| Trial name or title |
Rifapentine‐containing tuberculosis treatment shortening regimens |
| Methods |
Randomized, open‐label, parallel‐assignment, controlled phase 3 clinical trial |
| Participants |
Inclusion criteria:
Suspected pulmonary tuberculosis plus 1 or both of the following: (a) at least 1 sputum specimen positive for acid‐fast bacilli on smear microscopy OR (b) at least 1 sputum specimen positive for M tuberculosis by Xpert MTB/RIF testing, with semi‐quantitative result of 'medium' or 'high' and rifamycin resistance not detected Age 12 years or older Verifiable address or residence location that is readily accessible for visiting, and willingness to inform the study team of any change in address during treatment and follow‐up period Women of childbearing potential who are not surgically sterilized must agree to practice a barrier method of contraception or must 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 before screening -
Laboratory parameters done at or within 14 days before screening:
Serum or plasma alanine aminotransferase (ALT) less than or equal to 3 times upper limit of normal Serum or plasma total bilirubin less than or equal to 2.5 times upper limit of normal Serum or plasma creatinine level less than or equal to 2 times upper limit of normal Serum or plasma potassium level greater than or equal to 3.5 meq/L Hemoglobin level 7.0 g/dL or greater Platelet count 100,000/mm³ or greater
-
For women of childbearing potential, a negative pregnancy test at or within seven (7) days before screening:
Exclusion criteria:
Pregnant or breastfeeding 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 1 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 central nervous system and/or bones and/or joints, and/or miliary tuberculosis, and/or pericardial tuberculosis Current or planned use within 6 months following enrolment of 1 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 (ART) or for whom initiation of efavirenz‐based ART is planned within 17 weeks following enrolment may participate Weight less than 40.0 kg Known allergy or intolerance to any of the study medications Individuals will be excluded from enrolment if, at the time of enrolment, their M tuberculosis isolate is already known to be resistant to any 1 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
Anticipated sample size: 2500 |
| Interventions |
Interventions:
Standard ATT drugs: 4‐month (17 weeks) regimen
8 weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and ethambutol, followed by
9 weeks of daily treatment with rifapentine and isoniazid
Moxifloxin combination: 4‐month (17 weeks) regimen: moxifloxacin for 4 months substituting ethambutol in intensive phase
8 weeks of daily treatment with rifapentine, isoniazid, pyrazinamide, and moxifloxacin, followed by
9 weeks of daily treatment with rifapentine, isoniazid, and moxifloxacin
Control: standard 6‐month (26‐week) ATT regimen
8 weeks of daily treatment with rifampin, isoniazid, pyrazinamide, and ethambutol, followed by
18 weeks of daily treatment with rifampin and isoniazid
Dosing:
All drugs are administered orally, 7 days/week, directly observed by a healthcare worker at least 5 of the 7 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 < 55 kg 1000 mg, ≥ 55 to 75 kg 1500 mg, > 75 kg 2000 mg; ethambutol < 55 kg 800 mg, ≥ 55 to 75 kg 1200 mg, > 75 kg 1600 mg |
| Outcomes |
Primary outcome measures:
TB disease‐free survival at 12 months after study treatment assignment [Time Frame: 12 months after treatment assignment] Proportion of participants with grade 3 or higher adverse events during study drug treatment [Time Frame: 4 or 6 months]
Secondary outcome measures:
TB disease‐free survival at 18 months after study treatment assignment [Time Frame: 18 months after treatment assignment] Proportion of participants who are culture negative at 8 weeks [Time Frame: 8 weeks]
Solid and liquid media considered separately:
Time to stable sputum culture conversion [Time Frame: 4 or 6 months] ‐ solid and liquid media considered separately Speed of decline of sputum viable bacilli by automated MGIT days to detection [Time Frame: 4 or 6 months] TB disease‐free survival at 12 and 18 months after study treatment assignment, assuming all losses to follow‐up and non‐tuberculosis deaths have an unfavourable outcome [Time Frame: 18 months after study treatment assignment]. Sensitivity analyses, assuming all losses to follow‐up and non‐tuberculosis deaths have an unfavourable outcome TB disease‐free survival at 12 and 18 months after study treatment assignment, assuming all losses to follow‐up and non‐tuberculosis deaths have a favourable outcome [Time Frame: 18 months after study treatment assignment]. Sensitivity analyses, assuming all losses to follow‐up and non‐tuberculosis deaths have a favourable outcome Discontinuation of assigned treatment for a reason other than microbiological ineligibility [Time Frame: 4 or 6 months] Efavirenz maximum concentration, area under the time‐concentration curve, and half‐life [Time Frame: 4 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 |
| Starting date |
January 2016; estimated study completion date: December 2019 |
| Contact information |
Stefan Goldberg, Centers for Disease Control and Prevention. Ph: 404‐639‐5339; Email: ssg3@cdc.gov |
| Notes |
Study locations: 38 including Brazil, China, India, and Malawi
Registration number:NCT02410772
Sponsor: Centers for Disease Control and Prevention
Collaborator: AIDS Clinical Trials Group |
