Program for Rifampicin-Resistant Disease With Stratified Medicine for Tuberculosis

Tuberculosis, Pulmonary Clinical Trial

— PRISM-TB  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06441006
• Other study ID #: 24-41176
• Secondary ID: 7200AA22CA00005
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: November 1, 2024
• Est. completion date: November 30, 2029

Study information

• Verified date: May 2024
• Source: University of California, San Francisco
• Contact: Gustavo E Velásquez, MD, MPH
• Phone: (628) 206-2400
• Email: gustavo.velasquez[@]ucsf.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

PRISM-TB is an international, multicenter, open-label, randomized, controlled, pragmatic, stratified medicine, treatment shortening, noninferiority Phase 3 clinical trial for fluoroquinolone-susceptible multidrug-resistant/rifampin-resistant pulmonary tuberculosis (FQ-S MDR/RR-TB). The trial objective is to evaluate whether stratified medicine treatment strategies for FQ-S MDR/RR-TB, defined by a pre-specified risk stratification algorithm, have noninferior efficacy to a one-size-fits-all control regimen (the local standard-of-care [SOC] regimen consistent with preferred regimen(s) in international guidelines), as measured by TB-related unfavorable outcomes at Week 73.

Description:

690 participants will be randomized to the following arms in a 1:1:1 randomization: Strategy 1 (control strategy): Control regimen for all with FQ-S MDR/RR-TB. The local SOC regimen consistent with preferred regimen(s) in international guidelines. In most cases this will be 26 weeks of bedaquiline, pretomanid, linezolid, and moxifloxacin (6BPaLM). Doses and durations of each component may change based on the latest WHO guidelines and the local SOC. Strategy 2 (investigational strategy): 4BPaLM for all with FQ-S MDR/RR-TB. 17 weeks of bedaquiline, pretomanid, linezolid, and moxifloxacin (4BPaLM). Strategy 3 (investigational strategy): 3BPaLM or 6BPaLM stratified medicine strategy for those with FQ-S MDR/RR-TB. 13 weeks of bedaquiline, pretomanid, linezolid, and moxifloxacin (3BPaLM) for participants classified as having easier-to-treat TB and 26 weeks of bedaquiline, pretomanid, linezolid, and moxifloxacin (6BPaLM) for participants classified as having harder-to-treat TB.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 690
• Est. completion date: November 30, 2029
• Est. primary completion date: June 30, 2029
• Accepts healthy volunteers: No
• Gender: All
• Age group: 14 Years and older

Eligibility

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 accessible 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 = 100 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 (See Section 9.4).

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.

Related Conditions & MeSH terms

• Tuberculosis
• Tuberculosis, MDR
• Tuberculosis, Multidrug-Resistant
• Tuberculosis, Pulmonary

Intervention

Drug:
• Bedaquiline
Frequency: daily Route of administration: oral
• Linezolid
Frequency: daily Route of administration: oral
• Pretomanid
Frequency: daily Route of administration: oral
• Moxifloxacin
Frequency: daily Route of administration: oral
• Control Arm FQ-S MDR/RR-TB regimen, designed according to latest WHO guidelines
The local SOC regimen consistent with preferred regimen(s) in international guidelines. In most cases this will be 26 weeks of bedaquiline, pretomanid, linezolid, and moxifloxacin (6BPaLM). Doses and durations of each component may change based on the latest WHO guidelines and the local SOC.

Locations

Country	Name	City	State
Moldova, Republic of	Institute of Phthisiopneumology Chiril Dragniuc	Chisinau
Mongolia	National Center for Communicable Diseases	Ulaanbaatar
Pakistan	Institute of Chest Disease	Kotri
Pakistan	Civil Hospital Mirpurkhas	Mirpur
Peru	Hospital Nacional Hipólito Unanue	Lima
Peru	Hospital Nacional Sergio E. Bernales	Lima
Peru	Policlínico SES	Lima
Philippines	TB HIV Research Unit at De La Salle Medical and Health Sciences Institute	Dasmariñas
South Africa	King Dinuzulu Hospital Complex	Durban
South Africa	Perinatal HIV Research Unit Matlosana	Klerksdorp
South Africa	Isango Lethemba TB Research Unit at Jose Pearson TB Hospital	Port Elizabeth
Vietnam	Hanoi Lung Hospital	Hanoi

Sponsors (2)

Lead Sponsor	Collaborator
University of California, San Francisco	Johns Hopkins University

Countries where clinical trial is conducted

Moldova, Republic of,  Mongolia,  Pakistan,  Peru,  Philippines,  South Africa,  Vietnam, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Primary Efficacy Outcome: TB-Related Unfavorable Outcome at 73 Weeks	TB-related unfavorable outcome at 73 weeks post-randomization, defined as death, treatment failure, or recurrence of tuberculosis.	73 weeks
Secondary	TB-Related Unfavorable Outcome at 52 Weeks	TB-related unfavorable outcome at 52 weeks post-randomization, defined as death, treatment failure, or recurrence of tuberculosis.	52 weeks
Secondary	TB-Related Unfavorable Outcome at 104 Weeks	TB-related unfavorable outcome at 104 weeks post-randomization, defined as death, treatment failure, or recurrence of tuberculosis.	104 weeks
Secondary	Mortality	Mortality	104 weeks
Secondary	All Grade 3 or Higher AEs up to 30 Weeks	All Grade 3 or higher AEs up to 30 weeks post-randomization.	30 weeks
Secondary	All Grade 3 or Higher AEs up to 52 Weeks	All Grade 3 or higher AEs up to 52 weeks post-randomization.	52 weeks
Secondary	All AESIs up to 30 Weeks	All AESIs up to 30 weeks post-randomization.	30 weeks
Secondary	All AESIs up to 52 Weeks	All AESIs up to 52 weeks post-randomization.	52 weeks