Clinical trial NCT05556746: Ultra-Short Course Bedaquiline, Clofazimine, Pyrazinamide and Delamanid Versus Standard Therapy for Drug-Susceptible TB
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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Tuberculosis, Pulmonary
HIV
Keywords: Pulmonary Tuberculosis
Treatment Shortening
HIV
Drug-Susceptible Tuberculosis
Lead sponsor: Brigham and Women's Hospital
Sponsor class: OTHER
Collaborators: name: University of Cape Town
name: Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic
name: University of Stellenbosch
name: University of California, Los Angeles
name: Harvard School of Public Health (HSPH)
First posted: 2022-09-27
Enrollment: 156
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants will be randomized in a 1:1 ratio to the experimental or standard groups.
Primary purpose: TREATMENT

Brief summary: The PRESCIENT trial is a Phase IIc, open-label, randomized trial that will compare a 12-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.

Detailed description: The PRESCIENT trial is a Phase IIc, open-label, randomized trial that will compare a 12-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. Randomization will be stratified by presence of lung cavitation and HIV status.

Participants will be 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): 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 or with directly observed treatment. Participants in the experimental arm with evidence of poor clinical response 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. Participants will have 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 shall focus on QTcF prolongation and hepatitis as adverse events 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.

Eligibility criteria: 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 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 will be restricted to participants (n = 39) 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 will be 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 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.

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.

Primary outcomes:
measure: Time to stable liquid culture conversion
timeFrame: Measured through Week 8
Secondary outcomes:
measure: Proportion experiencing any Grade 3 or higher AE
timeFrame: Measured at Week 60
measure: Proportion with favorable composite outcome
timeFrame: Measured at Week 60
measure: Proportion who prematurely discontinue treatment
timeFrame: Measured at Week 12 in experimental group and Week 26 in standard group
measure: Change in skin coloration at weeks 8, 12, 16, 26, 60, and 86
timeFrame: Measured through Week 86
measure: Distress related to skin coloration at weeks 8, 12, 16, 26, 60, and 86
timeFrame: Measured through Week 86
measure: Mean change in QTcF from baseline to week 1, 2, 4, 8, 12, and 16
timeFrame: Measured through Week 16
measure: Mean change in QTcF from baseline to end of treatment
timeFrame: Measured at Week 12 in Arm 1 and Week 26 in Arm 2
measure: Occurrence of absolute QTcF ≥480 ms and <500 ms, and ≥500 ms
timeFrame: Measured through Week 16
measure: Occurrence of QTcF change from baseline of ≥30 ms and <60 ms, and ≥60 ms
timeFrame: Measured through Week 16
measure: Proportion of participants with one or more serious adverse events (SAEs)
timeFrame: Week 86
measure: Proportion with culture conversion in liquid and solid media (separately) at weeks 4, 8 and 12 after randomization
timeFrame: Measured at Weeks 4, 8, and 12
measure: Proportion with TB relapse (by M. tuberculosis genotyping) from end of treatment to 86 weeks
timeFrame: Measured through Week 86
measure: Proportion of treatment-emergent genotypic and phenotypic resistance to BCZD
timeFrame: Measured through Week 86
measure: Time (days) to positivity in liquid culture (MGIT) after start of treatment across study arms
timeFrame: Measured through Week 8
measure: Time to stable liquid culture conversion
timeFrame: Measured through Week 12
Other outcomes:
Locations:
city: Port-au-Prince
country: Haiti
facility: GHESKIO
city: Cape Town
country: South Africa
facility: University of Cape Town
Study officials:
affiliation: Brigham and Women's Hospital
name: Serena Koenig, MD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Cape Town
name: Sean Wasserman, MBChB, PhD
role: PRINCIPAL_INVESTIGATOR
References: