Short-course Regimens for the Treatment of Pulmonary Tuberculosis

Study Overview
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Brief Summary
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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.

Detailed Description
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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

Official Title
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Phase 2C Clinical Trial of Novel, Short-course Regimens for the Treatment of Pulmonary Tuberculosis: CRUSH-TB (Combination Regimens for Shortening TB Treatment)

Conditions
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Tuberculosis, Pulmonary, Tuberculosis Infection

Intervention / Treatment
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* Drug: Rifabutin
* Drug: Delamanid
* Drug: Bedaquiline
* Drug: Moxifloxacin
* Drug: Pyrazinamide
* Drug: Isoniazid
* Drug: Rifampin
* Drug: Ethambutol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pulmonary tuberculosis with or without suspected or proven concomitant extrapulmonary tuberculosis outside the central nervous system or bones Acid-fast bacilli (AFB) seen in an expectorated sputum specimen at least 1+ or positive GeneXpert (or GeneXpert Ultra) for M. tuberculosis, with semiquantitative results of medium or high. Age ≥12 years Documentation of negative HIV status within the past 3 months prior to enrollment or documentation confirming HIV infection. For participants with HIV: current use of dolutegravir-based ART (Anti Retroviral Therapy), or ability and willingness to start or transition to a dolutegravir-based antiretroviral therapy regimen CD4 T cell count greater than or equal to 100 cells/mm3 based on testing performed at or within 30 days prior to study enrollment Written informed consent/assent Karnofsky score of at least 60 (requiring some help, can take care of most personal requirements) 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. For all women who have not undergone a surgical sterilization procedure or who do not meet the study definition of post-menopausal, a negative pregnancy test at or within seven (7) days prior to screening For all individuals of child-bearing potential who are not surgically sterilized, agreement to practice a reliable method of contraception (barrier method or non-hormonal intrauterine device) or abstain from sexual activity that could lead to pregnancy while receiving study drug treatment and for 30 days after stopping study treatment Exclusion Criteria: Pregnant or breast-feeding More than 5 days of tuberculosis treatment in the previous 6 months Previous treatment with any drug or combination of drugs known to have activity against M. tuberculosis (e.g., isoniazid, rifamycins, pyrazinamide, ethambutol, fluoroquinolones, etc.) for more than five days in the thirty days prior to enrollment Unable to take oral medications Hypersensitivity or previous intolerance to any of the study drugs Current or planned use of medications that have unacceptable drug-drug interactions with any of the study drugs during study treatment Suspected or proven central nervous system tuberculosis Suspected or proven bone tuberculosis Screening ECG with QTcF >450 for men or >470 for women (Note: in case of hypokalemia or hypomagnesemia, ECG can be repeated following electrolyte supplementation) Clinically significant ECG abnormality in the opinion of the site investigator, including but not limited to second or third degree atrioventricular (AV) block, prolongation of the QRS complex over 120 ms (in both male and female participants), or clinically important arrhythmia Current clinically relevant cardiovascular disorder in the opinion of the site investigator, including but not limited to heart failure, coronary heart disease, arrhythmia, or tachyarrhythmia Known family history of Long QT Syndrome in a first-degree relative (i.e., parent, offspring, or sibling) History of aortic aneurysm or dissection Hepatic cirrhosis or other serious liver disease Other medical conditions, that, in the investigator's judgment, make study participation not in the individual's best interest. Laboratory parameters done at or within 14 days prior to screening: Serum or plasma alanine aminotransferase greater than 3 times the upper limit of normal Serum or plasma total bilirubin greater than 2.5 times the upper limit of normal Serum creatinine > 2 times the upper limit of normal Platelet count < 75,000 cells/mm3 Absolute neutrophil count <1,000 cells/mm3 Serum or plasma potassium <3.5 meq/L (note: potassium may be repleted and test repeated) Weight less than 40.0 kg Known or suspected resistance to isoniazid or rifamycins (by phenotypic or molecular test) Previously enrolled in this study or currently enrolled in another therapeutic clinical trial that, in the investigator's judgment, would compromise study integrity or participant safety Current or planned incarceration or other involuntary detention.

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 2BMZRb/2 BMRb<br>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) 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 once daily. Study drug doses: Bedaquiline (B): 200 mg once daily x 56 days, then 100 mg daily; Moxifloxacin (M): 400 mg once daily; Pyrazinamide (Z) 1500 mg (weight <75kg) or 2000mg(> 75kg) once daily x 56 days; Rifabutin (Rb): 300 mg once daily | Drug: Rifabutin<br>* Rifabutin (Rb) is added to the bedaquiline (B or BDQ), moxifloxacin (M), pyrazinamide (Z), (BMZ) regimen for first 8 weeks and continued for next 9 weeks with bedaquiline (B or BDQ) and moxifloxacin (M)<br>Drug: Bedaquiline<br>* Bedaquiline is part of interventional arms with bedaquiline (B or BDQ), moxifloxacin (M), pyrazinamide (Z)-- (BMZ).<br>* Other names: Sirturo;Drug: Moxifloxacin<br>* Moxifloxacin is part of interventional arms with bedaquiline (B or BDQ), moxifloxacin (M), pyrazinamide (Z)-- (BMZ).<br>Drug: Pyrazinamide<br>* Pyrazinamide is part of interventional arms with bedaquiline (B or BDQ), moxifloxacin (M), pyrazinamide (Z)-- (BMZ). Pyrazinamide is part of control regimen (HRZE).<br>|
| Experimental: 2 BMZD/2 BMD<br>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) 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 once daily. Study drug doses: Bedaquiline (B): 200 mg once daily x 56 days, then 100 mg daily; Moxifloxacin (M): 400 mg once daily; Pyrazinamide (Z) 1500 mg (weight <75kg) or 2000mg(> 75kg) once daily x 56 days; Delamanid (D):300 mg once daily | Drug: Delamanid<br>* Delamanid (D or DLM) is added to the bedaquiline (B or BDQ), moxifloxacin (M), pyrazinamide (Z), (BMZ) regimen for first 8 weeks and continued for next 9 weeks with bedaquiline (B or BDQ) and moxifloxacin (M)<br>* Other names: Deltyba;Drug: Bedaquiline<br>* Bedaquiline is part of interventional arms with bedaquiline (B or BDQ), moxifloxacin (M), pyrazinamide (Z)-- (BMZ).<br>* Other names: Sirturo;Drug: Moxifloxacin<br>* Moxifloxacin is part of interventional arms with bedaquiline (B or BDQ), moxifloxacin (M), pyrazinamide (Z)-- (BMZ).<br>Drug: Pyrazinamide<br>* Pyrazinamide is part of interventional arms with bedaquiline (B or BDQ), moxifloxacin (M), pyrazinamide (Z)-- (BMZ). Pyrazinamide is part of control regimen (HRZE).<br>|
| Active Comparator: 2RHZE/4RH<br>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 once daily study drug doses: Rifampin (R), 600 mg daily; Isoniazid (H), 300 mg daily; Pyrazinamide (Z) 1500 mg (weight <75kg) or 2000mg(> 75kg) once daily ; Ethambutol, 15 mg/kg once daily rounded up to nearest 400 mg dose | Drug: Pyrazinamide<br>* Pyrazinamide is part of interventional arms with bedaquiline (B or BDQ), moxifloxacin (M), pyrazinamide (Z)-- (BMZ). Pyrazinamide is part of control regimen (HRZE).<br>Drug: Isoniazid<br>* Isoniazid is part of control regimen (HRZE).<br>Drug: Rifampin<br>* Rifampin is part of control regimen (HRZE).<br>Drug: Ethambutol<br>* Ethambutol is part of control regimen (HRZE).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to sputum culture negative in liquid media after study treatment among participants in Experimental Regimens (2 BZMRb/ 2 BMRb, Arm 1) and (2 BMZD/ 2 BMD, Arm 2) compared to Control (2HRZE/4HR, Arm 3) in modified intention-to-treat group (ITT) | 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 time to culture negative will be defined as the time from randomization to the date of the first of at least two consecutive negative sputum cultures, collected on different study visits, irrespective of any subsequent positive cultures that may occur. Modified intention-to-treat group includes all participants in the ITT population (all enrolled participants who receive a treatment assignment) except late exclusions | 17 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of participants with a grade 3 or higher adverse event in Experimental Regimens (2 BZMRb/2 BMRb, Arm 1) and (2 BMZD/2 BMD, Arm 2) compared to Control Regimen (2HRZE/4HR, Arm 3) in the modified intention-to-treat group | To evaluate the safety of 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. Safety Analysis includes all participants in the ITT population that receive at least one dose of study medication | up to 78 weeks | 
| The proportion of participants experiencing lack of sustained cure in each experimental regimens (2BZMRb/2BMRb, Arm 1) and (2BMZD/2BMD, Arm 2) compared to Control Regimen (2HRZE/4HR, Arm 3) | Sustained Culture Negativity is achieved when a participant's last two culture results collected on different study visits are negative (without an intervening positive result), the last of which is collected no earlier than 48 weeks after randomization (allowing for a 4 week window prior to the 52 week timepoint | up to 52 weeks | 
| The proportion of participants experiencing lack of sustained cure in each experimental regimens (2BZMRb/2BMRb, Arm 1) and (2BMZD/2BMD, Arm 2) compared to Control Regimen (2HRZE/4HR, Arm 3) | Sustained Culture Negativity is achieved when a participant's last two culture results regimens (2BZMRb/2BMRb, Arm 1) and (2BMZD/2BMD, Arm 2) compared to Control Regimen (2HRZE/4HR, Arm 3)collected on different study visits are negative (without an intervening positive result), the last of which is collected no earlier than 48 weeks after randomization (allowing for a 4 week window prior to the 52 week timepoint | up to 78 weeks | 
| Time to sputum culture negative in solid media after study treatment assignment among participants in Experimental Regimens (2BZMRb/2BMRb, Arm 1) and (2BMZD/2BMD, Arm 2) compared to Control Regimen (2HRZE/4HR, Arm 3) in modified intention-to-treat group | 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 time to culture negative will be defined as the time from randomization to the date of the first of at least two consecutive negative sputum cultures, collected on different study visits, irrespective of any subsequent positive cultures that may occur. Modified intention-to-treat group includes all participants in the ITT population (all enrolled participants who receive a treatment assignment) except late exclusions | up to 78 weeks | 
| Proportion of participants with sputum culture negative by 8 weeks and by 12 weeks (solid and liquid media) in all 3 regimens | The time to culture negative will be defined as the time from randomization to the date of the first of at least two consecutive negative sputum cultures, collected on different study visits, irrespective of any subsequent positive cultures that may occur | 8 weeks and 12 weeks | 
| All-cause study drug discontinuation among participants in experimental regimens compared to control regimen | Any discontinuation in study treatment by the participant | up to 26 weeks | 
| The rate of change in time to sputum culture positivity (TTP) through 17 weeks in the Mycobacterial Growth Indicator Tube (Bactec MGIT960) among participants in all three regimens | rate of change in time to sputum culture positivity (TTP) through 17 weeks in the Mycobacterial Growth Indicator Tube (Bactec MGIT960) will be measured and compared | 17 weeks | 
| Clearance of bedaquiline | Population PK parameter, Clearance of bedaquiline with or without rifabutin co-administration, will be measured for each experimental arm | 17 weeks | 
| Volume of Distribution of bedaquiline | Population PK parameter, Volume of Distribution of bedaquiline with or without rifabutin co-administration, will be measured for each experimental arm | 17 weeks | 
| Rate of absorption of bedaquiline | Population PK parameter: rate of absorption of bedaquiline with or without rifabutin co-administration, will be measured for each experimental arm | 17 weeks |