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

Tuberculosis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04493671
• Other study ID #: TBAJ-876-CL-001
• Status: Completed
• Phase: Phase 1
• Start date: June 8, 2020
• Est. completion date: November 15, 2022

Study information

• Verified date: November 2022
• Source: Global Alliance for TB Drug Development
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Description:

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 107
• Est. completion date: November 15, 2022
• Est. primary completion date: June 16, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 19 Years to 50 Years

Eligibility

Inclusion Criteria:

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

participation:

1. Understands study procedures and voluntarily provides written informed consent prior to the start of any study-specific procedures.

2. Is a healthy adult male or female, 19 to 50 years of age (inclusive) at the time of screening.

3. Has a body mass index (BMI) =18.5 and =32.0 (kg/m2) and a body weight of no less than 50.0 kg.

4. 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.

5. Has not used tobacco- or nicotine-containing products (including smoking cessation products), for a minimum of 6 months before dosing.

6. 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.

7. 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

8. 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.

9. Is willing to answer inclusion and exclusion criteria questionnaire at check-in.

10. Is able to comply with the protocol and the assessments therein, including all restrictions.

11. Is willing and able to remain in the study unit for the entire duration of the assigned confinement period and return for outpatient visits.

12. 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:

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. Surgery within the past 90 days prior to dosing as determined by the Investigator to be clinically relevant.

4. History or presence of alcoholism or drug abuse within the past 2 years as determined by the Investigator to be clinically relevant.

5. Participation in another clinical trial within 30 days prior to dosing.

6. Female subjects who are pregnant or lactating.

7. Positive result on a urine drug/alcohol screen at screening or check-in.

8. Positive result on urine cotinine at screening.

9. Has the following laboratory abnormalities at screening:

1. ALT or AST Grade 2 or greater (> 2.0 times ULN)

2. Creatinine Grade 2 or greater (>1.6 times ULN)

3. Pancreatic lipase Grade 2 or greater (>1.6 times ULN)

4. Amylase Grade 2 or greater (>1.6 times ULN)

5. Total bilirubin Grade 2 or greater

6. CPK (> 1.25 times ULN) If exclusionary lab criteria are met, values may be confirmed by repeat evaluation.

10. Has a positive test for hepatitis B surface antigen, hepatitis C antibody, or HIV at screening.

11. 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.

12. 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.

13. 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

14. 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.

15. 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).

16. Use of any prescription medication within 14 days prior to dosing.

17. 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.

18. 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.

19. 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.

20. Blood donation or significant blood loss within 56 days before the first dose of study medication until the end-of-study visit.

21. Plasma donation within 7 days before the first dose of study medication until the end-of-study visit.

22. Has been on a significantly abnormal diet during the 4 weeks preceding the first dose of study medication.

23. Unwilling to remove any artificial nails (e.g. acrylic, gel) or fingernail polish and not use such products for the duration of the study.

24. History or presence of allergic or adverse response to Listerine breath strips or aspartame.

25. If assigned to the fasted/fed cohort, is lactose intolerant.

Related Conditions & MeSH terms

• Drug Sensitive Tuberculosis
• Drug-resistant Tuberculosis
• Latent Tuberculosis
• Multi Drug Resistant Tuberculosis
• Mycobacterium Tuberculosis Infection
• Pulmonary Disease
• Tuberculosis
• Tuberculosis, Multidrug-Resistant
• Tuberculosis, Pulmonary

Intervention

Drug:
• TBAJ-876 10mg
TBAJ-876 10mg tablets, oral suspension, orally administered
• TBAJ-876 25mg
TBAJ-876 25mg tablets,oral suspension, orally administered
• TBAJ-876 50mg
TBAJ-876 50mg tablets,oral suspension, orally administered
• TBAJ-876 100mg
TBAJ-876 100mg tablets, oral suspension, orally administered
• TBAJ-876 200mg
TBAJ-876 200mg tablets, oral suspension, orally administered
• TBAJ-876 400mg
TBAJ-876 400mg tablets, oral suspension, orally administered
• TBAJ-876 Dose XXXmg for Food cohort
Based on exposure levels from initial cohorts, a dose will be chosen for the food-effect cohort.
• TBAJ-876 XXXmg for Part 2
Part 2, Multiple ascending dose (MAD) cohorts doses to be determined.
• Matching Placebo for TBAJ-876 tablet
Matching Placebo for TBAJ-876 tablets, oral suspension, orally administered

Locations

Country	Name	City	State
United States	Worldwide Clinical Trials	San Antonio	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Global Alliance for TB Drug Development

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	Coagulation tests [Safety and Tolerability]	Coagulation Tests is for activated partial thromboplastin time (aPTT2), Prothrombin time (PT2).	Days -1 - Day 28
Primary	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
Primary	FSH test (Post-menopausal females) [Safety and Tolerability]	Females claiming postmenopausal status will have blood collected to measure FSH levels.	Day -28 - Day -2
Primary	PK blood collection [Safety and Tolerability]	PK samples to be collected at pre-dose and post-dose.	Day 1 - Day 28
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	?z [Pharmacokinetic Analysis]	PK parameters will be calculated from plasma concentrations of TBAJ-876 TBAJ-876, M2, and M3. ?z 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