A Phase 1, Partially-Blinded, Placebo-Controlled, Randomized, Multiple Ascending Dose Study to Include A Single Dose Food-Effect Study to Evaluate the Safety, Tolerability, and the PK Profile of TBI-223 in Healthy Subjects

This study was a partially-blinded, placebo-controlled, randomized multiple ascending dose (MAD) study conducted at one study center. Cohorts 1 (1800 mg) and 2 (2400mg) began dosing of TBI-223 or placebo on Day 1 under fasted conditions, followed by a 3-day washout period and then by multiple doses of TBI-223 administered after a high-calorie, high-fat meal (Fed) from Day 4 through Day 17 (total of 14 days). Cohort 1 subjects only received slow-release formulations (SR1) tablets and Cohort 2 subjects received a combination of SR1 tablets with one immediate-release (IR) tablet. Cohort 3 with higher doses was planned in the protocol but as allowed by the protocol, a decision was made to halt the study after the second cohort due to mean Cmax and AUC0-24 after 14 days of dosing at 2400 mg in the second cohort exceeded values that were predicted to be achieved at 3000 mg in the third cohort.

Safety was assessed throughout the study for all subjects. Safety assessments included physical and detailed neurological examinations, vital signs (blood pressure (BP), pulse rate (PR), respiration rate, temperature, and pulse oximetry), 12-lead electrocardiograms (12-lead ECGs), cardiac monitoring, adverse events (AEs), and clinical laboratory tests (including hematology, serology, serum chemistry, coagulation, and urinalysis).

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