Phase 2C Clinical Trial of Novel, Short-course Regimens for the Treatment of Pulmonary Tuberculosis: CRUSH-TB (Combination Regimens for Shortening TB Treatment)~Hypotheses:~The time to sputum culture negative in liquid media will be shorter in the 17-week regimen of 2 months of bedaquiline (B or BDQ), moxifloxacin (M), pyrazinamide (Z), (BMZ) plus rifabutin (Rb) followed by 2 months of bedaquiline (B or BDQ), moxifloxacin (M) and Rifabutin (Rb) (2BMZRb/2 BMRb, Arm 1) than in the control arm.~The time to sputum culture negative in liquid media will be shorter in the 17-week regimen of 2 months of bedaquiline (B or BDQ), moxifloxacin (M), pyrazinamide (Z); (BMZ) plus delamanid (D or DLM) followed by 2 months of bedaquiline (B or BDQ), moxifloxacin (M) and delamanid (D or DLM) (2 BMZD/2 BMD, Arm 2) than in the control arm.~Phase: 3 Design: Open label, randomized clinical trial, initially in three treatment groups, with adaptive design allowing for introduction of novel regimens once they are clinically ready for testing Population: newly diagnosed with sputum smear positive or GeneXpert positive pulmonary tuberculosis, aged 12 years or older, with normal QTcF (QTc interval, Fridericia calculation) on screening ECG.~Number of Sites: 13 National and International sites, primarily sites of the Tuberculosis Trials Consortium Group. Study Duration: Duration per participant is approximately 78 weeks Description of Agent or Intervention: After written informed consent, participants will be randomized 1:1:1 to receive BMZRb, BMZD, or HRZE (Control treatment) as below~Arm 1(investigational regimen): 2 BMZRb/2 BMRb~Eight weeks of daily treatment with bedaquiline (B or BDQ), moxifloxacin (M), pyrazinamide (Z), plus rifabutin (Rb), followed by~Nine weeks of daily treatment with bedaquiline (B or BDQ), moxifloxacin (M) and Rifabutin (Rb)~Arm 2 (investigational regimen): 2 BMZD/2 BMD~Eight weeks of daily treatment with bedaquiline (B or BDQ), moxifloxacin (M), pyrazinamide (Z), plus delamanid (D or DLM) followed by~Nine weeks of daily treatment with bedaquiline (B or BDQ), moxifloxacin (M) and delamanid (D or DLM)~Arm 3 (Control regimen): 2 RHZE/4 RH~Eight weeks of daily treatment with rifampin (R), isoniazid (H), pyrazinamide (Z), and ethambutol (E), (RHZE) followed by~Eighteen weeks of daily treatment with rifampin and isoniazid (RH)~Objectives~Primary Objectives:~To compare the efficacy of 17-week regimen 8 weeks of bedaquiline (B or BDQ), moxifloxacin (M), pyrazinamide (Z), (BMZ) plus rifabutin (Rb) followed by 9 weeks of bedaquiline (B or BDQ), moxifloxacin (M) and rifabutin (Rb) (2 BMZRb/2 BMRb) experimental regimen to the efficacy of standard treatment, using the intermediate endpoint of time to culture negative in liquid media.~To compare the efficacy of 17-week regimen 8 weeks of bedaquiline (B or BDQ), moxifloxacin (M), pyrazinamide (Z), (BMZ) plus delamanid (D or DLM) followed by 9 weeks of bedaquiline (B or BDQ), moxifloxacin (M) and delamanid (D or DLM) (2 BMZD/2 BMD) experimental regimen to the efficacy of standard treatment, using the intermediate endpoint of time to culture negative in liquid media.~Secondary Objectives:~To compare the proportion of participants with a grade 3 or higher adverse event in each experimental arm with the control arm~To describe the proportion of participants experiencing lack of sustained cure during treatment or follow-up to 52 weeks in each experimental arm as compared to control and make predictions as to how these regimens would perform in future phase III trials.~To compare the efficacy of each experimental regimen to the efficacy of standard treatment, using the intermediate endpoint of time to culture negative in solid media~To compare the proportion of participants in each arm who convert liquid and solid sputum cultures to negative by (a) 8 weeks of treatment and (b) 12 weeks of treatment~To describe the rate of all-cause study drug discontinuation in each arm~To compare time to sputum culture positivity curves through 17 weeks in the Mycobacterial Growth Indicator Tube (Bactec MGIT960) across arms~To describe the proportion of participants experiencing lack of sustained cure during treatment or follow-up up to 78 weeks in each experimental arm as compared to control and make predictions as to how these regimens would perform in future phase III trials.~To describe the population PK of bedaquiline and its M2 metabolite, with or without rifabutin co-administration (PK#1)~To conduct pharmacokinetic/pharmacodynamics study of the test drugs to determine relationships between pharmacokinetic parameters (AUC, Cmax) and outcome measures (time to culture negativity or rate of change in TTP) using non-linear mixed effects models, adjusting for key covariates that may affect outcomes (e.g. companion drugs, HIV status, cavitary disease) (PK#2)~Primary Endpoints:~1. Time to sputum culture negative in liquid media~Secondary Endpoints:~Proportion of participants with a Grade 3 or higher adverse event during 26 weeks from randomization~Lack of sustained cure during treatment or follow-up to 52 weeks~Time to sputum culture negative in solid media~Proportion of participants with sputum culture negative by 8 weeks and by 12 weeks (solid and liquid media).~All-cause study drug discontinuation~The rate of change in time to sputum culture positivity (TTP) through 17 weeks in the Mycobacterial Growth Indicator Tube (Bactec MGIT960)~Lack of sustained cure during treatment or follow-up to 78 weeks~Population pharmacokinetics (PK) of bedaquiline, with or without rifabutin Pharmacokinetic/pharmacodynamic (PK/PD) relationship between test drug PK parameters and microbiologic outcomes
The purpose of this study is to determine whether one or two 17-week regimens of tuberculosis treatment bedaquiline (B or BDQ), moxifloxacin (M), pyrazinamide (Z)-- (BMZ) plus either Rifabutin (Rb) or Delamanid (D or DLM) 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.~The first 17-week regimen is 2 months of bedaquiline (B or BDQ), moxifloxacin (M), pyrazinamide (Z), (BMZ) plus rifabutin (Rb) (BMZRB) followed by 2 months of bedaquiline (B or BDQ), moxifloxacin (M) and Rifabutin (Rb) (2 BMZRb/2 BMRb, Arm 1)~The Second 17-week regimen is 2 months of bedaquiline (B or BDQ), moxifloxacin (M), pyrazinamide (Z), (BMZ) plus delamanid (D or DLM); (BMZD) followed by 2 months of bedaquiline (B or BDQ), moxifloxacin (M) and delamanid (D or DLM) (2 BMZD/2 BMD, Arm 2)~The standard 26-week treatment control regimen which is two months of isoniazid, rifampin, ethambutol, and pyrazinamide (2HRZE) followed by four months of isoniazid and rifampin (4HR); (2HRZE/4HR, Arm 3)~Target enrollment is 288 male and female participants (96/arm). participants. Participants will be followed until 78 weeks post-randomization, or until the last enrolled participant completes 52 weeks post-randomization, whichever comes first.