Short-course TB Drug Regimens for Tuberculosis

(CRUSH-TB Trial)

Recruiting at 14 trial locations

Overseen By Kimberly Hedges, MPH

Age: Any Age

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: Centers for Disease Control and Prevention

Must be taking: Dolutegravir-based ART

Must not be taking: Unacceptable drug-drug interactions

Disqualifiers: Pregnancy, CNS TB, Bone TB, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 17-26 weeks

288 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot participate if you are using medications that have unacceptable interactions with the study drugs.

What data supports the effectiveness of the drug regimen for tuberculosis?

Research shows that combining bedaquiline, moxifloxacin, and pyrazinamide can help shorten tuberculosis treatment and manage drug-resistant cases. Additionally, rifampicin, when used with pyrazinamide and isoniazid, has been proven effective in a 6-month short-course therapy for tuberculosis. ^{1 2 3 4 5}

Is the short-course TB drug regimen safe for humans?

Research shows that regimens containing bedaquiline, delamanid, moxifloxacin, and pyrazinamide have been evaluated for safety in treating tuberculosis. These studies suggest that while these drugs can be effective, they may also cause side effects like ototoxicity (ear damage) and renal dysfunction (kidney problems), which need to be monitored during treatment. ^{3 6 7 8 9}

What makes this tuberculosis drug regimen unique?

This tuberculosis drug regimen is unique because it combines multiple drugs, including bedaquiline and delamanid, to create a shorter, simpler, and less toxic treatment option for multidrug-resistant tuberculosis (MDR-TB), potentially improving patient outcomes compared to traditional, longer regimens. ^{3 5 8 10 11}

Research Team

Kelly Dooley, MD

Principal Investigator

Johns Hopkins University

Daniel W Fitzgerald, MD

Principal Investigator

Weill Medical College of Cornell University

Ekaterina V Kurbatova, MD, PhD, MPH

Principal Investigator

Centers for Disease Control and Prevention

Wendy Carr, PhD

Principal Investigator

Centers for Disease Control and Prevention

Eligibility Criteria

This trial is for individuals with pulmonary tuberculosis, including those with HIV if their CD4 count is above 100 cells/mm3. Participants must be at least 12 years old, have a negative pregnancy test if applicable, and agree to use reliable contraception. Exclusion criteria include certain heart conditions, inability to take oral meds, recent TB treatment or drug resistance.

Inclusion Criteria

I am on or willing to start dolutegravir-based HIV treatment.

It is unclear what specific exclusion criteria are being referred to for participants with HIV. Could you please provide more details or the specific exclusion criteria for participants with HIV?

You have signs of tuberculosis in your sputum sample or a positive GeneXpert test for M. tuberculosis.

Exclusion Criteria

Your lab test results are not within the specified normal ranges.

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

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive one of the three regimens: 2BMZRb/2BMRb, 2BMZD/2BMD, or 2RHZE/4RH, administered daily for 17 or 26 weeks.

17-26 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, with a focus on sustained culture negativity and adverse events.

52 weeks

Long-term Follow-up

Participants are followed until 78 weeks post-randomization to assess long-term outcomes and safety.

26 weeks

Treatment Details

Interventions

• Bedaquiline
• Delamanid
• Ethambutol
• Isoniazid
• Moxifloxacin
• Pyrazinamide
• Rifabutin
• Rifampin

Trial Overview The study tests two short-course treatments against standard six-month therapy for TB. One group receives bedaquiline, moxifloxacin, pyrazinamide plus rifabutin (BMZRB) for four months; another gets the same drugs plus delamanid (BMZD). The control group follows the conventional regimen of isoniazid and rifampin (2HRZE/4HR).

Participant Groups

Group I: 2BMZRb/2 BMRb Experimental Treatment 4 Interventions

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

Group II: 2 BMZD/2 BMD Experimental Treatment 4 Interventions

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

Group III: 2RHZE/4RH Active Control 4 Interventions

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

Bedaquiline is already approved in United States, European Union for the following indications:

Approved in United States as Sirturo for:

• Multidrug-resistant tuberculosis (MDR-TB)

Approved in European Union as Sirturo for:

• Multidrug-resistant tuberculosis (MDR-TB)

Who Is Running the Clinical Trial?

Centers for Disease Control and Prevention

Lead Sponsor

Trials

902

Recruited

25,020,000+

Tuberculosis Trials Consortium

Collaborator

Trials

1

Recruited

290+

Findings from Research

Rifampicin has revolutionized tuberculosis treatment by reducing the duration from 18-24 months to just 6 months, but its high cost limits access in economically underdeveloped countries where tuberculosis is prevalent.

The combination of isoniazid, rifampicin, and pyrazinamide is essential for effective short-course therapy, with pyrazinamide being particularly important in the first 2 months to enhance efficacy while minimizing adverse reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Short-course therapy for tuberculosis. Aquinas, M.[2018]

Higher doses of rifamycins are being tested in shorter treatment regimens for tuberculosis, which could potentially reduce the duration of therapy compared to the standard six-to-nine month course.

New drugs like moxifloxacin, gatifloxacin, and SQ109 show promise in shortening treatment times and enhancing the effectiveness of existing regimens, but it may take at least a decade for these new treatments to be fully developed and used in practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New drugs for tuberculosis treatment. Sánchez, F., López Colomés, JL., Villarino, E., et al.[2015]

In a study involving 240 patients with drug-susceptible and rifampicin-resistant tuberculosis, the B200PaZ regimen showed the highest bactericidal activity, suggesting it could effectively shorten treatment duration compared to standard therapy.

While B200PaZ and BloadPaZ demonstrated promising efficacy, they also had higher rates of treatment discontinuation due to adverse events, particularly liver enzyme elevations, indicating a need for careful monitoring in future trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bedaquiline, moxifloxacin, pretomanid, and pyrazinamide during the first 8 weeks of treatment of patients with drug-susceptible or drug-resistant pulmonary tuberculosis: a multicentre, open-label, partially randomised, phase 2b trial. Tweed, CD., Dawson, R., Burger, DA., et al.[2023]

The combination of bedaquiline, pretomanid, and pyrazinamide (B-Pa-Z) showed the highest bactericidal activity against tuberculosis in a 14-day study with 15 treatment-naive patients, suggesting it could be an effective new treatment regimen.

Clofazimine (C) demonstrated no significant activity when used alone or in combination with other drugs during the first 14 days, indicating it may not be beneficial in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bactericidal activity of pyrazinamide and clofazimine alone and in combinations with pretomanid and bedaquiline. Diacon, AH., Dawson, R., von Groote-Bidlingmaier, F., et al.[2019]

In a study of 99 patients with multidrug-resistant tuberculosis (MDR-TB), the bedaquiline (BDQ) regimen showed a higher success rate (52.9%) compared to the standard shorter regimen (STR) (35.4%), suggesting BDQ may be more effective in this high TB-burden setting.

Despite the higher success rate with the BDQ regimen, both treatment regimens had overall success rates below national and global averages, primarily due to a high rate of patients lost to follow-up, indicating a need for improved patient retention strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment Outcomes of Multidrug-Resistant Tuberculosis Patients in East Java, Indonesia: A Retrospective Cohort Analysis. Indarti, HT., Kristin, E., Soedarsono, S., et al.[2022]

In South Africa, over 75% of patients were switched to bedaquiline (BDQ) primarily due to toxicity issues, such as ototoxicity or renal dysfunction, rather than for drug resistance.

This highlights the importance of BDQ as a safe alternative for managing adverse effects in patients undergoing treatment for rifampin-resistant tuberculosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Switching to bedaquiline for treatment of rifampicin-resistant tuberculosis in South Africa: A retrospective cohort analysis. Bouton, TC., de Vos, M., Ragan, EJ., et al.[2023]

In a study of 2296 patients undergoing treatment for multidrug-resistant tuberculosis (MDR/RR-TB), the most common adverse events were peripheral neuropathy (26.4%), electrolyte depletion (26.0%), and hearing loss (13.2%), indicating significant safety concerns associated with the treatment regimens.

Adverse events were more frequently linked to linezolid and injectable drugs than to bedaquiline and delamanid, suggesting that treatment monitoring should prioritize the safety profiles of these drugs to ensure better patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of Treatment Regimens Containing Bedaquiline and Delamanid in the endTB Cohort. Hewison, C., Khan, U., Bastard, M., et al.[2023]

In a study of 165 adults with multidrug-resistant tuberculosis (MDR-TB), an entirely oral regimen combining Bedaquiline, Delamanid, Linezolid, and Clofazimine resulted in a 91% favorable treatment outcome after 24-36 weeks, indicating high efficacy for patients with additional drug resistance.

The treatment was generally safe, with minimal cardiotoxicity and manageable side effects; while over half of the patients experienced myelosuppression, it was detected early and effectively treated, allowing for sustained success in most patients after 48 weeks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bedaquiline, Delamanid, Linezolid and Clofazimine for Treatment of Pre-extensively Drug-Resistant Tuberculosis. Padmapriyadarsini, C., Vohra, V., Bhatnagar, A., et al.[2023]

This clinical trial is investigating the safety and pharmacokinetics of a high-dose regimen of pyrazinamide (40 mg/kg) and rifampicin (35 mg/kg) in treating drug-susceptible tuberculosis (TB) over 4 months, compared to the standard 6-month treatment.

The study will monitor adverse effects and measure drug exposure to determine if this high-dose approach can effectively shorten treatment duration and prevent relapse, with results expected to contribute valuable insights into TB management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and pharmacokinetics-pharmacodynamics of a shorter tuberculosis treatment with high-dose pyrazinamide and rifampicin: a study protocol of a phase II clinical trial (HighShort-RP). Ekqvist, D., Bornefall, A., Augustinsson, D., et al.[2022]

A new simplified bedaquiline regimen for treating multidrug-resistant tuberculosis (MDR-TB) has been proposed, consisting of 200 mg once daily for 8 weeks followed by 100 mg once daily, which offers similar drug exposure to the currently approved regimen.

This alternative regimen is currently being evaluated in clinical trials, potentially making treatment easier for patients while maintaining efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daily Dosing for Bedaquiline in Patients with Tuberculosis. Salinger, DH., Nedelman, JR., Mendel, C., et al.[2020]

In a study of 159 patients with multi-drug/rifampin-resistant tuberculosis (MDR/RR-TB), prolonged treatment with bedaquiline (Bdq) for up to 12 months was found to be safe and effective, with treatment success rates of approximately 89-90% across different durations.

The main side effects observed were anemia, thrombocytopenia, and liver dysfunction, but these were consistent across all treatment durations, indicating that extending Bdq treatment does not significantly increase the risk of adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Safety and Efficacy of Prolonged Use of Bedaquiline for the Treatment of Patients with Pulmonary Multi-Drug Resistant/Rifampin-Resistant Tuberculosis: A Prospective, Cohort Study in China. Ke, H., Gui, X., Sun, W., et al.[2023]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Short-course therapy for tuberculosis. [2018]

2. Spain pubmed.ncbi.nlm.nih.gov

New drugs for tuberculosis treatment. [2015]

3. England pubmed.ncbi.nlm.nih.gov

Bedaquiline, moxifloxacin, pretomanid, and pyrazinamide during the first 8 weeks of treatment of patients with drug-susceptible or drug-resistant pulmonary tuberculosis: a multicentre, open-label, partially randomised, phase 2b trial. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Bactericidal activity of pyrazinamide and clofazimine alone and in combinations with pretomanid and bedaquiline. [2019]

5. India pubmed.ncbi.nlm.nih.gov

Treatment Outcomes of Multidrug-Resistant Tuberculosis Patients in East Java, Indonesia: A Retrospective Cohort Analysis. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Switching to bedaquiline for treatment of rifampicin-resistant tuberculosis in South Africa: A retrospective cohort analysis. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Safety of Treatment Regimens Containing Bedaquiline and Delamanid in the endTB Cohort. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Bedaquiline, Delamanid, Linezolid and Clofazimine for Treatment of Pre-extensively Drug-Resistant Tuberculosis. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Safety and pharmacokinetics-pharmacodynamics of a shorter tuberculosis treatment with high-dose pyrazinamide and rifampicin: a study protocol of a phase II clinical trial (HighShort-RP). [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Daily Dosing for Bedaquiline in Patients with Tuberculosis. [2020]

11. New Zealand pubmed.ncbi.nlm.nih.gov

The Safety and Efficacy of Prolonged Use of Bedaquiline for the Treatment of Patients with Pulmonary Multi-Drug Resistant/Rifampin-Resistant Tuberculosis: A Prospective, Cohort Study in China. [2023]