S31/A5349: TBTC Study 31: Rifapentine-containing Tuberculosis Treatment Shortening Regimens

Sponsor
Centers for Disease Control and Prevention (U.S. Fed)
Overall Status
Completed
CT.gov ID
NCT02410772
Collaborator
AIDS Clinical Trials Group (Other)
2,516
33
3
63.2
76.2
1.2

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 3

Detailed Description

Title:

Rifapentine-containing treatment shortening regimens for pulmonary tuberculosis: a randomized, open-label, controlled, phase 3 clinical trial

Hypotheses:
  1. 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.

  2. 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

Study Design

Study Type:
Interventional
Actual Enrollment :
2516 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Rifapentine-containing Treatment Shortening Regimens for Pulmonary Tuberculosis: A Randomized, Open-label, Controlled Phase 3 Clinical Trial. TBTC Study 31, ACTG Study A5349
Actual Study Start Date :
Jan 25, 2016
Actual Primary Completion Date :
Jul 1, 2020
Actual Study Completion Date :
May 1, 2021

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Regimen 1

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

Drug: control
standard six-month treatment

Experimental: Regimen 2

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

Drug: rifapentine
Regimen 2: Rifapentine is substituted for rifampin as the basis of 4-month treatment
Other Names:
  • Priftin
  • Experimental: Regimen 3

    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; moxifloxacin, 400 mg

    Drug: rifapentine and moxifloxacin
    Regimen 3: In addition to the single substitution described for regimen 2, a second substitution is added, of moxifloxacin for ethambutol.
    Other Names:
  • Priftin and Avelox
  • Outcome Measures

    Primary Outcome Measures

    1. 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.

    2. 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.

    3. 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

    Secondary Outcome Measures

    1. TB Disease-free Survival at Eighteen Months After Study Treatment Assignment [eighteen months after treatment assignment]

    2. Proportion of Participants Who Are Culture Negative at Eight Weeks [eight weeks]

      solid and liquid media considered separately

    3. Time to Stable Sputum Culture Conversion [four or six months]

      solid and liquid media considered separately

    4. Speed of Decline of Sputum Viable Bacilli by Automated MGIT Days to Detection [four or six months]

    5. TB Disease-free Survival at Twelve and Eighteen Months After Study Treatment Assignment Assuming All Losses to Follow-up and Non-tuberculosis Deaths Have an Unfavorable Outcome [eighteen months after study treatment assignment]

      Sensitivity analyses assuming all losses to follow-up and non-tuberculosis deaths have an unfavorable outcome

    6. TB Disease-free Survival at Twelve and Eighteen Months After Study Treatment Assignment Assuming All Losses to Follow-up and Non-tuberculosis Deaths Have a Favorable Outcome [eighteen months after study treatment assignment]

      Sensitivity analyses assuming all losses to follow-up and non-tuberculosis deaths have a favorable outcome

    7. Discontinuation of Assigned Treatment for a Reason Other Than Microbiological Ineligibility [four or six months]

    8. Efavirenz Maximum Concentration, Area Under the Time-concentration Curve, and Half Life [four months]

      Among participants with HIV infection receiving efavirenz-based antiretroviral therapy, these values will be used to estimate steady state efavirenz PK parameters including mid-dosing interval concentration

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    12 Years and Older
    Sexes Eligible for Study:
    All
    Accepts 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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 TBTC Site 82/ ACTG Site 801 USCF AIDS CRS San Francisco California United States 94110
    2 TBTC Site 24 Columbia Unversity New York New York United States 10032
    3 TBTC Site 20 UNTHSC (University of North Texas Health Science Center) Fort Worth Texas United States 76104
    4 TBTC Site 62 Baylor College of Medicine & Affiliated Hospitals/VA Houston Texas United States 77030
    5 TBTC Site 63 San Antonio VA Medical Center (South Texas Group) San Antonio Texas United States 78229-4404
    6 TBTC Site 94/ ACTG Site 12201 Hospital Nossa Senhora da Conceicao Porto Alegre RS Brazil 91350-200
    7 TBTC Site 91/ ACTG Site 12101 Insituto Nacional de Pesquisa ClĂ­nica Evandro Chagas Rio de Janeiro Brazil 21040-360
    8 TBTC Site 36 TB and Chest Service of Hong Kong, China Hong Kong China
    9 TBTC Site 45/ ACTG Site 30022: Les Centres Gheskio (INLR) Port au Prince Ouest Haiti HT6110
    10 TBTC Site 67/ ACTG Site 31730 GHESKIO centers IMIS Port-au-Prince Ouest Haiti HT 6124
    11 TBTC Site 43/ ACTG Site 31441 BJ Medical College Pune Maharashtra India 4110011
    12 TBTC Site 44/ ACTG Site 11701 CART CRS, YRGCARE Medical Centre VHS Chennai Tamilnadu India 600113
    13 TBTC Site 02/ ACTG 12501 Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS Kericho Kericho County Kenya 20200
    14 TBTC Site 39/ ACTG Site 31460 Kisumu CRS Kisumu Nyanza Province Kenya 40100
    15 TBTC Site 03/ ACTG Site 12601 Moi University Clinical Research Site Eldoret Kenya 30100
    16 TBTC Site 04/ ACTG Site 30301 Blantyre CRS (or College of Medicine - Johns Hopkins Research Project, COM-JHP) Blantyre Malawi
    17 TBTC Site 05/ ACTG Site 12001 UNC Project Tidziwe Centre Lilongwe Malawi
    18 TBTC Site 90/ ACTG Site 11301 Asociacion Civil Impacta Salud y Educacion Lima Peru Lima 04
    19 TBTC Site 93/ ACTG Site 11302 CRS San Miguel Lima Peru Lima 32
    20 TBTC Site 10/ ACTG Site 31718 TASK Applied Science Bellville Cape Town South Africa 7530
    21 TBTC Site 09/ ACTG Site 31792 University of Cape Town Lung Institute (Pty) Ltd Mowbray Cape Town South Africa 7700
    22 TBTC Site 34 Wits Health Consortium Perinatal HIV Research Unit (PHRU) Soweto Gauteng South Africa 1864
    23 TBTC Site 49/ ACTG Site 12301 Soweto ACTG CRS Soweto Johannesburg South Africa 2013
    24 TBTC Site 06/ ACTG Site 11201 Durban International Clinical Research Site Durban KwaZulu Natal South Africa 4093
    25 TBTC Site 01/ACTG Site 8950 FAM CRU Parow Valley Western Cape South Africa 7505
    26 TBTC Site 08/ ACTG Site 31793 South African Tuberculosis Vaccine Initiative (SATVI) Cape Town Western Province South Africa 7705
    27 TBTC Site 07/ ACTG Site 11101 Wits Helen Joseph CRS Johannesburg South Africa 2092
    28 TBTC Site 42/ ACTG Site 31802 The Thai Red Cross AIDS Research Centre Pathumwan Bangkok Thailand 10330
    29 TBTC Site 69/ ACTG Site 31784 Thai-CTIU, CMU HIV Treatment CRS Muang Chiang Mai Chiang Mai Thailand 50200
    30 TBTC Site 11/ ACTG Site 12401 Joint Clinical Research Centre, Kampala Clinical Research Site Kampala Uganda
    31 TBTC Site 30 Uganda-Case Western Reserve Research Collaboration Kampala Uganda
    32 TBTC Site 37 Vietnam NTP/UCSF Research Collaboration Hanoi Vietnam 10000
    33 TBTC Site 41/ ACTG Site 30313 Parirenyatwa Clinical Research Site Harare Zimbabwe 263

    Sponsors and Collaborators

    • Centers for Disease Control and Prevention
    • AIDS Clinical Trials Group

    Investigators

    • Study Chair: Susan Dorman, MD, Medical University of South Carolina
    • Study Chair: Payam Nahid, MD, MPH, University of California at San Francisco
    • Study Chair: Susan Swindells, MBBS, University of Nebraska
    • Study Chair: Richard Chaisson, MD, Johns Hopkins University
    • Study Chair: Ekaterina V Kurbatova, MD, PhD, MPH, Centers for Disease Control and Prevention

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Centers for Disease Control and Prevention
    ClinicalTrials.gov Identifier:
    NCT02410772
    Other Study ID Numbers:
    • 6655
    First Posted:
    Apr 8, 2015
    Last Update Posted:
    Sep 28, 2021
    Last Verified:
    Jul 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:

    Study Results

    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 Detail 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
    Arm/Group Title Regimen 1 (2HRZE/4HR) Regimen 2 (2HPZ/2HP) Regimen 3 (2HPMZ/2HPM)
    Arm/Group Description 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 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 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.
    Period Title: Overall Study
    STARTED 829 838 849
    Microbiologically Eligible Analysis Population 768 784 791
    Assessable Population 726 752 756
    COMPLETED 726 752 756
    NOT COMPLETED 103 86 93

    Baseline Characteristics

    Arm/Group Title Regimen 1 (2HRZE/4HR) Regimen 2 (2HPZ/2HP) Regimen 3 (2HPMZ/2HPM) Total
    Arm/Group Description 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 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 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. Total of all reporting groups
    Overall Participants 768 784 791 2343
    Age (Count of Participants)
    <=18 years
    19
    2.5%
    19
    2.4%
    25
    3.2%
    63
    2.7%
    Between 18 and 65 years
    743
    96.7%
    755
    96.3%
    755
    95.4%
    2253
    96.2%
    >=65 years
    6
    0.8%
    10
    1.3%
    11
    1.4%
    27
    1.2%
    Age (years) [Median (Inter-Quartile Range) ]
    Median (Inter-Quartile Range) [years]
    30.9
    31.0
    31.0
    31.0
    Sex: Female, Male (Count of Participants)
    Female
    224
    29.2%
    221
    28.2%
    228
    28.8%
    673
    28.7%
    Male
    544
    70.8%
    563
    71.8%
    563
    71.2%
    1670
    71.3%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    27
    3.5%
    20
    2.6%
    27
    3.4%
    74
    3.2%
    Not Hispanic or Latino
    287
    37.4%
    283
    36.1%
    297
    37.5%
    867
    37%
    Unknown or Not Reported
    454
    59.1%
    481
    61.4%
    467
    59%
    1402
    59.8%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    86
    11.2%
    93
    11.9%
    89
    11.3%
    268
    11.4%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    553
    72%
    571
    72.8%
    552
    69.8%
    1676
    71.5%
    White
    15
    2%
    8
    1%
    13
    1.6%
    36
    1.5%
    More than one race
    111
    14.5%
    111
    14.2%
    135
    17.1%
    357
    15.2%
    Unknown or Not Reported
    3
    0.4%
    1
    0.1%
    2
    0.3%
    6
    0.3%
    Region of Enrollment (Count of Participants)
    United States
    8
    1%
    7
    0.9%
    10
    1.3%
    25
    1.1%
    Africa
    565
    73.6%
    573
    73.1%
    578
    73.1%
    1716
    73.2%
    South Asia
    86
    11.2%
    89
    11.4%
    88
    11.1%
    263
    11.2%
    South America
    109
    14.2%
    115
    14.7%
    115
    14.5%
    339
    14.5%
    HIV Status (Count of Participants)
    HIV Negative
    704
    91.7%
    716
    91.3%
    729
    92.2%
    2149
    91.7%
    HIV Positive
    64
    8.3%
    68
    8.7%
    62
    7.8%
    194
    8.3%
    Cavitation status at Baseline (Count of Participants)
    Cavitation on chest radiograph
    558
    72.7%
    573
    73.1%
    572
    72.3%
    1703
    72.7%
    No cavitation on chest radiograph
    204
    26.6%
    205
    26.1%
    210
    26.5%
    619
    26.4%
    Unknown
    6
    0.8%
    6
    0.8%
    9
    1.1%
    21
    0.9%

    Outcome Measures

    1. Primary Outcome
    Title 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)
    Description 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

    Outcome Measure Data

    Analysis Population Description
    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/Group Title Regimen 1 (2HRZE/4HR) Regimen 2 (2HPZ/2HP) Regimen 3 (2HPMZ/2HPM)
    Arm/Group Description 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 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 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.
    Measure Participants 768 784 791
    Favorable Outcome
    656
    85.4%
    645
    82.3%
    668
    84.5%
    Unfavorable Outcome
    112
    14.6%
    139
    17.7%
    123
    15.5%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Regimen 1 (2HRZE/4HR), Regimen 3 (2HPMZ/2HPM)
    Comments 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<δ
    Type of Statistical Test Non-Inferiority
    Comments Non-inferiority was assessed using the upper bound of the two-sided 95% CI for the difference between the percentage of patients who are classified as having an unfavorable status on the control regimen (2HRZE/ 4 HR) and the investigational regimens, Regimen 2 (2HPZ/2HP) and Regimen 3 (2HPZM/2HPM). If the upper bound of the confidence interval is less than , then the non-inferiority of Arm 2 or Arm 3 to Arm 1 with a significance level of 0.05 is established (equivalent to one-sided α=0.025).
    Statistical Test of Hypothesis p-Value 0.05
    Comments For a significance level of 0.05, the statistical test is equivalent to obtaining the two-sided 95% confidence interval for the difference of r_b-r_a.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 1
    Confidence Interval (2-Sided) 95%
    -2.6 to 4.5
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Regimen 1 (2HRZE/4HR), Regimen 3 (2HPMZ/2HPM)
    Comments 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<δ
    Type of Statistical Test Non-Inferiority
    Comments Non-inferiority was assessed using the upper bound of the two-sided 95% CI for the difference between the percentage of patients who are classified as having an unfavorable status on the control regimen (2HRZE/ 4 HR) and the investigational regimens, Regimen 2 (2HPZ/2HP) and Regimen 3 (2HPZM/2HPM). If the upper bound of the confidence interval is less than , then the non-inferiority of Arm 2 or Arm 3 to Arm 1 with a significance level of 0.05 is established (equivalent to one-sided α=0.025).
    Statistical Test of Hypothesis p-Value 0.05
    Comments
    Method Cochran-Mantel-Haenszel
    Comments For a significance level of 0.05, the statistical test is equivalent to obtaining the two-sided 95% confidence interval for the difference of r_b-r_a.
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 3
    Confidence Interval (2-Sided) 95%
    -0.6 to 6.6
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Primary Outcome
    Title 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)
    Description 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

    Outcome Measure Data

    Analysis Population Description
    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/Group Title Regimen 1 (2HRZE/4HR) Regimen 2 (2HPZ/2HP) Regimen 3 (2HPMZ/2HPM)
    Arm/Group Description 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 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 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.
    Measure Participants 726 752 756
    Favorable
    656
    85.4%
    645
    82.3%
    668
    84.5%
    Unfavorable
    70
    9.1%
    107
    13.6%
    88
    11.1%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Regimen 1 (2HRZE/4HR), Regimen 3 (2HPMZ/2HPM)
    Comments 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<δ
    Type of Statistical Test Non-Inferiority
    Comments Non-inferiority was assessed using the upper bound of the two-sided 95% CI for the difference between the percentage of patients who are classified as having an unfavorable status on the control regimen (2HRZE/ 4 HR) and the investigational regimens, Regimen 2 (2HPZ/2HP) and Regimen 3 (2HPZM/2HPM). If the upper bound of the confidence interval is less than , then the non-inferiority of Arm 2 or Arm 3 to Arm 1 with a significance level of 0.05 is established (equivalent to one-sided α=0.025).
    Statistical Test of Hypothesis p-Value 0.05
    Comments For a significance level of 0.05, the statistical test is equivalent to obtaining the two-sided 95% confidence interval for the difference of r_b-r_a
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 2
    Confidence Interval (2-Sided) 95%
    -1.1 to 5.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Regimen 1 (2HRZE/4HR), Regimen 2 (2HPZ/2HP)
    Comments 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<δ
    Type of Statistical Test Non-Inferiority
    Comments Non-inferiority was assessed using the upper bound of the two-sided 95% CI for the difference between the percentage of patients who are classified as having an unfavorable status on the control regimen (2HRZE/ 4 HR) and the investigational regimens, Regimen 2 (2HPZ/2HP) and Regimen 3 (2HPZM/2HPM). If the upper bound of the confidence interval is less than , then the non-inferiority of Arm 2 or Arm 3 to Arm 1 with a significance level of 0.05 is established (equivalent to one-sided α=0.025).
    Statistical Test of Hypothesis p-Value 0.05
    Comments For a significance level of 0.05, the statistical test is equivalent to obtaining the two-sided 95% confidence interval for the difference of r_b-r_a
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value 4.4
    Confidence Interval (2-Sided) 95%
    1.2 to 7.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Primary Outcome
    Title 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)
    Description 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)

    Outcome Measure Data

    Analysis Population Description
    Safety analyses included all randomized participants who received at least one dose of study treatment
    Arm/Group Title Regimen 1 (2HRZE/4HR) Regimen 2 (2HPZ/2HP) Regimen 3 (2HPMZ/2HPM)
    Arm/Group Description 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 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 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.
    Measure Participants 825 835 846
    Participants with Grade 3 or higher Adverse events
    159
    20.7%
    119
    15.2%
    159
    20.1%
    Participants with less than Grade 3 Adverse Events or no adverse events
    666
    86.7%
    716
    91.3%
    687
    86.9%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Regimen 1 (2HRZE/4HR), Regimen 3 (2HPMZ/2HPM)
    Comments 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<δ
    Type of Statistical Test Non-Inferiority
    Comments Non-inferiority was assessed using the upper bound of the two-sided 95% CI for the difference between the percentage of patients who are classified as having an unfavorable status on the control regimen (2HRZE/ 4 HR) and the investigational regimens, Regimen 2 (2HPZ/2HP) and Regimen 3 (2HPZM/2HPM). If the upper bound of the confidence interval is less than, then the non-inferiority of Arm 2 or Arm 3 to Arm 1 with a significance level of 0.05 is established (equivalent to one-sided α=0.025).
    Statistical Test of Hypothesis p-Value 0.05
    Comments For a significance level of 0.05, the statistical test is equivalent to obtaining the two-sided 95% confidence interval for the difference of r_b-r_a.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value -0.6
    Confidence Interval (2-Sided) 95%
    -4.3 to 3.2
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Regimen 1 (2HRZE/4HR), Regimen 2 (2HPZ/2HP)
    Comments 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<δ
    Type of Statistical Test Non-Inferiority
    Comments Non-inferiority was assessed using the upper bound of the two-sided 95% CI for the difference between the percentage of patients who are classified as having an unfavorable status on the control regimen (2HRZE/ 4 HR) and the investigational regimens, Regimen 2 (2HPZ/2HP) and Regimen 3 (2HPZM/2HPM). If the upper bound of the confidence interval is less than, then the non-inferiority of Arm 2 or Arm 3 to Arm 1 with a significance level of 0.05 is established (equivalent to one-sided α=0.025).
    Statistical Test of Hypothesis p-Value 0.05
    Comments For a significance level of 0.05, the statistical test is equivalent to obtaining the two-sided 95% confidence interval for the difference of r_b-r_a.
    Method Cochran-Mantel-Haenszel
    Comments
    Method of Estimation Estimation Parameter Risk Difference (RD)
    Estimated Value -5.1
    Confidence Interval (2-Sided) 95%
    -8.7 to -1.5
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    4. Secondary Outcome
    Title TB Disease-free Survival at Eighteen Months After Study Treatment Assignment
    Description
    Time Frame eighteen months after treatment assignment

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    5. Secondary Outcome
    Title Proportion of Participants Who Are Culture Negative at Eight Weeks
    Description solid and liquid media considered separately
    Time Frame eight weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    6. Secondary Outcome
    Title Time to Stable Sputum Culture Conversion
    Description solid and liquid media considered separately
    Time Frame four or six months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    7. Secondary Outcome
    Title Speed of Decline of Sputum Viable Bacilli by Automated MGIT Days to Detection
    Description
    Time Frame four or six months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    8. Secondary Outcome
    Title TB Disease-free Survival at Twelve and Eighteen Months After Study Treatment Assignment Assuming All Losses to Follow-up and Non-tuberculosis Deaths Have an Unfavorable Outcome
    Description Sensitivity analyses assuming all losses to follow-up and non-tuberculosis deaths have an unfavorable outcome
    Time Frame eighteen months after study treatment assignment

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    9. Secondary Outcome
    Title TB Disease-free Survival at Twelve and Eighteen Months After Study Treatment Assignment Assuming All Losses to Follow-up and Non-tuberculosis Deaths Have a Favorable Outcome
    Description Sensitivity analyses assuming all losses to follow-up and non-tuberculosis deaths have a favorable outcome
    Time Frame eighteen months after study treatment assignment

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    10. Secondary Outcome
    Title Discontinuation of Assigned Treatment for a Reason Other Than Microbiological Ineligibility
    Description
    Time Frame four or six months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    11. Secondary Outcome
    Title Efavirenz Maximum Concentration, Area Under the Time-concentration Curve, and Half Life
    Description Among participants with HIV infection receiving efavirenz-based antiretroviral therapy, these values will be used to estimate steady state efavirenz PK parameters including mid-dosing interval concentration
    Time Frame four months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description

    Adverse Events

    Time Frame Adverse Events were reported from randomization to up to 14 days after last dose of study treatment Regimen (4 months and up to 14 days or 6 months and up to 14 days); All cause Mortality is reported during study treatment and up to M18 study follow up visit (18 months)
    Adverse Event Reporting Description The Safety analysis population included all the randomized patients and received at least 1 dose of trial medication. Grade 3 or higher Adverse Events per CTCAE V4.03 are collected in systematic way through the laboratory tests and physical exam at regular study visits and also non-systematic way when self-reported by participants. All Cause Mortality is adjusted to reflect the deaths occurred up to M18 study visit.
    Arm/Group Title Regimen 1 (2HRZE/4HR) Regimen 2 (2HPZ/2HP) Regimen 3 (2HPMZ/2HPM)
    Arm/Group Description 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 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 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.
    All Cause Mortality
    Regimen 1 (2HRZE/4HR) Regimen 2 (2HPZ/2HP) Regimen 3 (2HPMZ/2HPM)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 12/825 (1.5%) 11/835 (1.3%) 13/846 (1.5%)
    Serious Adverse Events
    Regimen 1 (2HRZE/4HR) Regimen 2 (2HPZ/2HP) Regimen 3 (2HPMZ/2HPM)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 56/825 (6.8%) 39/835 (4.7%) 37/846 (4.4%)
    Blood and lymphatic system disorders
    Anemia 0/825 (0%) 0 1/835 (0.1%) 1 0/846 (0%) 0
    Leukopenia 0/825 (0%) 0 0/835 (0%) 0 1/846 (0.1%) 1
    Lymphopenia 0/825 (0%) 0 0/835 (0%) 0 1/846 (0.1%) 1
    Neutropenia 3/825 (0.4%) 3 1/835 (0.1%) 1 2/846 (0.2%) 2
    Thrombotic Thrombocytopenic Purpura 0/825 (0%) 0 0/835 (0%) 0 1/846 (0.1%) 1
    Cardiac disorders
    Cardiac Failure Congestive 0/825 (0%) 0 0/835 (0%) 0 1/846 (0.1%) 2
    Myocardial Ischemia 0/825 (0%) 0 1/835 (0.1%) 1 0/846 (0%) 0
    Right Ventricular Failure 0/825 (0%) 0 0/835 (0%) 0 1/846 (0.1%) 1
    Eye disorders
    Diabetic Retinopathy 1/825 (0.1%) 1 0/835 (0%) 0 0/846 (0%) 0
    Gastrointestinal disorders
    Acute Pancreatitis 1/825 (0.1%) 1 0/835 (0%) 0 0/846 (0%) 0
    Pneumatosis Intestinalis 1/825 (0.1%) 1 0/835 (0%) 0 0/846 (0%) 0
    Small Intestinal Obstruction 1/825 (0.1%) 1 0/835 (0%) 0 0/846 (0%) 0
    Upper Gastrointestinal Hemorrhage 1/825 (0.1%) 1 0/835 (0%) 0 0/846 (0%) 0
    Vomiting 0/825 (0%) 0 1/835 (0.1%) 1 0/846 (0%) 0
    General disorders
    Death 1/825 (0.1%) 1 1/835 (0.1%) 1 0/846 (0%) 0
    Drug Intolerance 1/825 (0.1%) 1 0/835 (0%) 0 0/846 (0%) 0
    Pyrexia 0/825 (0%) 0 0/835 (0%) 0 1/846 (0.1%) 1
    Hepatobiliary disorders
    Hepatitis 10/825 (1.2%) 10 5/835 (0.6%) 5 7/846 (0.8%) 7
    Infections and infestations
    Bone Tuberculosis 1/825 (0.1%) 1 0/835 (0%) 0 0/846 (0%) 0
    Dengue Fever 0/825 (0%) 0 1/835 (0.1%) 1 0/846 (0%) 0
    Extrapulmonary Tuberculosis 0/825 (0%) 0 1/835 (0.1%) 1 0/846 (0%) 0
    Hepatitis C 0/825 (0%) 0 0/835 (0%) 0 1/846 (0.1%) 1
    Orchitis 0/825 (0%) 0 1/835 (0.1%) 1 0/846 (0%) 0
    Paracoccidioidal Infection 1/825 (0.1%) 1 0/835 (0%) 0 0/846 (0%) 0
    Pneumonia 1/825 (0.1%) 1 1/835 (0.1%) 1 3/846 (0.4%) 3
    Pneumonia Bacterial 0/825 (0%) 0 1/835 (0.1%) 1 0/846 (0%) 0
    Pulmonary Tuberculosis 0/825 (0%) 0 0/835 (0%) 0 1/846 (0.1%) 1
    Sepsis 1/825 (0.1%) 1 0/835 (0%) 0 0/846 (0%) 0
    Tuberculosis 1/825 (0.1%) 1 0/835 (0%) 0 0/846 (0%) 0
    Injury, poisoning and procedural complications
    Alcohol Poisoning 0/825 (0%) 0 1/835 (0.1%) 1 0/846 (0%) 0
    Chest Injury 0/825 (0%) 0 1/835 (0.1%) 1 0/846 (0%) 0
    Craniocerebral Injury 0/825 (0%) 0 1/835 (0.1%) 1 0/846 (0%) 0
    Documented Hypersensitivity To Administered Product 1/825 (0.1%) 1 0/835 (0%) 0 0/846 (0%) 0
    Hand Fracture 1/825 (0.1%) 1 0/835 (0%) 0 0/846 (0%) 0
    Humerus Fracture 1/825 (0.1%) 1 0/835 (0%) 0 0/846 (0%) 0
    Limb Injury 1/825 (0.1%) 1 0/835 (0%) 0 0/846 (0%) 0
    Overdose 1/825 (0.1%) 1 1/835 (0.1%) 1 0/846 (0%) 0
    Road Traffic Accident 0/825 (0%) 0 1/835 (0.1%) 1 0/846 (0%) 0
    Stab Wound 1/825 (0.1%) 1 2/835 (0.2%) 2 0/846 (0%) 0
    Thermal Burn 1/825 (0.1%) 1 0/835 (0%) 0 0/846 (0%) 0
    Tibia Fracture 1/825 (0.1%) 1 0/835 (0%) 0 0/846 (0%) 0
    Traumatic Hemothorax 0/825 (0%) 0 1/835 (0.1%) 1 0/846 (0%) 0
    Investigations
    Electrocardiogram QT Prolonged 0/825 (0%) 0 0/835 (0%) 0 1/846 (0.1%) 1
    Metabolism and nutrition disorders
    Diabetes Mellitus, Inadequate Control 1/825 (0.1%) 1 1/835 (0.1%) 1 0/846 (0%) 0
    Diabetic Ketoacidosis 0/825 (0%) 0 0/835 (0%) 0 1/846 (0.1%) 1
    Gout 1/825 (0.1%) 1 0/835 (0%) 0 0/846 (0%) 0
    Musculoskeletal and connective tissue disorders
    Arthralgia 1/825 (0.1%) 1 0/835 (0%) 0 0/846 (0%) 0
    Sacroilitis 1/825 (0.1%) 1 0/835 (0%) 0 0/846 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Anogenital Warts 1/825 (0.1%) 1 0/835 (0%) 0 0/846 (0%) 0
    Lymphoma 0/825 (0%) 0 1/835 (0.1%) 1 0/846 (0%) 0
    Neoplasm, Malignant 1/825 (0.1%) 1 0/835 (0%) 0 0/846 (0%) 0
    Esophageal Carcinoma 0/825 (0%) 0 0/835 (0%) 0 1/846 (0.1%) 1
    Papillary Thyroid Cancer 1/825 (0.1%) 1 0/835 (0%) 0 0/846 (0%) 0
    Squamous Cell Carcinoma of Tongue 1/825 (0.1%) 1 0/835 (0%) 0 0/846 (0%) 0
    Seizure 1/825 (0.1%) 1 0/835 (0%) 0 0/846 (0%) 0
    Nervous system disorders
    Central Nervous System Lesion 1/825 (0.1%) 2 0/835 (0%) 0 0/846 (0%) 0
    Cerebral Infarction 0/825 (0%) 0 0/835 (0%) 0 1/846 (0.1%) 1
    Cerebrovascular Accident 0/825 (0%) 0 0/835 (0%) 0 1/846 (0.1%) 1
    Guillian-Barre Syndrome 0/825 (0%) 0 0/835 (0%) 0 1/846 (0.1%) 1
    Temporal Lobe Epilepsy 1/825 (0.1%) 1 0/835 (0%) 0 0/846 (0%) 0
    Pregnancy, puerperium and perinatal conditions
    Complication of Pregnancy 0/825 (0%) 0 0/835 (0%) 0 1/846 (0.1%) 1
    Pre-Eclampsia 1/825 (0.1%) 1 0/835 (0%) 0 0/846 (0%) 0
    Pregnancy 2/825 (0.2%) 2 3/835 (0.4%) 3 2/846 (0.2%) 2
    Psychiatric disorders
    Disorientation 0/825 (0%) 0 0/835 (0%) 0 1/846 (0.1%) 1
    Suicide Attempt 0/825 (0%) 0 1/835 (0.1%) 1 1/846 (0.1%) 1
    Renal and urinary disorders
    Renal Impairment 0/825 (0%) 0 0/835 (0%) 0 1/846 (0.1%) 1
    Renal Tubular Necrosis 0/825 (0%) 0 0/835 (0%) 0 1/846 (0.1%) 1
    Respiratory, thoracic and mediastinal disorders
    Bronchiectasis 0/825 (0%) 0 0/835 (0%) 0 1/846 (0.1%) 1
    Hemoptysis 5/825 (0.6%) 6 4/835 (0.5%) 5 1/846 (0.1%) 1
    Pneumothorax 0/825 (0%) 0 0/835 (0%) 0 1/846 (0.1%) 1
    Pulmonary Embolism 2/825 (0.2%) 2 1/835 (0.1%) 1 0/846 (0%) 0
    Skin and subcutaneous tissue disorders
    Drug Reaction with Eosinophilia and Systemic Symptoms 0/825 (0%) 0 1/835 (0.1%) 1 0/846 (0%) 0
    Rash Generalized 0/825 (0%) 0 1/835 (0.1%) 1 1/846 (0.1%) 1
    Rash, Maculopapular 0/825 (0%) 0 0/835 (0%) 0 1/846 (0.1%) 1
    Urticaria 0/825 (0%) 0 1/835 (0.1%) 1 3/846 (0.4%) 3
    Vascular disorders
    Aortic Thrombosis 1/825 (0.1%) 1 0/835 (0%) 0 0/846 (0%) 0
    Deep Vein Thrombosis 3/825 (0.4%) 3 2/835 (0.2%) 2 1/846 (0.1%) 1
    Other (Not Including Serious) Adverse Events
    Regimen 1 (2HRZE/4HR) Regimen 2 (2HPZ/2HP) Regimen 3 (2HPMZ/2HPM)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 74/825 (9%) 61/835 (7.3%) 94/846 (11.1%)
    Blood and lymphatic system disorders
    Neutropenia 48/825 (5.8%) 51 34/835 (4.1%) 39 56/846 (6.6%) 57
    Hepatobiliary disorders
    Hepatitis 26/825 (3.2%) 31 27/835 (3.2%) 31 38/846 (4.5%) 40

    Limitations/Caveats

    A study limitation is that placebos were not used, and therefore neither participants nor site staff were blinded to treatment assignment. Another limitation is that only 8% of participants were HIV-coinfected, limiting the power to compare regimens in this important population

    More Information

    Certain Agreements

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

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

    Results Point of Contact

    Name/Title Dr. Ekaterina Kurbatova, MD, PhD, MPH
    Organization Centers for Disease Control and Prevention
    Phone 4046392017
    Email ies3@cdc.gov
    Responsible Party:
    Centers for Disease Control and Prevention
    ClinicalTrials.gov Identifier:
    NCT02410772
    Other Study ID Numbers:
    • 6655
    First Posted:
    Apr 8, 2015
    Last Update Posted:
    Sep 28, 2021
    Last Verified:
    Jul 1, 2021