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

Phase 1

Completed

Conditions: Tuberculosis
Tuberculosis, Pulmonary

Interventions: Drug: TBI-223 oral suspension
Drug: Placebo suspension
Drug: TBI-223 SR Tablet Prototype 1
Drug: TBI-223 SR Tablet Prototype 2
Drug: TBI-223 SR Tablet Prototype 3
Drug: TBI-223 IR Tablet
Drug: TBI-223 enteric capsule

Registration Number: NCT03758612

Lead Sponsor: Global Alliance for TB Drug Development

Brief 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: 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).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 86

Inclusion Criteria

All volunteers must satisfy the following criteria to be considered for study participation:

Is a healthy adult male or female, 19 to 50 years of age (inclusive) at the time of screening.
Has a body mass index (BMI) ≥18.5 and ≤32.0 (kg/m2) and a body weight of no less than 50.0 kg.
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.
Has not used tobacco- or nicotine-containing products (including smoking cessation products), for a minimum of 6 months before dosing.
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

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.
Any presence of musculoskeletal toxicity (severe tenderness with marked impairment of activity, or frank necrosis).
Has a positive test for hepatitis B surface antigen, hepatitis C antibody, or HIV at screening.
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.
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).
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.
Lactose intolerant.
History of sensitivity or contraindication to use of linezolid, tedizolid, or any study investigational products

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
TBI-223 50 mg	TBI-223 oral suspension	Cohort 1, single dose of TBI-223 50 mg dosed under fasted conditions
TBI-223 100 mg	TBI-223 oral suspension	Cohort 2, single dose of TBI-223 100 mg dosed under fasted conditions
TBI-223 300 mg	TBI-223 oral suspension	Cohort 3a, Period 1 - gave a single dose of TBI-223 300 mg oral suspension dosed under fasted conditions. Cohort 3b, Period 2 - participants in cohort 3a were invited after a washout period to return for an additional single dose of TBI-223 300 mg enteric capsule dosed under fasted conditions
TBI-223 300 mg	TBI-223 enteric capsule	Cohort 3a, Period 1 - gave a single dose of TBI-223 300 mg oral suspension dosed under fasted conditions. Cohort 3b, Period 2 - participants in cohort 3a were invited after a washout period to return for an additional single dose of TBI-223 300 mg enteric capsule dosed under fasted conditions
TBI-223 600 mg	TBI-223 oral suspension	Cohort 4, single dose of TBI-223 600 mg dosed under fasted conditions
TBI-223 1200 mg	TBI-223 oral suspension	Cohort 5, Period 1, single dose of TBI-223 1200 mg dosed under fasted conditions. Cohort 5, Period 2, participants were invited to return after a washout period to continue in period 2 and receive a single dose of TBI-223 1200 mg dosed under fed conditions
TBI-223 2000 mg	TBI-223 oral suspension	Cohort 6, single dose of TBI-223 2000 mg dosed under fasted conditions
TBI-223 2600 mg	TBI-223 oral suspension	Cohort 7, single dose of TBI-223 2600 mg dosed under fasted conditions
TBI-223 placebo	Placebo suspension	Period 1 Single dose matching placebo for TBI-223 under fasted conditions for cohorts 1 to 7 Period 2 Placebo participants in cohort 5 were invited to return after a washout period and were administered a single dose matching placebo for TBI-223 1200mg under fed conditions
TBI-223 3x600 mg SR-1 tablet	TBI-223 SR Tablet Prototype 1	Cohort 8, arm 1 - Single dose TBI-223 of 1800 mg (3 x 600 mg) sustained release (SR) tablet formulation 1 under fed conditions
TBI-223 3x600 mg SR-2 tablet	TBI-223 SR Tablet Prototype 2	Cohort 8, arm 2 - Single dose TBI-223 of 1800 mg (3 x 600 mg) sustained release (SR) tablet formulation 2 under fed conditions
TBI-223 2x900 mg SR-3 tablet	TBI-223 SR Tablet Prototype 3	Cohort 8, arm 3 - Single dose TBI-223 of 1800 mg (2 x 900 mg) sustained release (SR) tablet formulation 3 under fed conditions
TBI-223 2x1000 mg IR tablet	TBI-223 IR Tablet	Cohort 8, arm 4 - Single dose TBI-223 of 2000 mg (2 x 1000 mg) immediate release (IR) tablet under fasted conditions Cohort 9 - Participants from cohort 8 arm 4 were invited to return and were administered a single dose TBI-223 of 2000 mg (2 x 1000 mg) immediate release (IR) tablet under fed conditions

Primary Outcome Measures

Name	Time	Method
Number of Participants With Treatment-related Adverse Events	Day 1 - Day 11	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.

Secondary Outcome Measures

Name	Time	Method
AUC0-t	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 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.
Maximum Plasma Concentration, Determined Directly From Individual Concentration-time- Data (Cmax)	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	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 of the Maximum Plasma Concentrations (Tmax)	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	Tmax will be calculated from plasma concentrations of TBI-223.
The Observed Terminal Elimination Half-life (t1/2)	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	T1/2 will be calculated from plasma concentrations of TBI-223 and calculated as T½ = ln(2)/λz
Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of 300 mg TBI-223 in Capsule to Oral Suspension Formulations	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	Geometric mean ratio of TBI-223 area under the (plasma concentration vs. time) curve and Cmax when administered as a Single 300 mg Dose of TBI-223 Capsule Formulation (Cohort 3 Repeat; Part 1; Test) and a Single 300 mg Dose of TBI-223 Oral Suspension (Cohort 3; Part 1; Reference).
Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of 1200 mg Oral Suspension Under Fasted to Fed Conditions	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	Geometric mean ratio of TBI-223 area under the (plasma concentration vs. time) curve and Cmax when administered as a Single 1200 mg Dose of TBI-223 Oral Suspension under Fed (Test) and Fasted (Reference) Conditions (Part 1; Cohort 5)
Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of 2000 mg of Immediate Release (IR) Tablets Under Fed to Fasted Conditions.	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	Geometric mean ratio of TBI-223 area under the (plasma concentration vs. time) curve and Cmax when administered as IR tablets, 2000 mg (2 x 1000 mg TBI-223 tablets) under Fed Conditions (Cohort 9; Test) and IR tablets, 2000 mg (2 x1000 mg TBI-223 tablets) under Fasted Conditions (Cohort 8; Reference)
Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of TBI-223 1800 mg Sustained Release (SR) Tablets Under Fed Conditions to 2000 mg IR Tablets Under Fasted Conditions	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	Geometric mean ratio of TBI-223 area under the (plasma concentration vs. time) curve and Cmax when administered as SR (Prototypes 1, 2, and 3) under Fed Conditions (Cohort 8; Test) and IR, 2000 mg (2 x 1000 mg TBI-223 tablets) under Fasted Conditions (Cohort 8; Reference)
Geometric Mean Ratio and 90% Confidence Interval (CI) of Cmax, AUC0-t and AUC 0-inf of 1800 mg SR Tablets (Prototypes 1, 2, 3,) to 2000 mg IR Tablets Under Fed Conditions	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	Geometric mean ratio of TBI-223 area under the (plasma concentration vs. time) curve and Cmax when administered as TBI-223 after 1800 mg SR tablets (Prototypes 1, 2, 3,) under Fed Conditions (Cohort 8; Test) and 2000 mg IR tablets (2 x 1000 mg TBI-223 tablets) under Fed Conditions (Cohort 8; Reference)
Area Under the Plasma Concentration-time- Curve From the Time of Dosing Extrapolated to Infinity (AUC0-inf)	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-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