S31/A5349: TBTC Study 31: Rifapentine-containing Tuberculosis Treatment Shortening Regimens
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:
-
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.
-
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
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:
|
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:
|
Outcome Measures
Primary Outcome Measures
- 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.
- 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.
- 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
- TB Disease-free Survival at Eighteen Months After Study Treatment Assignment [eighteen months after treatment assignment]
- Proportion of Participants Who Are Culture Negative at Eight Weeks [eight weeks]
solid and liquid media considered separately
- Time to Stable Sputum Culture Conversion [four or six months]
solid and liquid media considered separately
- Speed of Decline of Sputum Viable Bacilli by Automated MGIT Days to Detection [four or six months]
- 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
- 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
- Discontinuation of Assigned Treatment for a Reason Other Than Microbiological Ineligibility [four or six months]
- 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
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.- 6655
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
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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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 |
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[Not Specified] |
Arm/Group Title |
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Arm/Group Description |
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 |
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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 |
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[Not Specified] |
Arm/Group Title |
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Arm/Group Description |
Title | Discontinuation of Assigned Treatment for a Reason Other Than Microbiological Ineligibility |
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Description | |
Time Frame | four or six months |
Outcome Measure Data
Analysis Population Description |
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[Not Specified] |
Arm/Group Title |
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Arm/Group Description |
Title | Efavirenz Maximum Concentration, Area Under the Time-concentration Curve, and Half Life |
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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 |
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[Not Specified] |
Arm/Group Title |
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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) | |||||
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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 |
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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 |
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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 |
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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
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 |
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Organization | Centers for Disease Control and Prevention |
Phone | 4046392017 |
ies3@cdc.gov |
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