Tuberculosis
Conditions
Brief summary
The purpose of this study is to determine whether one or two four-month regimens of tuberculosis treatment are as effective as a standard six-month regimen for treatment of pulmonary tuberculosis (TB). All three regimens are administered daily, seven days each week, with direct observation of each dose by a health-care worker at least five of the seven days of each week. The standard six-month regimen is two months of isoniazid, rifampin, ethambutol, and pyrazinamide followed by four months of isoniazid and rifampin. The first short regimen is a single substitution of rifapentine for rifampin: two months of isoniazid, rifapentine, ethambutol, and pyrazinamide, followed by two months of isoniazid and rifapentine. The second short regimen is a double substitution of rifapentine for rifampin and moxifloxacin for ethambutol: two months of isoniazid, rifapentine, moxifloxacin, and pyrazinamide, followed by two months of isoniazid, rifapentine, and moxifloxacin. Target enrollment is 2500 participants. Each study participant will remain in the study for 18 months in order to include at least 12 months of evaluation of whether the participant's TB recurs.
Detailed description
Title: Rifapentine-containing treatment shortening regimens for pulmonary tuberculosis: a randomized, open-label, controlled, phase 3 clinical trial Hypotheses: A) Seventeen (17) week rifapentine-based regimen In previously untreated individuals with active drug-susceptible pulmonary tuberculosis treated with eight weeks of rifapentine (P), isoniazid (H), pyrazinamide (Z) and ethambutol (E) followed by nine weeks of rifapentine plus isoniazid, all given daily throughout, the proportion of participants who experience absence of cure (unfavorable outcome) will not be inferior to that observed in participants who are treated with a standard regimen (eight weeks of rifampin (R), isoniazid, pyrazinamide and ethambutol followed by eighteen weeks of rifampin plus isoniazid), all given daily throughout. B) Seventeen (17) week rifapentine- plus moxifloxacin-containing regimen In previously untreated individuals with active drug-susceptible pulmonary tuberculosis treated with eight weeks of rifapentine, isoniazid, pyrazinamide and moxifloxacin (M), followed by nine weeks of rifapentine, isoniazid, and moxifloxacin, all given daily throughout, the proportion of participants who experience absence of cure (unfavorable outcome) will not be inferior to that observed in participants who are treated with a standard regimen (eight weeks of rifampin, isoniazid, pyrazinamide and ethambutol followed by eighteen weeks of rifampin plus isoniazid), all given daily throughout. Phase: 3 Design: This will be an international, multicenter, randomized, controlled, open-label, 3-arm, phase 3 non-inferiority trial. Population: Patients with newly diagnosed, previously untreated pulmonary tuberculosis. Number of Sites: Multiple international sites, primarily sites of the Tuberculosis Trials Consortium and the AIDS Clinical Trials Group. Study Duration: Duration per participant is approximately 18 months. Description of Agent or Intervention: After written informed consent, participants will be randomly assigned to receive one of the following oral regimens: Regimen 1 (control regimen): 2RHZE/4RH * Eight weeks of daily treatment with rifampin, isoniazid, pyrazinamide, and ethambutol, followed by * Eighteen weeks of daily treatment with rifampin and isoniazid Regimen 2 (investigational regimen): 2PHZE/2PH * Eight weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and ethambutol, followed by * Nine weeks of daily treatment with rifapentine and isoniazid Regimen 3 (investigational regimen): 2PHZM/2PHM * Eight weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and moxifloxacin, followed by * Nine weeks of daily treatment with rifapentine, isoniazid, and moxifloxacin Objectives: Primary: * To evaluate the efficacy of a rifapentine-containing regimen to determine whether the single substitution of rifapentine for rifampin makes it possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis * To evaluate the efficacy of a rifapentine-containing regimen that in addition substitutes moxifloxacin for ethambutol and continues moxifloxacin during the continuation phase to determine whether it is possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis Secondary: * To evaluate the safety of the investigational regimens * To evaluate the tolerability of the investigational regimens * To collect and store biospecimens from consenting participants for the purpose of future research on discovery and validation of TB biomarkers * To determine the correlation of mycobacterial and clinical markers with time to culture conversion, culture status at completion of eight weeks of treatment, treatment failure, and relapse. * To conduct a pharmacokinetic/pharmacodynamic (PK/PD) study of the test drugs. The main objectives of the PK/PD study are to characterize study drug PK parameters and to determine relationships between treatment outcomes and PK parameters. * To evaluate the pharmacokinetics of efavirenz-based antiretroviral treatment among patients with TB/HIV co-infection taking efavirenz-based combination antiretroviral therapy and TB treatment with rifapentine Endpoints: Primary Endpoints: * Efficacy: TB disease-free survival at twelve months after study treatment assignment. * Safety: Proportion of participants with grade 3 or higher adverse events during study drug treatment Secondary Endpoints: * TB disease-free survival at eighteen months after study treatment assignment * Time to stable sputum culture conversion (solid and liquid media considered separately) * Speed of decline of sputum viable bacilli by automated liquid MGIT culture days to detection * Proportion of participants who are culture negative at completion of eight weeks of treatment (solid and liquid media considered separately) * Sensitivity analyses assuming all participants classified as 'not assessable' have a favorable outcome * Discontinuation of assigned treatment for a reason other than microbiological ineligibility * Estimated steady state efavirenz PK parameters including mid-dosing interval concentration
Interventions
DRUGrifapentine
Regimen 2: Rifapentine is substituted for rifampin as the basis of 4-month treatment
DRUGrifapentine and moxifloxacin
Regimen 3: In addition to the single substitution described for regimen 2, a second substitution is added, of moxifloxacin for ethambutol.
DRUGcontrol
standard six-month treatment
Sponsors
Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Centers for Disease Control and Prevention
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Suspected pulmonary tuberculosis plus one or both of the following: a) at least one sputum specimen positive for acid-fast bacilli on smear microscopy OR b) at least one sputum specimen positive for M. tuberculosis by Xpert MTB/RIF testing, with semiquantitative result of 'medium' or 'high' and rifamycin resistance not detected. * Age twelve (12) years or older * A verifiable address or residence location that is readily accessible for visiting, and willingness to inform the study team of any change of address during the treatment and follow-up period. * Women of child-bearing potential who are not surgically sterilized must agree to practice a barrier method of contraception or abstain from heterosexual intercourse during study drug treatment. * Documentation of HIV infection status. * For HIV-positive individuals, CD4 T cell count greater than or equal to 100 cells/mm3 based on testing performed at or within 30 days prior to screening. * Laboratory parameters done at or within 14 days prior to screening: * Serum or plasma alanine aminotransferase (ALT) less than or equal to 3 times the upper limit of normal * Serum or plasma total bilirubin less than or equal to 2.5 times the upper limit of normal * Serum or plasma creatinine level less than or equal to 2 times the upper limit of normal * Serum or plasma potassium level greater than or equal to 3.5 meq/L * Hemoglobin level of 7.0 g/dL or greater * Platelet count of 100,000/mm3 or greater * For women of childbearing potential, a negative pregnancy test at or within seven (7) days prior to screening * Karnofsky score greater than or equal to 60 * Written informed consent
Exclusion criteria
* Pregnant or breast-feeding. * Unable to take oral medications. * Previously enrolled in this study. * Received any investigational drug in the past 3 months. * More than five (5) days of treatment directed against active tuberculosis within 6 months preceding initiation of study drugs. * More than five (5) days of systemic treatment with any one or more of the following drugs within 30 days preceding initiation of study drugs: isoniazid, rifampin, rifabutin, rifapentine, ethambutol, pyrazinamide, kanamycin, amikacin, streptomycin, capreomycin, moxifloxacin, levofloxacin, gatifloxacin, ofloxacin, ciprofloxacin, other fluoroquinolones, ethionamide, prothionamide, cycloserine, terizidone, para-aminosalicylic acid, linezolid, clofazimine, delamanid or bedaquiline. * Known history of prolonged QT syndrome. * Suspected or documented tuberculosis involving the central nervous system and/or bones and/or joints, and/or miliary tuberculosis and/or pericardial tuberculosis. * Current or planned use within six months following enrollment of one or more of the following medications: HIV protease inhibitors, HIV integrase inhibitors, HIV entry and fusion inhibitors, HIV non-nucleoside reverse transcriptase inhibitors other than efavirenz, quinidine, procainamide, amiodarone, sotalol, disopyramide, ziprasidone, or terfenadine. Individuals who are currently taking efavirenz-based antiretroviral treatment or for whom initiation of efavirenz-based antiretroviral treatment is planned within 17 weeks following enrollment may participate. * Weight less than 40.0 kg. * Known allergy or intolerance to any of the study medications. * Individuals will be excluded from enrollment if, at the time of enrollment, their M. tuberculosis isolate is already known to be resistant to any one or more of the following: rifampin, isoniazid, pyrazinamide, ethambutol, or fluoroquinolones. * Other medical conditions, that, in the investigator's judgment, make study participation not in the individual's best interest. * Current or planned incarceration or other involuntary detention.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Participants With Grade 3 or Higher Adverse Events During Study Drug Treatment in Control Regimen (Regimen 1 2HRZE/4HR) Compared to Experimental Regimens, Regimen 3 (2HPZM/2HPM) and Regimen 2 (2HPZ/2HP) (Safety Analysis Population) | Four months and up to 14 days after last does of after study treatment (Regimen 2 and 3) or Six months and up to 14 days after last does of after study treatment (Regimen 1) | * To evaluate the Safety of a rifapentine-containing regimen to determine whether the single substitution of rifapentine for rifampin makes it possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis * To evaluate the Safety of a rifapentine-containing regimen that in addition substitutes moxifloxacin for ethambutol and continues moxifloxacin during the continuation phase, to determine whether it is possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis Grade 3 or higher Adverse Events are collected by Clinical sites in systematic way through the laboratory tests and physical exam during regular study follow up visits and also in a non-systematic way when it was self-reported by participants during the study visits. The events are graded by site investigators per Common Terminology Criteria for Adverse Events (CTCAE V4.03 |
| TB Disease-free Survival at 12M After Study Treatment Assignment Among Participants in Control Regimen, Regimen1 (2HRZE/4HR) to Experimental Regimens, Regimen3 (2HPZM/2HPM) and Regimen2 (2HPZ/2HP) (Assessable Population) | Twelve months after treatment assignment | * To evaluate the efficacy of a rifapentine-containing regimen to determine whether the single substitution of rifapentine for rifampin makes it possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis * To evaluate the efficacy of a rifapentine-containing regimen that in addition substitutes moxifloxacin for ethambutol and continues moxifloxacin during the continuation phase, to determine whether it is possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis A primary outcome status of favorable, unfavorable, or not assessable was assigned. For detailed definitions of outcomes please refer to: Dorman SE, at al. N Engl J Med. 2021 May 6;384(18):1705-1718. |
| TB Disease-free Survival at 12M After Study Treatment Assignment Among Participants in Control Regimen, Regimen1 (2HRZE/4HR) to Experimental Regimens, Regimen3 (2HPZM/2HPM) and Regimen2 (2HPZ/2HP) (Modified Intent to Treat [MITT] Population) | Twelve months after treatment assignment | To evaluate the efficacy of a rifapentine-containing regimen to determine whether the single substitution of rifapentine for rifampin makes it possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis To evaluate the efficacy of a rifapentine-containing regimen that in addition substitutes moxifloxacin for ethambutol and continues moxifloxacin during the continuation phase, to determine whether it is possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis A primary outcome status of favorable, unfavorable, or not assessable was assigned. For detailed definitions of outcomes please refer to: Dorman SE, at al. N Engl J Med. 2021 May 6;384(18):1705-1718. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Discontinuation of Assigned Treatment for a Reason Other Than Microbiological Ineligibility (Tolerability) | four or six months | Tolerability of the regimen is evaluated using the outcome of discontinuation of assigned treatment for a reason other than microbiological ineligibility. |
| TB Disease-free Survival at Eighteen Months After Study Treatment Assignment | Eighteen months after study treatment assignment. | * To evaluate the efficacy of a rifapentine-containing regimen to determine whether the single substitution of rifapentine for rifampin makes it possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis * To evaluate the efficacy of a rifapentine-containing regimen that in addition substitutes moxifloxacin for ethambutol and continues moxifloxacin during the continuation phase, to determine whether it is possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis |
| Speed of Decline of Sputum Viable Bacilli by Automated Liquid MGIT Culture Days to Detection | 12 months | Parameter estimates of the nonlinear mixed effect models describing longitudinal time to positive (TTP) |
| Estimated Steady State Efavirenz PK Parameters Including Mid-dosing Interval Concentration | four months | Among participants with HIV infection receiving efavirenz-based antiretroviral therapy, number of participants who maintained plasma efavirenz concentrations ≥1 mg/L during TB treatment. |
| Proportion of Participants Who Are Culture Negative at Eight Weeks | eight weeks | Proportion of participants who are culture negative at eight weeks, liquid media |
| Time to Stable Sputum Culture Conversion | four or six months | Time to stable sputum culture conversion, liquid media |
Other
| Measure | Time frame | Description |
|---|---|---|
| Sensitivity Analyses Assuming All Losses to Follow-up and Non-tuberculosis Deaths Have an Unfavorable Outcome | 12 months | A sensitivity analysis used to supplement the primary efficacy results and provide further insight into whether the intervention regimens should be considered to have non-inferior efficacy. This analysis considers the difference in proportion of unfavorable outcomes between the control arm and each of the experimental arms. Measurement Description: The difference in proportion unfavorable was calculated using a stratified analysis using Cochran-Mantel-Haenszel weights. The analysis was stratified by HIV status and presence of cavitation only, and the stratified difference was considered primary. |
| Sensitivity Analyses Assuming All Losses to Follow-up and Non-tuberculosis Deaths Have a Favorable Outcome | 12 months | A sensitivity analysis used to supplement the primary efficacy results and provide further insight into whether the intervention regimens should be considered to have non-inferior efficacy. This analysis considers the difference in proportion of unfavorable outcomes between the control arm and each of the experimental arms. Measurement Description: The difference in proportion unfavorable was calculated using a stratified analysis using Cochran-Mantel-Haenszel weights. The analysis was stratified by HIV status and presence of cavitation only, and the stratified difference was considered primary. |
Countries
Brazil, China, Haiti, India, Kenya, Malawi, Peru, South Africa, Thailand, Uganda, United States, Vietnam, Zimbabwe
Participant flow
Recruitment details
Participants were enrolled at 34 clinical research sites in 13 countries between January 2016 and October 2018. First participant was enrolled on 25 January 2016. Last participant was enrolled on 30 October 2018.
Pre-assignment details
Of 5214 participants screened, 2049 did not meet the eligible criteria, 405 declined to participate and site decided not to enroll 145 participants. 2516 participants were randomized Participants were required to have at least one sputum specimen positive for acid-fast bacilli by smear microscopy or positive for M. tuberculosis by Xpert MTB/RIF testing with semiquantitative result of medium or highand susceptible to isoniazid, rifampin, and fluoroquinolones
Participants by arm
| Arm | Count |
|---|---|
| Regimen 1 (2HRZE/4HR) Eight weeks of daily treatment with rifampin, isoniazid, pyrazinamide, and ethambutol, followed by Eighteen weeks of daily treatment with rifampin and isoniazid
All drugs are administered orally, seven days/week, directly observed by a health care worker at least five of the seven days each week. Pyridoxine (vitamin B6), 25 or 50 mg, is administered with each study dose. Study drug doses: rifampin, 600 mg; isoniazid, 300 mg; pyrazinamide, \< 55kg 1000 mg, \>= 55-75 kg 1500 mg, \>75 kg 2000 mg; ethambutol, \< 55kg 800 mg, \>= 55-75 kg 1200 mg, \>75 kg 1600 mg
study drug doses: rifampin, 600 mg; isoniazid, 300 mg; pyrazinamide, \< 55kg 1000 mg, \>= 55-75 kg 1500 mg, \>75 kg 2000 mg; ethambutol, \< 55kg 800 mg, \>= 55-75 kg 1200 mg, \>75 kg 1600 mg
control: standard six-month treatment | 768 |
| Regimen 2 (2HPZ/2HP) Eight weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and ethambutol, followed by Nine weeks of daily treatment with rifapentine and isoniazid
All drugs are administered orally, seven days/week, directly observed by a health care worker at least five of the seven days each week. Pyridoxine (vitamin B6), 25 or 50 mg, is administered with each study dose. Study drug doses: rifapentine 1200 mg; isoniazid, 300 mg; pyrazinamide, \< 55kg 1000 mg, \>= 55-75 kg 1500 mg, \>75 kg 2000 mg; ethambutol, \< 55kg 800 mg, \>= 55-75 kg 1200 mg, \>75 kg 1600 mg
study drug doses: rifapentine 1200 mg; isoniazid, 300 mg; pyrazinamide, \< 55kg 1000 mg, \>= 55-75 kg 1500 mg, \>75 kg 2000 mg; ethambutol, \< 55kg 800 mg, \>= 55-75 kg 1200 mg, \>75 kg 1600 mg
rifapentine: Regimen 2: Rifapentine is substituted for rifampin as the basis of 4-month treatment | 784 |
| Regimen 3 (2HPMZ/2HPM) Eight weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and moxifloxacin, followed by Nine weeks of daily treatment with rifapentine, isoniazid, and moxifloxacin
All drugs are administered orally, seven days/week, directly observed by a health care worker at least five of the seven days each week. Pyridoxine (vitamin B6), 25 or 50 mg, is administered with each study dose. Study drug doses: rifapentine 1200 mg; isoniazid, 300 mg; pyrazinamide, \< 55kg 1000 mg, \>= 55-75 kg 1500 mg, \>75 kg 2000 mg; ethambutol, \< 55kg 800 mg, \>= 55-75 kg 1200 mg, \>75 kg 1600 mg
study drug doses: rifapentine 1200 mg; isoniazid, 300 mg; pyrazinamide, \< 55kg 1000 mg, \>= 55-75 kg 1500 mg, \>75 kg 2000 mg; moxifloxacin, 400 mg
rifapentine and moxifloxacin: Regimen 3: In addition to the single substitution described for regimen 2, a second substitution is added, of moxifloxacin for ethambutol. | 791 |
| Total | 2,343 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Baseline Drug Resistance | 49 | 40 | 51 |
| Overall Study | Death | 3 | 4 | 8 |
| Overall Study | Lost to Follow-up | 31 | 23 | 22 |
| Overall Study | No positive Mycobacterium tuberculosis culture | 4 | 6 | 3 |
| Overall Study | Pregnancy | 8 | 4 | 5 |
| Overall Study | Protocol Violation | 8 | 8 | 4 |
| Overall Study | Reinfection with a new strain of MTB | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Regimen 1 (2HRZE/4HR) | Total | Regimen 3 (2HPMZ/2HPM) | Regimen 2 (2HPZ/2HP) |
|---|---|---|---|---|
| Age, Categorical <=18 years | 19 Participants | 63 Participants | 25 Participants | 19 Participants |
| Age, Categorical >=65 years | 6 Participants | 27 Participants | 11 Participants | 10 Participants |
| Age, Categorical Between 18 and 65 years | 743 Participants | 2253 Participants | 755 Participants | 755 Participants |
| Age, Continuous | 30.9 years | 31.0 years | 31.0 years | 31.0 years |
| Cavitation status at Baseline Cavitation on chest radiograph | 558 Participants | 1703 Participants | 572 Participants | 573 Participants |
| Cavitation status at Baseline No cavitation on chest radiograph | 204 Participants | 619 Participants | 210 Participants | 205 Participants |
| Cavitation status at Baseline Unknown | 6 Participants | 21 Participants | 9 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 27 Participants | 74 Participants | 27 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 287 Participants | 867 Participants | 297 Participants | 283 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 454 Participants | 1402 Participants | 467 Participants | 481 Participants |
| HIV Status HIV Negative | 704 Participants | 2149 Participants | 729 Participants | 716 Participants |
| HIV Status HIV Positive | 64 Participants | 194 Participants | 62 Participants | 68 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 86 Participants | 268 Participants | 89 Participants | 93 Participants |
| Race (NIH/OMB) Black or African American | 553 Participants | 1676 Participants | 552 Participants | 571 Participants |
| Race (NIH/OMB) More than one race | 111 Participants | 357 Participants | 135 Participants | 111 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 6 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 15 Participants | 36 Participants | 13 Participants | 8 Participants |
| Region of Enrollment Africa | 565 Participants | 1716 Participants | 578 Participants | 573 Participants |
| Region of Enrollment South America | 109 Participants | 339 Participants | 115 Participants | 115 Participants |
| Region of Enrollment South Asia | 86 Participants | 263 Participants | 88 Participants | 89 Participants |
| Region of Enrollment United States | 8 Participants | 25 Participants | 10 Participants | 7 Participants |
| Sex: Female, Male Female | 224 Participants | 673 Participants | 228 Participants | 221 Participants |
| Sex: Female, Male Male | 544 Participants | 1670 Participants | 563 Participants | 563 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 12 / 825 | 11 / 835 | 13 / 846 |
| other Total, other adverse events | 74 / 825 | 61 / 835 | 94 / 846 |
| serious Total, serious adverse events | 56 / 825 | 39 / 835 | 37 / 846 |
Outcome results
Primary
Percentage Participants With Grade 3 or Higher Adverse Events During Study Drug Treatment in Control Regimen (Regimen 1 2HRZE/4HR) Compared to Experimental Regimens, Regimen 3 (2HPZM/2HPM) and Regimen 2 (2HPZ/2HP) (Safety Analysis Population)
* To evaluate the Safety of a rifapentine-containing regimen to determine whether the single substitution of rifapentine for rifampin makes it possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis * To evaluate the Safety of a rifapentine-containing regimen that in addition substitutes moxifloxacin for ethambutol and continues moxifloxacin during the continuation phase, to determine whether it is possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis Grade 3 or higher Adverse Events are collected by Clinical sites in systematic way through the laboratory tests and physical exam during regular study follow up visits and also in a non-systematic way when it was self-reported by participants during the study visits. The events are graded by site investigators per Common Terminology Criteria for Adverse Events (CTCAE V4.03
Time frame: Four months and up to 14 days after last does of after study treatment (Regimen 2 and 3) or Six months and up to 14 days after last does of after study treatment (Regimen 1)
Population: Safety analyses included all randomized participants who received at least one dose of study treatment
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Regimen 1 (2HRZE/4HR) | Percentage Participants With Grade 3 or Higher Adverse Events During Study Drug Treatment in Control Regimen (Regimen 1 2HRZE/4HR) Compared to Experimental Regimens, Regimen 3 (2HPZM/2HPM) and Regimen 2 (2HPZ/2HP) (Safety Analysis Population) | Participants with Grade 3 or higher Adverse events | 159 Participants |
| Regimen 1 (2HRZE/4HR) | Percentage Participants With Grade 3 or Higher Adverse Events During Study Drug Treatment in Control Regimen (Regimen 1 2HRZE/4HR) Compared to Experimental Regimens, Regimen 3 (2HPZM/2HPM) and Regimen 2 (2HPZ/2HP) (Safety Analysis Population) | Participants with less than Grade 3 Adverse Events or no adverse events | 666 Participants |
| Regimen 2 (2HPZ/2HP) | Percentage Participants With Grade 3 or Higher Adverse Events During Study Drug Treatment in Control Regimen (Regimen 1 2HRZE/4HR) Compared to Experimental Regimens, Regimen 3 (2HPZM/2HPM) and Regimen 2 (2HPZ/2HP) (Safety Analysis Population) | Participants with Grade 3 or higher Adverse events | 119 Participants |
| Regimen 2 (2HPZ/2HP) | Percentage Participants With Grade 3 or Higher Adverse Events During Study Drug Treatment in Control Regimen (Regimen 1 2HRZE/4HR) Compared to Experimental Regimens, Regimen 3 (2HPZM/2HPM) and Regimen 2 (2HPZ/2HP) (Safety Analysis Population) | Participants with less than Grade 3 Adverse Events or no adverse events | 716 Participants |
| Regimen 3 (2HPMZ/2HPM) | Percentage Participants With Grade 3 or Higher Adverse Events During Study Drug Treatment in Control Regimen (Regimen 1 2HRZE/4HR) Compared to Experimental Regimens, Regimen 3 (2HPZM/2HPM) and Regimen 2 (2HPZ/2HP) (Safety Analysis Population) | Participants with Grade 3 or higher Adverse events | 159 Participants |
| Regimen 3 (2HPMZ/2HPM) | Percentage Participants With Grade 3 or Higher Adverse Events During Study Drug Treatment in Control Regimen (Regimen 1 2HRZE/4HR) Compared to Experimental Regimens, Regimen 3 (2HPZM/2HPM) and Regimen 2 (2HPZ/2HP) (Safety Analysis Population) | Participants with less than Grade 3 Adverse Events or no adverse events | 687 Participants |
Comparison: For primary Safety endpoint, unfavorable outcomes for Arm1(control) vs Arm3(2PHZM/2PHM) will be considered first, if non-inferiority criteria are met, then Arm 1 vs Arm 2(2PHZE/2PH) will be compared. The proportion of participants with unfavorable outcome can be estimated as: if r\_a and r\_b are the proportions of unfavorable outcome for the two study arms (a=Arm1 and b = Arm2 or Arm3) and if δ is the non-inferiority margin (=6.6%), statistical hypothesis is H\_0:r\_b-r\_a≥δ vs.H\_1:r\_b-r\_a\<δp-value: 0.0595% CI: [-4.3, 3.2]Cochran-Mantel-Haenszel
Comparison: For primary Safety endpoint, unfavorable outcomes for Arm1(control) vs Arm3(2PHZM/2PHM) will be considered first, if non-inferiority criteria are met, then Arm 1 vs Arm 2(2PHZE/2PH) will be compared. The proportion of participants with unfavorable outcome can be estimated as: if r\_a and r\_b are the proportions of unfavorable outcome for the two study arms (a=Arm1 and b = Arm2 or Arm3) and if δ is the non-inferiority margin (=6.6%), statistical hypothesis is H\_0:r\_b-r\_a≥δ vs.H\_1:r\_b-r\_a\<δp-value: 0.0595% CI: [-8.7, -1.5]Cochran-Mantel-Haenszel
Primary
TB Disease-free Survival at 12M After Study Treatment Assignment Among Participants in Control Regimen, Regimen1 (2HRZE/4HR) to Experimental Regimens, Regimen3 (2HPZM/2HPM) and Regimen2 (2HPZ/2HP) (Assessable Population)
* To evaluate the efficacy of a rifapentine-containing regimen to determine whether the single substitution of rifapentine for rifampin makes it possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis * To evaluate the efficacy of a rifapentine-containing regimen that in addition substitutes moxifloxacin for ethambutol and continues moxifloxacin during the continuation phase, to determine whether it is possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis A primary outcome status of favorable, unfavorable, or not assessable was assigned. For detailed definitions of outcomes please refer to: Dorman SE, at al. N Engl J Med. 2021 May 6;384(18):1705-1718.
Time frame: Twelve months after treatment assignment
Population: Excluded Microbiologically eligible participants without an assessable outcomes, if they were not already classified as unfavorable and also did not attend 12M visit but were culture negative when last seen, or had treatment changed due to pregnancy, or died during follow-up with cause unrelated to tuberculosis, or received additional treatment for tuberculosis following exogenous reinfection demonstrated by whole genome sequencing, or died from a violent or accidental death during treatment
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Regimen 1 (2HRZE/4HR) | TB Disease-free Survival at 12M After Study Treatment Assignment Among Participants in Control Regimen, Regimen1 (2HRZE/4HR) to Experimental Regimens, Regimen3 (2HPZM/2HPM) and Regimen2 (2HPZ/2HP) (Assessable Population) | Favorable | 656 Participants |
| Regimen 1 (2HRZE/4HR) | TB Disease-free Survival at 12M After Study Treatment Assignment Among Participants in Control Regimen, Regimen1 (2HRZE/4HR) to Experimental Regimens, Regimen3 (2HPZM/2HPM) and Regimen2 (2HPZ/2HP) (Assessable Population) | Unfavorable | 70 Participants |
| Regimen 2 (2HPZ/2HP) | TB Disease-free Survival at 12M After Study Treatment Assignment Among Participants in Control Regimen, Regimen1 (2HRZE/4HR) to Experimental Regimens, Regimen3 (2HPZM/2HPM) and Regimen2 (2HPZ/2HP) (Assessable Population) | Favorable | 645 Participants |
| Regimen 2 (2HPZ/2HP) | TB Disease-free Survival at 12M After Study Treatment Assignment Among Participants in Control Regimen, Regimen1 (2HRZE/4HR) to Experimental Regimens, Regimen3 (2HPZM/2HPM) and Regimen2 (2HPZ/2HP) (Assessable Population) | Unfavorable | 107 Participants |
| Regimen 3 (2HPMZ/2HPM) | TB Disease-free Survival at 12M After Study Treatment Assignment Among Participants in Control Regimen, Regimen1 (2HRZE/4HR) to Experimental Regimens, Regimen3 (2HPZM/2HPM) and Regimen2 (2HPZ/2HP) (Assessable Population) | Favorable | 668 Participants |
| Regimen 3 (2HPMZ/2HPM) | TB Disease-free Survival at 12M After Study Treatment Assignment Among Participants in Control Regimen, Regimen1 (2HRZE/4HR) to Experimental Regimens, Regimen3 (2HPZM/2HPM) and Regimen2 (2HPZ/2HP) (Assessable Population) | Unfavorable | 88 Participants |
Comparison: For primary efficacy endpoint, unfavorable outcomes for Arm1(control) vs Arm3(2PHZM/2PHM) will be considered first, if non-inferiority criteria are met, then Arm 1 vs Arm 2(2PHZE/2PH) will be compared. The proportion of participants with unfavorable outcome can be estimated as: if r\_a and r\_b are the proportions of unfavorable outcome for the two study arms (a=Arm1 and b = Arm2 or Arm3) and if δ is the non-inferiority margin (=6.6%), statistical hypothesis is H\_0:r\_b-r\_a≥δ vs.H\_1:r\_b-r\_a\<δp-value: 0.0595% CI: [-1.1, 5.1]Cochran-Mantel-Haenszel
Comparison: For primary efficacy endpoint, unfavorable outcomes for Arm1(control) vs Arm3(2PHZM/2PHM) will be considered first, if non-inferiority criteria are met, then Arm 1 vs Arm 2(2PHZE/2PH) will be compared. The proportion of participants with unfavorable outcome can be estimated as: if r\_a and r\_b are the proportions of unfavorable outcome for the two study arms (a=Arm1 and b = Arm2 or Arm3) and if δ is the non-inferiority margin (=6.6%), statistical hypothesis is H\_0:r\_b-r\_a≥δ vs.H\_1:r\_b-r\_a\<δp-value: 0.0595% CI: [1.2, 7.7]Cochran-Mantel-Haenszel
Primary
TB Disease-free Survival at 12M After Study Treatment Assignment Among Participants in Control Regimen, Regimen1 (2HRZE/4HR) to Experimental Regimens, Regimen3 (2HPZM/2HPM) and Regimen2 (2HPZ/2HP) (Modified Intent to Treat [MITT] Population)
To evaluate the efficacy of a rifapentine-containing regimen to determine whether the single substitution of rifapentine for rifampin makes it possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis To evaluate the efficacy of a rifapentine-containing regimen that in addition substitutes moxifloxacin for ethambutol and continues moxifloxacin during the continuation phase, to determine whether it is possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis A primary outcome status of favorable, unfavorable, or not assessable was assigned. For detailed definitions of outcomes please refer to: Dorman SE, at al. N Engl J Med. 2021 May 6;384(18):1705-1718.
Time frame: Twelve months after treatment assignment
Population: The population is the Microbiologically eligible population that included the randomized participants excluding the ones with no evidence of cultures positive for M. tuberculosis, or with resistance to one or more of isoniazid, rifampin or fluoroquinolones, or are enrolled in violation of eligibility criteria
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Regimen 1 (2HRZE/4HR) | TB Disease-free Survival at 12M After Study Treatment Assignment Among Participants in Control Regimen, Regimen1 (2HRZE/4HR) to Experimental Regimens, Regimen3 (2HPZM/2HPM) and Regimen2 (2HPZ/2HP) (Modified Intent to Treat [MITT] Population) | Favorable Outcome | 656 Participants |
| Regimen 1 (2HRZE/4HR) | TB Disease-free Survival at 12M After Study Treatment Assignment Among Participants in Control Regimen, Regimen1 (2HRZE/4HR) to Experimental Regimens, Regimen3 (2HPZM/2HPM) and Regimen2 (2HPZ/2HP) (Modified Intent to Treat [MITT] Population) | Unfavorable Outcome | 112 Participants |
| Regimen 2 (2HPZ/2HP) | TB Disease-free Survival at 12M After Study Treatment Assignment Among Participants in Control Regimen, Regimen1 (2HRZE/4HR) to Experimental Regimens, Regimen3 (2HPZM/2HPM) and Regimen2 (2HPZ/2HP) (Modified Intent to Treat [MITT] Population) | Favorable Outcome | 645 Participants |
| Regimen 2 (2HPZ/2HP) | TB Disease-free Survival at 12M After Study Treatment Assignment Among Participants in Control Regimen, Regimen1 (2HRZE/4HR) to Experimental Regimens, Regimen3 (2HPZM/2HPM) and Regimen2 (2HPZ/2HP) (Modified Intent to Treat [MITT] Population) | Unfavorable Outcome | 139 Participants |
| Regimen 3 (2HPMZ/2HPM) | TB Disease-free Survival at 12M After Study Treatment Assignment Among Participants in Control Regimen, Regimen1 (2HRZE/4HR) to Experimental Regimens, Regimen3 (2HPZM/2HPM) and Regimen2 (2HPZ/2HP) (Modified Intent to Treat [MITT] Population) | Favorable Outcome | 668 Participants |
| Regimen 3 (2HPMZ/2HPM) | TB Disease-free Survival at 12M After Study Treatment Assignment Among Participants in Control Regimen, Regimen1 (2HRZE/4HR) to Experimental Regimens, Regimen3 (2HPZM/2HPM) and Regimen2 (2HPZ/2HP) (Modified Intent to Treat [MITT] Population) | Unfavorable Outcome | 123 Participants |
Comparison: For primary efficacy endpoint, unfavorable outcomes for Arm1(control) vs Arm3(2PHZM/2PHM) will be considered first, if non-inferiority criteria are met, then Arm 1 vs Arm 2(2PHZE/2PH) will be compared. The proportion of participants with unfavorable outcome can be estimated as: if r\_a and r\_b are the proportions of unfavorable outcome for the two study arms (a=Arm1 and b = Arm2 or Arm3) and if δ is the non-inferiority margin (=6.6%), statistical hypothesis is H\_0:r\_b-r\_a≥δ vs.H\_1:r\_b-r\_a\<δp-value: 0.0595% CI: [-2.6, 4.5]Cochran-Mantel-Haenszel
Comparison: For primary efficacy endpoint, unfavorable outcomes for Arm1(control) vs Arm3(2PHZM/2PHM) will be considered first, if non-inferiority criteria are met, then Arm 1 vs Arm 2(2PHZE/2PH) will be compared. The proportion of participants with unfavorable outcome can be estimated as: if r\_a and r\_b are the proportions of unfavorable outcome for the two study arms (a=Arm1 and b = Arm2 or Arm3) and if δ is the non-inferiority margin (=6.6%), statistical hypothesis is H\_0:r\_b-r\_a≥δ vs.H\_1:r\_b-r\_a\<δp-value: 0.0595% CI: [-0.6, 6.6]Cochran-Mantel-Haenszel
Secondary
Discontinuation of Assigned Treatment for a Reason Other Than Microbiological Ineligibility (Tolerability)
Tolerability of the regimen is evaluated using the outcome of discontinuation of assigned treatment for a reason other than microbiological ineligibility.
Time frame: four or six months
Population: Safety population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Regimen 1 (2HRZE/4HR) | Discontinuation of Assigned Treatment for a Reason Other Than Microbiological Ineligibility (Tolerability) | 61 Participants |
| Regimen 2 (2HPZ/2HP) | Discontinuation of Assigned Treatment for a Reason Other Than Microbiological Ineligibility (Tolerability) | 37 Participants |
| Regimen 3 (2HPMZ/2HPM) | Discontinuation of Assigned Treatment for a Reason Other Than Microbiological Ineligibility (Tolerability) | 55 Participants |
Secondary
Estimated Steady State Efavirenz PK Parameters Including Mid-dosing Interval Concentration
Among participants with HIV infection receiving efavirenz-based antiretroviral therapy, number of participants who maintained plasma efavirenz concentrations ≥1 mg/L during TB treatment.
Time frame: four months
Population: Analysis Population Description: This analysis population includes participants in EFV group 1 who were already on an EFV-containing ART regimen when initiating RPT-based TB treatment (experimental arms only). That is, this analysis was pre-specified to report data by pooling participants from Regimen 2 (2HPZE/2HP) and Regimen 3 (2HPMZ/2HPM) who were on an EFV-containing ART regimen.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Regimen 1 (2HRZE/4HR) | Estimated Steady State Efavirenz PK Parameters Including Mid-dosing Interval Concentration | 62 Participants |
Secondary
Proportion of Participants Who Are Culture Negative at Eight Weeks
Proportion of participants who are culture negative at eight weeks, liquid media
Time frame: eight weeks
Population: Microbiologically eligible analysis population, evaluable patients (positive or negative culture result)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Regimen 1 (2HRZE/4HR) | Proportion of Participants Who Are Culture Negative at Eight Weeks | 523 Participants |
| Regimen 2 (2HPZ/2HP) | Proportion of Participants Who Are Culture Negative at Eight Weeks | 616 Participants |
| Regimen 3 (2HPMZ/2HPM) | Proportion of Participants Who Are Culture Negative at Eight Weeks | 641 Participants |
Secondary
Speed of Decline of Sputum Viable Bacilli by Automated Liquid MGIT Culture Days to Detection
Parameter estimates of the nonlinear mixed effect models describing longitudinal time to positive (TTP)
Time frame: 12 months
Population: The population is the Microbiologically eligible population that included the randomized participants excluding the ones with no evidence of cultures positive for M. tuberculosis, or with resistance to one or more of isoniazid, rifampin or fluoroquinolones, or are enrolled in violation of eligibility criteria.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Regimen 1 (2HRZE/4HR) | Speed of Decline of Sputum Viable Bacilli by Automated Liquid MGIT Culture Days to Detection | 0.14 log10 DTP / day |
| Regimen 2 (2HPZ/2HP) | Speed of Decline of Sputum Viable Bacilli by Automated Liquid MGIT Culture Days to Detection | 0.20 log10 DTP / day |
| Regimen 3 (2HPMZ/2HPM) | Speed of Decline of Sputum Viable Bacilli by Automated Liquid MGIT Culture Days to Detection | 0.24 log10 DTP / day |
Secondary
TB Disease-free Survival at Eighteen Months After Study Treatment Assignment
* To evaluate the efficacy of a rifapentine-containing regimen to determine whether the single substitution of rifapentine for rifampin makes it possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis * To evaluate the efficacy of a rifapentine-containing regimen that in addition substitutes moxifloxacin for ethambutol and continues moxifloxacin during the continuation phase, to determine whether it is possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis
Time frame: Eighteen months after treatment assignment
Population: Assessable Population: Excluded the Microbiologically eligible pts without an assessable outcomes as if they were not already classified as unfavorable and add did not attend mo12 visit but were culture negative when last seen, or had treatment changed due to pregnancy, or died during follow-up with cause unrelated to tuberculosis, or received additional treatment for tuberculosis following exogenous reinfection demonstrated by WGS, or died from a violent or accidental death during treatment
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Regimen 1 (2HRZE/4HR) | TB Disease-free Survival at Eighteen Months After Study Treatment Assignment | Favorable | 656 Participants |
| Regimen 1 (2HRZE/4HR) | TB Disease-free Survival at Eighteen Months After Study Treatment Assignment | Unfavorable | 69 Participants |
| Regimen 2 (2HPZ/2HP) | TB Disease-free Survival at Eighteen Months After Study Treatment Assignment | Favorable | 636 Participants |
| Regimen 2 (2HPZ/2HP) | TB Disease-free Survival at Eighteen Months After Study Treatment Assignment | Unfavorable | 97 Participants |
| Regimen 3 (2HPMZ/2HPM) | TB Disease-free Survival at Eighteen Months After Study Treatment Assignment | Favorable | 667 Participants |
| Regimen 3 (2HPMZ/2HPM) | TB Disease-free Survival at Eighteen Months After Study Treatment Assignment | Unfavorable | 79 Participants |
95% CI: [-2.01, 4.11]
95% CI: [0.42, 6.9]
Secondary
TB Disease-free Survival at Eighteen Months After Study Treatment Assignment
* To evaluate the efficacy of a rifapentine-containing regimen to determine whether the single substitution of rifapentine for rifampin makes it possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis * To evaluate the efficacy of a rifapentine-containing regimen that in addition substitutes moxifloxacin for ethambutol and continues moxifloxacin during the continuation phase, to determine whether it is possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis
Time frame: Eighteen months after study treatment assignment.
Population: The population is the Microbiologically eligible population that included the randomized participants excluding the ones with no evidence of cultures positive for M. tuberculosis, or with resistance to one or more of isoniazid, rifampin or fluoroquinolones, or are enrolled in violation of eligibility criteria
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Regimen 1 (2HRZE/4HR) | TB Disease-free Survival at Eighteen Months After Study Treatment Assignment | Favorable | 656 Participants |
| Regimen 1 (2HRZE/4HR) | TB Disease-free Survival at Eighteen Months After Study Treatment Assignment | Unfavorable | 112 Participants |
| Regimen 2 (2HPZ/2HP) | TB Disease-free Survival at Eighteen Months After Study Treatment Assignment | Favorable | 636 Participants |
| Regimen 2 (2HPZ/2HP) | TB Disease-free Survival at Eighteen Months After Study Treatment Assignment | Unfavorable | 148 Participants |
| Regimen 3 (2HPMZ/2HPM) | TB Disease-free Survival at Eighteen Months After Study Treatment Assignment | Favorable | 667 Participants |
| Regimen 3 (2HPMZ/2HPM) | TB Disease-free Survival at Eighteen Months After Study Treatment Assignment | Unfavorable | 124 Participants |
95% CI: [-2.45, 4.63]
95% CI: [0.45, 7.79]
Secondary
Time to Stable Sputum Culture Conversion
Time to stable sputum culture conversion, liquid media
Time frame: four or six months
Population: Microbiologically Eligible Analysis Population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Regimen 1 (2HRZE/4HR) | Time to Stable Sputum Culture Conversion | 8.14 weeks |
| Regimen 2 (2HPZ/2HP) | Time to Stable Sputum Culture Conversion | 8.14 weeks |
| Regimen 3 (2HPMZ/2HPM) | Time to Stable Sputum Culture Conversion | 8.14 weeks |
Other Pre-specified
Sensitivity Analyses Assuming All Losses to Follow-up and Non-tuberculosis Deaths Have a Favorable Outcome
A sensitivity analysis used to supplement the primary efficacy results and provide further insight into whether the intervention regimens should be considered to have non-inferior efficacy. This analysis considers the difference in proportion of unfavorable outcomes between the control arm and each of the experimental arms. Measurement Description: The difference in proportion unfavorable was calculated using a stratified analysis using Cochran-Mantel-Haenszel weights. The analysis was stratified by HIV status and presence of cavitation only, and the stratified difference was considered primary.
Time frame: 12 months
Population: Assessable analysis population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Regimen 1 (2HRZE/4HR) | Sensitivity Analyses Assuming All Losses to Follow-up and Non-tuberculosis Deaths Have a Favorable Outcome | 671 Participants |
| Regimen 2 (2HPZ/2HP) | Sensitivity Analyses Assuming All Losses to Follow-up and Non-tuberculosis Deaths Have a Favorable Outcome | 650 Participants |
| Regimen 3 (2HPMZ/2HPM) | Sensitivity Analyses Assuming All Losses to Follow-up and Non-tuberculosis Deaths Have a Favorable Outcome | 673 Participants |
95% CI: [2.8, 8.9]
95% CI: [0.5, 6.3]
Other Pre-specified
Sensitivity Analyses Assuming All Losses to Follow-up and Non-tuberculosis Deaths Have an Unfavorable Outcome
A sensitivity analysis used to supplement the primary efficacy results and provide further insight into whether the intervention regimens should be considered to have non-inferior efficacy. This analysis considers the difference in proportion of unfavorable outcomes between the control arm and each of the experimental arms. Measurement Description: The difference in proportion unfavorable was calculated using a stratified analysis using Cochran-Mantel-Haenszel weights. The analysis was stratified by HIV status and presence of cavitation only, and the stratified difference was considered primary.
Time frame: 12 months
Population: Microbiologically eligible analysis population.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Regimen 1 (2HRZE/4HR) | Sensitivity Analyses Assuming All Losses to Follow-up and Non-tuberculosis Deaths Have an Unfavorable Outcome | 656 Participants |
| Regimen 2 (2HPZ/2HP) | Sensitivity Analyses Assuming All Losses to Follow-up and Non-tuberculosis Deaths Have an Unfavorable Outcome | 645 Participants |
| Regimen 3 (2HPMZ/2HPM) | Sensitivity Analyses Assuming All Losses to Follow-up and Non-tuberculosis Deaths Have an Unfavorable Outcome | 668 Participants |
95% CI: [-0.6, 6.6]
95% CI: [-1.12, 5.7]