<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03758612</url>
  </required_header>
  <id_info>
    <org_study_id>TBI-223-CL-001</org_study_id>
    <nct_id>NCT03758612</nct_id>
  </id_info>
  <brief_title>A Phase 1 Study to Evaluate Safety, Tolerability, and Pharmacokinetics of TBI-223 in Healthy Adults</brief_title>
  <official_title>A Phase 1, Partially-Blinded, Placebo-Controlled, Randomized, Single Ascending Dose (SAD) With a Food Effect Cohort Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of TBI-223 in Healthy Adult Participants.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Global Alliance for TB Drug Development</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Global Alliance for TB Drug Development</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Partially-Blinded, Placebo-Controlled, Randomized, Single Ascending Dose (SAD) with a Food&#xD;
      Effect Cohort to Evaluate the Safety, Tolerability, and Pharmacokinetics of TBI-223 in&#xD;
      Healthy Adults.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In Part 1, up to 50 subjects in 6 dosing cohorts are planned to be enrolled; within each&#xD;
      cohort, 6 subjects will be assigned to active treatment and 2 to placebo. Each subject will&#xD;
      participate in one dose level. Based on interim pharmacokinetic data obtained during the dose&#xD;
      escalation, a dose cohort will be selected to return for additional dosing after a&#xD;
      high-calorie, high-fat meal (food-effect cohort). Each cohort will be dosed in two groups in&#xD;
      order to monitor subjects for adverse experiences, in particular, convulsions (in the dog&#xD;
      toxicity studies, tremors were observed at Cmax or plasma concentration of ≥82µg/mL, and&#xD;
      convulsions were observed at plasma concentration or Cmax of ≥ 158µg/mL).&#xD;
&#xD;
      In the first cohort, a sentinel group of 3 subjects (2 active and 1 placebo) will be dosed at&#xD;
      least 24 hours before the remaining 5 subjects (4 active and 1 placebo).&#xD;
&#xD;
      The remaining cohorts will be dosed in 2 groups of 4 subjects each (3 active and 1 placebo),&#xD;
      at least 24 hours apart. One cohort (10 subjects) will be brought back to receive a dose (8&#xD;
      active and 2 placebo) under fed conditions (Food-effect Cohort).&#xD;
&#xD;
      In Part 2, it is planned to enroll a minimum of 24 subjects in a total of four arms with 6&#xD;
      subjects each. Each group of 6 subjects will receive a single dose of 1 of 3 sustained&#xD;
      release (SR) tablet formulations of TBI-223 under fed conditions, and one will receive an&#xD;
      immediate release (IR) formulation under fasted conditions.The group that received the IR&#xD;
      formulation will be brought back later to receive the same formulation under fed conditions.&#xD;
&#xD;
      Additional cohorts may be enrolled if deemed appropriate (e.g., if bioavailability is lower&#xD;
      than expected) by the Sponsor to repeat a dose level, to study other dose levels, change&#xD;
      proposed cohorts, or to study a different dosage formulation. These decisions regarding&#xD;
      changed or additional cohorts will not take place until the Sponsor, in conjunction with the&#xD;
      Principal Investigator and dose escalating committee, has determined that adequate safety,&#xD;
      tolerability, and pharmacokinetics from the previous cohort have been demonstrated to permit&#xD;
      proceeding to the next cohort. The Institutional Review Board (IRB) should be immediately&#xD;
      notified of this revised approach for review and approval.&#xD;
&#xD;
      Safety will be assessed throughout the study for all subjects. Safety assessments will&#xD;
      include physical and neurological examinations, vital signs, electrocardiograms (ECGs),&#xD;
      cardiac monitoring, adverse events (AEs), and clinical laboratory tests (including&#xD;
      hematology, serum chemistry, coagulation, and urinalysis).&#xD;
&#xD;
      Blood and urine will be collected for clinical laboratory evaluations. Female subjects will&#xD;
      have blood collected for serum pregnancy testing. Postmenopausal females will have blood&#xD;
      collected to measure follicle-stimulating hormone (FSH) levels.&#xD;
&#xD;
      Blood will be collected for pharmacokinetic analysis. Dose escalation to the next cohort&#xD;
      (i.e., dose level) will not take place until the Sponsor, in conjunction with the Principal&#xD;
      Investigator, has determined that adequate safety, tolerability and pharmacokinetic data from&#xD;
      the previous cohorts have been demonstrated to permit proceeding to the next cohort.&#xD;
&#xD;
      The Principal Investigator, in conjunction with the Sponsor may collect additional blood if&#xD;
      necessary, for repeat laboratory or safety evaluations including AE follow up.&#xD;
&#xD;
      The study will be conducted at one study center in the United States.This study will have up&#xD;
      to 6 planned dose levels. Based on interim pharmacokinetic data obtained during the dose&#xD;
      escalation, a dose cohort will be selected to return for additional dosing after a high&#xD;
      calorie, high-fat meal (Food-effect Cohort).&#xD;
&#xD;
      Trial Monitoring: Sponsor personnel (or designees) will be responsible for monitoring the&#xD;
      study to ensure compliance with the protocol and Good Clinical Practices (GCP). Compliance&#xD;
      may be verified by one or more of the following methods: on-site visits, frequent&#xD;
      communication with the Investigator, and/or review of case report forms (CRFs) and source&#xD;
      documents. The Investigator agrees to permit such monitoring as well as audits or reviews by&#xD;
      regulatory authorities and the IRB.&#xD;
&#xD;
      Safety Monitoring and Procedures: Subjects will be instructed to inform the study physician&#xD;
      and/or research personnel of any AEs that occur at any time during the study. Subjects will&#xD;
      be monitored for AEs from the first dose through the end-of-study visit.&#xD;
&#xD;
      Adverse Events: The Investigator or a suitably medically qualified designee are responsible&#xD;
      for eliciting adverse events by observing and questioning the subject and recording all&#xD;
      adverse events observed by him/her or reported by the subject during the trial.&#xD;
&#xD;
      Serious Adverse Event (SAE) Reporting:The Investigator or designee will notify the&#xD;
      appropriate Sponsor contact immediately after the SAE detection, observation, or report of&#xD;
      occurrence (regardless of the relationship to test article).&#xD;
&#xD;
      Analytical Methodology: Plasma samples will be analyzed for TBI-223 and M2 using validated&#xD;
      assays. Plasma samples from subjects who receive placebo for TBI-223 oral suspension will not&#xD;
      be analyzed.&#xD;
&#xD;
      Statistical Analysis: : Final statistical analyses will be performed using appropriate&#xD;
      software, e.g. Phoenix™ WinNonlin® (Version 8.1 or higher, Certara, L.P. in conjunction with&#xD;
      the internet-accessible implementation of Pharsight® Knowledgebase Server™ [PKSO; Version&#xD;
      4.0.4 or higher, Certara, L.P.]) and/or SAS® (Version 9.4 or higher, SAS Institute Inc.).&#xD;
      Pharmacokinetic parameters will be summarized by cohort using descriptive statistics. Summary&#xD;
      statistics will also be presented by gender within each cohort. Dose proportionality will be&#xD;
      assessed using a power model approach.&#xD;
&#xD;
      Food-effect cohort: The effect of food will be assessed comparing pharmacokinetic parameters&#xD;
      (maximum plasma concentration (Cmax), area under plasma concentration versus time curves&#xD;
      (AUCs)) under fed versus fasting conditions using an analysis of variance (ANOVA) approach.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 16, 2019</start_date>
  <completion_date type="Actual">March 14, 2020</completion_date>
  <primary_completion_date type="Actual">February 22, 2020</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
    <masking_description>This study is partially blinded. The repeat cohort (3b) using a different dosage formulation in Part 1 and subjects in Part 2 will be non-randomized and unblinded.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Number of participants with treatment-related and other adverse events as assessed by the Division of Microbiology and Infectious Disease (DMID) Toxicity Table</measure>
    <time_frame>Day 1 - Day 4 Post Dose</time_frame>
    <description>Safety assessments will include physical and detailed neurological examinations (including assessments of mental status, cranial nerves, motor system, sensory system, reflexes, coordination and gait), vital signs including heart rate and respiratory rate, ECGs, cardiac monitor (Holter monitoring starting 24 hours prior to dose and continuing for 48 hours post dose), collection of all AEs (including treatment- related AEs and SAEs) and clinical laboratory tests (including hematology, serum chemistry, coagulation, and urinalysis prior to dosing and at protocol defined time points up to 72 hours post dose). Subjects will be called 11 days post dose to query for AEs.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Noncompartmental pharmacokinetic parameters of TBI-223 and its metabolite M2 after single doses of TBI-223 using AUClast</measure>
    <time_frame>Day 1 - Day 2</time_frame>
    <description>AUClast will be calculated from plasma concentrations of TBI-223 and M2. AUClast is area under the concentration-time curve from time-zero to the time of the last quantifiable concentration; calculated using the linear trapezoidal rule.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Noncompartmental pharmacokinetic parameters of TBI-223 and its metabolite M2 after single doses of TBI-223 using AUCinf</measure>
    <time_frame>Day 1 - Day 2</time_frame>
    <description>AUCinf will be calculated from plasma concentrations of TBI-223 and M2. AUCinf is area under the concentration-time curve from time-zero extrapolated to infinity.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Noncompartmental pharmacokinetic parameters of TBI-223 and its metabolite M2 after single doses of TBI-223 using Cmax</measure>
    <time_frame>Day 1 - Day 2</time_frame>
    <description>Cmax will be calculated from plasma concentrations of TBI-223 and M2. Cmax is maximum concentration, determined directly from individual concentration-time data.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Noncompartmental pharmacokinetic parameters of TBI-223 and its metabolite M2 after single doses of TBI-223 using Tmax</measure>
    <time_frame>Day 1 - Day 2</time_frame>
    <description>Tmax will be calculated from plasma concentrations of TBI-223 and M2. Tmax is time of the maximum concentration.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Noncompartmental pharmacokinetic parameters of TBI-223 after single doses of TBI-223 using CL/F</measure>
    <time_frame>Day 1 - Day 2</time_frame>
    <description>CL/F will be calculated from plasma concentrations of TBI-223 only. CL/F is apparent total clearance after single administration.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Noncompartmental pharmacokinetic parameters of TBI-223 after single doses of TBI-223 using Vz/F</measure>
    <time_frame>Day 1 - Day 2</time_frame>
    <description>Vz/F will be calculated from plasma concentrations of TBI-223 only. Vz/F is apparent volume of distribution in the terminal phase.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Noncompartmental pharmacokinetic parameters of TBI-223 and its metabolite M2 after single doses of TBI-223 using λz</measure>
    <time_frame>Day 1 - Day 2</time_frame>
    <description>λz will be calculated from plasma concentrations of TBI-223 and M2. λz is the observed terminal rate constant; estimated by linear regression through at least three data points in the terminal phase of the log concentration-time profile.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Noncompartmental pharmacokinetic parameters of TBI-223 and its metabolite M2 after single doses of TBI-223 using T1/2</measure>
    <time_frame>Day 1 - Day 2</time_frame>
    <description>T1/2 will be calculated from plasma concentrations of TBI-223 and M2. T½ or t½ is the observed terminal half-life.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Compare the rate and extent of absorption of a single dose of TBI-223 using AUClast, when administered after a high-calorie, high-fat meal versus in fasting state in healthy adult subjects</measure>
    <time_frame>Day 1 - Day 2</time_frame>
    <description>AUClast will be calculated from plasma concentrations of TBI-223 and M2 with and without high-fat meal. AUClast is area under the concentration-time curve from time-zero to the time of the last quantifiable concentration; calculated using the linear trapezoidal rule.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Compare the rate and extent of absorption of a single dose of TBI-223 using AUCinf, when administered after a high-calorie, high-fat meal versus in fasting state in healthy adult subjects</measure>
    <time_frame>Day 1 - Day 2</time_frame>
    <description>AUCinf will be calculated from plasma concentrations of TBI-223 and M2 with and without high-fat meal. AUCinf is area under the concentration-time curve from time-zero extrapolated to infinity.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Compare the rate and extent of absorption of a single dose of TBI-223 using Cmax, when administered after a high-calorie, high-fat meal versus in fasting state in healthy adult subjects</measure>
    <time_frame>Day 1 - Day 2</time_frame>
    <description>Cmax will be calculated from plasma concentrations of TBI-223 and M2 with and without high-fat meal. Cmax is maximum concentration, determined directly from individual concentration-time data.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Compare the rate and extent of absorption of a single dose of TBI-223 using Tmax, when administered after a high-calorie, high-fat meal versus in fasting state in healthy adult subjects</measure>
    <time_frame>Day 1 - Day 2</time_frame>
    <description>Tmax will be calculated from plasma concentrations of TBI-223 and M2 with and without high-fat meal. Tmax is time of the maximum concentration.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Compare the rate and extent of absorption of a single dose of TBI-223 using CL/F, when administered after a high-calorie, high-fat meal versus in fasting state in healthy adult subjects</measure>
    <time_frame>Day 1 - Day 2</time_frame>
    <description>CL/F will be calculated from plasma concentrations of TBI-223 and M2 with and without high-fat meal. CL/F is apparent total clearance after single administration.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Compare the rate and extent of absorption of a single dose of TBI-223 using Vz/F, when administered after a high-calorie, high-fat meal versus in fasting state in healthy adult subjects</measure>
    <time_frame>Day 1 - Day 2</time_frame>
    <description>Vz/F will be calculated from plasma concentrations of TBI-223 and M2 with and without high-fat meal. Vz/F is apparent volume of distribution in the terminal phase.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Compare the rate and extent of absorption of a single dose of TBI-223 using λz, when administered after a high-calorie, high-fat meal versus in fasting state in healthy adult subjects</measure>
    <time_frame>Day 1 - Day 2</time_frame>
    <description>λz will be calculated from plasma concentrations of TBI-223 and M2 with and without high-fat meal. λz is the observed terminal rate constant; estimated by linear regression through at least three data points in the terminal phase of the log concentration-time profile.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Compare the rate and extent of absorption of a single dose of TBI-223 using T1/2, when administered after a high-calorie, high-fat meal versus in fasting state in healthy adult subjects</measure>
    <time_frame>Day 1 - Day 2</time_frame>
    <description>T1/2 will be calculated from plasma concentrations of TBI-223 and M2 with and without high-fat meal. T½ or t½ is the observed terminal half-life.</description>
  </secondary_outcome>
  <number_of_arms>13</number_of_arms>
  <enrollment type="Actual">91</enrollment>
  <condition>Tuberculosis</condition>
  <condition>Tuberculosis, Pulmonary</condition>
  <arm_group>
    <arm_group_label>Cohort 1 (sentinel group) - Active</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Single dose of TBI-223 50 mg (n=2) dosed at least 24 hours before the Cohort 1 (remainder of cohort).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 1 (sentinel group) - Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Single dose of Placebo for TBI-223 50 mg (n=1) dosed at least 24 hours before the Cohort 1 (remainder of cohort).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 1 (remainder of cohort) - Active</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Single dose of TBI-223 50 mg (n=4).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 1 (remainder of cohort) - Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Single dose of Placebo for TBI-223 50 mg (n=1).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 2 - Cohort 7 - Active</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Single dose of TBI-223 100, 300, 600, 1200, 2000, 2600 mg; n=3 per dosing group.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 2 - Cohort 7 - Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Single dose of matching Placebo for TBI-223 100, 300, 600, 1200, 2000, 2600 mg, n=1 per dosing group.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 3b - Active - Oral Capsule</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Single dose of 300 mg in oral enteric capsule, n=4 per dosing group.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 3b - Placebo - Oral Capsule</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Single dose of placebo for 300 mg in oral enteric capsule, n=1 per dosing group.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 8 - Prototype Tablet 1</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Single dose of TBI-223 sustained-release (SR) tablet prototype 1, 3 x 600 mg, n=6 per cohort.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 8 - Prototype Tablet 2</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Single dose of TBI-223 SR tablet prototype 2, 3 x 600 mg, n=6 per cohort.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 8 - Prototype Tablet 3</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Single dose of TBI-223 SR tablet prototype 3, 2 x 900 mg, n=6 per cohort.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 8 - IR Tablet fasted</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Single dose of TBI-223 immediate-release (IR) tablet prototype 4, 2 x 1000 mg, n=6 per cohort; fasted prior to dose.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 9 - IR Tablet with meal</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Single dose of TBI-223 immediate-release (IR) tablet, 2 x 1000 mg, n=6 per cohort; fed prior to dose.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>TBI-223 50mg</intervention_name>
    <description>TBI-223 50 mg supplied for oral administration.</description>
    <arm_group_label>Cohort 1 (remainder of cohort) - Active</arm_group_label>
    <arm_group_label>Cohort 1 (sentinel group) - Active</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo for TBI-223 50mg</intervention_name>
    <description>Matching placebo for TBI-223 50mg supplied for oral administration.</description>
    <arm_group_label>Cohort 1 (remainder of cohort) - Placebo</arm_group_label>
    <arm_group_label>Cohort 1 (sentinel group) - Placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>TBI-223 100, 300, 600, 1200, 2000, 2600 mg</intervention_name>
    <description>TBI-223 100, 300, 600, 1200, 2000, 2600 mg supplied for oral administration.</description>
    <arm_group_label>Cohort 2 - Cohort 7 - Active</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo for TBI-223 100, 300, 600, 1200, 2000, 2600 mg</intervention_name>
    <description>Matching placebo for 100, 300, 600, 1200, 2000, 2600 mg TBI-223 supplied for oral administration.</description>
    <arm_group_label>Cohort 2 - Cohort 7 - Placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>TBI-223 300 mg capsule</intervention_name>
    <description>TBI-223 300 mg capsule supplied for oral administration</description>
    <arm_group_label>Cohort 3b - Active - Oral Capsule</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo for TBI-223 300 mg capsule</intervention_name>
    <description>Placebo for TBI-223 300 mg capsule supplied for oral administration</description>
    <arm_group_label>Cohort 3b - Placebo - Oral Capsule</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>TBI-223 Prototype 1 SR Tablet</intervention_name>
    <description>Prototype 1 TBI-223 600 mg sustained-release (SR) tablet</description>
    <arm_group_label>Cohort 8 - Prototype Tablet 1</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>TBI-223 Prototype 2 SR Tablet</intervention_name>
    <description>Prototype 2 TBI-223 600 mg SR tablet</description>
    <arm_group_label>Cohort 8 - Prototype Tablet 2</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>TBI-223 Prototype 3 SR Tablet</intervention_name>
    <description>Prototype 3 TBI-223 900 mg SR tablet</description>
    <arm_group_label>Cohort 8 - Prototype Tablet 3</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>TBI-223 IR Tablet</intervention_name>
    <description>TBI-223 1000 mg immediate release (IR) tablet</description>
    <arm_group_label>Cohort 8 - IR Tablet fasted</arm_group_label>
    <arm_group_label>Cohort 9 - IR Tablet with meal</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        All volunteers must satisfy the following criteria to be considered for study&#xD;
        participation:&#xD;
&#xD;
          1. Understands study procedures and voluntarily provides written informed consent prior&#xD;
             to the start of any study-specific procedures.&#xD;
&#xD;
          2. Is a healthy adult male or a healthy adult female of non-childbearing potential, 19 to&#xD;
             50 years of age (inclusive) at the time of screening.&#xD;
&#xD;
          3. Has a body mass index (BMI) ≥18.5 and ≤32.0 (kg/m2) and a body weight of no less than&#xD;
             50.0 kg.&#xD;
&#xD;
          4. Is medically healthy with no clinically significant screening results, as determined&#xD;
             by the Principal Investigator (e.g., laboratory profiles are normal up to and&#xD;
             including Grade 1 per DMID toxicity tables; Appendix 3), medical history, vital signs,&#xD;
             ECG, or physical/neurological examination findings. Note: If exclusionary lab criteria&#xD;
             are met, values may be confirmed by repeat evaluation.&#xD;
&#xD;
          5. Has not used tobacco- or nicotine-containing products (including smoking cessation&#xD;
             products), for a minimum of 6 months before dosing.&#xD;
&#xD;
          6. If female, she has undergone one of the following sterilization procedures at least 6&#xD;
             months before dosing:&#xD;
&#xD;
               -  Hysteroscopic sterilization;&#xD;
&#xD;
               -  Bilateral tubal ligation or bilateral salpingectomy;&#xD;
&#xD;
               -  Hysterectomy; or&#xD;
&#xD;
               -  Bilateral oophorectomy;&#xD;
&#xD;
               -  Or is postmenopausal with amenorrhea for at least 1 year before the first dose&#xD;
                  with serum follicle-stimulating hormone (FSH) levels consistent with&#xD;
                  postmenopausal status (i.e., greater than 40 mIU/mL) at screening.&#xD;
&#xD;
               -  Or, if female of childbearing potential, must agree to use an allowable form of&#xD;
                  birth control from screening until 14 days after study completion. The following&#xD;
                  are allowed birth control methods for this study:&#xD;
&#xD;
               -  Vasectomized partner (at least 6 months before dosing);&#xD;
&#xD;
               -  Non-surgical permanent sterilization (e.g., Essure procedure) at least 3 months&#xD;
                  before dosing;&#xD;
&#xD;
               -  Double barrier method (e.g., diaphragm with spermicide; condoms with spermicide);&#xD;
&#xD;
               -  Intrauterine device (IUD);&#xD;
&#xD;
               -  Abstinence (and must agree to use a double barrier method if they become sexually&#xD;
                  active during the study);&#xD;
&#xD;
               -  Implanted or intrauterine hormonal contraceptives in use for at least 6&#xD;
                  consecutive months before study dosing; and/or&#xD;
&#xD;
               -  Oral, patch, or injected contraceptives, or vaginal hormonal device (NuvaRing),&#xD;
                  in use for at least 3 consecutive months before study dosing.&#xD;
&#xD;
          7. If a non-vasectomized male (or male vasectomized less than 120 days prior to study&#xD;
             start) he must agree to the following during study participation and for 90 days after&#xD;
             the last administration of study drug:&#xD;
&#xD;
               -  Use a condom with spermicide while engaging in sexual activity or be sexually&#xD;
                  abstinent,&#xD;
&#xD;
               -  Not donate sperm during this time. In the event the sexual partner is surgically&#xD;
                  sterile or postmenopausal, use of a condom with spermicide is not necessary. None&#xD;
                  of the birth control restrictions listed above are required for vasectomized&#xD;
                  males whose procedure was performed more than 120 days before study start.&#xD;
&#xD;
          8. Is willing to answer inclusion and exclusion criteria questionnaire at check-in.&#xD;
&#xD;
          9. Is able to comply with the protocol and the assessments therein, including all&#xD;
             restrictions.&#xD;
&#xD;
         10. Is willing and able to remain in the study unit for the entire duration of the&#xD;
             assigned confinement period(s), return for outpatient visit(s), and receive a phone&#xD;
             call for follow-up questioning about AEs.&#xD;
&#xD;
         11. If enrolled in the food-effect cohort, is willing and able to consume the entire&#xD;
             high-calorie, high-fat breakfast meal in the timeframe required.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Volunteers will be excluded from study participation for any of the following:&#xD;
&#xD;
          1. History or presence of clinically significant cardiovascular, pulmonary, hepatic,&#xD;
             renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic,&#xD;
             neurological (including epilepsy), oncologic, or psychiatric disease or any other&#xD;
             condition that, in the opinion of the Investigator, would jeopardize the safety of the&#xD;
             subject or the validity of the study results.&#xD;
&#xD;
          2. Evidence on physical exam and targeted neurologic exam of specific findings such as&#xD;
             resting or intention tremor, dysmetria, nystagmus or ataxia, or abnormal deep tendon&#xD;
             reflexes (either zero or hyper-reflexia).&#xD;
&#xD;
          3. History of any illness that, in the opinion of the Investigator, might confound the&#xD;
             results of the study or pose an additional risk to the subject by their participation&#xD;
             in the study.&#xD;
&#xD;
          4. Surgery within the past 90 days prior to dosing as determined by the Investigator to&#xD;
             be clinically relevant, or any history of cholecystectomy.&#xD;
&#xD;
          5. History or presence of alcoholism or drug abuse within the past 2 years as determined&#xD;
             by the Investigator to be clinically relevant.&#xD;
&#xD;
          6. History of sensitivity or contraindication to use of linezolid, sulfa drugs, or any&#xD;
             study investigational products.&#xD;
&#xD;
          7. Participation in another clinical trial within 30 days prior to dosing.&#xD;
&#xD;
          8. Female subjects who are pregnant or lactating.&#xD;
&#xD;
          9. Positive result on a urine drug/alcohol/cotinine screen at Baseline or check-in.&#xD;
&#xD;
         10. Seated blood pressure is less than 90/40 mmHg or greater than 140/90 mmHg at&#xD;
             screening. Out-of-range vital signs may be repeated once for confirmation.&#xD;
&#xD;
         11. Seated heart rate is lower than 40 bpm or higher than 99 bpm at screening.&#xD;
             Out-of-range vital signs may be repeated once for confirmation.&#xD;
&#xD;
         12. Any clinically significant ECG abnormality at Screening (as deemed by decision of the&#xD;
             Investigator and the Sponsor's Medical Monitor). NOTE: The following may be considered&#xD;
             not clinically significant without consulting the Sponsor's Medical Monitor:&#xD;
&#xD;
               -  Mild first degree A-V block (P-R interval &lt;0.23 sec)&#xD;
&#xD;
               -  Right or left axis deviation&#xD;
&#xD;
               -  Incomplete right bundle branch block&#xD;
&#xD;
               -  Isolated left anterior fascicular block (left anterior hemiblock) in younger&#xD;
                  athletic subjects&#xD;
&#xD;
               -  Early repolarization&#xD;
&#xD;
               -  Tall T waves&#xD;
&#xD;
               -  RSR in V1/V2 consistent with right ventricular conduction delay (with acceptable&#xD;
                  QRS)&#xD;
&#xD;
               -  Sinus rhythm or sinus bradycardia with sinus arrhythmia&#xD;
&#xD;
               -  Minimal or moderate voltage criteria for left ventricular hypertrophy (LVH).&#xD;
&#xD;
         13. QTcF interval &gt;450 msec for males or &gt;470 msec for females at screening, Day -1, or&#xD;
             Day 1 (pre-dose), or history of prolonged QT syndrome. For the triplicate ECGs taken&#xD;
             at screening and on Day -1, the average QTcF interval of the three ECG recordings will&#xD;
             be used to determine qualification.&#xD;
&#xD;
         14. Family history of long-QT syndrome or sudden death without a preceding diagnosis of a&#xD;
             condition that could be causative of sudden death (such as known coronary artery&#xD;
             disease, congestive heart failure, or terminal cancer).&#xD;
&#xD;
         15. History of one or any combination of, the following:&#xD;
&#xD;
               -  Seizures or seizure disorders, other than childhood febrile seizures&#xD;
&#xD;
               -  Brain surgery&#xD;
&#xD;
               -  History of head injury in the last 5 years&#xD;
&#xD;
               -  Any serious disorder of the central nervous system (CNS) or related neurological&#xD;
                  system, particularly one that may lower the seizure threshold.&#xD;
&#xD;
         16. Lactose intolerant.&#xD;
&#xD;
         17. History or presence of allergic or adverse response to Listerine breath strips or&#xD;
             aspartame.&#xD;
&#xD;
             Specific Treatments&#xD;
&#xD;
         18. Use of any prescription medication within 14 days prior to dosing.&#xD;
&#xD;
         19. Use of any of the following medications within 30 days before the first dose of study&#xD;
             drug or during the study drug treatment period: monoamine oxidase (MAO) inhibitors&#xD;
             (phenelzine, tranylcypromine), tricyclic antidepressants (amitriptyline,&#xD;
             nortriptyline, protriptyline, doxepin, amoxapine, etc.), antipsychotics such as&#xD;
             chlorpromazine and buspirone, serotonin re-uptake inhibitors (fluoxetine, paroxetine,&#xD;
             sertraline, etc.), bupropion, agents known to prolong the QTc interval (erythromycin,&#xD;
             clarithromycin, astemizole, type Ia [quinidine, procainamide, disopyramide] and III&#xD;
             [amiodarone, sotalol] anti-arrhythmics, carbamazepine, sulfonylureas, and meperidine).&#xD;
&#xD;
         20. Use of any over-the-counter (OTC) medication, including herbal products and vitamins,&#xD;
             within 7 days prior to dosing, except acetaminophen. Up to 3 grams per day of&#xD;
             acetaminophen is allowed at the discretion of the Investigator prior to dosing.&#xD;
&#xD;
         21. Use of any drugs or substances known to be significant inhibitors of cytochrome P450&#xD;
             (CYP) enzymes and/or significant inhibitors or substrates of P-glycoprotein (P-gp)&#xD;
             and/or organic anion transporting polypeptides (OATP) within 14 days prior to the&#xD;
             first dose of study drug.&#xD;
&#xD;
         22. Use of any drugs or substances known to be inducers of CYP enzymes and/or Pgp,&#xD;
             including St. John's Wort, within 30 days prior to the first dose of study drug.&#xD;
&#xD;
         23. Use of any drugs or substance known to lower the seizure threshold. Laboratory&#xD;
             Abnormalities&#xD;
&#xD;
         24. Serum magnesium, potassium, or calcium laboratory values outside of the normal range&#xD;
             at screening. If exclusionary lab criteria are met, values may be confirmed by repeat&#xD;
             evaluation.&#xD;
&#xD;
         25. Positive results at screening for human immunodeficiency virus (HIV), hepatitis B&#xD;
             surface antigen (HBsAg), or hepatitis C antibodies (HCV).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>19 Years</minimum_age>
    <maximum_age>50 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Paul Bruinenberg, MD, MBA</last_name>
    <role>Study Chair</role>
    <affiliation>Global Alliance for TB Drug Development</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Worldwide Clinical Trials (WCT)</name>
      <address>
        <city>San Antonio</city>
        <state>Texas</state>
        <zip>78217</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2021</verification_date>
  <study_first_submitted>November 20, 2018</study_first_submitted>
  <study_first_submitted_qc>November 28, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 29, 2018</study_first_posted>
  <last_update_submitted>September 2, 2021</last_update_submitted>
  <last_update_submitted_qc>September 2, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">September 5, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>TB</keyword>
  <keyword>Tuberculosis</keyword>
  <keyword>TBI-223</keyword>
  <keyword>Pulmonary Tuberculosis</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tuberculosis</mesh_term>
    <mesh_term>Tuberculosis, Pulmonary</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03758612
org study id: TBI-223-CL-001
nct id: NCT03758612
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
masking description: This study is partially blinded. The repeat cohort (3b) using a different dosage formulation in Part 1 and subjects in Part 2 will be non-randomized and unblinded.
measure: Number of participants with treatment-related and other adverse events as assessed by the Division of Microbiology and Infectious Disease (DMID) Toxicity Table
time frame: Day 1 - Day 4 Post Dose
description: Safety assessments will include physical and detailed neurological examinations (including assessments of mental status, cranial nerves, motor system, sensory system, reflexes, coordination and gait), vital signs including heart rate and respiratory rate, ECGs, cardiac monitor (Holter monitoring starting 24 hours prior to dose and continuing for 48 hours post dose), collection of all AEs (including treatment- related AEs and SAEs) and clinical laboratory tests (including hematology, serum chemistry, coagulation, and urinalysis prior to dosing and at protocol defined time points up to 72 hours post dose). Subjects will be called 11 days post dose to query for AEs.
measure: Noncompartmental pharmacokinetic parameters of TBI-223 and its metabolite M2 after single doses of TBI-223 using AUClast
time frame: Day 1 - Day 2
description: AUClast will be calculated from plasma concentrations of TBI-223 and M2. AUClast is area under the concentration-time curve from time-zero to the time of the last quantifiable concentration; calculated using the linear trapezoidal rule.
measure: Noncompartmental pharmacokinetic parameters of TBI-223 and its metabolite M2 after single doses of TBI-223 using AUCinf
time frame: Day 1 - Day 2
description: AUCinf will be calculated from plasma concentrations of TBI-223 and M2. AUCinf is area under the concentration-time curve from time-zero extrapolated to infinity.
measure: Noncompartmental pharmacokinetic parameters of TBI-223 and its metabolite M2 after single doses of TBI-223 using Cmax
time frame: Day 1 - Day 2
description: Cmax will be calculated from plasma concentrations of TBI-223 and M2. Cmax is maximum concentration, determined directly from individual concentration-time data.
measure: Noncompartmental pharmacokinetic parameters of TBI-223 and its metabolite M2 after single doses of TBI-223 using Tmax
time frame: Day 1 - Day 2
description: Tmax will be calculated from plasma concentrations of TBI-223 and M2. Tmax is time of the maximum concentration.
measure: Noncompartmental pharmacokinetic parameters of TBI-223 after single doses of TBI-223 using CL/F
time frame: Day 1 - Day 2
description: CL/F will be calculated from plasma concentrations of TBI-223 only. CL/F is apparent total clearance after single administration.
measure: Noncompartmental pharmacokinetic parameters of TBI-223 after single doses of TBI-223 using Vz/F
time frame: Day 1 - Day 2
description: Vz/F will be calculated from plasma concentrations of TBI-223 only. Vz/F is apparent volume of distribution in the terminal phase.
measure: Noncompartmental pharmacokinetic parameters of TBI-223 and its metabolite M2 after single doses of TBI-223 using λz
time frame: Day 1 - Day 2
description: λz will be calculated from plasma concentrations of TBI-223 and M2. λz is the observed terminal rate constant; estimated by linear regression through at least three data points in the terminal phase of the log concentration-time profile.
measure: Noncompartmental pharmacokinetic parameters of TBI-223 and its metabolite M2 after single doses of TBI-223 using T1/2
time frame: Day 1 - Day 2
description: T1/2 will be calculated from plasma concentrations of TBI-223 and M2. T½ or t½ is the observed terminal half-life.
measure: Compare the rate and extent of absorption of a single dose of TBI-223 using AUClast, when administered after a high-calorie, high-fat meal versus in fasting state in healthy adult subjects
time frame: Day 1 - Day 2
description: AUClast will be calculated from plasma concentrations of TBI-223 and M2 with and without high-fat meal. AUClast is area under the concentration-time curve from time-zero to the time of the last quantifiable concentration; calculated using the linear trapezoidal rule.
measure: Compare the rate and extent of absorption of a single dose of TBI-223 using AUCinf, when administered after a high-calorie, high-fat meal versus in fasting state in healthy adult subjects
time frame: Day 1 - Day 2
description: AUCinf will be calculated from plasma concentrations of TBI-223 and M2 with and without high-fat meal. AUCinf is area under the concentration-time curve from time-zero extrapolated to infinity.
measure: Compare the rate and extent of absorption of a single dose of TBI-223 using Cmax, when administered after a high-calorie, high-fat meal versus in fasting state in healthy adult subjects
time frame: Day 1 - Day 2
description: Cmax will be calculated from plasma concentrations of TBI-223 and M2 with and without high-fat meal. Cmax is maximum concentration, determined directly from individual concentration-time data.
measure: Compare the rate and extent of absorption of a single dose of TBI-223 using Tmax, when administered after a high-calorie, high-fat meal versus in fasting state in healthy adult subjects
time frame: Day 1 - Day 2
description: Tmax will be calculated from plasma concentrations of TBI-223 and M2 with and without high-fat meal. Tmax is time of the maximum concentration.
measure: Compare the rate and extent of absorption of a single dose of TBI-223 using CL/F, when administered after a high-calorie, high-fat meal versus in fasting state in healthy adult subjects
time frame: Day 1 - Day 2
description: CL/F will be calculated from plasma concentrations of TBI-223 and M2 with and without high-fat meal. CL/F is apparent total clearance after single administration.
measure: Compare the rate and extent of absorption of a single dose of TBI-223 using Vz/F, when administered after a high-calorie, high-fat meal versus in fasting state in healthy adult subjects
time frame: Day 1 - Day 2
description: Vz/F will be calculated from plasma concentrations of TBI-223 and M2 with and without high-fat meal. Vz/F is apparent volume of distribution in the terminal phase.
measure: Compare the rate and extent of absorption of a single dose of TBI-223 using λz, when administered after a high-calorie, high-fat meal versus in fasting state in healthy adult subjects
time frame: Day 1 - Day 2
description: λz will be calculated from plasma concentrations of TBI-223 and M2 with and without high-fat meal. λz is the observed terminal rate constant; estimated by linear regression through at least three data points in the terminal phase of the log concentration-time profile.
measure: Compare the rate and extent of absorption of a single dose of TBI-223 using T1/2, when administered after a high-calorie, high-fat meal versus in fasting state in healthy adult subjects
time frame: Day 1 - Day 2
description: T1/2 will be calculated from plasma concentrations of TBI-223 and M2 with and without high-fat meal. T½ or t½ is the observed terminal half-life.
arm group label: Cohort 1 (sentinel group) - Active
arm group type: Active Comparator
description: Single dose of TBI-223 50 mg (n=2) dosed at least 24 hours before the Cohort 1 (remainder of cohort).
arm group label: Cohort 1 (sentinel group) - Placebo
arm group type: Placebo Comparator
description: Single dose of Placebo for TBI-223 50 mg (n=1) dosed at least 24 hours before the Cohort 1 (remainder of cohort).
arm group label: Cohort 1 (remainder of cohort) - Active
arm group type: Active Comparator
description: Single dose of TBI-223 50 mg (n=4).
arm group label: Cohort 1 (remainder of cohort) - Placebo
arm group type: Placebo Comparator
description: Single dose of Placebo for TBI-223 50 mg (n=1).
arm group label: Cohort 2 - Cohort 7 - Active
arm group type: Active Comparator
description: Single dose of TBI-223 100, 300, 600, 1200, 2000, 2600 mg; n=3 per dosing group.
arm group label: Cohort 2 - Cohort 7 - Placebo
arm group type: Placebo Comparator
description: Single dose of matching Placebo for TBI-223 100, 300, 600, 1200, 2000, 2600 mg, n=1 per dosing group.
arm group label: Cohort 3b - Active - Oral Capsule
arm group type: Active Comparator
description: Single dose of 300 mg in oral enteric capsule, n=4 per dosing group.
arm group label: Cohort 3b - Placebo - Oral Capsule
arm group type: Placebo Comparator
description: Single dose of placebo for 300 mg in oral enteric capsule, n=1 per dosing group.
arm group label: Cohort 8 - Prototype Tablet 1
arm group type: Active Comparator
description: Single dose of TBI-223 sustained-release (SR) tablet prototype 1, 3 x 600 mg, n=6 per cohort.
arm group label: Cohort 8 - Prototype Tablet 2
arm group type: Active Comparator
description: Single dose of TBI-223 SR tablet prototype 2, 3 x 600 mg, n=6 per cohort.
arm group label: Cohort 8 - Prototype Tablet 3
arm group type: Active Comparator
description: Single dose of TBI-223 SR tablet prototype 3, 2 x 900 mg, n=6 per cohort.
arm group label: Cohort 8 - IR Tablet fasted
arm group type: Active Comparator
description: Single dose of TBI-223 immediate-release (IR) tablet prototype 4, 2 x 1000 mg, n=6 per cohort; fasted prior to dose.
arm group label: Cohort 9 - IR Tablet with meal
arm group type: Active Comparator
description: Single dose of TBI-223 immediate-release (IR) tablet, 2 x 1000 mg, n=6 per cohort; fed prior to dose.
intervention type: Drug
intervention name: TBI-223 50mg
description: TBI-223 50 mg supplied for oral administration.
arm group label: Cohort 1 (remainder of cohort) - Active
arm group label: Cohort 1 (sentinel group) - Active
intervention type: Drug
intervention name: Placebo for TBI-223 50mg
description: Matching placebo for TBI-223 50mg supplied for oral administration.
arm group label: Cohort 1 (remainder of cohort) - Placebo
arm group label: Cohort 1 (sentinel group) - Placebo
intervention type: Drug
intervention name: TBI-223 100, 300, 600, 1200, 2000, 2600 mg
description: TBI-223 100, 300, 600, 1200, 2000, 2600 mg supplied for oral administration.
arm group label: Cohort 2 - Cohort 7 - Active
intervention type: Drug
intervention name: Placebo for TBI-223 100, 300, 600, 1200, 2000, 2600 mg
description: Matching placebo for 100, 300, 600, 1200, 2000, 2600 mg TBI-223 supplied for oral administration.
arm group label: Cohort 2 - Cohort 7 - Placebo
intervention type: Drug
intervention name: TBI-223 300 mg capsule
description: TBI-223 300 mg capsule supplied for oral administration
arm group label: Cohort 3b - Active - Oral Capsule
intervention type: Drug
intervention name: Placebo for TBI-223 300 mg capsule
description: Placebo for TBI-223 300 mg capsule supplied for oral administration
arm group label: Cohort 3b - Placebo - Oral Capsule
intervention type: Drug
intervention name: TBI-223 Prototype 1 SR Tablet
description: Prototype 1 TBI-223 600 mg sustained-release (SR) tablet
arm group label: Cohort 8 - Prototype Tablet 1
intervention type: Drug
intervention name: TBI-223 Prototype 2 SR Tablet
description: Prototype 2 TBI-223 600 mg SR tablet
arm group label: Cohort 8 - Prototype Tablet 2
intervention type: Drug
intervention name: TBI-223 Prototype 3 SR Tablet
description: Prototype 3 TBI-223 900 mg SR tablet
arm group label: Cohort 8 - Prototype Tablet 3
intervention type: Drug
intervention name: TBI-223 IR Tablet
description: TBI-223 1000 mg immediate release (IR) tablet
arm group label: Cohort 8 - IR Tablet fasted
arm group label: Cohort 9 - IR Tablet with meal
criteria: 
gender: All
minimum age: 19 Years
maximum age: 50 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Paul Bruinenberg, MD, MBA
role: Study Chair
affiliation: Global Alliance for TB Drug Development
facility: 
country: United States
responsible party type: Sponsor
mesh term: Tuberculosis
mesh term: Tuberculosis, Pulmonary