Evaluation of the Safety, Tolerability, PK of TBAJ-587 in Healthy Adults
Condition: Tuberculosis
MeSH terms: Tuberculosis
Study type: Interventional
Phase: Phase 1

Summary: 
      Phase 1, Partially Blinded, Placebo-Controlled, Randomized, Combined Single Ascending Dose
      with Food Effect Cohort Trial (Part 1) and Multiple Ascending Dose Trial (Part 2) to Evaluate
      the Safety, Tolerability, and PK of TBAJ-587 in Healthy Adults
    

Detailed description: 
      This is a two-part, partially blinded, placebo-controlled, combined single ascending dose
      (SAD) trial with a food-effect cohort (Part 1) and multiple ascending dose (MAD) trial (Part
      2) to be conducted in one trial centre in Europe.

      Part 1: Has a single ascending dose (SAD) design with up to 6 planned dose levels with a
      food-effect cohort at one of the dose levels.

      The first SAD cohort will be separated into 2 groups. A sentinel group of two participants (1
      active and 1 placebo) will be dosed at least 72 hours before the remaining 6 participants (5
      active and 1 placebo). The other cohorts will not be separated.

      Other Dose Level cohorts: scheduling of safety and PK sample collection will be based on the
      PK data collected from previous cohorts.

      Food-Effect Cohort: Based on exposure levels from preceding SAD cohorts, one of the planned
      cohorts and the specific dose will be selected for the food effect (FE) cohort which will
      study the effect on PK after a high-calorie, high-fat meal. Additional participants will be
      recruited to reach a total of 9 active participants, inclusive of the previously dosed
      participants, in the fasted group, and 9 additional active participants will be recruited for
      the group dosed with food.

      Note: The decision to proceed to the next cohort will be based on a Dose Escalation Meeting
      (DEM) which will take place after the Day 7 PK profile and approximately 14 days of safety
      data is available depending on the time required for PK analysis. The EC will be notified on
      the outcome of the DEM and the next cohort will start once the EC grants approval. The
      scheduling and duration of the PK and safety data collection for the DEM may be revised based
      on what is learned about the PK and safety from the initial cohorts during Part 1 of the
      trial. This PK and safety data might also impact the scheduling of the PK collection/sampling
      and safety assessments for the remainder of the cohorts in Part 1 and Part 2.

      Participants will continue to be monitored for safety which may continue up to approximately
      20 weeks after the last dose if indicated by interim PK analysis.

      At the end of Part 1 (SAD), pharmacokinetic and safety data along with rationale for choosing
      the doses for the multiple ascending dose (MAD) part, Part 2, will be submitted to the Ethics
      Committee (EC). The trial will not proceed to Part 2 until the Sponsor, in conjunction with
      the Principal Investigator (PI) and members of the Safety Review Committee (SRC) at the DEM,
      has determined that adequate safety, tolerability, and PKs from the Part 1 cohorts have been
      demonstrated and all required parties, including the EC, have provided approval.

      Part 2: Has a multiple ascending dose (MAD) design. Three cohorts are planned for Part 2 and
      will be determined based on model predictions of steady state AUC exposures and safety from
      Part 1.

      In this MAD part, each participant, based on current assumptions, is expected to be
      administered TBAJ-587 or matching placebo daily for 28 days with corresponding PK and safety
      measurements.

      Note: The DEM will be scheduled after the Day 14 PK profile data is available depending on
      the time required for PK analysis. The EC will be notified, and the next cohort will start
      once the EC grants approval.

      The safety and PK collection/sampling schedule for the MAD may be revised based on what is
      learned about the PK and safety from Part 1 of the trial. Furthermore, with regard to the
      DEM, the timing and duration of the safety and PK sampling needed to decide on escalating to
      the next dose will also be determined and finalized based on the PK data obtained from Part
      1.

      Participants will continue to be monitored for safety at time points up to approximately 20
      weeks after the last dose if indicated by interim PK analysis.

      Additional cohorts: up to three additional cohorts in Part 1 and one additional cohort in
      Part 2 may be enrolled if deemed appropriate by the Sponsor to repeat a dose level or to
      study another dose level.

      Dose escalation to the next cohort (i.e. next dose level), the decision for the trial to
      progress to the planned MAD cohorts (Part 2), any changes to the PK sampling and safety
      assessment time points, or the decisions on additional cohorts will not take place until the
      Sponsor, in conjunction with the PI and members of the SRC at the DEM, has determined that
      adequate safety, tolerability, and pharmacokinetics from the previous cohort have been
      demonstrated to permit proceeding to the next cohort. The EC should be notified, and the
      decision can only be implemented once the EC grants approval.

      Interim PK analyses (the prediction PK model may be modified if necessary) and safety
      assessments will be performed for the dose escalation decisions, to select the intermediate
      dose for the food effect cohort, and to reconsider (if needed) the sampling time points as
      the trial progresses. All samples will be sent for analysis and the bioanalytical lab will be
      unblinded and run the analysis on active treatment participants only. Data from the analysis
      used for the dose escalation meetings will only include active treatment participants and
      will be blinded by participant for the Sponsor trial team, PI and SRC members.

      Safety will be assessed throughout the trial. Physical examinations, safety laboratory, vital
      signs, serial Electrocardiograms (ECGs), Holter monitoring and serial blood samples will be
      collected for safety and PK assessment of TBAJ-587 and metabolites.

      As data from each cohort is informative for dose escalation decisions in subsequent cohorts,
      review of unblinded data will be conducted by 2 experienced individuals not directly involved
      in the study, one of whom must be a physician. Upon completion of the review, they will
      communicate to the study team and SRC modifications, if any, that should be implemented for
      subsequent cohorts.
    

Intervention name(s): TBAJ-587; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): oral suspension; matching placebo oral suspension for TBAJ-587
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Phase I