Evaluate Safety, Tolerability, PK of TBAJ-876 in Healthy Adults

Study Overview
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Brief Summary
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A Phase 1, Partially Blind, Placebo Controlled, Randomized, Combined Single Ascending Dose with a Food Effect Cohort (Part 1) and Multiple Ascending Dose Study (Part 2) Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of TBAJ-876 in Healthy Adult Subjects

Detailed Description
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This study is a two-part, partially blinded, placebo controlled, combined single ascending dose (SAD) with food-effect and multiple ascending dose (MAD) study conducted in one study center in the United States. Safety will be assessed throughout the study for all subjects. Safety assessments will include physical examinations, vital signs, serial ECGs, cardiac monitoring, adverse events (AEs), and clinical laboratory tests (including hematology, serum chemistry, coagulation, and urinalysis).

Official Title
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A Phase 1, Partially Blind, Placebo Controlled, Randomized, Combined Single Ascending Dose With a Food Effect Cohort and Multiple Ascending Dose Study Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of TBAJ-876 in Healthy Adult Subjects

Conditions
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Pulmonary Disease, Tuberculosis, Pulmonary, Tuberculosis, Multi Drug Resistant Tuberculosis, Drug Sensitive Tuberculosis, Drug-resistant Tuberculosis, Mycobacterium Tuberculosis Infection

Intervention / Treatment
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* Drug: TBAJ-876 10mg
* Drug: TBAJ-876 25mg
* Drug: TBAJ-876 50mg
* Drug: TBAJ-876 100mg
* Drug: TBAJ-876 200mg
* Drug: TBAJ-876 400mg
* Drug: TBAJ-876 Dose XXXmg for Food cohort
* Drug: TBAJ-876 XXXmg for Part 2
* Drug: Matching Placebo for TBAJ-876 tablet


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 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 DMID Toxicity Tables), as deemed by the Investigator. Note: Lab results within the testing facility's normal range will not be considered AEs when referenced to the DMID assessment/grading scale. 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. If female of non-childbearing potential, she has 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. If female of childbearing potential, must be using effective birth control methods, as defined below and is willing to continue practicing birth control methods and not planning to conceive throughout treatment and for 12 weeks (male participants) or 6 weeks (female participants) after the last dose of trial medication. The following are allowed birth control methods for this study: 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); Vasectomized partner (at least 6 months before dosing); Non-surgical permanent sterilization (e.g., Essure® procedure) at least 3 months before dosing; Implanted or intrauterine hormonal contraceptives in use for at least 6 consecutive months before study dosing; and/or If a non-vasectomized male (or male vasectomized less than 120 days prior to study start) he 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; and 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 and return for outpatient visits. 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. Exclusion Criteria: Volunteers will be excluded from study participation for any of the following: 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). Surgery within the past 90 days prior to dosing as determined by the Investigator to be clinically relevant. History or presence of alcoholism or drug abuse within the past 2 years as determined by the Investigator to be clinically relevant. 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 screen at screening or check-in. Positive result on urine cotinine at screening. Has the following laboratory abnormalities at screening: ALT or AST Grade 2 or greater (> 2.0 times ULN) Creatinine Grade 2 or greater (>1.6 times ULN) Pancreatic lipase Grade 2 or greater (>1.6 times ULN) Amylase Grade 2 or greater (>1.6 times ULN) Total bilirubin Grade 2 or greater CPK (> 1.25 times ULN) If exclusionary lab criteria are met, values may be confirmed by repeat evaluation. Has a positive test for hepatitis B surface antigen, hepatitis C antibody, or HIV at screening. Seated blood pressure (BP) is less than 90/40 mmHg or greater than 140/90 mmHg at screening, Day -1 (check-in) or predose. Out-of-range vital signs may be repeated once for confirmation. Out of range values will not be considered AEs if the repeat assessment is in range. Seated heart rate is lower than 40 beat per minute (bpm) or higher than 99 bpm at screening, Day -1 (check-in) or predose. Out-of-range vital signs may be repeated once for confirmation. Out of range values will not be considered AEs if the repeat assessment is in range. 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 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 3 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). Use of any prescription medication within 14 days prior to dosing. 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 only at occasional use and 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. Blood donation or significant blood loss within 56 days before the first dose of study medication until the end-of-study visit. Plasma donation within 7 days before the first dose of study medication until the end-of-study visit. Has been on a significantly abnormal diet during the 4 weeks preceding the first dose of study medication. Unwilling to remove any artificial nails (e.g. acrylic, gel) or fingernail polish and not use such products for the duration of the study. History or presence of allergic or adverse response to Listerine breath strips or aspartame. If assigned to the fasted/fed cohort, is lactose intolerant.

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: SAD (Part 1): Cohort 1, TBAJ-876 10mg<br>In cohort 1 with 8 subjects, n= 6 will receive TBAJ-876 10mg under fasting conditions. | Drug: TBAJ-876 10mg<br>* TBAJ-876 10mg tablets, oral suspension, orally administered<br>* Other names: TBAJ-876 tablets;|
| Placebo Comparator: SAD (Part 1): Cohort 1, placebo for TBAJ-876 10mg<br>In cohort 1 with 8 subjects, n= 2 will receive matching placebo for TBAJ-876 10mg under fasting conditions. | Drug: Matching Placebo for TBAJ-876 tablet<br>* Matching Placebo for TBAJ-876 tablets, oral suspension, orally administered<br>* Other names: TBAJ-876 placebo;|
| Active Comparator: SAD (Part 1): Cohort 2, TBAJ-876 25mg<br>In cohort 2 with 8 subjects, n= 6 will receive TBAJ-876 25mg under fasting conditions. | Drug: TBAJ-876 25mg<br>* TBAJ-876 25mg tablets,oral suspension, orally administered<br>* Other names: TBAJ-876 tablets;|
| Placebo Comparator: SAD (Part 1): Cohort 2, Placebo for TBAJ-876 25mg<br>In cohort 2 with 8 subjects, n= 2 will receive matching placebo for TBAJ-876 25mg under fasting conditions. | Drug: Matching Placebo for TBAJ-876 tablet<br>* Matching Placebo for TBAJ-876 tablets, oral suspension, orally administered<br>* Other names: TBAJ-876 placebo;|
| Active Comparator: SAD (Part 1): Cohort 3, TBAJ-876 50mg<br>In cohort 3 with 8 subjects, n= 6 will receive TBAJ-876 50mg under fasting conditions. | Drug: TBAJ-876 50mg<br>* TBAJ-876 50mg tablets,oral suspension, orally administered<br>* Other names: TBAJ-876 tablets;|
| Placebo Comparator: SAD (Part 1): Cohort 3, Placebo for TBAJ-876 50mg<br>In cohort 3 with 8 subjects, n= 2 will receive matching placebo for TBAJ-876 50mg under fasting conditions. | Drug: Matching Placebo for TBAJ-876 tablet<br>* Matching Placebo for TBAJ-876 tablets, oral suspension, orally administered<br>* Other names: TBAJ-876 placebo;|
| Active Comparator: SAD (Part 1): Cohort 4, TBAJ-876 100mg<br>In cohort 4 with 8 subjects, n= 6 will receive TBAJ-876 100mg under fasting conditions. | Drug: TBAJ-876 100mg<br>* TBAJ-876 100mg tablets, oral suspension, orally administered<br>* Other names: TBAJ-876 tablets;|
| Placebo Comparator: SAD (Part 1): Cohort 4, Placebo for TBAJ-876 100mg<br>In cohort 4 with 8 subjects, n= 2 will receive matching placebo for TBAJ-876 100mg under fasting conditions. | Drug: Matching Placebo for TBAJ-876 tablet<br>* Matching Placebo for TBAJ-876 tablets, oral suspension, orally administered<br>* Other names: TBAJ-876 placebo;|
| Active Comparator: SAD (Part 1): Cohort 5, TBAJ-876 200mg<br>In cohort 5 with 8 subjects, n= 6 will receive TBAJ-876 200mg under fasting conditions. | Drug: TBAJ-876 200mg<br>* TBAJ-876 200mg tablets, oral suspension, orally administered<br>* Other names: TBAJ-876 tablets;|
| Placebo Comparator: SAD (Part 1): Cohort 5, Placebo for TBAJ-876 200mg<br>In cohort 5 with 8 subjects, n= 2 will receive matching placebo for TBAJ-876 200mg under fasting conditions. | Drug: Matching Placebo for TBAJ-876 tablet<br>* Matching Placebo for TBAJ-876 tablets, oral suspension, orally administered<br>* Other names: TBAJ-876 placebo;|
| Active Comparator: SAD (Part 1): Cohort 6, TBAJ-876 400mg<br>In cohort 6 with 8 subjects, n= 6 will receive TBAJ-876 400mg under fasting conditions. | Drug: TBAJ-876 400mg<br>* TBAJ-876 400mg tablets, oral suspension, orally administered<br>* Other names: TBAJ-876 tablets;|
| Placebo Comparator: SAD (Part 1): Cohort 6, Placebo TBAJ-876 400mg<br>In cohort 6 with 8 subjects, n= 2 will receive matching placebo for TBAJ-876 400mg under fasting conditions. | Drug: Matching Placebo for TBAJ-876 tablet<br>* Matching Placebo for TBAJ-876 tablets, oral suspension, orally administered<br>* Other names: TBAJ-876 placebo;|
| Active Comparator: SAD (Part 1): Food effect Cohort, TBAJ-876<br>In food-effect cohort with 10 subjects, n=8 will return after plasma concentrations are expected to be below LLQ, for at least 7 days to receive the chosen dose of TBAJ-876 under fed conditions. | Drug: TBAJ-876 Dose XXXmg for Food cohort<br>* Based on exposure levels from initial cohorts, a dose will be chosen for the food-effect cohort.<br>* Other names: TBAJ-876 tablets;|
| Placebo Comparator: SAD (Part 1): Food effect Cohort, Placebo<br>In food-effect cohort with 10 subjects, n=2 will return after plasma concentrations are expected to be below LLQ, for at least 7 days to receive matching placebo for the chosen dose of TBAJ-876 under fed conditions. | Drug: Matching Placebo for TBAJ-876 tablet<br>* Matching Placebo for TBAJ-876 tablets, oral suspension, orally administered<br>* Other names: TBAJ-876 placebo;|
| Active Comparator: MAD (Part 2): Cohort 1, TBAJ-876 Dose 1<br>In cohort 1 with 12 subjects, n=9 is expected to receive TBAJ-876 for 28 days with corresponding PK and safety measurements. | Drug: TBAJ-876 XXXmg for Part 2<br>* Part 2, Multiple ascending dose (MAD) cohorts doses to be determined.<br>* Other names: TBAJ-876 tablets;|
| Placebo Comparator: MAD (Part 2): Cohort 1, Placebo<br>In cohort 1 with 12 subjects, n=3 is expected to receive the matching placebo for TBAJ-876 for 28 days with corresponding PK and safety measurements. | Drug: Matching Placebo for TBAJ-876 tablet<br>* Matching Placebo for TBAJ-876 tablets, oral suspension, orally administered<br>* Other names: TBAJ-876 placebo;|
| Active Comparator: MAD (Part 2): Cohort 2, TBAJ-876 Dose 2<br>In cohort 2 with 12 subjects, n=9 is expected to receive TBAJ-876 for 28 days with corresponding PK and safety measurements. | Drug: TBAJ-876 XXXmg for Part 2<br>* Part 2, Multiple ascending dose (MAD) cohorts doses to be determined.<br>* Other names: TBAJ-876 tablets;|
| Placebo Comparator: MAD (Part 2): Cohort 2, Placebo<br>In cohort 2 with 12 subjects, n=3 is expected to receive matching placebo for TBAJ-876 for 28 days with corresponding PK and safety measurements. | Drug: Matching Placebo for TBAJ-876 tablet<br>* Matching Placebo for TBAJ-876 tablets, oral suspension, orally administered<br>* Other names: TBAJ-876 placebo;|
| Active Comparator: MAD (Part 2): Cohort 3, TBAJ-876 Dose 3<br>In cohort 3 with 12 subjects, n=9 is expected to receive TBAJ-876 for 28 days with corresponding PK and safety measurements | Drug: TBAJ-876 XXXmg for Part 2<br>* Part 2, Multiple ascending dose (MAD) cohorts doses to be determined.<br>* Other names: TBAJ-876 tablets;|
| Placebo Comparator: MAD (Part 2): Cohort 3, Placebo<br>In cohort 3 with 12 subjects, n=3 is expected to receive matching placebo for TBAJ-876 for 28 days with corresponding PK and safety measurements. | Drug: Matching Placebo for TBAJ-876 tablet<br>* Matching Placebo for TBAJ-876 tablets, oral suspension, orally administered<br>* Other names: TBAJ-876 placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Physical examination [Safety and Tolerability] | Safety assessments will include physical examination which will comprise measuring height in cm, weight in kg, and presence of heart murmur. | Days -1 | 
| Vital signs [Safety and Tolerability] | Vital signs (blood pressure, pulse rate, temperature, respiration rate, and pulse oximetry) will be measured within 90 minutes prior to dosing and within 15 minutes of the defined time points. | Days -1 - Day 60 | 
| 12-lead safety ECGs [Safety and Tolerability] | Continuous 12-lead ECGs (Holter) will be recorded for 1 hours prior to dose and continue for at least 24 hours post dose. | Days -1 - Day 28 | 
| Coagulation tests [Safety and Tolerability] | Coagulation Tests is for activated partial thromboplastin time (aPTT2), Prothrombin time (PT2). | Days -1 - Day 28 | 
| Urine pregnancy test (females only) [Safety and Tolerability] | Female subjects will have a urine pregnancy test done at the end-of-study Day 60 or early withdrawal. | Day 28 | 
| FSH test (Post-menopausal females) [Safety and Tolerability] | Females claiming postmenopausal status will have blood collected to measure FSH levels. | Day -28 - Day -2 | 
| PK blood collection [Safety and Tolerability] | PK samples to be collected at pre-dose and post-dose. | Day 1 - Day 28 | 
| 12-lead safety ECGs [Safety and Tolerability] | ECGs will be performed pre-dose and post-dose at various time points. | Day 1 - Day 60 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUCExtrap [Pharmacokinetic Analysis] | PK parameters will be calculated from plasma concentrations of TBAJ-876 TBAJ-876, M2, and M3. AUCExtrap the percentage of extrapolated AUC to AUCinf based on extrapolation. | Days 1 - 28 | 
| AUCinf [Pharmacokinetic Analysis] | PK parameters will be calculated from plasma concentrations of TBAJ-876 TBAJ-876, M2, and M3. AUCinf is area under the concentration-time curve from time-zero extrapolated to infinity. | Days 1 - 28 | 
| AUClast [Pharmacokinetic Analysis] | PK parameters will be calculated from plasma concentrations of TBAJ-876 TBAJ-876, M2, and M3. AUClast area under the concentration-time curve from time-zero to the time of the last quantifiable concentration; calculated using the linear trapezoidal rule. | Days 1 - 28 | 
| AUCtau [Pharmacokinetic Analysis] | PK parameters will be calculated from plasma concentrations of TBAJ-876 TBAJ-876, M2, and M3. AUCtau is area under the concentration-time curve during the dosing interval; calculated using the linear trapezoidal rule. | Days 1 - 28 | 
| Cavg [Pharmacokinetic Analysis] | PK parameters will be calculated from plasma concentrations of TBAJ-876 TBAJ-876, M2, and M3. Cavg is average concentration during the dosing interval. | Days 1 - 28 | 
| Clast [Pharmacokinetic Analysis] | PK parameters will be calculated from plasma concentrations of TBAJ-876 TBAJ-876, M2, and M3. Clast is the last quantifiable concentration determined directly from individual concentration-time data. | Days 1 - 28 | 
| CL/F [Pharmacokinetic Analysis] | PK parameters will be calculated from plasma concentrations of TBAJ-876 TBAJ-876, M2, and M3. CL/F is apparent total clearance after single administration. | Days 1 - 28 | 
| CLss/F [Pharmacokinetic Analysis] | PK parameters will be calculated from plasma concentrations of TBAJ-876 TBAJ-876, M2, and M3. CLss/F is apparent total clearance after multiple administration. | Days 1 - 28 | 
| Cmax [Pharmacokinetic Analysis] | PK parameters will be calculated from plasma concentrations of TBAJ-876 TBAJ-876, M2, and M3. Cmax is maximum concentration, determined directly from individual concentration-time data. | Days 1 - 28 | 
| RAUC [Pharmacokinetic Analysis] | PK parameters will be calculated from plasma concentrations of TBAJ-876 TBAJ-876, M2, and M3. RAUC is accumulation factor during multiple dosing, based on AUCtau. | Days 1 - 28 | 
| RCmax [Pharmacokinetic Analysis] | PK parameters will be calculated from plasma concentrations of TBAJ-876 TBAJ-876, M2, and M3. RCmax is accumulation factor during multiple dosing, based on Cmax. | Days 1 - 28 | 
| Tlast [Pharmacokinetic Analysis] | PK parameters will be calculated from plasma concentrations of TBAJ-876 TBAJ-876, M2, and M3. Tlast is time of the last quantifiable concentration. | Days 1 - 28 | 
| Tmax [Pharmacokinetic Analysis] | PK parameters will be calculated from plasma concentrations of TBAJ-876 TBAJ-876, M2, and M3. Tmax is time of the maximum concentration. | Days 1 - 28 | 
| T1/2 [Pharmacokinetic Analysis] | PK parameters will be calculated from plasma concentrations of TBAJ-876 TBAJ-876, M2, and M3. T1/2 is the observed terminal half-life. | Days 1 - 28 | 
| Vz/F [Pharmacokinetic Analysis] | PK parameters will be calculated from plasma concentrations of TBAJ-876 TBAJ-876, M2, and M3. Vz/F is apparent volume of distribution in the terminal phase. | Days 1 - 28 | 
| λz [Pharmacokinetic Analysis] | PK parameters will be calculated from plasma concentrations of TBAJ-876 TBAJ-876, M2, and M3. λz is the observed terminal rate constant; estimated by linear regression through at least 3 data points in the terminal phase of the log concentration-time profile. | Days 1 - 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TBAJ-876, Diarylquinoline, DARQ