Tuberculosis, Tuberculosis, Pulmonary
Conditions
Keywords
tuberculosis, TBA7371, TBA-7371, TB Alliance, TB, Pulmonary Tuberculosis
Brief summary
The primary objective of the study is to evaluate the safety and tolerability of single and multiple doses of TBA-7371 in healthy subjects
Detailed description
Three - part, partially-blinded, placebo controlled, combined single ascending dose with a food effect cohort and multiple ascending dose and a drug-drug interaction study to be conducted in one study center in the United States. Part 1 has a single ascending dose (SAD) design with up to 5 planned dose levels. Based on the interim PK for the dose escalation decisions, a dose cohort will be selected to return for an additional dose after a high calorie, high fat meal. Safety will be assessed throughout the study; serial ECGs and serial blood samples will be collected for the safety and PK assessment of TBA-7371. Dose escalation to the next cohort (i.e., dose level) will not take place until the Sponsor, in conjunction with the Principal Investigator, has determined that adequate safety, tolerability and PK from the previous cohort has been demonstrated to permit proceeding to the next cohort. Interim PK analyses will be performed for the dose escalation decisions, to select the intermediate dose for the food effect cohort, and to reconsider the sampling time points as the study progresses. All samples will be sent for analysis and the bioanalytical lab will be unblinded and only run the analysis on active treatment subjects. Data from the analysis used for the escalation meetings will only include active treatment subjects, and will be blinded by subject. Subjects will be housed in the WCT clinic from at least 24 hours prior (from Day -2), until 48 hours after dosing. Subjects will return for subsequent follow up safety and PK assessments on Day 4 and will be contacted via a phone call for follow-up questioning about adverse events 7 days later (Study Day 11). One cohort will return after a washout of at least 7 days or five half-lives (whichever is longer) of their fasting dose to receive the same intermediate dose (TBD mg) under fed conditions. Part 2 has a multiple ascending dose design. The dose cohorts for Part 2 will be determined based on model predictions to determine the steady-state Cmax exposure, and safety from Part 1. In this multiple ascending dose part, each subject will be administered TBA-7371 or matching placebo for 14 days with corresponding PK measurements. Three dose cohorts are planned. After each dose cohort, the Sponsor and Investigator will review the PK and safety data before proceeding to the next dose level. Part 3 has an open-label, multi-dose, fixed sequence drug-drug interaction study design. The dose of TBA-7371 to be studied will dependent on the interim PK analyses and safety from Part 2. In this DDI part, each subject (n=14) will be administered midazolam (2 mg suspension) and bupropion (150 mg, tablet) together on Day 1, followed by a 7-day washout, followed by administration of TBA-7371 on Days 8 through 21, followed by administration of midazolam, and bupropion on Day 22. PK will be assessed for midazolam on Days 1 and 22, bupropion on Days 1 - 5 and 22 - 26, and TBA-7371 on Days 8-21. At the end of Part 1 and at the end of Part 2, pharmacokinetic and safety data along with reasons for doses for the next part (Part 2 and Part 3, respectively) will be sent to the Food and Drug Administration (FDA) for review and approval. The study will not proceed to Part 2 or Part 3 until the FDA provides approval.
Interventions
DRUGTBA-7371
The test product is TBA-7371 25 mg/ml oral suspension formulation and TBA-7371 matching placebo oral suspension.
DRUGPlacebo
The test product is TBA-7371 25 mg/ml oral suspension formulation and TBA-7371 matching placebo oral suspension.
Sponsors
Global Alliance for TB Drug Development
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Masking description
Part 1 and Part 2 participants will be masked, Part 3 participants will not be masked.
Eligibility
Sex/Gender
ALL
Age
19 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
Subjects must fulfill all of the following inclusion criteria and none of the
Exclusion criteria
to be eligible for participation in the study, unless otherwise specified. 1. Healthy adult male and females of non-childbearing potential, 19 to 50 years of age (inclusive) at the time of screening. 2. Body mass index (BMI) ≥ 18.5 and ≤ 32.0 (kg/m2) and a body weight of no less than 50.0 kg. 3. Medically healthy with no clinically significant screening results (e.g., laboratory profiles, medical histories, vital signs, ECGs, physical examination) as deemed by the Investigator. 4. No use of tobacco or nicotine containing products (including smoking cessation products), for a minimum of 6 months prior to dosing. 5. Females of non-childbearing potential, having undergone one of the following sterilization procedures at least 6 months prior to dosing: i. Hysteroscopic sterilization ii. Bilateral tubal ligation or bilateral salpingectomy iii. Hysterectomy iv. Bilateral oophorectomy v. or be postmenopausal with amenorrhea for at least 1 year prior to the first dose with serum follicle stimulating hormone (FSH) levels consistent with postmenopausal status at screening. 6. Non-vasectomized males (or males vasectomized less than 120 days prior to study start), must agree to the following during study participation and for 90 days following the last administration of study drug: 1. use a condom with spermicide while engaging in sexual activity or be sexually abstinent 2. not donate sperm during this time. In the event the sexual partner is surgically sterile, use of a condom with spermicide is not necessary. None of the restrictions listed above are required for vasectomized males whose procedure was performed more than 120 days prior to study start. 7. Willing to answer inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and tolerability of single and multiple doses of TBA-7371 in healthy subjects by number and severity of treatment emergent adverse events (TEAEs) | Days 0-28 (depending on dosing schedule) | The primary endpoint of the study will be the number and severity of treatment emergent adverse events (TEAEs) following single doses of TBA-7371 and placebo |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics (PK) of single and multiple doses of TBA-7371 using Cmax | Days 0-28 (depending on dosing schedule) | This will be measured through Cmax. , Cmax = maximum observed concentration |
| Pharmacokinetics (PK) of single and multiple doses of TBA-7371 using Tmax | Days 0-28 (depending on dosing schedule) | This will be measured through Tmax, Tmax = Time of the maximum drug concentration (obtained without interpolation) |
| Compare the rate and extent of absorption of a single oral dose of TBA-7371 using AUC, when administered after a high-calorie, high-fat meal versus when it's administered fasting in healthy adult subjects | Days 0-28 (depending on dosing schedule) | This will be measured through PK parameters like AUC; AUC = Area under the curve |
| Compare the rate and extent of absorption of a single oral dose of TBA-7371 using Cmax, when administered after a high-calorie, high-fat meal versus when it's administered fasting in healthy adult subjects | Days 0-28 (depending on dosing schedule) | This will be measured through PK parameters like Cmax; Cmax = maximum observed concentration |
| Pharmacokinetics (PK) of single and multiple doses of TBA-7371 AUC(0-t) | Days 0-28 (depending on dosing schedule) | This will be measured through AUC(0-t). AUC = Area under the curve, t = determined time point |
| Effects of multiple-dose administration of TBA-7371 on the pharmacokinetics of midazolam and bupropion using AUC | Days 0-28 (depending on dosing schedule) | This will be measured through PK parameters like AUC; AUC = Area under the curve |
| Effects of multiple-dose administration of TBA-7371 on the pharmacokinetics of midazolam and bupropion using Cmax | Days 0-28 (depending on dosing schedule) | This will be measured through PK parameters like Cmax; Cmax = maximum observed concentration |
| Effects of multiple-dose administration of TBA-7371 on the pharmacokinetics of midazolam and bupropion using Tmax | Days 0-28 (depending on dosing schedule) | This will be measured through PK parameters like Tmax; Tmax = Time of the maximum drug concentration (obtained without interpolation) |
| Safety and tolerability of the combination of TBA7371 with midazolam and bupropion by the number and severity of treatment emergent adverse events (TEAEs) | Days 0-28 (depending on dosing schedule) | The primary endpoint of the study will be the number and severity of treatment emergent adverse events (TEAEs) following single doses of TBA-7371 and placebo |
| Compare the rate and extent of absorption of a single oral dose of TBA-7371 using Tmax, when administered after a high-calorie, high-fat meal versus when it's administered fasting in healthy adult subjects | Days 0-28 (depending on dosing schedule) | This will be measured through PK parameters like Tmax; Tmax = Time of the maximum drug concentration (obtained without interpolation) |
Countries
United States
Outcome results
None listed