Short-course Regimens for the Treatment of Pulmonary Tuberculosis (CRUSH-TB)
Tuberculosis, Pulmonary, Tuberculosis Infection
About this trial
This is an interventional treatment trial for Tuberculosis, Pulmonary
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.
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
Experimental
Experimental
Active Comparator
2BMZRb/2 BMRb
2 BMZD/2 BMD
2RHZE/4RH
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