PRESCIENT: Ultra-Short Course Bedaquiline, Clofazimine, Pyrazinamide and Delamanid Versus Standard Therapy for Drug-Susceptible TB

Sponsor

Brigham and Women's Hospital (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05556746

Collaborator

University of Cape Town (Other), Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic (Other), University of Stellenbosch (Other), University of California, Los Angeles (Other), Harvard School of Public Health (HSPH) (Other)

156

Enrollment

Locations

Arms

34.1

Anticipated Duration (Months)

Patients Per Site

2.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The PRESCIENT trial is a Phase IIc, open-label, randomized trial that will compare an 8-week regimen of bedaquiline (BDQ), clofazimine (CFZ), pyrazinamide (PZA), and delamanid (DLM) with standard treatment for drug-susceptible pulmonary tuberculosis. Eligible participants will be randomized in a 1:1 ratio to BDQ, CFZ, PZA, and DLM (BCZD) or standard anti-TB therapy.

Participants in the experimental arm with evidence of poor clinical response at the end of therapy will be re-treated with standard TB therapy. The primary analysis is a superiority efficacy comparison of time to liquid culture conversion through 8 weeks in the experimental (BCZD) arm vs. the standard therapy arm. The other key secondary outcome is safety.

Condition or Disease	Intervention/Treatment	Phase
Tuberculosis, Pulmonary HIV	Drug: Bedaquiline Drug: Clofazimine Drug: Pyrazinamide Drug: Delamanid Drug: Rifampin Drug: Isoniazid Drug: Ethambutol Drug: Pyrazinamide	Phase 2

Detailed Description

Participants will be randomized to one of two arms:

Arm 1 (Experimental): BDQ 200 mg for 8 weeks + PZA 1000 - 2000 mg (according to weight) for 8 weeks + CFZ 300 mg for 2 weeks, followed by 100 mg for 6 weeks + DLM 200 mg for 8 weeks, all given once daily.

Arm 2 (Standard of Care): RIF, INH, EMB and PZA for 8 weeks, followed by RIF and INH for 18 weeks.

Medications will be given daily in fixed dose combinations at standard weight-based doses. Adherence will be supported through automated reminders and monitored remotely in real time with Wisepill electronic adherence monitoring devices. Participants in the experimental arm with evidence of poor clinical response at the end of therapy, defined as persistent symptoms consistent with active TB, lack of improvement or worsening disease on chest X-ray, or sputum smear positivity on two samples, will be re-treated with standard TB therapy, as will be those with positive Mtb culture collected at week 8 or later. The primary analysis is a superiority efficacy comparison of time to liquid culture conversion through 8 weeks in the experimental (BCZD) arm vs. the standard therapy arm. Participants will have extended post-treatment follow up to evaluate clinical efficacy as a secondary composite outcome measure at 56 weeks after randomization (48 weeks after completion of experimental therapy, when most relapses are expected to occur). The other key secondary outcome is safety, measured as the proportion with new Grade 3 or higher adverse events; we shall focus on QTcF prolongation as an adverse event of special interest. Through an efficient Phase IIc design, the PRESCIENT trial will test microbiological efficacy, evaluate safety, and detect treatment-emergent resistance with the ultra-short BCZD regimen. PRESCIENT will provide rapid evidence for microbiological efficacy as well as key information on safety and clinical treatment outcomes to inform the feasibility and promise of a subsequent phase III treatment-shortening trial.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

156 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Participants will be randomized in a 1:1 ratio to the experimental or standard groups.Participants will be randomized in a 1:1 ratio to the experimental or standard groups.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase IIc, Open-Label, Randomized Controlled Trial of Ultra-Short Course Bedaquiline, Clofazimine, Pyrazinamide and Delamanid Versus Standard Therapy for Drug-Susceptible Tuberculosis (PRESCIENT)

Anticipated Study Start Date :

Mar 1, 2023

Anticipated Primary Completion Date :

Nov 1, 2024

Anticipated Study Completion Date :

Jan 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BCZD Bedaquiline 200 mg for 8 weeks + pyrazinamide 1000 - 2000 mg (according to weight) for 8 weeks + clofazimine 300 mg for 2 weeks, followed by 100 mg for 6 weeks + delamanid 200 mg for 8 weeks, all given once daily.	Drug: Bedaquiline Daily therapy for 8 weeks Drug: Clofazimine Daily therapy for 8 weeks Drug: Pyrazinamide Daily therapy for 8 weeks Drug: Delamanid Daily therapy for 8 weeks
Active Comparator: Standard TB Treatment Rifampin, isoniazid, ethambutol and pyrazinamide for 8 weeks, followed by rifampin and isoniazid for 18 weeks; given daily in fixed dose combinations at standard weight-based doses.	Drug: Rifampin Daily therapy for 26 weeks Drug: Isoniazid Daily therapy for 26 weeks Drug: Ethambutol Daily therapy for 8 weeks Drug: Pyrazinamide Daily therapy for 8 weeks

Arm

Intervention/Treatment

Experimental: BCZD

Bedaquiline 200 mg for 8 weeks + pyrazinamide 1000 - 2000 mg (according to weight) for 8 weeks + clofazimine 300 mg for 2 weeks, followed by 100 mg for 6 weeks + delamanid 200 mg for 8 weeks, all given once daily.

Drug: Bedaquiline

Daily therapy for 8 weeks

Drug: Clofazimine

Daily therapy for 8 weeks

Drug: Pyrazinamide

Daily therapy for 8 weeks

Drug: Delamanid

Daily therapy for 8 weeks

Active Comparator: Standard TB Treatment

Rifampin, isoniazid, ethambutol and pyrazinamide for 8 weeks, followed by rifampin and isoniazid for 18 weeks; given daily in fixed dose combinations at standard weight-based doses.

Drug: Rifampin

Daily therapy for 26 weeks

Drug: Isoniazid

Daily therapy for 26 weeks

Drug: Ethambutol

Daily therapy for 8 weeks

Drug: Pyrazinamide

Daily therapy for 8 weeks

Outcome Measures

Primary Outcome Measures

Time to stable liquid culture conversion [Measured through Week 8]
Defined as the first of two negative sputum cultures, consecutive or not, without an intervening positive culture, and/or visits wherein the participant is unable to produce sputum and has no signs of active TB

Secondary Outcome Measures

Proportion experiencing any Grade 3 or higher AE that is at least a one-grade increase from baseline [Measured at Week 56]
Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Corrected Version 2.1, July 2017
Proportion with favorable composite outcome [Measured at Week 56]
Defined as no failure, relapse, or non-accidental death
Proportion who prematurely discontinue treatment [Measured at Week 8 in experimental group and Week 26 in standard group]
Defined as discontinuation other than due to violent death, natural disaster, or administrative censoring
Change in skin coloration [Measured through Week 56]
Mean change in subjective 10-point numeric rating scale where 0=none, 10=worst possible change in coloration
Distress related to skin coloration [Measured through Week 56]
Mean subjective distress related to skin coloration on 10-point rating scale where 0=non, 10-worst possible distress due to coloration
Mean change in QTcF from baseline to week 2, 8, 12, and 16 [Measured through Week 16]
The QTcF is derived from ECG readings, which the sites conduct in triplicate (three ECGs 5-10 minutes apart). The mean of all measurements (up to 3) that are readable and available will be used
Mean change in QTcF from baseline to end of treatment [Measured at week 8 in Arm 1 and Week 26 in Arm 2]
The QTcF is derived from ECG readings, which the sites conduct in triplicate (three ECGs 5-10 minutes apart). The mean of all measurements (up to 3) that are readable and available will be used at baseline (screening visit), week 8 (experimental group) and week 26 (standard group)
Occurrence of absolute QTcF ≥480 ms and <500 ms, and ≥500 ms [Measured through week 16 in Arm 1 and through Week 26 in Arm 2]
The QTcF is derived from ECG readings, which the sites conduct in triplicate (three ECGs 5-10 minutes apart). The mean of all measurements (up to 3) that are readable and available will be used at week 16 (experimental group) and week 26 (standard group).
Occurrence of QTcF change from baseline of ≥30 ms and <60 ms, and ≥60 ms [Measured through week 16 in experimental group and Week 26 in standard group]
The QTcF is derived from ECG readings, which the sites conduct in triplicate (three ECGs 5-10 minutes apart). The mean of all measurements (up to 3) that are readable and available will be used at week 16 (experimental group) and week 26 (standard group).
Proportion of participants with one or more serious adverse events (SAEs) [Week 56]
Serious adverse events reported at any time during participation in the trial
Proportion with culture conversion in liquid and solid media (separately) at weeks 4 and 8 after randomization [Measured at Week 4 and Week 8]
Proportion of participants who have achieved stable culture conversion, defined as two negative sputum cultures, consecutive or not, without an intervening positive culture and/or visits wherein the participant is unable to produce sputum and has no signs of active TB; occurring before or at the week 4 or 8 visit, respectively
Proportion with TB relapse (by M. tuberculosis genotyping) from end of treatment to 56 weeks [Measured through Week 56]
For participants who had successful culture conversion through the end of study treatment, TB relapse is defined as a recurrence of TB emanating from the same strain as the participant's originally diagnosed TB, which will be determined through whole genome sequencing
Proportion of treatment-emergent genotypic and phenotypic resistance to BCZD [Measured through Week 56]
For participants in experimental group only. MIC values will be evaluated against resistance-associated variants for paired baseline and failure isolates. Frequencies and proportions with phenotypic and/or genotypic resistance to any drug will be reported
Time (days) to positivity in liquid culture (MGIT) after start of treatment across study arms [Measured through Week 8]
Median (Q1, Q3) times to positivity in liquid culture at each time point (weeks 1, 2, 3, 4, 6, and 8) in the experimental and standard groups

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Informed consent obtained and signed.
Male or female, aged ≥18 years.
Pulmonary TB diagnosed by Xpert MTB/RIF, Xpert MTB/RIF Ultra, Line Probe Assay (LPA), or mycobacterial culture.
Sputum positive for acid fast bacilli (at least 1+ grade on the WHO scale).
Pulmonary TB diagnosed without known INH resistance (by LPA or Xpert MTB/XDR) and without known RIF resistance (by either LPA or Xpert). Note that phenotypic DST for INH resistance will be done on screening cultures (using MGIT). If baseline molecular or phenotypic test results that become available after enrollment detect resistance to INH or RIF, the participant will be a late exclusion from the study.
Newly diagnosed with TB and have a history of being untreated for at least 6 months after cure from a previous episode of TB.
For participants living with HIV, CD4+ cell count ≥200 cells/mm3, obtained within 30 days prior to study entry. Enrollment of participants living with HIV will be limited to no more than 20% of the total study population.
For participants living with HIV, must be currently receiving or planning to initiate ART at or before study week 8.
Laboratory values at study screening:
Alanine aminotransferase (ALT) ≤3x the upper limit of normal (ULN)
Total bilirubin ≤2.5 x ULN
Creatinine ≤2 x ULN
Potassium ≥3.5 mEq/L, ≤5.5 mEq/L
Absolute neutrophil count (ANC) ≥650/mm3
Hemoglobin ≥7.0g/dL
Platelet count ≥50,000/mm3
For females of reproductive potential, negative serum or urine pregnancy test within 3 days prior to entry and willingness to use effective contraception for the duration of the study. Female participants who are not of reproductive potential must have documentation of menopause, hysterectomy, or bilateral oophorectomy or bilateral tubal ligation. Acceptable forms of contraception include: condoms, intrauterine device or intrauterine system, cervical cap with spermicide, diaphragm with spermicide.

Exclusion Criteria:

More than 3 days of treatment directed against active TB for the current TB episode preceding study entry.
Current extrapulmonary TB (e.g. neurological, skeletal, abdominal, or nodal), not including pleural TB, in the opinion of the site investigator.
Pregnant or breastfeeding.
Weight <30kg.
Inability to take oral medications.
Current or planned use of any drug known to severely prolong the QTc interval, including, but not limited to: amiodarone, amitriptyline, chloroquine, chlorpromazine, cisapride, disopyramide, erthyromycin, moxifloxacin, procainamide, quinidine, or sotalol.
Current or planned use of one or more of the following HIV medications: HIV protease inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, elvitegravir/cobicistat, or bictegravir.
Current or past use of clofazimine, bedaquiline or delamanid.
QTcF >450ms for men or >470 ms for women.
Current or history of known personal or family long QT syndrome.
Known allergy/sensitivity to components of study TB drugs or their formulation.

Microbiologic confirmation of drug-susceptible TB is not always available at the time of enrollment. Enrolled individuals who are subsequently determined to meet either of the following criteria will be classified as late exclusions and study treatment will be discontinued. These participants will be transitioned to routine care but requested to remain in study follow up for safety evaluations.

Screening, baseline study, and Week 1 visit sputum cultures fail to grow M. tuberculosis.
Resistance to RIF or INH is detected from baseline molecular or phenotypic testing results that become available after enrollment.