Program for Rifampicin-Resistant Disease With Stratified Medicine for Tuberculosis (PRISM-TB)
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.
⁃ An individual must meet all of the following inclusion criteria at the time of enrollment in order to participate in this study:
• 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.
• Aged ≥ 14 years.
• 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.
• 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.
• Documentation of negative HIV infection status within 30 days prior to study entry or documentation confirming HIV infection at any time before study entry.
• For individuals with HIV: CD4+ cell count ≥ 50 cells/mm3 based on testing performed within 30 days prior to study entry.
• 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.
• 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.
• Chest radiograph obtained within 14 days prior to study entry.