Secondary
Nevirapine (NVP) Plasma Concentrations in Arm A
Mean and standard deviation
Time frame: Measured at Weeks 0, 2, and 4
Population: Only measured in the first 90 participants randomized to Arm A who enter the study taking NVP and who meet dose timing criteria. For weeks 0, 2, 4, some samples were missing or contaminated.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RPT Plus INH Regimen (Arm A) | Nevirapine (NVP) Plasma Concentrations in Arm A | Week0 | 7573 nanograms per mL | Standard Deviation 3789 |
| RPT Plus INH Regimen (Arm A) | Nevirapine (NVP) Plasma Concentrations in Arm A | Week 2 | 6234 nanograms per mL | Standard Deviation 4283 |
| RPT Plus INH Regimen (Arm A) | Nevirapine (NVP) Plasma Concentrations in Arm A | Week 4 | 5797 nanograms per mL | Standard Deviation 3963 |
Secondary
Number of Participants in Each Category of Ordered Categorical Variable Indicating Most Stringent Level of Study Drug Management Due to Toxicity That Was Required Over the Treatment Period
Ordered categories include: 1. Premature permanent treatment discontinuation 2. Treatment hold for more than 7 consecutive days 3. None of the above
Time frame: From entry to end of treatment (up to 8 weeks for Arm A; up to 54 weeks for Arm B)
Population: All participants who started study treatment
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| RPT Plus INH Regimen (Arm A) | Number of Participants in Each Category of Ordered Categorical Variable Indicating Most Stringent Level of Study Drug Management Due to Toxicity That Was Required Over the Treatment Period | Premature permanent treatment discontinuation | 16 Participants |
| RPT Plus INH Regimen (Arm A) | Number of Participants in Each Category of Ordered Categorical Variable Indicating Most Stringent Level of Study Drug Management Due to Toxicity That Was Required Over the Treatment Period | Treatment held for more than 7 days | 11 Participants |
| RPT Plus INH Regimen (Arm A) | Number of Participants in Each Category of Ordered Categorical Variable Indicating Most Stringent Level of Study Drug Management Due to Toxicity That Was Required Over the Treatment Period | None of the above | 1461 Participants |
| INH Regimen (Arm B) | Number of Participants in Each Category of Ordered Categorical Variable Indicating Most Stringent Level of Study Drug Management Due to Toxicity That Was Required Over the Treatment Period | Premature permanent treatment discontinuation | 25 Participants |
| INH Regimen (Arm B) | Number of Participants in Each Category of Ordered Categorical Variable Indicating Most Stringent Level of Study Drug Management Due to Toxicity That Was Required Over the Treatment Period | Treatment held for more than 7 days | 31 Participants |
| INH Regimen (Arm B) | Number of Participants in Each Category of Ordered Categorical Variable Indicating Most Stringent Level of Study Drug Management Due to Toxicity That Was Required Over the Treatment Period | None of the above | 1442 Participants |
Comparison: Odds ratio of being in higher category estimated from proportional odds model~H0: Odds ratio of being in higher category for Arm A vs Arm B = 195% CI: [1.315, 3.332]
Secondary
Number of Participants With Antibiotic Resistance Among Mycobacterium Tuberculosis (MTB) Isolates in Participants Who Develop Active Tuberculosis
Among MTB-diagnosed participants who underwent drug-susceptibility testing, the number who had any resistance to a particular drug.
Time frame: After TB diagnosis
Population: Participants with a culture-confirmed TB diagnosis who underwent drug susceptibility testing
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| RPT Plus INH Regimen (Arm A) | Number of Participants With Antibiotic Resistance Among Mycobacterium Tuberculosis (MTB) Isolates in Participants Who Develop Active Tuberculosis | Isoniazid | Developed Resistance | 2 Participants |
| RPT Plus INH Regimen (Arm A) | Number of Participants With Antibiotic Resistance Among Mycobacterium Tuberculosis (MTB) Isolates in Participants Who Develop Active Tuberculosis | Rifampin | Developed Resistance | 1 Participants |
| RPT Plus INH Regimen (Arm A) | Number of Participants With Antibiotic Resistance Among Mycobacterium Tuberculosis (MTB) Isolates in Participants Who Develop Active Tuberculosis | Rifampin | Did not Develop Resistance | 14 Participants |
| RPT Plus INH Regimen (Arm A) | Number of Participants With Antibiotic Resistance Among Mycobacterium Tuberculosis (MTB) Isolates in Participants Who Develop Active Tuberculosis | Isoniazid | Did not Develop Resistance | 12 Participants |
| RPT Plus INH Regimen (Arm A) | Number of Participants With Antibiotic Resistance Among Mycobacterium Tuberculosis (MTB) Isolates in Participants Who Develop Active Tuberculosis | Ethambutol | Developed Resistance | 0 Participants |
| RPT Plus INH Regimen (Arm A) | Number of Participants With Antibiotic Resistance Among Mycobacterium Tuberculosis (MTB) Isolates in Participants Who Develop Active Tuberculosis | Ethambutol | Did not Develop Resistance | 7 Participants |
| RPT Plus INH Regimen (Arm A) | Number of Participants With Antibiotic Resistance Among Mycobacterium Tuberculosis (MTB) Isolates in Participants Who Develop Active Tuberculosis | Pyrazinamide | Developed Resistance | 0 Participants |
| RPT Plus INH Regimen (Arm A) | Number of Participants With Antibiotic Resistance Among Mycobacterium Tuberculosis (MTB) Isolates in Participants Who Develop Active Tuberculosis | Pyrazinamide | Did not Develop Resistance | 6 Participants |
| INH Regimen (Arm B) | Number of Participants With Antibiotic Resistance Among Mycobacterium Tuberculosis (MTB) Isolates in Participants Who Develop Active Tuberculosis | Pyrazinamide | Did not Develop Resistance | 6 Participants |
| INH Regimen (Arm B) | Number of Participants With Antibiotic Resistance Among Mycobacterium Tuberculosis (MTB) Isolates in Participants Who Develop Active Tuberculosis | Isoniazid | Developed Resistance | 1 Participants |
| INH Regimen (Arm B) | Number of Participants With Antibiotic Resistance Among Mycobacterium Tuberculosis (MTB) Isolates in Participants Who Develop Active Tuberculosis | Ethambutol | Developed Resistance | 1 Participants |
| INH Regimen (Arm B) | Number of Participants With Antibiotic Resistance Among Mycobacterium Tuberculosis (MTB) Isolates in Participants Who Develop Active Tuberculosis | Rifampin | Developed Resistance | 1 Participants |
| INH Regimen (Arm B) | Number of Participants With Antibiotic Resistance Among Mycobacterium Tuberculosis (MTB) Isolates in Participants Who Develop Active Tuberculosis | Pyrazinamide | Developed Resistance | 0 Participants |
| INH Regimen (Arm B) | Number of Participants With Antibiotic Resistance Among Mycobacterium Tuberculosis (MTB) Isolates in Participants Who Develop Active Tuberculosis | Rifampin | Did not Develop Resistance | 11 Participants |
| INH Regimen (Arm B) | Number of Participants With Antibiotic Resistance Among Mycobacterium Tuberculosis (MTB) Isolates in Participants Who Develop Active Tuberculosis | Ethambutol | Did not Develop Resistance | 7 Participants |
| INH Regimen (Arm B) | Number of Participants With Antibiotic Resistance Among Mycobacterium Tuberculosis (MTB) Isolates in Participants Who Develop Active Tuberculosis | Isoniazid | Did not Develop Resistance | 11 Participants |
Secondary
Number of Participants With a Targeted Adverse Event
Targeted adverse events include each new grade 3 or 4 laboratory value or sign or symptom that is at least one grade increase from baseline for the following: nausea and vomiting; cutaneous; drug-associated fever; elevated aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]), alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]), or bilirubin; and peripheral neuropathy
Time frame: From entry to occurrence of event, up to end of follow-up 3 years after last participant enrolled (median follow-up time: 3.3 years)
Population: All participants who started study treatment
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| RPT Plus INH Regimen (Arm A) | Number of Participants With a Targeted Adverse Event | No Targeted Safety Event | 1445 Participants |
| RPT Plus INH Regimen (Arm A) | Number of Participants With a Targeted Adverse Event | Occurrence of Targeted Safety Event | 43 Participants |
| INH Regimen (Arm B) | Number of Participants With a Targeted Adverse Event | No Targeted Safety Event | 1446 Participants |
| INH Regimen (Arm B) | Number of Participants With a Targeted Adverse Event | Occurrence of Targeted Safety Event | 52 Participants |
Comparison: Comparison of the proportion of participants with any targeted adverse event occurrence between arms A and B.~H0: Proportion of participants with a targeted adverse event in Arm A = Proportion of participants with a targeted adverse event in Arm B.p-value: 0.40595% CI: [-0.019, 0.007]Fisher Exact
Secondary
Number of Participants With Occurrence of One or More Serious Adverse Events (SAEs) Versus no SAEs
Occurrence of any SAE that meets the ICH definition of an SAE
Time frame: From entry to occurrence of event, up to end of follow-up 3 years after last participant enrolled (median follow-up time: 3.3 years)
Population: All participants who started study treatment
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| RPT Plus INH Regimen (Arm A) | Number of Participants With Occurrence of One or More Serious Adverse Events (SAEs) Versus no SAEs | No SAE occurred | 1405 Participants |
| RPT Plus INH Regimen (Arm A) | Number of Participants With Occurrence of One or More Serious Adverse Events (SAEs) Versus no SAEs | At least one SAE occurred | 83 Participants |
| INH Regimen (Arm B) | Number of Participants With Occurrence of One or More Serious Adverse Events (SAEs) Versus no SAEs | No SAE occurred | 1390 Participants |
| INH Regimen (Arm B) | Number of Participants With Occurrence of One or More Serious Adverse Events (SAEs) Versus no SAEs | At least one SAE occurred | 108 Participants |
Comparison: Comparison of the proportion of participants with any SAE occurrence between arms A and B.~H0: Proportion of participants with SAE in Arm A = Proportion of participants with SAE in Arm B.p-value: 0.07395% CI: [-0.035, 0.002]Fisher Exact