Short-course TB Drug Regimens for Tuberculosis
(CRUSH-TB Trial)
Recruiting in Palo Alto (17 mi)
+14 other locations
Age: Any Age
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2 & 3
Recruiting
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
Prior Safety Data
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.
12345Is 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.
36789What 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.
3581011Eligibility 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.
+10 more
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
+16 more
Trial 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
Participant Groups
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).
3Treatment groups
Experimental Treatment
Active Control
Group I: 2BMZRb/2 BMRbExperimental Treatment4 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 BMDExperimental Treatment4 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/4RHActive Control4 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)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
TBTC Site 64A New York City Department of Health and Mental Hygiene- Corona Chest CenterJackson Heights, NY
TBTC Site 26 Seattle & King County TB Control ProgramSeattle, WA
TBTC Site 63 San Antonio VA Medical Center (South Texas Group)San Antonio, TX
TBTC Site 22 Denver Health and HospitalsDenver, CO
More Trial Locations
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Who Is Running the Clinical Trial?
Centers for Disease Control and PreventionLead Sponsor
Tuberculosis Trials ConsortiumCollaborator
References
Short-course therapy for tuberculosis. [2018]The discovery of rifampicin was the turning point away from the standard long term treatment for tuberculosis of 18 to 24 months and towards a 6-month curative programme. Rifampicin has proven to be highly effective and vital to short-course tuberculosis therapy, but its disadvantage is its cost. This makes it relatively unavailable where it is most needed, i.e. in countries where tuberculosis is still rampant, but which are economically underdeveloped. In such areas other needs take precedence over a chronic and non-spectacular medical condition like tuberculosis. During the past 10 years pyrazinamide has been 'rediscovered' and restudied, and when used in combination with rifampicin has been shown to play an important role in short-course chemotherapy. Its contribution to efficacy does not appear to extend beyond the first 2 months of therapy, and it should be discontinued after 2 months. This relatively short administration period helps to minimise adverse reactions to the drug. The main measure of success in short-course chemotherapy is the relapse rate, and this has been higher, sometimes unacceptably so, in regimens where bacteriostatic drugs were substituted for bactericidal ones. In conclusion, isoniazid, rifampicin and pyrazinamide in combination may be deemed essential to an effective short-course regimen of 6 months' duration. Curtailing the duration of treatment to less than 6 months in smear-positive tuberculosis results in high relapse rates and thus is not acceptable. Several studies have been undertaken varying the drug combinations, the dosages and the drug administration routines (i.e. whether daily followed by intermittent or intermittent throughout), in an effort to arrive at the simplest, most effective, least toxic and most economical all-round treatment programme. Such studies are still in progress. When recommended dosage regiments are followed, the incidence of adverse reactions is low with short-course therapy, and in only 5% or less of patients is it necessary to withdraw one or more drugs.
New drugs for tuberculosis treatment. [2015]Available data on anti-tuberculosis drug research reveal different properties of the agents and provoke speculation about future directions. Higher doses of the rifamycins are promising and are currently being evaluated in regimens of shorter duration that the isoniazid plus rifampin-based, six-to-nine month-course therapy. Moxifloxacin and gatifloxacin might shorten tuberculosis treatment as well, possibly in combination with rifapentine, while SQ109 could enhance the activity of rifampin-containing regimens. On the other hand, co-administration of moxifloxacin and PA-824 could be active against latent tuberculosis, whereas linezolid, PA-824 and TMC207 are candidates for a rifampin-free regimen in multidrug-resistant and extensively-resistant tuberculosis. Unfortunately, shorter than existent treatment regimens based on the new agents discussed here are likely to take at least another decade to be fully developed and implemented in clinical practice.
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]New anti-tuberculosis regimens that are shorter, simpler, and less toxic than those that are currently available are needed as part of the global effort to address the tuberculosis epidemic. We aimed to investigate the bactericidal activity and safety profile of combinations of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide in the first 8 weeks of treatment of pulmonary tuberculosis.
Bactericidal activity of pyrazinamide and clofazimine alone and in combinations with pretomanid and bedaquiline. [2019]New regimens to shorten tuberculosis treatment and manage patients with drug-resistant tuberculosis who are infected with HIV are urgently needed. Experimental and clinical evidence suggests that the new drugs bedaquiline (B) and pretomanid (Pa), combined with an existing drug, pyrazinamide (Z), and a repurposed drug, clofazimine (C), may assist treatment shortening of drug-susceptible and drug-resistant tuberculosis.
Treatment Outcomes of Multidrug-Resistant Tuberculosis Patients in East Java, Indonesia: A Retrospective Cohort Analysis. [2022]The drug regimen for the treatment of multidrug-resistant tuberculosis (MDR-TB) has lower potency, is more costly, and has a greater risk of adverse effects than first-line anti-TB drugs. We aimed to compare the treatment outcomes of patients using standard shorter regimen (STR regimen) versus bedaquiline (BDQ)-containing individual regimen in a high TB-burden setting.
Switching to bedaquiline for treatment of rifampicin-resistant tuberculosis in South Africa: A retrospective cohort analysis. [2023]South Africa led the world with guidelines on bedaquiline (BDQ) use as a single drug substitution to manage rifampin resistant tuberculosis regimen toxicity. We examined reasons for giving BDQ in a retrospective cohort: >75% of patients were switched to BDQ for toxicity (ototoxicity or renal dysfunction) rather than drug resistance.
Safety of Treatment Regimens Containing Bedaquiline and Delamanid in the endTB Cohort. [2023]Safety of treatment for multidrug-resistant tuberculosis (MDR/RR-TB) can be an obstacle to treatment completion. Evaluate safety of longer MDR/RR-TB regimens containing bedaquiline and/or delamanid.
Bedaquiline, Delamanid, Linezolid and Clofazimine for Treatment of Pre-extensively Drug-Resistant Tuberculosis. [2023]Treatment success rates for multidrug-resistant tuberculosis (MDR-TB) remain low globally. Availability of newer drugs has given scope to develop regimens that can be patient-friendly, less toxic, with improved outcomes. We proposed to determine the effectiveness of an entirely oral, short-course regimen with Bedaquiline and Delamanid in treating MDR-TB with additional resistance to fluoroquinolones (MDR-TBFQ+) or second-line injectable (MDR-TBSLI+).
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]Increased dosing of rifampicin and pyrazinamide seems a viable strategy to shorten treatment and prevent relapse of drug-susceptible tuberculosis (TB), but safety and efficacy remains to be confirmed. This clinical trial aims to explore safety and pharmacokinetics-pharmacodynamics of a high-dose pyrazinamide-rifampicin regimen.
Daily Dosing for Bedaquiline in Patients with Tuberculosis. [2020]The bedaquiline regimen for the treatment of multidrug-resistant tuberculosis (MDR-TB) in adults is a loading dose of 400 mg QD for 2 weeks followed by 200 mg thrice weekly (TIW) for 22 weeks. Most TB antibiotics administered with bedaquiline are given QD. Using pharmacokinetic simulations, we explored alternative QD bedaquiline regimens and determined that 200 mg QD for 8 weeks followed by 100 mg QD provides comparable exposures to the approved regimen. This simpler regimen is under clinical evaluation.
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]To evaluate the safety, tolerability, and efficacy of prolonged bedaquiline (Bdq) treatment in patients with multi-drug/rifampin-resistant tuberculosis (MDR/RR-TB).