Tuberculosis, Pulmonary, Tuberculosis, Multidrug-Resistant, Tuberculosis, MDR
Conditions
Keywords
Tuberculosis, BPaLM, Bedaquiline, Pretomanid, Linezolid, Moxifloxacin
Brief summary
PRISM-TB is an international, seamless, multicenter, open-label, randomized, controlled, pragmatic, stratified medicine, treatment shortening, multi-arm multi-stage (MAMS), noninferiority Phase 2/3 clinical trial for fluoroquinolone-susceptible multidrug-resistant/rifampin-resistant pulmonary tuberculosis (FQ-S MDR/RR-TB). In Stage 1, participants will be randomized among one of three treatment arms (one control and two experimental). Following the interim analysis (at the end of Stage 1) based on DOOR outcome comparisons and the entirety of the data, one of the four possible experimental strategies will be identified and continue into Stage 2. In Stage 2, participants will be randomized among one of two treatment arms (one control and one experimental). The trial objective is to identify, among participants with fluoroquinolone-susceptible multidrug-resistant/rifampicin-resistant tuberculosis (FQ-S MDR/RR-TB), the preferred BPaLM strategy of 13 or 17 weeks for participants stratified to receive shorter treatment and 17 or 24 weeks for participants stratified to receive longer treatment, as defined by a prespecified stratification algorithm, and to evaluate whether this BPaLM strategy has noninferior efficacy to the control strategy at Week 73.
Detailed description
At least 200 participants across three treatment arms (67 in each arm) will be enrolled in Stage 1 and at least an additional 200 participants across two treatment arms (100 in each arm) will be enrolled in Stage 2. Stage 1: After written informed consent, participants with FQ-S MDR/RR-TB will be randomly assigned to receive one of Stage 1 Strategies 1-3. Stage 1 Strategy 1 (control strategy): Control regimen for all with FQ-S MDR/RR-TB. The local standard of care (SOC) regimen consistent with preferred regimen(s) in international guidelines. In most cases this will be 24 weeks of bedaquiline, pretomanid, linezolid, and moxifloxacin (6BPaLM). Doses and durations of each component may change based on the latest international guidelines and the local SOC. Stage 1 Strategy 2 (investigational strategy): 4BPaLM for all with FQ-S MDR/RR-TB. 17 weeks of bedaquiline, pretomanid, linezolid, and moxifloxacin (4BPaLM). Stage 1 Strategy 3 (investigational strategy): 3BPaLM or 6BPaLM stratified medicine strategy for FQ-S MDR/RR-TB. 13 weeks of bedaquiline, pretomanid, linezolid, and moxifloxacin (3BPaLM) for participants stratified to receive shorter treatment and 24 weeks of bedaquiline, pretomanid, linezolid, and moxifloxacin (6BPaLM) for participants stratified to receive longer treatment. Stage 2: After written informed consent, participants with FQ-S MDR/RR-TB will be randomly assigned to receive one of the Stage 2 Strategies 1-2. Stage 2 Strategy 1 (control strategy): Control regimen for all with FQ-S MDR/RR-TB. The local standard of care (SOC) regimen consistent with preferred regimen(s) in international guidelines. In most cases this will be 24 weeks of bedaquiline, pretomanid, linezolid, and moxifloxacin (6BPaLM). Doses and durations of each component may change based on the latest international guidelines and the local SOC. Stage 2 Strategy 2 (investigational strategy): Preferred strategy from Stage 1 for FQ-S MDR/RR-TB. Number of weeks of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) for participants stratified to receive shorter treatment and for participants stratified to receive longer treatment to be determined from the preferred strategy identified in Stage 1. The sites listed below are the planned sites for Stage 1 and/or Stage 2.
Interventions
DRUGBedaquiline
Frequency: daily Route of administration: oral
DRUGLinezolid
Frequency: daily Route of administration: oral
DRUGPretomanid
Frequency: daily Route of administration: oral
DRUGMoxifloxacin
Frequency: daily Route of administration: oral
DRUGControl Arm FQ-S MDR/RR-TB regimen, designed according to latest international guidelines
The local SOC regimen consistent with preferred regimen(s) in international guidelines. In most cases this will be 24 weeks of bedaquiline, pretomanid, linezolid, and moxifloxacin (6BPaLM). Doses and durations of each component may change based on the latest international guidelines and the local SOC.
Sponsors
University of California, San Francisco
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
PRISM-TB will not include any placebo. Participants, providers, and pharmacists will be aware of strategy and treatment allocation. Masking of participants to treatment allocation would obscure differences in durations and affect behavior in shortened regimens that would not be reflective of future use and is therefore not included as a feature of this trial.
Eligibility
Sex/Gender
ALL
Age
14 Years to No maximum
Healthy volunteers
No
Inclusion criteria
An individual must meet all of the following inclusion criteria at the time of enrollment in order to participate in this study: 1. Confirmed fluoroquinolone-susceptible rifampicin-resistant pulmonary tuberculosis, based on sputum Xpert MTB/RIF and Xpert MTB/XDR, and/or other validated molecular test, and/or phenotypic drug susceptibility testing. a. NOTE: TB diagnosis for purposes of meeting this inclusion criterion can be from a study testing laboratory or from an outside laboratory. 2. Aged ≥ 14 years. 3. A verifiable address or residence location that is readily available for visiting, willingness to consent to home visits and phone calls, and willingness to inform the study team of any change of address during the treatment and follow-up period. 4. Ability and willingness of individual to provide written informed consent or written consent from a parent, guardian, or caregiver and assent of the child participant per local ethics committee guidance. 5. Documentation of negative HIV infection status within 30 days prior to study entry or documentation confirming HIV infection at any time before study entry. 6. For individuals with HIV: CD4+ cell count ≥ 50 cells/mm3 based on testing performed within 30 days prior to study entry. 7. For individuals with HIV: Currently being treated with dolutegravir-based antiretroviral therapy (ART), or plan to initiate dolutegravir-based ART at or before study week 8. a. NOTE: Dosing of ART and chemoprophylaxis for opportunistic infections should be reflective of local standard of care based on WHO or national guidelines. The following antiretrovirals are disallowed given significant drug-drug interactions with bedaquiline: efavirenz, etravirine, all protease inhibitors, and cobicistat-boosted elvitegravir. The following antiretroviral is disallowed given risk of myelosuppression with linezolid: zidovudine. 8. For individuals who are pregnant: at screening, evidence by ultrasound of a viable singleton pregnancy with an estimated gestational age at enrollment of ≥ 14 weeks as per screening ultrasound. 9. Chest radiograph obtained within 14 days prior to study entry.
Exclusion criteria
An individual meeting any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Efficacy Outcome: Desirability of Outcome Ranking (DOOR) | 73 weeks | Desirability of outcome ranking (DOOR) outcome combining efficacy at the end of follow-up (a minimum of 28 weeks post-randomization) and safety at 28 weeks post-randomization. DOOR outcomes do not aggregate measures, but rather create distinct ordinal categories that participants will fall under. DOOR ordinal categories are as follows: 1. Cured or treatment completed by end of follow-up and no Grade 3+ AEs and treatment changes; 2. Cured or treatment completed by end of follow-up and no Grade 3+ with treatment change for any reason; 3. Cured or treatment completed by end of follow-up and at least one Grade 3+ AE; 4. Treatment failure or recurrence by end of follow-up and no Grade 3+ AE; 5. Treatment failure or recurrence by end of follow-up and at least one Grade 3+ AE; 6. Death by end of follow-up. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mortality | 73 weeks | Mortality |
| All Grade 3 or Higher AEs up to 28 Weeks | 28 weeks | All Grade 3 or higher AEs up to 28 weeks post-randomization. |
| All AESIs up to 28 Weeks | 28 weeks | All AESIs up to 28 weeks post-randomization. |
Countries
Mongolia, Pakistan, Peru, Uganda, Vietnam
Contacts
CONTACTGustavo E Velásquez, MD, MPH
CONTACTAriana F Austin, MS
PRINCIPAL_INVESTIGATORGustavo E Velásquez, MD, MPH
University of California, San Francisco
Outcome results
None listed