Program for Rifampicin-Resistant Disease With Stratified Medicine for Tuberculosis

NCT06441006 | Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: 7200AA22CA00005
• Study Type: interventional
• Target: 400
• Locations: 5 countries
• Sites: 6

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.

Conditions

Tuberculosis, Pulmonary; Tuberculosis, Multidrug-Resistant; Tuberculosis, MDR

Keywords

Tuberculosis; BPaLM; Bedaquiline; Pretomanid; Linezolid; Moxifloxacin

Outcome Measures

Primary Outcomes (1)

• Primary Efficacy Outcome: Desirability of Outcome Ranking (DOOR)

  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.

  73 weeks

Secondary Outcomes (3)

• Mortality

  73 weeks

• All Grade 3 or Higher AEs up to 28 Weeks

  28 weeks

• All AESIs up to 28 Weeks

  28 weeks

Study Arms (3)

Strategy 1: Control regimen for all with FQ-S MDR/RR-TB

ACTIVE COMPARATOR

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.

Drug: Control Arm FQ-S MDR/RR-TB regimen, designed according to latest international guidelines

Strategy 2: 4BPaLM for all with FQ-S MDR/RR-TB

EXPERIMENTAL

17 weeks of bedaquiline, pretomanid, linezolid, and moxifloxacin (4BPaLM). Bedaquiline 400 mg orally once daily for 2 weeks, then 200 mg once daily; pretomanid 200 mg orally once daily; linezolid 600 mg orally once daily; and moxifloxacin 400 mg orally once daily.

Drug: Bedaquiline; Drug: Linezolid; Drug: Pretomanid; Drug: Moxifloxacin

Strategy 3: 3BPaLM or 6BPaLM stratified medicine strategy for those with FQ-S MDR/RR-TB

EXPERIMENTAL

13 weeks of bedaquiline, pretomanid, linezolid, and moxifloxacin (3BPaLM) for participants classified as having easier-to-treat TB and 24 weeks of bedaquiline, pretomanid, linezolid, and moxifloxacin (6BPaLM) for participants classified as having harder-to-treat TB. 3BPaLM: 13 weeks of bedaquiline 400 mg orally once daily for 2 weeks, then 200 mg once daily; pretomanid 200 mg orally once daily, linezolid 600 mg orally once daily, and moxifloxacin 400 mg orally once daily. 6BPaLM: 24 weeks of bedaquiline 400 mg orally once daily for 2 weeks, then 200 mg once daily; pretomanid 200 mg orally once daily, linezolid 600 mg orally once daily, and moxifloxacin 400 mg orally once daily.

Drug: Bedaquiline; Drug: Linezolid; Drug: Pretomanid; Drug: Moxifloxacin

Interventions

Bedaquiline DRUG

Frequency: daily Route of administration: oral

Also known as: Sirturo

Strategy 2: 4BPaLM for all with FQ-S MDR/RR-TB; Strategy 3: 3BPaLM or 6BPaLM stratified medicine strategy for those with FQ-S MDR/RR-TB

Linezolid DRUG

Frequency: daily Route of administration: oral

Also known as: Zyvox

Strategy 2: 4BPaLM for all with FQ-S MDR/RR-TB; Strategy 3: 3BPaLM or 6BPaLM stratified medicine strategy for those with FQ-S MDR/RR-TB

Pretomanid DRUG

Frequency: daily Route of administration: oral

Also known as: Pretamyl

Strategy 2: 4BPaLM for all with FQ-S MDR/RR-TB; Strategy 3: 3BPaLM or 6BPaLM stratified medicine strategy for those with FQ-S MDR/RR-TB

Moxifloxacin DRUG

Frequency: daily Route of administration: oral

Also known as: Avelox

Strategy 2: 4BPaLM for all with FQ-S MDR/RR-TB; Strategy 3: 3BPaLM or 6BPaLM stratified medicine strategy for those with FQ-S MDR/RR-TB

Control Arm FQ-S MDR/RR-TB regimen, designed according to latest international guidelines DRUG

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.

Strategy 1: Control regimen for all with FQ-S MDR/RR-TB

Eligibility Criteria

• Age: 14 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• Known allergy/sensitivity, intolerance, or any hypersensitivity to components of study TB drugs or their formulation.
• One or more of the following laboratory parameters:
• Absolute neutrophil count (ANC) \< 1000/mm3.
• Hemoglobin level \< 8.0 g/dL.
• Serum or plasma alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3 times the upper limit of normal.
• Serum or plasma total bilirubin ≥ 3 times the upper limit of normal.
• Serum or plasma creatinine level ≥ 3 times the upper limit of normal.
• Evidence of laboratory values consistent with or equivalent to grade 4 toxicity (i.e., potentially life-threatening).
• NOTE: Persons found not to be eligible due to laboratory abnormalities may be reevaluated within the screening window.
• QTcF interval ≥ 480 ms within 5 days prior to study entry.
• 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).
• Current grade 2 or higher peripheral neuropathy.
• a. NOTE: Peripheral neuropathy assessment must be obtained within 7 days prior to study entry.
• Documentation of Karnofsky Performance Status Score \< 50 obtained within 14 days prior to study entry.
• Known resistance to bedaquiline, pretomanid, delamanid, linezolid, or fluoroquinolones.

Sponsors & Collaborators

• University of California, San Francisco: lead
• Johns Hopkins University: collaborator

Study Sites (6)

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

MeSH Terms

Conditions

Tuberculosis, Pulmonary; Tuberculosis, Multidrug-Resistant; Tuberculosis

Interventions

bedaquiline; Linezolid; pretomanid; Moxifloxacin

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Acetamides; Amides; Organic Chemicals; Acetates; Acids, Acyclic; Carboxylic Acids; Oxazolidinones; Oxazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluoroquinolones; 4-Quinolones; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Gustavo E Velásquez, MD, MPH

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Gustavo E Velásquez, MD, MPH

CONTACT

(628) 206-2400; gustavo.velasquez@ucsf.edu

Ariana F Austin, MS

CONTACT

prism.central@ucsf.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 28, 2024
• First Posted: June 4, 2024
• Study Start: October 3, 2025
• Primary Completion (Estimated): August 1, 2031
• Study Completion (Estimated): August 1, 2031
• Last Updated: January 20, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

PE (2); UG (1); PA (1); VN (1); MO (1)