Phase 2C Clinical Trial of Novel, Short-course Regimens for the Treatment of Pulmonary Tuberculosis: CRUSH-TB (Combination Regimens for Shortening TB Treatment)
Hypotheses:
1. 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.
2. 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:
1. 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.
2. 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:
1. To compare the proportion of participants with a grade 3 or higher adverse event in each experimental arm with the control arm
2. 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.
3. 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
4. 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
5. To describe the rate of all-cause study drug discontinuation in each arm
6. To compare time to sputum culture positivity curves through 17 weeks in the Mycobacterial Growth Indicator Tube (Bactec MGIT960) across arms
7. 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.
8. To describe the population PK of bedaquiline and its M2 metabolite, with or without rifabutin co-administration (PK#1)
9. 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:
1. Proportion of participants with a Grade 3 or higher adverse event during 26 weeks from randomization
2. Lack of sustained cure during treatment or follow-up to 52 weeks
3. Time to sputum culture negative in solid media
4. Proportion of participants with sputum culture negative by 8 weeks and by 12 weeks (solid and liquid media).
5. All-cause study drug discontinuation
6. The rate of change in time to sputum culture positivity (TTP) through 17 weeks in the Mycobacterial Growth Indicator Tube (Bactec MGIT960)
7. Lack of sustained cure during treatment or follow-up to 78 weeks
8. Population pharmacokinetics (PK) of bedaquiline, with or without rifabutin Pharmacokinetic/pharmacodynamic (PK/PD) relationship between test drug PK parameters and microbiologic outcomes
