A Phase 1 Study to Evaluate Safety, Tolerability, PK, and PK Interactions of TBA-7371

• Status: Completed
• Trial end date: 2018-07-08
• Target enrollment: 0
• Participant gender: All

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

• Phase: Phase 1
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: Global Alliance for TB Drug Development
• Treatments: Bupropion; Midazolam

Criteria

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 exclusion criteria questionnaire at check-in.

8. Subject understands study procedures and provides written informed consent for the trial.

9. Be able to comply with the protocol and the assessments therein, including all restrictions.

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

11. If enrolled in Part 1 and assigned to the fasted/fed cohort, is willing and able to consume the entire high-calorie, high-fat breakfast meal in the timeframe required.

Exclusion Criteria:

Subjects will be excluded from the study if there is evidence of any of the following criteria at screening or check-in, as appropriate.

1. History or presence of significant cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic, neurological, or psychiatric disease as determined by the Investigator to be clinically relevant.

2. History of any illness that, in the opinion of the Investigator, might confound the results of the study or poses an additional risk to the subject by their participation in the study.

3. Surgery within the past 90 days prior to dosing as determined by the Investigator to be clinically relevant, or any history of cholecystectomy.

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

5. Female subjects who are pregnant or lactating.

6. Positive results for the urine drug/alcohol screen at screening or check-in.

7. Positive urine cotinine at screening or check in.

8. Serum magnesium potassium, or calcium laboratory values outside of the normal range at screening.

9. Positive results at screening for Human Immunodeficiency Virus (HIV), Hepatitis B Surface Antigen (HBsAg), or Hepatitis C antibodies (HCV).

10. Seated blood pressure is less than 90/40 mmHg or greater than 140/90 mmHg at screening, Day -2 (check-in), Day -1, or predose. Out-of-range vital signs may be repeated once for confirmation.

11. Seated heart rate is lower than 40 bpm or higher than 99 bpm at screening, Day -2 (check-in), Day -1, or predose. Out-of-range vital signs may be repeated once for confirmation.

12. Any electrocardiogram abnormality at Screening (as deemed by decision of the Investigator and the Sponsor's Medical Monitor).

NOTE: The following can be considered not clinically significant without consulting the Sponsor's Medical Monitor:

i. Mild first degree A-V block (P-R interval <0.23 sec) ii. Right or left axis deviation iii. Incomplete right bundle branch block iv. Isolated left anterior fascicular block (left anterior hemiblock) in younger athletic subjects

13. QTcF interval >450 msec for males or >470 msec for females at screening, Day -2, Day -1, or Day 1 (pre-dose), or history of prolonged QT syndrome.

14. 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).

15. History of one or any combination of, the following:

i. Seizures or seizure disorders ii. Brain surgery. iii. History of head injury in the last five years iv. Any serious disorder of the CNS or related neurological system, particularly one that may lower the seizure threshold.

v. History of seizures

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 the 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.

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 P-gp, including St. John's Wort, within 30 days prior to the first dose of study drug.

20. Use of any drugs or substance known to lower the seizure threshold.

21. Blood donation or significant blood loss within 56 days prior to dosing.

22. Plasma donation within 7 days prior to dosing.

23. Participation in another clinical trial within 28 days prior to dosing. Consumption of foods and beverages containing the following substances will be prohibited

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

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

26. Is colorblind (assessed using the Ishihara Color Vision Test)

Additionally, the following exclusion applies only to subjects in Part 1, the SAD study:

27. Is lactose intolerant.

Additionally, the following exclusion applies only to subjects in Part 1 and 2, the SAD and MAD studies:

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

Additionally, the following exclusions apply only to subjects in Part 3, the DDI study:

29. History or presence of allergic or adverse response to midazolam, bupropion, or related drugs.

30. History of presence of acute narrow-angle or untreated open-angle glaucoma

31. Current or prior diagnosis of bulimia or anorexia nervosa

32. Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or anti-epileptic drugs within 14 days prior to the first dose of study treatment

33. Discontinued the use of monoamine oxidase inhibitors (MAOs) within 14 days prior to the first dose of study treatment

34. History or presence of suicidal ideation or suicidal behavior as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS, Baseline/Screening Version) at the Screening Visit.