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

Study Overview
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Brief Summary
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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
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This is a partially-blinded, placebo-controlled, randomized multiple ascending dose (MAD) study to be conducted at one study center. Thirty-six (36) subjects will be enrolled in 3 cohorts with 12 subjects per cohort. Within each cohort, 9 subjects will be assigned to receive active treatment and 3 subjects will receive placebo. Each subject will participate in one dose level. The first 2 cohorts (food-effect cohorts) will begin dosing of TBI-223 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 from Day 4 through Day 17 (total of 14 days). The third cohort (nonfood- effect cohort) will begin dosing of TBI-223 on Day 1 and continue through Day 14, all doses administered after a high-calorie, high-fat meal. Each subject will be administered TBI-223 tablets (SR1 or IR or a combination of both formulations) or placebo once daily for 14 days with corresponding pharmacokinetic measurements. After each dose cohort, the Sponsor and Investigator will review the pharmacokinetic and safety data before proceeding to the next dose level. Dose escalation to the next cohort (i.e., dose level) or decisions regarding changed or additional cohorts will not take place until the Sponsor, in conjunction with the Principal Investigator and dose escalating committee, has determined that adequate safety, tolerability, and pharmacokinetics from the previous cohort(s) have been demonstrated to permit proceeding to the next cohort. Additional cohorts (up to 12 subjects per cohort) may be enrolled if deemed appropriate by the Sponsor to study other dose levels, change proposed cohorts, or to study a different dosage formulation The Institutional Review Board (IRB) should be immediately notified of the dose escalation or any revised approach for review and approval. Safety will be assessed throughout the study for all subjects. Safety assessments will include physical and detailed neurological examinations, vital signs (blood pressure, pulse rate, respiration rate, temperature and pulse oximetry), electrocardiograms (ECGs), cardiac monitoring, adverse events (AEs), and clinical laboratory tests (including hematology, serology, serum chemistry, coagulation, and urinalysis). Blood and urine will be collected for clinical laboratory evaluations. The Principal Investigator, in conjunction with the Sponsor may collect additional blood if necessary, for repeat laboratory or safety evaluations including AE follow up. Female subjects will have blood collected for serum pregnancy testing. Females claiming postmenopausal status will have blood collected to measure follicle stimulating hormone (FSH) levels. During each cohort, blood samples (trough samples) will be obtained before each dose of study drug, and at the time points on the events schedule. Plasma pharmacokinetic samples will be analyzed for TBI-223 and M2 using validated analytical methods. Appropriate pharmacokinetic parameters will be calculated using non compartmental methods.

Official Title
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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

Conditions
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Tuberculosis, Tuberculosis, Pulmonary

Intervention / Treatment
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* Drug: 1800 mg TBI-223
* Drug: 2400mg TBI-223
* Drug: 3000mg TBI-223
* Drug: TBI-223 Placebo
* Drug: TBI-223 Placebo
* Drug: TBI-223 Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All volunteers must satisfy the following criteria to be considered for study participation: Understands study procedures and voluntarily provides written informed consent prior to the start of any study-specific procedures. Is a healthy adult male or a healthy adult 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 at the time of screening and check-in. Is medically healthy with no clinically significant screening results, as determined by the Principal Investigator (e.g., laboratory profiles are normal up to and including Grade 1 per DMID toxicity tables; Appendix 3), medical history, vital signs, ECG, or physical/neurological examination findings. Note: If exclusionary lab criteria are met, values may be confirmed by repeat evaluation. Has not used tobacco- or nicotine-containing products (including smoking cessation products), for a minimum of 6 months before dosing. Females of non-childbearing potential, based on having undergone one of the following sterilization procedures at least 6 months before dosing: Hysteroscopic sterilization. Bilateral tubal ligation or bilateral salpingectomy; Hysterectomy; or Bilateral oophorectomy. Or is postmenopausal with amenorrhea for at least 1 year before the first dose with serum FSH levels consistent with postmenopausal status (i.e., greater than 40 mIU/mL) at screening. Or, if female of childbearing potential, must agree to use an allowable form of birth control from screening until 14 days after study completion. The following are allowed birth control methods for this study: Vasectomized partner (at least 6 months before dosing); Non-surgical permanent sterilization (e.g., Essure® procedure) at least 3 months before dosing. Double barrier method (e.g., diaphragm with spermicide; condoms with spermicide). Intrauterine device (IUD). Abstinence (and must agree to use a double barrier method if they become sexually active during the study); Implanted or intrauterine hormonal contraceptives in use for at least 6 consecutive months before study dosing; and/or Oral, patch, or injected contraceptives, or vaginal hormonal device (i.e. NuvaRing®), in use for at least 3 consecutive months before study dosing. If a non-vasectomized male (or male vasectomized less than 120 days prior to study start) must agree to the following during study participation and for 90 days after the last administration of study drug: Use a condom with spermicide while engaging in sexual activity or be sexually abstinent Not donate sperm during this time. In the event the sexual partner is surgically sterile or postmenopausal, use of a condom with spermicide is not necessary. None of the birth control restrictions listed above are required for vasectomized males whose procedure was performed more than 120 days before study start. Is willing to answer inclusion and exclusion criteria questionnaire at check-in. Is able to comply with the protocol and the assessments therein, including all restrictions. Is willing and able to remain in the study unit for the entire duration of the assigned confinement period(s), return for outpatient visit(s), and receive a phone call for follow-up questioning about AEs. Exclusion Criteria: Volunteers will be excluded from study participation for any of the following: History or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic, neurological (including epilepsy), oncologic, or 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 abnormality on neurologic exam. History of any illness that, in the opinion of the Investigator, might confound the results of the study or pose an additional risk to the subject by their participation in the study. Surgery within the past 90 days prior to dosing as determined by the Investigator to be clinically relevant, or any history of cholecystectomy. History or presence of alcoholism or drug abuse within the past 2 years as determined by the Investigator to be clinically relevant. History of sensitivity or contraindication to use of linezolid, tedizolid, or any study investigational products. Participation in another clinical trial within 30 days prior to dosing. Female subjects who are pregnant or lactating. Positive result on a urine drug/alcohol/cotinine screen at Baseline or check-in. Seated blood pressure is less than 90/40 mmHg or greater than 140/90 mmHg at screening. Out-of-range vital signs may be repeated once for confirmation. Seated heart rate is lower than 40 bpm or higher than 99 bpm at screening. Out-of-range vital signs may be repeated once for confirmation. Any clinically significant ECG abnormality at Screening (as deemed by decision of the Investigator and the Sponsor's Medical Monitor). NOTE: The following may be considered not clinically significant without consulting the Sponsor's Medical Monitor: Mild first-degree A-V block (P-R interval <0.23 sec) Right or left axis deviation Incomplete right bundle branch block Isolated left anterior fascicular block (left anterior hemiblock) in younger athletic subjects Early repolarization Tall T waves RSR in V1/V2 consistent with right ventricular conduction delay (with acceptable QRS) Sinus rhythm or sinus bradycardia with sinus arrhythmia Minimal or moderate voltage criteria for left ventricular hypertrophy (LVH). 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 ECGs taken at screening and on Day -1, the average QTcF interval of the three ECG recordings will be used to determine qualification. Family history of long-QT syndrome or sudden death without a preceding diagnosis of a condition that could be 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 may lower the seizure threshold. Lactose intolerant. Specific Treatments Use of any prescription medication within 14 days prior to dosing. Use of any of the following medications within 30 days before the first dose of study drug or during the study drug treatment period: monoamine oxidase (MAO) inhibitors (phenelzine, tranylcypromine), tricyclic antidepressants (amitriptyline, nortriptyline, protriptyline, doxepin, amoxapine, etc.), antipsychotics such as chlorpromazine and buspirone, serotonin re-uptake inhibitors (fluoxetine, paroxetine, sertraline, etc.), bupropion, agents known to prolong the QTc interval (erythromycin, clarithromycin, astemizole, type Ia [quinidine, procainamide, disopyramide] and III [amiodarone, sotalol] anti-arrhythmics, carbamazepine, sulfonylureas, and meperidine). Use of any over-the-counter (OTC) medication, including herbal products and vitamins, within 7 days prior to dosing, except acetaminophen. Up to 3 grams per day of acetaminophen is allowed at the discretion of the Investigator prior to dosing. Use of any drugs or substances known to be significant inhibitors of cytochrome P450 (CYP) enzymes and/or significant inhibitors or substrates of P-glycoprotein (P-gp) and/or organic anion transporting polypeptides (OATP) within 14 days prior to the first dose of study drug. Use of any drugs or substances known to be inducers of CYP enzymes and/or Pgp, including St. John's Wort, within 30 days prior to the first dose of study drug. Use of any drugs or substance known to lower the seizure threshold. Specific Laboratory Abnormalities Serum magnesium, potassium, or calcium laboratory values outside of the normal range at screening. If exclusionary lab criteria are met, values may be confirmed by repeat evaluation. Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C antibodies (HCV). ALT or AST greater than ULN.

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cohort 1 TBI-223 1800 mg, fasting<br>1800 mg, fasting | Drug: 1800 mg TBI-223<br>* 3 x 600 mg SR1 tablets<br>|
| Active Comparator: Cohort 1 TBI-23 1800, fed<br>TBI-23 1800, fed | Drug: 1800 mg TBI-223<br>* 3 x 600 mg SR1 tablets<br>|
| Placebo Comparator: Cohort 1 Placebo, fed<br>Placebo, fed | Drug: TBI-223 Placebo<br>* 3 x Placebo tablets<br>|
| Placebo Comparator: Cohort 1 Placebo fasting<br>Placebo fasting | Drug: TBI-223 Placebo<br>* 3 x Placebo tablets<br>|
| Active Comparator: Cohort 2 TBI-223, 2400mg,fed<br>2400mg,fed | Drug: 2400mg TBI-223<br>* 3 x 600 mg SR1 tablets and 1 x 600 mg IR tablets<br>|
| Active Comparator: Cohort 2 TBI-223, 2400 mg fasting<br>2400 mg fasting | Drug: 2400mg TBI-223<br>* 3 x 600 mg SR1 tablets and 1 x 600 mg IR tablets<br>|
| Placebo Comparator: Cohort 2 Placebo, fed<br>Placebo, fed | Drug: TBI-223 Placebo<br>* 4 x Placebo tablets<br>|
| Placebo Comparator: Cohort 2 Placebo, fasting<br>Placebo, fasting | Drug: TBI-223 Placebo<br>* 4 x Placebo tablets<br>|
| Active Comparator: Cohort 3 3000mg, fed<br>3000mg, fed | Drug: 3000mg TBI-223<br>* 4 x 600 mg SR1 tablets and 1 x 600 mg IR tablets<br>|
| Placebo Comparator: Cohort 3 placebo, fed<br>placebo, fed | Drug: TBI-223 Placebo<br>* 5 x Placebo tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety assessment Vital Signs - Blood pressure | Blood pressure measured. | through study completion, 12 weeks. | 
| Safety assessment Vital Signs - Pulse rate | Pulse rate measured. | through study completion, 12 weeks. | 
| Safety assessment Vital Signs - Respiration rate | Respiration rate measured. | through study completion, 12 weeks. | 
| Safety assessment Vital Signs - Temperature | Temperature measured. | through study completion, 12 weeks. | 
| Safety assessment Vital Signs - Pulse oximetry | Pulse oximetry measured. | through study completion, 12 weeks. | 
| Safety assessment - Cardiac monitoring | Safety 12-lead ECGs including ECG QT interval will be recorded and printed for on-site review by the Principal Investigator or designee. | through study completion, 12 weeks. | 
| Safety assessment - Adverse Events (AEs) | AEs recorded. | through study completion, 12 weeks. | 
| Safety assessment Clinical Laboratory Tests - Hematology | Hematology recorded: hemoglobin, hematocrit, total and differential leukocyte count, red blood cell count (RBC), and platelet count. | through study completion, 12 weeks. | 
| Safety assessment Clinical Laboratory Tests - Serology | Serology tests recorded: hepatitis B surface antigen, hepatitis C antibody, and HIV. | through study completion, 12 weeks. | 
| Safety assessment Clinical Laboratory Tests - Serum Chemistry | 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. | through study completion, 12 weeks. | 
| Safety assessment Clinical Laboratory Tests - Coagulation | Coagulation recorded: prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ratio (INR). | through study completion, 12 weeks. | 
| Safety assessment Clinical Laboratory Tests - Urinalysis | Urinalysis recorded. | through study completion, 12 weeks. | 
| Safety assessment - Serum Pregnancy Testing | Blood collection from female subjects for serum pregnancy testing. | through study completion, 12 weeks. | 
| Safety assessment - Follicle-stimulating hormone (FSH) Levels | Blood collection from postmenopausal women to measure FSH levels. | through study completion, 12 weeks. | 
| Pharmacokinetics, non-food-effect cohorts - AUCtau | AUCtau measured. | Day 1 | 
| Pharmacokinetics, non-food-effect cohorts - Cmax | Cmax measured. | Day 1 | 
| Pharmacokinetics, non-food-effect cohorts - C24 | C24 measured. | Day 1 | 
| Pharmacokinetics, non-food-effect cohorts - Cavg | Cavg measured. | Day 1 | 
| Pharmacokinetics, non-food-effect cohorts - Tmax | Tmax measured. | Day 1 | 
| Pharmacokinetics, non-food-effect cohorts - AUCinf | AUCinf measured if AUCtau ≥ 70% of AUCinf. | Day 1 | 
| Pharmacokinetics, non-food-effect cohorts - AUCextrap | AUCextrap measured if AUCtau ≥ 70% of AUCinf. | Day 1 | 
| Pharmacokinetics, non-food-effect cohorts - CL/F | CL/F measured if AUCtau ≥ 70% of AUCinf. | Day 1 | 
| Pharmacokinetics, non-food-effect cohorts - Vz/F | Vz/F measured if AUCtau ≥ 70% of AUCinf. | Day 1 | 
| Pharmacokinetics, non-food-effect cohorts - lambaZ | lambaZ measured if AUCtau ≥ 70% of AUCinf. | Day 1 | 
| Pharmacokinetics, non-food-effect cohorts - t1/2 | t1/2 measured if AUCtau ≥ 70% of AUCinf. | Day 1 | 
| Pharmacokinetics, non-food-effect cohorts - AUCtau | AUCtau measured. | Day 14 | 
| Pharmacokinetics, non-food-effect cohorts - Cmax | Cmax measured. | Day 14 | 
| Pharmacokinetics, non-food-effect cohorts - Cmin | Cmin measured. | Day 14 | 
| Pharmacokinetics, non-food-effect cohorts - Ctrough | Ctrough (i.e., C0) measured. | Day 14 | 
| Pharmacokinetics, non-food-effect cohorts - C24 | C24 measured. | Day 14 | 
| Pharmacokinetics, non-food-effect cohorts - Cavg | Cavg measured. | Day 14 | 
| Pharmacokinetics, non-food-effect cohorts - Tmax | Tmax measured. | Day 14 | 
| Pharmacokinetics, non-food-effect cohorts - CL/F | CL/F measured. | Day 14 | 
| Pharmacokinetics, non-food-effect cohorts - Vz/F | Vz/F measured. | Day 14 | 
| Pharmacokinetics, non-food-effect cohorts - lambaZ | lambaZ measured. | Day 14 | 
| Pharmacokinetics, non-food-effect cohorts - t1/2 | t1/2 measured. | Day 14 | 
| Pharmacokinetics, non-food-effect cohorts - RAUC | RAUC measured. | Day 14 | 
| Pharmacokinetics, non-food-effect cohorts - RCmax measured. | RCmax measured. | Day 14 | 
| Pharmacokinetics, food-effect cohorts - AUCtau | AUCtau measured. | Day 1 | 
| Pharmacokinetics, food-effect cohorts - AUCextrap | AUCextrap measured. | Day 1 | 
| Pharmacokinetics, food-effect cohorts - AUCinf | AUCinf measured. | Day 1 | 
| Pharmacokinetics, food-effect cohorts - Cmax | Cmax measured. | Day 1 | 
| Pharmacokinetics, food-effect cohorts - C24 | C24 measured | Day 1 | 
| Pharmacokinetics, food-effect cohorts - Clast | Clast measured. | Day 1 | 
| Pharmacokinetics, food-effect cohorts - Tmax | Tmax measured. | Day 1 | 
| Pharmacokinetics, food-effect cohorts - Tlast | Tlast measured. | Day 1 | 
| Pharmacokinetics, food-effect cohorts - CL/F | CL/F measured. | Day 1 | 
| Pharmacokinetics, food-effect cohorts - Vz/F | Vz/F measured. | Day 1 | 
| Pharmacokinetics, food-effect cohorts - lambaZ | lambaZ measured. | Day 1 | 
| Pharmacokinetics, food-effect cohorts - t1/2 | t1/2 measured. | Day 1 | 
| Pharmacokinetics, food-effect cohorts - AUCtau | AUCtau measured. lambaZ, t1/2 should be included if AUCtau ≥ 70% of AUCinf | Day 4 | 
| Pharmacokinetics, food-effect cohorts - Cmax | Cmax measured. | Day 4 | 
| Pharmacokinetics, food-effect cohorts - C24 | C24 measured. | Day 4 | 
| Pharmacokinetics, food-effect cohorts - Cavg | Cavg measured. | Day 4 | 
| Pharmacokinetics, food-effect cohorts - Tmax | Tmax measured. | Day 4 | 
| Pharmacokinetics, food-effect cohorts - AUCinf | AUCinf measured if AUCtau ≥ 70% of AUCinf. | Day 4 | 
| Pharmacokinetics, food-effect cohorts - AUCextrap | AUCextrap measured if AUCtau ≥ 70% of AUCinf. | Day 4 | 
| Pharmacokinetics, food-effect cohorts - CL/F | CL/F measured if AUCtau ≥ 70% of AUCinf. | Day 4 | 
| Pharmacokinetics, food-effect cohorts - Vz/F | Vz/F measured if AUCtau ≥ 70% of AUCinf. | Day 4 | 
| Pharmacokinetics, food-effect cohorts - lambaZ | lambaZ measured if AUCtau ≥ 70% of AUCinf. | Day 4 | 
| Pharmacokinetics, food-effect cohorts - t1/2 | t1/2 measured if AUCtau ≥ 70% of AUCinf. | Day 4 | 
| Pharmacokinetics, food-effect cohorts - AUCtau | AUCtau measured. | Day 17 | 
| Pharmacokinetics, food-effect cohorts - Cmax | Cmax measured. | Day 17 | 
| Pharmacokinetics, food-effect cohorts - Cmin | Cmin measured. | Day 17 | 
| Pharmacokinetics, food-effect cohorts - Ctrough | Ctrough (i.e., C0) measured. | Day 17 | 
| Pharmacokinetics, food-effect cohorts - C24 | C24 measured. | Day 17 | 
| Pharmacokinetics, food-effect cohorts - Cavg | Cavg measured. | Day 17 | 
| Pharmacokinetics, food-effect cohorts - Tmax | Tmax measured. | Day 17 | 
| Pharmacokinetics, food-effect cohorts - CL/F | CL/F measured. | Day 17 | 
| Pharmacokinetics, food-effect cohorts - Vz/F | Vz/F measured. | Day 17 | 
| Pharmacokinetics, food-effect cohorts - lambaZ | lambaZ measured. | Day 17 | 
| Pharmacokinetics, food-effect cohorts - t1/2 | t1/2 measured. | Day 17 | 
| Pharmacokinetics, food-effect cohorts - RAUC | RAUC measured. | Day 17 | 
| Pharmacokinetics, food-effect cohorts - RCmax | RCmax measured. | Day 17 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TB, Tuberculosis, TBI-223, Pulmonary Tuberculosis