Stratified BPaLM treatment strategies for rifampicin-resistant pulmonary tuberculosis.

Program for Rifampicin-Resistant Disease With Stratified Medicine for Tuberculosis (PRISM-TB)

This trial tests whether shorter BPaLM regimens (13- or 17-week courses) can work as well as the usual 24-week regimen for people aged 14 and older with fluoroquinolone-susceptible multidrug-resistant/rifampicin-resistant pulmonary TB.

Quick facts

• Phase: Phase2; Phase3
• Study type: Interventional
• Enrollment: 400 (estimated)
• Ages: 14 Years and up
• Sex: All
• Sponsor: University of California, San Francisco (Academic / other)
• Locations: 6 sites (Ulaanbaatar and 5 other locations)
• Trial ID: NCT06441006 on ClinicalTrials.gov

What this trial studies

PRISM-TB is an international, open-label, randomized, multi-arm multi-stage trial that compares different durations and strategies using bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) for fluoroquinolone-susceptible MDR/RR pulmonary TB. In Stage 1 participants are randomized across three strategies (control 24-week 6BPaLM, 17-week 4BPaLM, or a stratified 13- or 24-week strategy) with an interim DOOR-based analysis to select the preferred experimental approach. The selected experimental strategy then advances to Stage 2 where participants are randomized between that strategy and the control arm. The design aims to identify whether a 13- or 17-week BPaLM approach can provide noninferior outcomes while shortening therapy and is powered across at least ~200 participants per stage.

Who should consider this trial

Good fit: Ideal candidates are people aged 14 or older with laboratory-confirmed fluoroquinolone-susceptible rifampicin-resistant pulmonary tuberculosis who can provide informed consent and agree to clinic visits, home visits, and phone follow-up.

Not a fit: Patients with fluoroquinolone-resistant TB, extrapulmonary-only TB, or those unable to tolerate BPaLM drugs or complete required follow-up are unlikely to benefit from the tested regimens.

Why it matters

Potential benefit: If successful, the trial could shorten effective treatment for certain drug-resistant TB patients, reducing time on antibiotics, side effects, and barriers to adherence.

How similar studies have performed: Regimens based on bedaquiline, pretomanid, and linezolid (with or without additional drugs) have shown promising results in other drug-resistant TB trials, but this specific stratified, multi-arm multi-stage approach to select a 13- or 17-week BPaLM strategy is novel.

Eligibility criteria

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 exclusion criteria at the time of enrollment or initiation of study drugs will be excluded from study participation:

1. Known allergy/sensitivity, intolerance, or any hypersensitivity to components of study TB drugs or their formulation.
2. One or more of the following laboratory parameters:

   1. Absolute neutrophil count (ANC) \< 1000/mm3.
   2. Hemoglobin level \< 8.0 g/dL.
   3. Serum or plasma alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3 times the upper limit of normal.
   4. Serum or plasma total bilirubin ≥ 3 times the upper limit of normal.
   5. Serum or plasma creatinine level ≥ 3 times the upper limit of normal.
   6. Evidence of laboratory values consistent with or equivalent to grade 4 toxicity (i.e., potentially life-threatening).
   7. NOTE: Persons found not to be eligible due to laboratory abnormalities may be reevaluated within the screening window.
3. QTcF interval ≥ 480 ms within 5 days prior to study entry.
4. One or more risk factors for QT prolongation (apart from age and sex) or other uncorrected risk factors for torsades de pointes: evidence of ventricular pre-excitation (Wolff-Parkinson-White syndrome); electrocardiographic evidence of either complete left bundle branch block or right bundle branch block, or incomplete left bundle branch block or right bundle branch block and QRS complex duration ≥ 120 ms on at least one ECG; current pacemaker implant; congestive heart failure; evidence of second- or third-degree heart block; bradycardia defined by sinus rate less than 50 bpm; personal or family history of long QT syndrome; personal history of arrhythmic cardiac disease, with the exception of sinus arrhythmia; personal history of syncope (i.e., cardiac syncope not including syncope due to vasovagal or epileptic causes).
5. Current grade 2 or higher peripheral neuropathy.

   a. NOTE: Peripheral neuropathy assessment must be obtained within 7 days prior to study entry.
6. Documentation of Karnofsky Performance Status Score \< 50 obtained within 14 days prior to study entry.
7. Known resistance to bedaquiline, pretomanid, delamanid, linezolid, or fluoroquinolones.
8. Previous use of any second-line anti-TB drugs for more than 14 days during the 12 months prior to the screening visit date.
9. Known or presumed central nervous system TB, osteoarticular TB, or miliary/disseminated TB in the current TB episode.
10. Taking any medication that is contraindicated with study medicines which cannot be stopped (with or without replacement) or requires a washout period longer than 2 weeks.
11. Any condition (social or medical or psychological) which, in the opinion of the investigator, would make participation unsafe or interfere with adherence to study requirements.
12. Current enrollment in other therapeutic trials will not be eligible. a. NOTE: Current enrollment of index cases in prevention trials will be allowed on a case-by-case basis, provided that the prevention trial does not include a therapeutic intervention that could affect response to TB treatment.

All persons who are not eligible for the PRISM-TB trial will be managed according to local routine practice and may enroll in other studies.

Criteria for Exclusion after Entry ('Late Exclusion'):

Enrolled individuals who are subsequently determined to meet the following criteria will be classified as 'late exclusions' and study treatment will be discontinued:

1\. Bedaquiline, pretomanid, delamanid, linezolid, or fluoroquinolone resistance on phenotypic or molecular drug- susceptibility testing from samples collected up to 4 weeks after randomization.

Where this trial is running

Ulaanbaatar and 5 other locations

• National Center for Communicable Diseases — Ulaanbaatar, Mongolia (Recruiting)
• Institute of Chest Diseases — Kotri, Pakistan (Not_yet_recruiting)
• Hospital Nacional Sergio E. Bernales — Lima, Peru (Not_yet_recruiting)
• Policlínico SES — Lima, Peru (Not_yet_recruiting)
• Mulago National Referral Hospital — Kampala, Uganda (Not_yet_recruiting)
• Hanoi Lung Hospital — Hanoi, Vietnam (Not_yet_recruiting)

Study contacts

• Principal investigator: Gustavo E Velásquez, MD, MPH — University of California, San Francisco
• Study coordinator: Gustavo E Velásquez, MD, MPH

Conditions Tuberculosis, Pulmonary; Tuberculosis, Multidrug-Resistant; Tuberculosis, MDR; Tuberculosis; BPaLM; Bedaquiline; Pretomanid; Linezolid