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)
Trial Snapshot
- Phase
- Phase 2
- Status
- Active, not recruiting
- Sponsor
- Brigham and Women's Hospital
- Enrollment
- 94
- Locations
- 2
- Primary Endpoint
- Time to stable liquid culture conversion
Study Overview
Brief Summary
The PRESCIENT trial is a Phase IIc, open-label, randomized trial that compared a 12-week regimen of bedaquiline (BDQ), clofazimine (CFZ), pyrazinamide (PZA), and delamanid (DLM) with standard treatment for drug-susceptible pulmonary tuberculosis (TB). Eligible participants were 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 were 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.
Detailed Description
The PRESCIENT trial is a Phase IIc, open-label, randomized trial that compared a 12-week regimen of bedaquiline (BDQ), clofazimine (CFZ), pyrazinamide (PZA), and delamanid (DLM) with standard treatment for drug-susceptible pulmonary tuberculosis. Eligible participants were randomized in a 1:1 ratio to BDQ, CFZ, PZA, and DLM (BCZD) or standard anti-TB therapy. Randomization was stratified by presence of lung cavitation and HIV status.
Participants were randomized to one of two arms:
Arm 1 (Experimental): BDQ 200 mg for 12 weeks + PZA 1000 - 2000 mg (according to weight) for 12 weeks + CFZ 300 mg for 2 weeks, followed by 100 mg for 10 weeks + DLM 200 mg for 12 weeks, all given once daily.
Arm 2 (Standard of Care): Rifampicin (RIF), Isoniazid (INH), Ethambutol (EMB) and Pyrazinamide (PZA) for 8 weeks, followed by RIF and INH for 18 weeks.
Medications were given daily in fixed dose combinations at standard weight-based doses. Adherence was supported through automated reminders and monitored remotely in real time with Wisepill electronic adherence monitoring devices or with directly observed treatment. Participants in the experimental arm with evidence of poor clinical response were 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 (RHZE) arm. Participants had extended post-treatment follow up to evaluate clinical efficacy as a secondary composite outcome measure at 86 weeks after randomization (74 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 focused on prolonged QT interval corrected using Fridericia's formula (QTcF) and hepatitis as adverse events of special interest. Through an efficient Phase IIc design, the PRESCIENT trial tested microbiological efficacy, evaluated safety, and detected treatment-emergent resistance with the ultra-short BCZD regimen.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Informed consent obtained and signed.
- •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 was 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 was 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 was 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
- •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 5 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.
- •The initial 25% of enrollment (n = 39) was restricted to participants with mild or moderate disease, defined as having sputum with higher Xpert MTB/RIF cycle threshold (Ct) values (> 17 cycles) and the absence of extensive lung disease on chest X-ray (involvement of at least half of the area of the entire thoracic cavity). Thereafter, all eligible patients were offered participation without a pause in enrollment.
Exclusion Criteria
- •More than 5 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 were classified as late exclusions and study treatment was discontinued. These participants were transitioned to routine care but requested to remain in study follow up for safety evaluations.
- •A. Screening, baseline study, and Week 1 visit sputum cultures fail to grow M. tuberculosis.
- •B. Resistance to RIF or INH is detected from baseline molecular or phenotypic testing results that become available after enrollment.
Arms & Interventions
Arm 1 BCZD
BDQ 200 mg for 12 weeks + PZA 1000 - 2000 mg (according to weight) for 12 weeks + CFZ 300 mg for 2 weeks, followed by 100 mg for 10 weeks + DLM 200 mg for 12 weeks, all given once daily.
Intervention: Clofazimine (CFZ) (Drug)
Arm 1 BCZD
BDQ 200 mg for 12 weeks + PZA 1000 - 2000 mg (according to weight) for 12 weeks + CFZ 300 mg for 2 weeks, followed by 100 mg for 10 weeks + DLM 200 mg for 12 weeks, all given once daily.
Intervention: Pyrazinamide (PZA) (Drug)
Arm 1 BCZD
BDQ 200 mg for 12 weeks + PZA 1000 - 2000 mg (according to weight) for 12 weeks + CFZ 300 mg for 2 weeks, followed by 100 mg for 10 weeks + DLM 200 mg for 12 weeks, all given once daily.
Intervention: Bedaquiline (BDQ) (Drug)
Arm 2 RHZE
RIF, INH, EMB and PZA for 8 weeks, followed by RIF and INH for 18 weeks; given daily in fixed dose combinations at standard weight-based doses.
Intervention: Rifampicin (RIF) (Drug)
Arm 2 RHZE
RIF, INH, EMB and PZA for 8 weeks, followed by RIF and INH for 18 weeks; given daily in fixed dose combinations at standard weight-based doses.
Intervention: Isoniazid (INH) (Drug)
Arm 2 RHZE
RIF, INH, EMB and PZA for 8 weeks, followed by RIF and INH for 18 weeks; given daily in fixed dose combinations at standard weight-based doses.
Intervention: Ethambutol (EMB) (Drug)
Arm 1 BCZD
BDQ 200 mg for 12 weeks + PZA 1000 - 2000 mg (according to weight) for 12 weeks + CFZ 300 mg for 2 weeks, followed by 100 mg for 10 weeks + DLM 200 mg for 12 weeks, all given once daily.
Intervention: Delamanid (DLM) (Drug)
Arm 2 RHZE
RIF, INH, EMB and PZA for 8 weeks, followed by RIF and INH for 18 weeks; given daily in fixed dose combinations at standard weight-based doses.
Intervention: Pyrazinamide (PZA) (Drug)
Outcomes
Primary Outcomes
Time to stable liquid culture conversion
Time Frame: 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 or symptoms of active TB.
Median Time to Stable Liquid Culture Conversion by Week 8
Time Frame: Measured through Week 8
Culture conversion is 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 or symptoms of active tuberculosis (TB).
Secondary Outcomes
- Proportion experiencing any Grade 3 or higher AE(Measured at Week 60)
- Proportion with favorable composite outcome(Measured at Week 60)
- Proportion who prematurely discontinue treatment(Measured at Week 12 in experimental group and Week 26 in standard group)
- Change in skin coloration at weeks 8, 12, 16, 26, 60, and 86(Measured through Week 86)
- Distress related to skin coloration at weeks 8, 12, 16, 26, 60, and 86(Measured through Week 86)
- Mean change in QTcF from baseline to week 1, 2, 4, 8, 12, and 16(Measured through Week 16)
- Mean change in QTcF from baseline to end of treatment(Measured at Week 12 in Arm 1 and Week 26 in Arm 2)
- Occurrence of absolute QTcF ≥480 ms and <500 ms, and ≥500 ms(Measured through Week 16)
- Occurrence of QTcF change from baseline of ≥30 ms and <60 ms, and ≥60 ms(Measured through Week 16)
- Proportion of participants with one or more serious adverse events (SAEs)(Week 86)
- Proportion with culture conversion in liquid and solid media (separately) at weeks 4, 8 and 12 after randomization(Measured at Weeks 4, 8, and 12)
- Proportion with TB relapse (by M. tuberculosis genotyping) from end of treatment to 86 weeks(Measured through Week 86)
- Proportion of treatment-emergent genotypic and phenotypic resistance to BCZD(Measured through Week 86)
- Time (days) to positivity in liquid culture (MGIT) after start of treatment across study arms(Measured through Week 8)
- Time to stable liquid culture conversion(Measured through Week 12)
- Cumulative Probability of Experiencing Any Grade 3 or Higher Adverse Event (AE)(Measured at Week 60)
- Cumulative Probability of Having a Favorable Composite Outcome(Measured at Week 60)
- Proportion Who Prematurely Discontinue Treatment(Measured at Week 12 in Arm 1 and Week 26 in Arm 2)
- Median Time to Stable Liquid Culture Conversion by Week 12(Measured through Week 12)
- Mean Change in Skin Coloration Since TB Treatment Started at Weeks 8, 12, 16, 26, 60, and 86(Weeks 8, 12, 16, 26, 60, and 86)
- Mean Distress Related to Skin Coloration Since TB Treatment Started at Weeks 8, 12, 16, 26, 60, and 86(Weeks 8, 12, 16, 26, 60, and 86)
- Mean Change in QTcF From Baseline to Week 1, 2, 4, 8, 12, and 16(Baseline (screening visit) and weeks 1, 2, 4, 8, 12, and 16)
- Mean Change in QTcF From Baseline to End of Treatment(Measured at Week 12 in Arm 1 and Week 26 in Arm 2)
- Occurrence of Absolute QTcF >480 ms and ≤500 ms, and >500 ms(Measured through Week 16)
- Occurrence of QTcF Change From Baseline of >30 ms and ≤60 ms, and >60 ms(Measured through Week 16)
- Cumulative Probability of Having One or More Serious Adverse Events (SAEs)(Measured through Week 86)
- Proportion With Culture Conversion in Liquid Media at Weeks 4, 8 and 12(Measured at Weeks 4, 8, and 12)
- Proportion With Culture Conversion in Solid Media at Weeks 4, 8 and 12(Measured at Weeks 4, 8, and 12)
- Cumulative Probability of TB Relapse (by M. Tuberculosis Genotyping)(Measured from end of treatment (week 12 for Arm 1 and week 26 for Arm2) through Week 86)
- Proportion of Treatment-emergent Genotypic and Phenotypic Resistance to BCZD(Measured through Week 86)
- Median Time (Days) to Positivity in Liquid Culture(Weeks 1, 2, 3, 4, 6, and 8)
Investigators
Serena Patricia Koenig
Associate Professor
Brigham and Women's Hospital