Study to Evaluate Safety, Tolerability, and the PK Profile of TBI-223 in Healthy Subjects

Phase 1

Completed

• Conditions: Tuberculosis; Tuberculosis, Pulmonary
• Interventions: Drug: TBI-223 Placebo; Drug: TBI-223 1800 mg; Drug: TBI-223 2400mg

• Registration Number: NCT04865536
• Lead Sponsor: Global Alliance for TB Drug Development

Brief Summary

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

Detailed Description

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).

Study Timeline

• Study Start: 2021-02-03
• Study First Submitted: 2021-02-22
• Study First Submitted QC: 2021-04-28
• Study First Posted: 2021-04-29
• Primary Completion: 2021-05-17
• Study Completion: 2022-05-17
• Status Verified: 2025-06
• Last Update Submitted: 2025-06-02
• Last Update Posted: 2025-06-05

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 28

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
TBI-223 Placebo	TBI-223 Placebo	Dose matching placebo tablets. Administered on Day 1 under fasted conditions, followed by a 3-day washout period and then by multiple doses of dose matched placebo administered after a high-calorie, high-fat meal (Fed) from Day 4 through Day 17 (total of 14 days), (n=6)
TBI-223 1800 mg	TBI-223 1800 mg	Cohort 1, 3 x 600 mg slow release (SR1) tablets. Administered 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), (n=9)
TBI-223 2400mg	TBI-223 2400mg	Cohort 2, 3 x 600 mg SR1 tablets and 1 x 600 mg immediate release (IR) tablets. Administered 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), (n=13)

Primary Outcome Measures

Name	Time	Method
Safety assessment Vital Signs - Blood pressure	through study completion, 12 weeks.	Blood pressure measured.
Safety assessment Vital Signs - Respiration rate	through study completion, 12 weeks.	Respiration rate measured.
Safety assessment Vital Signs - Pulse rate	through study completion, 12 weeks.	Pulse rate measured.
Safety assessment Vital Signs - Temperature	through study completion, 12 weeks.	Temperature measured.
Safety assessment Vital Signs - Pulse oximetry	through study completion, 12 weeks.	Pulse oximetry measured.
Safety assessment - Cardiac monitoring	through study completion, 12 weeks.	Safety 12-lead ECGs including ECG QT interval will be recorded and printed for on-site review by the Principal Investigator or designee.
Safety assessment - Adverse Events (AEs)	through study completion, 12 weeks.	AEs recorded.
Safety assessment Clinical Laboratory Tests - Serum Chemistry	through study completion, 12 weeks.	Serum chemistry recorded: albumin, blood urea nitrogen (BUN), creatinine, total bilirubin, alkaline phosphatase (ALP), aspartate transaminase (AST), alanine transaminase (ALT), sodium (Na+), potassium (K+), chloride (Cl-), lactate dehydrogenase (LDH), calcium (Ca), uric acid, glucose, gamma-glutamyltransferase (GGT), and magnesium.
Safety assessment Clinical Laboratory Tests - Coagulation	through study completion, 12 weeks.	Coagulation recorded: prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ratio (INR).
Safety assessment Clinical Laboratory Tests - Urinalysis	through study completion, 12 weeks.	Urinalysis recorded.
Safety assessment Clinical Laboratory Tests - Hematology	through study completion, 12 weeks.	Hematology recorded: hemoglobin, hematocrit, total and differential leukocyte count, red blood cell count (RBC), and platelet count.
Safety assessment Clinical Laboratory Tests - Serology	through study completion, 12 weeks.	Serology tests recorded: hepatitis B surface antigen, hepatitis C antibody, and HIV.
Safety assessment - Serum Pregnancy Testing	through study completion, 12 weeks.	Blood collection from female subjects for serum pregnancy testing.
Safety assessment - Follicle-stimulating hormone (FSH) Levels	through study completion, 12 weeks.	Blood collection from postmenopausal women to measure FSH levels.
Pharmacokinetics, non-food-effect cohorts - AUCtau	Day 14	AUCtau measured.
Pharmacokinetics, non-food-effect cohorts - Cmax	Day 14	Cmax measured.
Pharmacokinetics, non-food-effect cohorts - C24	Day 14	C24 measured.
Pharmacokinetics, non-food-effect cohorts - Cavg	Day 14	Cavg measured.
Pharmacokinetics, non-food-effect cohorts - Tmax	Day 14	Tmax measured.
Pharmacokinetics, non-food-effect cohorts - Vz/F	Day 14	Vz/F measured.
Pharmacokinetics, non-food-effect cohorts - AUCinf	Day 1	AUCinf measured if AUCtau ≥ 70% of AUCinf.
Pharmacokinetics, non-food-effect cohorts - AUCextrap	Day 1	AUCextrap measured if AUCtau ≥ 70% of AUCinf.
Pharmacokinetics, non-food-effect cohorts - CL/F	Day 14	CL/F measured.
Pharmacokinetics, food-effect cohorts - Cmax	Day 17	Cmax measured.
Pharmacokinetics, food-effect cohorts - Cmin	Day 17	Cmin measured.
Pharmacokinetics, food-effect cohorts - Ctrough	Day 17	Ctrough (i.e., C0) measured.
Pharmacokinetics, non-food-effect cohorts - lambaZ	Day 14	lambaZ measured.
Pharmacokinetics, non-food-effect cohorts - Cmin	Day 14	Cmin measured.
Pharmacokinetics, food-effect cohorts - AUCinf	Day 4	AUCinf measured if AUCtau ≥ 70% of AUCinf.
Pharmacokinetics, food-effect cohorts - C24	Day 17	C24 measured.
Pharmacokinetics, food-effect cohorts - CL/F	Day 17	CL/F measured.
Pharmacokinetics, food-effect cohorts - Vz/F	Day 17	Vz/F measured.
Pharmacokinetics, non-food-effect cohorts - t1/2	Day 14	t1/2 measured.
Pharmacokinetics, non-food-effect cohorts - Ctrough	Day 14	Ctrough (i.e., C0) measured.
Pharmacokinetics, non-food-effect cohorts - RAUC	Day 14	RAUC measured.
Pharmacokinetics, non-food-effect cohorts - RCmax measured.	Day 14	RCmax measured.
Pharmacokinetics, food-effect cohorts - AUCtau	Day 17	AUCtau measured.
Pharmacokinetics, food-effect cohorts - Tmax	Day 17	Tmax measured.
Pharmacokinetics, food-effect cohorts - Tlast	Day 1	Tlast measured.
Pharmacokinetics, food-effect cohorts - AUCextrap	Day 4	AUCextrap measured if AUCtau ≥ 70% of AUCinf.
Pharmacokinetics, food-effect cohorts - Clast	Day 1	Clast measured.
Pharmacokinetics, food-effect cohorts - lambaZ	Day 17	lambaZ measured.
Pharmacokinetics, food-effect cohorts - RAUC	Day 17	RAUC measured.
Pharmacokinetics, food-effect cohorts - RCmax	Day 17	RCmax measured.
Pharmacokinetics, food-effect cohorts - t1/2	Day 17	t1/2 measured.
Pharmacokinetics, food-effect cohorts - Cavg	Day 17	Cavg measured.

Trial Locations

Locations (1)

TKL Research, Inc.; 🇺🇸 Fair Lawn, New Jersey, United States