A Phase 1 Study to Evaluate Safety, Tolerability, and Pharmacokinetics of TBI-223 in Healthy Adults

Summary

Participation Requirements

Description

In Part 1, up to 50 subjects in 6 dosing cohorts are planned to be enrolled; within each cohort, 6 subjects will be assigned to active treatment and 2 to placebo. Each subject will participate in one dose level. Based on interim pharmacokinetic data obtained during the dose escalation, a dose cohort...

In Part 1, up to 50 subjects in 6 dosing cohorts are planned to be enrolled; within each cohort, 6 subjects will be assigned to active treatment and 2 to placebo. Each subject will participate in one dose level. Based on interim pharmacokinetic data obtained during the dose escalation, a dose cohort will be selected to return for additional dosing after a high-calorie, high-fat meal (food-effect cohort). Each cohort will be dosed in two groups in order to monitor subjects for adverse experiences, in particular, convulsions (in the dog toxicity studies, tremors were observed at Cmax or plasma concentration of ?82µg/mL, and convulsions were observed at plasma concentration or Cmax of ? 158µg/mL). In the first cohort, a sentinel group of 3 subjects (2 active and 1 placebo) will be dosed at least 24 hours before the remaining 5 subjects (4 active and 1 placebo). The remaining cohorts will be dosed in 2 groups of 4 subjects each (3 active and 1 placebo), at least 24 hours apart. One cohort (10 subjects) will be brought back to receive a dose (8 active and 2 placebo) under fed conditions (Food-effect Cohort). In Part 2, it is planned to enroll a minimum of 24 subjects in a total of four arms with 6 subjects each. Each group of 6 subjects will receive a single dose of 1 of 3 sustained release (SR) tablet formulations of TBI-223 under fed conditions, and one will receive an immediate release (IR) formulation under fasted conditions.The group that received the IR formulation will be brought back later to receive the same formulation under fed conditions. Additional cohorts may be enrolled if deemed appropriate (e.g., if bioavailability is lower than expected) by the Sponsor to repeat a dose level, to study other dose levels, change proposed cohorts, or to study a different dosage formulation. These decisions regarding changed or additional cohorts will not take place until the Sponsor, in conjunction with the Principal Investigator and dose escalating committee, has determined that adequate safety, tolerability, and pharmacokinetics from the previous cohort have been demonstrated to permit proceeding to the next cohort. The Institutional Review Board (IRB) should be immediately notified of this revised approach for review and approval. Safety will be assessed throughout the study for all subjects. Safety assessments will include physical and neurological examinations, vital signs, electrocardiograms (ECGs), cardiac monitoring, adverse events (AEs), and clinical laboratory tests (including hematology, serum chemistry, coagulation, and urinalysis). Blood and urine will be collected for clinical laboratory evaluations. Female subjects will have blood collected for serum pregnancy testing. Postmenopausal females will have blood collected to measure follicle-stimulating hormone (FSH) levels. Blood will be collected for pharmacokinetic analysis. Dose escalation to the next cohort (i.e., dose level) will not take place until the Sponsor, in conjunction with the Principal Investigator, has determined that adequate safety, tolerability and pharmacokinetic data from the previous cohorts have been demonstrated to permit proceeding to the next cohort. The Principal Investigator, in conjunction with the Sponsor may collect additional blood if necessary, for repeat laboratory or safety evaluations including AE follow up. The study will be conducted at one study center in the United States.This study will have up to 6 planned dose levels. Based on interim pharmacokinetic data obtained during the dose escalation, a dose cohort will be selected to return for additional dosing after a high calorie, high-fat meal (Food-effect Cohort). Trial Monitoring: Sponsor personnel (or designees) will be responsible for monitoring the study to ensure compliance with the protocol and Good Clinical Practices (GCP). Compliance may be verified by one or more of the following methods: on-site visits, frequent communication with the Investigator, and/or review of case report forms (CRFs) and source documents. The Investigator agrees to permit such monitoring as well as audits or reviews by regulatory authorities and the IRB. Safety Monitoring and Procedures: Subjects will be instructed to inform the study physician and/or research personnel of any AEs that occur at any time during the study. Subjects will be monitored for AEs from the first dose through the end-of-study visit. Adverse Events: The Investigator or a suitably medically qualified designee are responsible for eliciting adverse events by observing and questioning the subject and recording all adverse events observed by him/her or reported by the subject during the trial. Serious Adverse Event (SAE) Reporting:The Investigator or designee will notify the appropriate Sponsor contact immediately after the SAE detection, observation, or report of occurrence (regardless of the relationship to test article). Analytical Methodology: Plasma samples will be analyzed for TBI-223 and M2 using validated assays. Plasma samples from subjects who receive placebo for TBI-223 oral suspension will not be analyzed. Statistical Analysis: : Final statistical analyses will be performed using appropriate software, e.g. Phoenix™ WinNonlin® (Version 8.1 or higher, Certara, L.P. in conjunction with the internet-accessible implementation of Pharsight® Knowledgebase Server™ [PKSO; Version 4.0.4 or higher, Certara, L.P.]) and/or SAS® (Version 9.4 or higher, SAS Institute Inc.). Pharmacokinetic parameters will be summarized by cohort using descriptive statistics. Summary statistics will also be presented by gender within each cohort. Dose proportionality will be assessed using a power model approach. Food-effect cohort: The effect of food will be assessed comparing pharmacokinetic parameters (maximum plasma concentration (Cmax), area under plasma concentration versus time curves (AUCs)) under fed versus fasting conditions using an analysis of variance (ANOVA) approach.

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