A Phase 1 Study to Evaluate Safety, Tolerability, and Pharmacokinetics of TBI-223 in Healthy Adults
Condition: Tuberculosis; Tuberculosis, Pulmonary
MeSH terms: Tuberculosis; Tuberculosis, Pulmonary
Study type: Interventional
Phase: Phase 1

Summary: 
      Partially-Blinded, Placebo-Controlled, Randomized, Single Ascending Dose (SAD) with a Food
      Effect Cohort to Evaluate the Safety, Tolerability, and Pharmacokinetics of TBI-223 in
      Healthy Adults.
    

Detailed 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 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.
    

Intervention name(s): TBI-223 50mg; Placebo for TBI-223 50mg; TBI-223 100, 300, 600, 1200, 2000, 2600 mg; Placebo for TBI-223 100, 300, 600, 1200, 2000, 2600 mg; TBI-223 300 mg capsule; Placebo for TBI-223 300 mg capsule; TBI-223 Prototype 1 SR Tablet; TBI-223 Prototype 2 SR Tablet; TBI-223 Prototype 3 SR Tablet; TBI-223 IR Tablet
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): TBI-223 50 mg supplied for oral administration.; Matching placebo for TBI-223 50mg supplied for oral administration.; TBI-223 100, 300, 600, 1200, 2000, 2600 mg supplied for oral administration.; Matching placebo for 100, 300, 600, 1200, 2000, 2600 mg TBI-223 supplied for oral administration.; TBI-223 300 mg capsule supplied for oral administration; Placebo for TBI-223 300 mg capsule supplied for oral administration; Prototype 1 TBI-223 600 mg sustained-release (SR) tablet; Prototype 2 TBI-223 600 mg SR tablet; Prototype 3 TBI-223 900 mg SR tablet; TBI-223 1000 mg immediate release (IR) tablet
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: TB; Tuberculosis; TBI-223; Pulmonary Tuberculosis