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
