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

Global Alliance for TB Drug Development

Status and phase: Completed; Phase 1

Conditions: Tuberculosis; Tuberculosis, Pulmonary

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

Study type: Interventional

Funder types: Other

Identifiers

NCT03758612

TBI-223-CL-001

Details and patient eligibility

About

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.

Full 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).

Enrollment: 86 patients

Sex: All

Ages: 19 to 50 years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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86 participants in 12 patient groups, including a placebo group

TBI-223 50 mg

Active Comparator group

Description:

Cohort 1, single dose of TBI-223 50 mg dosed under fasted conditions

Treatment:

Drug: TBI-223 oral suspension

TBI-223 100 mg

Active Comparator group

Description:

Cohort 2, single dose of TBI-223 100 mg dosed under fasted conditions

Treatment:

Drug: TBI-223 oral suspension

TBI-223 300 mg

Active Comparator group

Description:

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

Treatment:

Drug: TBI-223 oral suspension

Drug: TBI-223 enteric capsule

TBI-223 600 mg

Active Comparator group

Description:

Cohort 4, single dose of TBI-223 600 mg dosed under fasted conditions

Treatment:

Drug: TBI-223 oral suspension

TBI-223 1200 mg

Active Comparator group

Description:

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

Treatment:

Drug: TBI-223 oral suspension

TBI-223 2000 mg

Active Comparator group

Description:

Cohort 6, single dose of TBI-223 2000 mg dosed under fasted conditions

Treatment:

Drug: TBI-223 oral suspension

TBI-223 2600 mg

Active Comparator group

Description:

Cohort 7, single dose of TBI-223 2600 mg dosed under fasted conditions

Treatment:

Drug: TBI-223 oral suspension

TBI-223 placebo

Placebo Comparator group

Description:

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

Treatment:

Drug: Placebo suspension

TBI-223 3x600 mg SR-1 tablet

Active Comparator group

Description:

Cohort 8, arm 1 - Single dose TBI-223 of 1800 mg (3 x 600 mg) sustained release (SR) tablet formulation 1 under fed conditions

Treatment:

Drug: TBI-223 SR Tablet Prototype 1

TBI-223 3x600 mg SR-2 tablet

Active Comparator group

Description:

Cohort 8, arm 2 - Single dose TBI-223 of 1800 mg (3 x 600 mg) sustained release (SR) tablet formulation 2 under fed conditions

Treatment:

Drug: TBI-223 SR Tablet Prototype 2

TBI-223 2x900 mg SR-3 tablet

Active Comparator group

Description:

Cohort 8, arm 3 - Single dose TBI-223 of 1800 mg (2 x 900 mg) sustained release (SR) tablet formulation 3 under fed conditions

Treatment:

Drug: TBI-223 SR Tablet Prototype 3

TBI-223 2x1000 mg IR tablet

Active Comparator group

Description:

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

Treatment:

Drug: TBI-223 IR Tablet