Evaluation of the Safety, Tolerability, PK of TBAJ-587 in Healthy Adults

Summary

Participation Requirements

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 plann...

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. First cohort: current total duration and scheduling of safety and PK sampling is based on the assumption that the expected t1/2 will be 26 days which will ensure coverage for PK and safety out to approximately 5 half-lives. Refer to Section 1.2.1 Schedule of Assessments & Procedures for more details. However, the sampling schedule may change depending on the observed PK profile. Other Dose Level cohorts: scheduling of safety and PK sample collection will be based on the PK data collected from previous cohorts and could require that the participants return to the clinic for up to 20 weeks or longer after dosing, depending on what is learned about the half-life of TBAJ-587. 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. The food effect on the PK of TBAJ-587 will be studied in one of the previously completed cohorts using a parallel group design involving two groups, one group dosed fasted and the other group dosed after a 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 7 days of PK (24-Hour sample for Day 7 collected on the morning of Day 8) and approximately 14 days of safety data. A Dose Escalation Meeting (DEM) will take place after the Day 7 PK profile 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 at time points indicated in the Schedule of Assessments and Procedures in Section 1.2.1 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: It is anticipated that the safety and PK sampling for deciding on escalating to the next dose will be through the morning of Day 15, which will include the PK profile on Day 14 and approximately 21 days of safety data. 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 indicated in the Schedule of Assessments and Procedures in Section 1.2.2 and may continue up to approximately 20 weeks after the last dose if indicated by interim PK analysis. Parts 1 and 2: 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.

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