Short-course treatments for pulmonary tuberculosis

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

This study is testing two new 17-week treatment plans for pulmonary tuberculosis to see if they work better than the standard six-month treatment for patients aged 12 and older who have just been diagnosed.

Quick facts

• Phase: PHASE2; PHASE3
• Study type: Interventional
• Enrollment: 288 (estimated)
• Ages: 12 Years and up
• Sex: All
• Sponsor: Centers for Disease Control and Prevention (fed)
• Locations: 12 sites (Jackson Heights, New York and 11 other locations)
• Trial ID: NCT05766267 on ClinicalTrials.gov

What this trial studies

This clinical trial aims to evaluate the effectiveness of two novel 17-week treatment regimens for pulmonary tuberculosis, comparing them to a standard six-month regimen. The regimens involve combinations of bedaquiline, moxifloxacin, pyrazinamide, and either rifabutin or delamanid, administered daily. The study is designed as an open-label, randomized trial with adaptive features, allowing for the introduction of new regimens as they become ready for testing. Participants include newly diagnosed patients aged 12 and older with positive sputum tests for tuberculosis.

Who should consider this trial

Good fit: Ideal candidates are individuals aged 12 years or older with newly diagnosed sputum smear-positive or GeneXpert-positive pulmonary tuberculosis.

Not a fit: Patients with central nervous system or bone tuberculosis, or those not meeting the inclusion criteria, may not benefit from this study.

Why it matters

Potential benefit: If successful, this study could significantly shorten the treatment duration for pulmonary tuberculosis, improving patient adherence and outcomes.

How similar studies have performed: Other studies have shown promise in using shorter regimens for tuberculosis treatment, but this specific combination approach is novel.

Eligibility criteria

Inclusion Criteria:

1. Pulmonary tuberculosis with or without suspected or proven concomitant extrapulmonary tuberculosis outside the central nervous system or bones
2. 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".
3. Age ≥12 years
4. Documentation of negative HIV status within the past 3 months prior to enrollment or documentation confirming HIV infection.
5. For participants with HIV:

   1. current use of dolutegravir-based ART (Anti Retroviral Therapy), or ability and willingness to start or transition to a dolutegravir-based antiretroviral therapy regimen
   2. 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
6. Written informed consent/assent
7. Karnofsky score of at least 60 ("requiring some help, can take care of most personal requirements")
8. 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.
9. 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
10. 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:

1. Pregnant or breast-feeding
2. More than 5 days of tuberculosis treatment in the previous 6 months
3. 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
4. Unable to take oral medications
5. Hypersensitivity or previous intolerance to any of the study drugs
6. Current or planned use of medications that have unacceptable drug-drug interactions with any of the study drugs during study treatment
7. Suspected or proven central nervous system tuberculosis
8. Suspected or proven bone tuberculosis
9. 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)
10. 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
11. 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
12. Known family history of Long QT Syndrome in a first-degree relative (i.e., parent, offspring, or sibling)
13. History of aortic aneurysm or dissection
14. Hepatic cirrhosis or other serious liver disease
15. Other medical conditions, that, in the investigator's judgment, make study participation not in the individual's best interest.
16. Laboratory parameters done at or within 14 days prior to screening:

    1. Serum or plasma alanine aminotransferase greater than 3 times the upper limit of normal
    2. Serum or plasma total bilirubin greater than 2.5 times the upper limit of normal
    3. Serum creatinine \> 2 times the upper limit of normal
    4. Platelet count \< 75,000 cells/mm3
    5. Absolute neutrophil count \<1,000 cells/mm3
    6. Serum or plasma potassium \<3.5 meq/L (note: potassium may be repleted and test repeated)
17. Weight less than 40.0 kg
18. Known or suspected resistance to isoniazid or rifamycins (by phenotypic or molecular test)
19. 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
20. Current or planned incarceration or other involuntary detention.

Where this trial is running

Jackson Heights, New York and 11 other locations

• TBTC Site 64A New York City Department of Health and Mental Hygiene- Corona Chest Center — Jackson Heights, New York, United States (NOT_YET_RECRUITING)
• TBTC Site 63 San Antonio VA Medical Center (South Texas Group) — San Antonio, Texas, United States (NOT_YET_RECRUITING)
• TBTC Site 26 Seattle & King County TB Control Program — Seattle, Washington, United States (NOT_YET_RECRUITING)
• McGill University Health Centre — Montréal, Canada (NOT_YET_RECRUITING)
• Vancouver, British Columbia Centre for Disease Control — Vancouver, Canada (NOT_YET_RECRUITING)
• TBTC Site 45 Les Centres Gheskio (INLR) — Port au Prince, Ouest, Haiti (NOT_YET_RECRUITING)
• TBTC Site 67 GHESKIO centers IMIS — Port-au-Prince, Ouest, Haiti (NOT_YET_RECRUITING)
• TBTC Site 09 University of Cape Town Lung Institute (Pty) Ltd — Mowbray, Cape Town, South Africa (RECRUITING)
• TBTC Site 30 Uganda-Case Western Reserve Research Collaboration — Kampala, Uganda (RECRUITING)
• TBTC Site 76 CAB-V. Can Tho Province, Vietnam - Thot Not District TB Unit — Cần Thơ, Can Tho, Vietnam (NOT_YET_RECRUITING)
• TBTC Site 74 CAB-V. Ho Chi Minh City, Vietnam - District 6 TB Unit — Ho Chi Minh City, Ho Chi Minh, Vietnam (NOT_YET_RECRUITING)
• TBTC Site 75 CAB-V. Ho Chi Minh City, Vietnam - Phoi Viet Respiratory Centre — Ho Chi Minh City, Ho Chi Minh, Vietnam (NOT_YET_RECRUITING)

Study contacts

• Study coordinator: Ekaterina V Kurbatova, MD, PhD, MPH

Conditions: Tuberculosis, Pulmonary, Tuberculosis Infection