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

Global Alliance for TB Drug Development86 enrolled

Overview

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.

This study was a partially-blinded, placebo-controlled, randomized SAD study conducted at one study center. The primary objective of the study was to evaluate the safety and tolerability of single doses of TBI-223 oral suspension, TBI-223 oral enteric capsules, and TBI-223 tablet formulations in healthy adult subjects. The secondary objectives of the study were to determine the PK of TBI-223 and its metabolite M2 after single doses of TBI-223 oral suspension, TBI-223 oral enteric capsules, and TBI-223 tablet formulations in healthy adult subjects, and to compare the rate and extent of absorption of a single dose of TBI-223 oral suspension and TBI-223 tablet formulations when administered in healthy adult subjects either after a high-calorie, high-fat meal or in the fasting state. Safety was assessed throughout the study for all subjects. Safety assessments included physical examinations, vital signs, serial ECGs, cardiac monitoring, adverse events (AEs), and clinical laboratory tests (including hematology, serum chemistry, coagulation, and urinalysis).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

Conditions

Tuberculosis Tuberculosis, Pulmonary

Interventions

TBI-223 oral suspensionDRUG

TBI-223 oral suspension, orally administered.

TBI-223 enteric capsuleDRUG

TBI-223 enteric capsules filled with 150 mg of TBI-223 powder, orally administered.

TBI-223 SR Tablet Prototype 1DRUG

TBI-223 600 mg sustained-release (SR) tablet Prototype 1, orally administered.

Eligibility

Sex: ALLMin age: 19 YearsMax age: 50 YearsHealthy volunteers:

Medical Language ↔ Plain English

Key Inclusion Criteria: All volunteers must satisfy the following criteria to be considered for study participation: 1. Is a healthy adult male or female, 19 to 50 years of age (inclusive) at the time of screening. 2. Has a body mass index (BMI) ≥18.5 and ≤32.0 (kg/m2) and a body weight of no less than 50.0 kg. 3. Is medically healthy with no clinically significant screening results (e.g., laboratory profiles normal or up to Grade 1 per Division of Microbiology and Infectious Diseases Toxicity Tables), as deemed by the Investigator. 4. Has not used tobacco- or nicotine-containing products (including smoking cessation products), for a minimum of 6 months before dosing. 5. If assigned to receive study drug under fed conditions, is willing and able to consume the entire high-calorie, high-fat breakfast meal in the timeframe required. Key Exclusion Criteria: 1. History or presence of clinically significant cardiovascular (heart murmur), pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, psychiatric disease or any other condition that, in the opinion of the Investigator, would jeopardize the safety of the subject or the validity of the study results. 2. Any presence of musculoskeletal toxicity (severe tenderness with marked impairment of activity, or frank necrosis). 3. Has a positive test for hepatitis B surface antigen, hepatitis C antibody, or HIV at screening. 4. QTcF interval \>450 msec for males or \>470 msec for females at screening, Day -1, or Day 1 (predose), or history of prolonged QT syndrome. For the triplicate 12-lead ECGs taken at screening and on Day -1, the average QTcF interval of the three 12-lead ECG recordings were used to determine qualification. 5. Family history of long-QT syndrome or sudden death without a preceding diagnosis of a condition that was causative of sudden death (such as known coronary artery disease, congestive heart failure, or terminal cancer). 6. History of any of the following: * Serotonin syndrome * Seizures or seizure disorders, other than childhood febrile seizures * Brain surgery * History of head injury in the last 5 years * Any serious disorder of the nervous system particularly one that lowered the seizure threshold. 7. Lactose intolerant. 8. History of sensitivity or contraindication to use of linezolid, tedizolid, or any study investigational products

Locations (1)

Worldwide Clinical Trials (WCT)

San Antonio, Texas, United States

Outcomes

Primary Outcomes

Number of Participants With Treatment-related Adverse Events

A treatment-related adverse event (AE) is defined for this study as any AE classified as possibly, probably or certainly related to the study drug. Adverse events (AEs) for participants who received at least one dose of study treatment were collected from the signing of informed consent till the end of study visit. An Investigator reviewed each AE collected and assessed its relationship to drug treatment based on all available information at the time of the completion of the study.

Time frame: Day 1 - Day 11

Secondary Outcomes

Area Under the Plasma Concentration-time- Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf)

AUC0-inf will be calculated from plasma concentrations of TBI-223 AND M2 and calculated as AUC0-inf = AUC0-t + Clast/λz, where λz is the apparent terminal elimination rate constant calculated by linear regression of the terminal linear portion of the log concentration versus time curve

Time frame: predose (0 hour) and at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 30, 36, 42, 48, and 72 hours after administration of the investigational product

AUC0-t

AUC0-t will be calculated from plasma concentrations of TBI-223. Area under the plasma concentration-time curve from time-zero to the time of the last quantifiable concentration (Clast), as calculated by the linear trapezoidal rule.

Time frame: predose (0 hour) and at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 30, 36, 42, 48, and 72 hours after administration of the investigational product

Maximum Plasma Concentration, Determined Directly From Individual Concentration-time- Data (Cmax)

Cmax will be calculated from plasma concentrations of TBI-223. Cmax is calculated as the maximum plasma concentration, determined directly from individual concentration-time- data

Time frame: predose (0 hour) and at 0.5, 1.0, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 30, 36, 42, 48, and 72 hours after administration of the investigational product

Data from ClinicalTrials.gov

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