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Short-course Regimens for the Treatment of Pulmonary Tuberculosis (CRUSH-TB)

Primary Purpose

Tuberculosis, Pulmonary, Tuberculosis Infection

Status
Not yet recruiting
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Rifabutin
Delamanid
Bedaquiline
Moxifloxacin
Pyrazinamide
Isoniazid
Rifampin
Ethambutol
Sponsored by
Centers for Disease Control and Prevention
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Tuberculosis, Pulmonary

Eligibility Criteria

12 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • TBTC Site 22 Denver Health and Hospitals
  • TBTC Site 64 Brooklyn Campus of the VA NY Harbor Healthcare System
  • TBTC Site 64A New York City Department of Health and Mental Hygiene- Corona Chest Center
  • TBTC Site 63 San Antonio VA Medical Center (South Texas Group)
  • TBTC Site 26 Seattle & King County TB Control Program
  • TBTC Site 77 CAB-V. Centre National Hospitalier Universitaire de Pneumo-Phtisiologie de Cotonou
  • McGill University Health Centre
  • Vancouver, British Columbia Centre for Disease Control
  • TBTC Site 45 Les Centres Gheskio (INLR)
  • TBTC Site 67 GHESKIO centers IMIS
  • TBTC Site 09 University of Cape Town Lung Institute (Pty) Ltd
  • TBTC Site 30 Uganda-Case Western Reserve Research Collaboration
  • TBTC Site 76 CAB-V. Can Tho Province, Vietnam - Thot Not District TB Unit
  • TBTC Site 74 CAB-V. Ho Chi Minh City, Vietnam - District 6 TB Unit
  • TBTC Site 75 CAB-V. Ho Chi Minh City, Vietnam - Phoi Viet Respiratory Centre

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Active Comparator

Arm Label

2BMZRb/2 BMRb

2 BMZD/2 BMD

2RHZE/4RH

Arm Description

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

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

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

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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
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
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
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
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
All-cause study drug discontinuation among participants in experimental regimens compared to control regimen
Any discontinuation in study treatment by the participant
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
Clearance of bedaquiline
Population PK parameter, Clearance of bedaquiline with or without rifabutin co-administration, will be measured for each experimental arm
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
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

Full Information

First Posted
October 5, 2022
Last Updated
March 2, 2023
Sponsor
Centers for Disease Control and Prevention
Collaborators
Tuberculosis Trials Consortium
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1. Study Identification

Unique Protocol Identification Number
NCT05766267
Brief Title
Short-course Regimens for the Treatment of Pulmonary Tuberculosis
Acronym
CRUSH-TB
Official Title
Phase 2C Clinical Trial of Novel, Short-course Regimens for the Treatment of Pulmonary Tuberculosis: CRUSH-TB (Combination Regimens for Shortening TB Treatment)
Study Type
Interventional

2. Study Status

Record Verification Date
November 2022
Overall Recruitment Status
Not yet recruiting
Study Start Date
March 1, 2023 (Anticipated)
Primary Completion Date
October 30, 2024 (Anticipated)
Study Completion Date
April 30, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Centers for Disease Control and Prevention
Collaborators
Tuberculosis Trials Consortium

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Tuberculosis, Pulmonary, Tuberculosis Infection

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
288 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
2BMZRb/2 BMRb
Arm Type
Experimental
Arm Description
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
Arm Title
2 BMZD/2 BMD
Arm Type
Experimental
Arm Description
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
Arm Title
2RHZE/4RH
Arm Type
Active Comparator
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Rifabutin
Intervention Description
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)
Intervention Type
Drug
Intervention Name(s)
Delamanid
Other Intervention Name(s)
Deltyba
Intervention Description
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)
Intervention Type
Drug
Intervention Name(s)
Bedaquiline
Other Intervention Name(s)
Sirturo
Intervention Description
Bedaquiline is part of interventional arms with bedaquiline (B or BDQ), moxifloxacin (M), pyrazinamide (Z)-- (BMZ).
Intervention Type
Drug
Intervention Name(s)
Moxifloxacin
Intervention Description
Moxifloxacin is part of interventional arms with bedaquiline (B or BDQ), moxifloxacin (M), pyrazinamide (Z)-- (BMZ).
Intervention Type
Drug
Intervention Name(s)
Pyrazinamide
Intervention Description
Pyrazinamide is part of interventional arms with bedaquiline (B or BDQ), moxifloxacin (M), pyrazinamide (Z)-- (BMZ). Pyrazinamide is part of control regimen (HRZE).
Intervention Type
Drug
Intervention Name(s)
Isoniazid
Intervention Description
Isoniazid is part of control regimen (HRZE).
Intervention Type
Drug
Intervention Name(s)
Rifampin
Intervention Description
Rifampin is part of control regimen (HRZE).
Intervention Type
Drug
Intervention Name(s)
Ethambutol
Intervention Description
Ethambutol is part of control regimen (HRZE).
Primary Outcome Measure Information:
Title
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)
Description
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
Time Frame
17 weeks
Secondary Outcome Measure Information:
Title
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
Description
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
Time Frame
up to 78 weeks
Title
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)
Description
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
Time Frame
up to 52 weeks
Title
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)
Description
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
Time Frame
up to 78 weeks
Title
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
Description
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
Time Frame
up to 78 weeks
Title
Proportion of participants with sputum culture negative by 8 weeks and by 12 weeks (solid and liquid media) in all 3 regimens
Description
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
Time Frame
8 weeks and 12 weeks
Title
All-cause study drug discontinuation among participants in experimental regimens compared to control regimen
Description
Any discontinuation in study treatment by the participant
Time Frame
up to 26 weeks
Title
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
Description
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
Time Frame
17 weeks
Title
Clearance of bedaquiline
Description
Population PK parameter, Clearance of bedaquiline with or without rifabutin co-administration, will be measured for each experimental arm
Time Frame
17 weeks
Title
Volume of Distribution of bedaquiline
Description
Population PK parameter, Volume of Distribution of bedaquiline with or without rifabutin co-administration, will be measured for each experimental arm
Time Frame
17 weeks
Title
Rate of absorption of bedaquiline
Description
Population PK parameter: rate of absorption of bedaquiline with or without rifabutin co-administration, will be measured for each experimental arm
Time Frame
17 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Ekaterina V Kurbatova, MD, PhD, MPH
Phone
404-639-2017
Email
ies3@cdc.gov
First Name & Middle Initial & Last Name or Official Title & Degree
Kimberly Hedges, MPH
Phone
404-718-8626
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kelly Dooley, MD
Organizational Affiliation
Johns Hopkins University
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Daniel W Fitzgerald, MD
Organizational Affiliation
Weill Medical College of Cornell University
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Ekaterina V Kurbatova, MD, PhD, MPH
Organizational Affiliation
Centers for Disease Control and Prevention
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Wendy Carr, PhD
Organizational Affiliation
Centers for Disease Control and Prevention
Official's Role
Study Chair
Facility Information:
Facility Name
TBTC Site 22 Denver Health and Hospitals
City
Denver
State/Province
Colorado
ZIP/Postal Code
80204
Country
United States
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Juanita Lovato
Phone
303-602-7247
Email
juanita.lovato@dhha.org
First Name & Middle Initial & Last Name & Degree
Robert Belknap, MD
Facility Name
TBTC Site 64 Brooklyn Campus of the VA NY Harbor Healthcare System
City
Brooklyn
State/Province
New York
ZIP/Postal Code
11209
Country
United States
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kin Fong Pun
Email
kpun@health.nyc.gov
First Name & Middle Initial & Last Name & Degree
Jana Preis, MD
Facility Name
TBTC Site 64A New York City Department of Health and Mental Hygiene- Corona Chest Center
City
Jackson Heights
State/Province
New York
ZIP/Postal Code
11372
Country
United States
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kin Fong H Pun
Email
kpun@health.nyc.gov
First Name & Middle Initial & Last Name & Degree
Joseph Burzynski, MD
Facility Name
TBTC Site 63 San Antonio VA Medical Center (South Texas Group)
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229-4404
Country
United States
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Melissa Engle, CRT, CCRC
Phone
210-617-5300
Ext
16381
Email
englem2@uthscsa.edu
First Name & Middle Initial & Last Name & Degree
Jose Cadena-Zuluaga, MD
Facility Name
TBTC Site 26 Seattle & King County TB Control Program
City
Seattle
State/Province
Washington
ZIP/Postal Code
98104
Country
United States
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Yoseph Soori
Email
Yoseph.Soori@kingcounty.gov
First Name & Middle Initial & Last Name & Degree
Masa Narita, MD
Facility Name
TBTC Site 77 CAB-V. Centre National Hospitalier Universitaire de Pneumo-Phtisiologie de Cotonou
City
Cotonou
Country
Benin
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Frimège Djohoun
Email
frimege@gmail.com
First Name & Middle Initial & Last Name & Degree
Menonli Adjobimey, MD
First Name & Middle Initial & Last Name & Degree
Dissou Affolabi, MD
Facility Name
McGill University Health Centre
City
Montréal
Country
Canada
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Richard Menzies, MD
Phone
514-934-1934
Ext
32128
Facility Name
Vancouver, British Columbia Centre for Disease Control
City
Vancouver
Country
Canada
Facility Name
TBTC Site 45 Les Centres Gheskio (INLR)
City
Port au Prince
State/Province
Ouest
ZIP/Postal Code
HT6110
Country
Haiti
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Patrice Severe, MD
Phone
509-3764-1180
Email
patsevere@gheskio.org
First Name & Middle Initial & Last Name & Degree
Samuel Pierre, MD
Phone
509-3740-7711
Email
pierresamuel1@yahoo.fr
First Name & Middle Initial & Last Name & Degree
Jean William Pape, MD
First Name & Middle Initial & Last Name & Degree
Daniel W Fritzgerald, MD
First Name & Middle Initial & Last Name & Degree
Marie Marcelle Deschamps, MD
Facility Name
TBTC Site 67 GHESKIO centers IMIS
City
Port-au-Prince
State/Province
Ouest
ZIP/Postal Code
HT 6124
Country
Haiti
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sandy Nerette Fontain, MD
Phone
509-3170-8270
Email
sandnerette@yahoo.fr; snerette@gheskio.org
First Name & Middle Initial & Last Name & Degree
Marie Marcelle Deschamps, MD
First Name & Middle Initial & Last Name & Degree
Daniel W Fritzgerald, MD
First Name & Middle Initial & Last Name & Degree
Jean William Pape, MD
Facility Name
TBTC Site 09 University of Cape Town Lung Institute (Pty) Ltd
City
Mowbray
State/Province
Cape Town
ZIP/Postal Code
7700
Country
South Africa
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Christie Eichberg
Phone
706-537-3280
Email
eichberg@musc.edu
First Name & Middle Initial & Last Name & Degree
Suraya Beukes, MD
Email
suraya.beukes@uct.ac.za
First Name & Middle Initial & Last Name & Degree
Susan Dorman, MD
First Name & Middle Initial & Last Name & Degree
Rodney Dawson, MD
Facility Name
TBTC Site 30 Uganda-Case Western Reserve Research Collaboration
City
Kampala
Country
Uganda
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Harriet Mayanja-Kizza, MBChB,MMed
Phone
+256 772 593 482
Email
hmk@chs.mak.ac.ug
First Name & Middle Initial & Last Name & Degree
Grace Muzanyi, MBChB, MSc
Phone
256 786 638 198
Email
gxm62@case.edu
First Name & Middle Initial & Last Name & Degree
John Johnson, MD
First Name & Middle Initial & Last Name & Degree
Harriet Mayanja-Kizza, MBChB,MMed
Facility Name
TBTC Site 76 CAB-V. Can Tho Province, Vietnam - Thot Not District TB Unit
City
Cần Thơ
State/Province
Can Tho
ZIP/Postal Code
70000
Country
Vietnam
Facility Name
TBTC Site 74 CAB-V. Ho Chi Minh City, Vietnam - District 6 TB Unit
City
Ho Chi Minh City
State/Province
Ho Chi Minh
ZIP/Postal Code
70000
Country
Vietnam
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Nguyen T Binh Hoa, MD
Email
nguyenbinhhoatb@yahoo.com
First Name & Middle Initial & Last Name & Degree
Phu Truong Thien
Email
Truongthienphu78@yahoo.com
First Name & Middle Initial & Last Name & Degree
Greg Fox, MD
First Name & Middle Initial & Last Name & Degree
Nguyen Binh Hoa, MD
First Name & Middle Initial & Last Name & Degree
Phu Truong Thien, MD
Facility Name
TBTC Site 75 CAB-V. Ho Chi Minh City, Vietnam - Phoi Viet Respiratory Centre
City
Ho Chi Minh City
State/Province
Ho Chi Minh
ZIP/Postal Code
70000
Country
Vietnam
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Binh Nguyen Cam
Email
binh.nguyencam@sydney.edu.au
First Name & Middle Initial & Last Name & Degree
Greg Fox, MD
First Name & Middle Initial & Last Name & Degree
Nguyen Binh Hoa, MD
First Name & Middle Initial & Last Name & Degree
Binh Nguyen Cam, MD

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Data being collected in CDISC format
IPD Sharing Time Frame
After the study completion and during results submission
IPD Sharing Access Criteria
Upon request

Learn more about this trial

Short-course Regimens for the Treatment of Pulmonary Tuberculosis

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