Short-course Regimens for the Treatment of Pulmonary Tuberculosis

NCT05766267 | Active Not Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: 7406
• Study Type: interventional
• Target: 288
• Locations: 6 countries
• Sites: 8

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.

Conditions

Tuberculosis, Pulmonary; Tuberculosis Infection

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (10)

• 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

  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)

  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)

  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

  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

  8 weeks and 12 weeks

Study Arms (3)

2BMZRb/2 BMRb

EXPERIMENTAL

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; Drug: Bedaquiline; Drug: Moxifloxacin; Drug: Pyrazinamide

2 BMZD/2 BMD

EXPERIMENTAL

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; Drug: Bedaquiline; Drug: Moxifloxacin; Drug: Pyrazinamide

2RHZE/4RH

ACTIVE COMPARATOR

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; Drug: Isoniazid; Drug: Rifampin; Drug: Ethambutol

Interventions

Rifabutin DRUG

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)

2BMZRb/2 BMRb

Delamanid DRUG

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)

Also known as: Deltyba

2 BMZD/2 BMD

Bedaquiline DRUG

Bedaquiline is part of interventional arms with bedaquiline (B or BDQ), moxifloxacin (M), pyrazinamide (Z)-- (BMZ).

Also known as: Sirturo

2 BMZD/2 BMD; 2BMZRb/2 BMRb

Moxifloxacin DRUG

Moxifloxacin is part of interventional arms with bedaquiline (B or BDQ), moxifloxacin (M), pyrazinamide (Z)-- (BMZ).

2 BMZD/2 BMD; 2BMZRb/2 BMRb

Pyrazinamide DRUG

Pyrazinamide is part of interventional arms with bedaquiline (B or BDQ), moxifloxacin (M), pyrazinamide (Z)-- (BMZ). Pyrazinamide is part of control regimen (HRZE).

2 BMZD/2 BMD; 2BMZRb/2 BMRb; 2RHZE/4RH

Isoniazid DRUG

Isoniazid is part of control regimen (HRZE).

2RHZE/4RH

Rifampin DRUG

Rifampin is part of control regimen (HRZE).

2RHZE/4RH

Ethambutol DRUG

Ethambutol is part of control regimen (HRZE).

2RHZE/4RH

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Centers for Disease Control and Prevention: lead
• Tuberculosis Trials Consortium: collaborator

Study Sites (8)

TBTC Site 26 Seattle & King County TB Control Program

Seattle, Washington, 98104, United States

Location

McGill University Health Centre

Montreal, Canada

Location

Vancouver, British Columbia Centre for Disease Control

Vancouver, Canada

Location

TBTC Site 67 GHESKIO centers IMIS

Port-au-Prince, Ouest, HT 6124, Haiti

Location

TBTC Site 45 Les Centres Gheskio (INLR)

Port-au-Prince, Ouest, HT6110, Haiti

Location

TBTC Site 09 University of Cape Town Lung Institute (Pty) Ltd

Mowbray, Cape Town, 7700, South Africa

Location

TBTC Site 30 Uganda-Case Western Reserve Research Collaboration

Kampala, Uganda

Location

TBTC Site 76 CAB-V. Can Tho Province, Vietnam - Thot Not District TB Unit

Can Tho, Can Tho City, 70000, Vietnam

Location

Related Publications (1)

• Kurbatova EV, Dooley KE, Carr W, Stout JE, Nuermberger EL, Phillips PPJ, Scott NA, Upton CM, Ignatius E, Haas M, Walter ND, Traxler RM, Brown NE, Boyd R, Bryant KE, Dixon MG, Savic R, Eichberg C, Hesseling A, Bark C, Benator DA, Muzanyi G, Twycross NS, Fox GJ, Pierre S, Burzynski J, Fitzgerald DW; TBTC Study 38 CRUSH-TB Team. Phase 2C clinical trial of novel short-course regimens for the treatment of pulmonary tuberculosis: TBTC study 38/CRUSH-TB design. Contemp Clin Trials. 2025 Nov;158:108075. doi: 10.1016/j.cct.2025.108075. Epub 2025 Sep 5.

  PMID: 40915316 DERIVED

MeSH Terms

Conditions

Tuberculosis, Pulmonary; Latent Tuberculosis

Interventions

Rifabutin; OPC-67683; bedaquiline; Moxifloxacin; Pyrazinamide; Isoniazid; Rifampin; Ethambutol

Condition Hierarchy (Ancestors)

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases; Latent Infection

Intervention Hierarchy (Ancestors)

Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Pyrazines; Heterocyclic Compounds, 1-Ring; Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Pyridines; Ethylenediamines; Diamines; Polyamines; Amines

Study Officials

• Kelly Dooley, MD

  Johns Hopkins University

  STUDY CHAIR

• Daniel W Fitzgerald, MD

  Weill Medical College of Cornell University

  STUDY CHAIR

• Ekaterina V Kurbatova, MD, PhD, MPH

  Centers for Disease Control and Prevention

  STUDY CHAIR

• Wendy Carr, PhD

  Centers for Disease Control and Prevention

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 5, 2022
• First Posted: March 13, 2023
• Study Start: November 21, 2023
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2027
• Last Updated: September 19, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF
• Time Frame: After the study completion and during results submission
• Access Criteria: Upon request

Locations

ZA (1); VN (1); UG (1); US (1); CA (2); HA (2)