TBTC Study 31: Rifapentine-containing Tuberculosis Treatment Shortening Regimens
- Conditions
- Tuberculosis
- Interventions
- Registration Number
- NCT02410772
- Lead Sponsor
- Centers for Disease Control and Prevention
- Brief Summary
The purpose of this study is to determine whether one or two four-month regimens of tuberculosis treatment are as effective as a standard six-month regimen for treatment of pulmonary tuberculosis (TB). All three regimens are administered daily, seven days each week, with direct observation of each dose by a health-care worker at least five of the seven days of each week.
The standard six-month regimen is two months of isoniazid, rifampin, ethambutol, and pyrazinamide followed by four months of isoniazid and rifampin.
The first short regimen is a single substitution of rifapentine for rifampin: two months of isoniazid, rifapentine, ethambutol, and pyrazinamide, followed by two months of isoniazid and rifapentine.
The second short regimen is a double substitution of rifapentine for rifampin and moxifloxacin for ethambutol: two months of isoniazid, rifapentine, moxifloxacin, and pyrazinamide, followed by two months of isoniazid, rifapentine, and moxifloxacin.
Target enrollment is 2500 participants. Each study participant will remain in the study for 18 months in order to include at least 12 months of evaluation of whether the participant's TB recurs.
- Detailed Description
Title:
Rifapentine-containing treatment shortening regimens for pulmonary tuberculosis: a randomized, open-label, controlled, phase 3 clinical trial
Hypotheses:
A) Seventeen (17) week rifapentine-based regimen In previously untreated individuals with active drug-susceptible pulmonary tuberculosis treated with eight weeks of rifapentine (P), isoniazid (H), pyrazinamide (Z) and ethambutol (E) followed by nine weeks of rifapentine plus isoniazid, all given daily throughout, the proportion of participants who experience absence of cure (unfavorable outcome) will not be inferior to that observed in participants who are treated with a standard regimen (eight weeks of rifampin (R), isoniazid, pyrazinamide and ethambutol followed by eighteen weeks of rifampin plus isoniazid), all given daily throughout.
B) Seventeen (17) week rifapentine- plus moxifloxacin-containing regimen In previously untreated individuals with active drug-susceptible pulmonary tuberculosis treated with eight weeks of rifapentine, isoniazid, pyrazinamide and moxifloxacin (M), followed by nine weeks of rifapentine, isoniazid, and moxifloxacin, all given daily throughout, the proportion of participants who experience absence of cure (unfavorable outcome) will not be inferior to that observed in participants who are treated with a standard regimen (eight weeks of rifampin, isoniazid, pyrazinamide and ethambutol followed by eighteen weeks of rifampin plus isoniazid), all given daily throughout.
Phase: 3
Design: This will be an international, multicenter, randomized, controlled, open-label, 3-arm, phase 3 non-inferiority trial.
Population: Patients with newly diagnosed, previously untreated pulmonary tuberculosis.
Number of Sites: Multiple international sites, primarily sites of the Tuberculosis Trials Consortium and the AIDS Clinical Trials Group.
Study Duration: Duration per participant is approximately 18 months.
Description of Agent or Intervention: After written informed consent, participants will be randomly assigned to receive one of the following oral regimens:
Regimen 1 (control regimen): 2RHZE/4RH
* Eight weeks of daily treatment with rifampin, isoniazid, pyrazinamide, and ethambutol, followed by
* Eighteen weeks of daily treatment with rifampin and isoniazid
Regimen 2 (investigational regimen): 2PHZE/2PH
* Eight weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and ethambutol, followed by
* Nine weeks of daily treatment with rifapentine and isoniazid
Regimen 3 (investigational regimen): 2PHZM/2PHM
* Eight weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and moxifloxacin, followed by
* Nine weeks of daily treatment with rifapentine, isoniazid, and moxifloxacin
Objectives:
Primary:
* To evaluate the efficacy of a rifapentine-containing regimen to determine whether the single substitution of rifapentine for rifampin makes it possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis
* To evaluate the efficacy of a rifapentine-containing regimen that in addition substitutes moxifloxacin for ethambutol and continues moxifloxacin during the continuation phase to determine whether it is possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis
Secondary:
* To evaluate the safety of the investigational regimens
* To evaluate the tolerability of the investigational regimens
* To collect and store biospecimens from consenting participants for the purpose of future research on discovery and validation of TB biomarkers
* To determine the correlation of mycobacterial and clinical markers with time to culture conversion, culture status at completion of eight weeks of treatment, treatment failure, and relapse.
* To conduct a pharmacokinetic/pharmacodynamic (PK/PD) study of the test drugs. The main objectives of the PK/PD study are to characterize study drug PK parameters and to determine relationships between treatment outcomes and PK parameters.
* To evaluate the pharmacokinetics of efavirenz-based antiretroviral treatment among patients with TB/HIV co-infection taking efavirenz-based combination antiretroviral therapy and TB treatment with rifapentine
Endpoints:
Primary Endpoints:
* Efficacy: TB disease-free survival at twelve months after study treatment assignment.
* Safety: Proportion of participants with grade 3 or higher adverse events during study drug treatment
Secondary Endpoints:
* TB disease-free survival at eighteen months after study treatment assignment
* Time to stable sputum culture conversion (solid and liquid media considered separately)
* Speed of decline of sputum viable bacilli by automated liquid MGIT culture days to detection
* Proportion of participants who are culture negative at completion of eight weeks of treatment (solid and liquid media considered separately)
* Sensitivity analyses assuming all participants classified as 'not assessable' have a favorable outcome
* Discontinuation of assigned treatment for a reason other than microbiological ineligibility
* Estimated steady state efavirenz PK parameters including mid-dosing interval concentration
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 2516
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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.
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Age twelve (12) years or older
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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.
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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.
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Documentation of HIV infection status.
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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.
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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
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For women of childbearing potential, a negative pregnancy test at or within seven (7) days prior to screening
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Karnofsky score greater than or equal to 60
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Written informed consent
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Regimen 1 control 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 Regimen 3 rifapentine and moxifloxacin 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 Regimen 2 rifapentine 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
- Primary Outcome Measures
Name Time Method 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 V4.03TB Disease-free Survival at 12M After Study Treatment Assignment Among Participants in Control Regimen, Regimen1 (2HRZE/4HR) to Experimental Regimens, Regimen3 (2HPZM/2HPM) and Regimen2 (2HPZ/2HP) (Modified Intent to Treat [MITT] Population) Twelve months after treatment assignment To evaluate the efficacy of a rifapentine-containing regimen to determine whether the single substitution of rifapentine for rifampin makes it possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis To evaluate the efficacy of a rifapentine-containing regimen that in addition substitutes moxifloxacin for ethambutol and continues moxifloxacin during the continuation phase, to determine whether it is possible to reduce to seventeen weeks the duration of treatment for drug-susceptible pulmonary tuberculosis A primary outcome status of "favorable", "unfavorable", or "not assessable" was assigned. For detailed definitions of outcomes please refer to: Dorman SE, at al. N Engl J Med. 2021 May 6;384(18):1705-1718.
- Secondary Outcome Measures
Name Time Method Proportion of Participants Who Are Culture Negative at Eight Weeks eight weeks Proportion of participants who are culture negative at eight weeks, liquid media
Time to Stable Sputum Culture Conversion four or six months Time to stable sputum culture conversion, liquid media
Discontinuation of Assigned Treatment for a Reason Other Than Microbiological Ineligibility (Tolerability) four or six months Tolerability of the regimen is evaluated using the outcome of discontinuation of assigned treatment for a reason other than microbiological ineligibility.
Estimated Steady State Efavirenz PK Parameters Including Mid-dosing Interval Concentration four months Among participants with HIV infection receiving efavirenz-based antiretroviral therapy, number of participants who maintained plasma efavirenz concentrations ≥1 mg/L during TB treatment.
TB Disease-free Survival at Eighteen Months After Study Treatment Assignment Eighteen 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 tuberculosisSpeed of Decline of Sputum Viable Bacilli by Automated Liquid MGIT Culture Days to Detection 12 months Parameter estimates of the nonlinear mixed effect models describing longitudinal time to positive (TTP)
Trial Locations
- Locations (33)
TBTC Site 36 TB and Chest Service of Hong Kong, China
🇨🇳Hong Kong, China
TBTC Site 02/ ACTG 12501 Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS
🇰🇪Kericho, Kericho County, Kenya
TBTC Site 01/ACTG Site 8950 FAM CRU
🇿🇦Parow Valley, Western Cape, South Africa
TBTC Site 63 San Antonio VA Medical Center (South Texas Group)
🇺🇸San Antonio, Texas, United States
TBTC Site 30 Uganda-Case Western Reserve Research Collaboration
🇺🇬Kampala, Uganda
TBTC Site 11/ ACTG Site 12401 Joint Clinical Research Centre, Kampala Clinical Research Site
🇺🇬Kampala, Uganda
TBTC Site 04/ ACTG Site 30301 Blantyre CRS (or College of Medicine - Johns Hopkins Research Project, COM-JHP)
🇲🇼Blantyre, Malawi
TBTC Site 05/ ACTG Site 12001 UNC Project Tidziwe Centre
🇲🇼Lilongwe, Malawi
TBTC Site 42/ ACTG Site 31802 The Thai Red Cross AIDS Research Centre
🇹🇭Pathumwan, Bangkok, Thailand
TBTC Site 91/ ACTG Site 12101 Insituto Nacional de Pesquisa Clínica Evandro Chagas
🇧🇷Rio de Janeiro, Brazil
TBTC Site 03/ ACTG Site 12601 Moi University Clinical Research Site
🇰🇪Eldoret, Kenya
TBTC Site 90/ ACTG Site 11301 Asociacion Civil Impacta Salud y Educacion
🇵🇪Lima, Peru
TBTC Site 37 Vietnam NTP/UCSF Research Collaboration
🇻🇳Hanoi, Vietnam
TBTC Site 94/ ACTG Site 12201 Hospital Nossa Senhora da Conceicao
🇧🇷Porto Alegre, RS, Brazil
TBTC Site 93/ ACTG Site 11302 CRS San Miguel
🇵🇪Lima, Peru
TBTC Site 41/ ACTG Site 30313 Parirenyatwa Clinical Research Site
🇿🇼Harare, Zimbabwe
TBTC Site 45/ ACTG Site 30022: Les Centres Gheskio (INLR)
🇭🇹Port au Prince, Ouest, Haiti
TBTC Site 69/ ACTG Site 31784 Thai-CTIU, CMU HIV Treatment CRS
🇹🇭Muang Chiang Mai, Chiang Mai, Thailand
TBTC Site 82/ ACTG Site 801 USCF AIDS CRS
🇺🇸San Francisco, California, United States
TBTC Site 62 Baylor College of Medicine & Affiliated Hospitals/VA
🇺🇸Houston, Texas, United States
TBTC Site 20 UNTHSC (University of North Texas Health Science Center)
🇺🇸Fort Worth, Texas, United States
TBTC Site 24 Columbia Unversity
🇺🇸New York, New York, United States
TBTC Site 67/ ACTG Site 31730 GHESKIO centers IMIS
🇭🇹Port-au-Prince, Ouest, Haiti
TBTC Site 43/ ACTG Site 31441 BJ Medical College
🇮🇳Pune, Maharashtra, India
TBTC Site 44/ ACTG Site 11701 CART CRS, YRGCARE Medical Centre VHS
🇮🇳Chennai, Tamilnadu, India
TBTC Site 39/ ACTG Site 31460 Kisumu CRS
🇰🇪Kisumu, Nyanza Province, Kenya
TBTC Site 10/ ACTG Site 31718 TASK Applied Science
🇿🇦Bellville, Cape Town, South Africa
TBTC Site 09/ ACTG Site 31792 University of Cape Town Lung Institute (Pty) Ltd
🇿🇦Mowbray, Cape Town, South Africa
TBTC Site 34 Wits Health Consortium Perinatal HIV Research Unit (PHRU)
🇿🇦Soweto, Gauteng, South Africa
TBTC Site 06/ ACTG Site 11201 Durban International Clinical Research Site
🇿🇦Durban, KwaZulu Natal, South Africa
TBTC Site 49/ ACTG Site 12301 Soweto ACTG CRS
🇿🇦Soweto, Johannesburg, South Africa
TBTC Site 08/ ACTG Site 31793 South African Tuberculosis Vaccine Initiative (SATVI)
🇿🇦Cape Town, Western Province, South Africa
TBTC Site 07/ ACTG Site 11101 Wits Helen Joseph CRS
🇿🇦Johannesburg, South Africa