Food Effect Study on the Bioavailability and PK of PA-824 Tablets in Healthy Adult Subjects (CL-009)

Tuberculosis Clinical Trial

— CL-009  

Official title:

A Phase 1, Randomized, Balanced, Single-Dose, Two-Period, Two-Sequence, Crossover, Open-Label Study of the Effect of Food on the Bioavailability and Pharmacokinetics of PA-824 Tablets in Healthy Adult Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01830439
• Other study ID #: PA-824-CL-009
• Status: Completed
• Phase: Phase 1
• Start date: September 2009
• Est. completion date: January 2010

Study information

• Verified date: September 2019
• Source: Global Alliance for TB Drug Development
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This will be a Phase 1, single-center, randomized, balanced, single-dose, two-period, two-sequence, crossover, open-label study to evaluate the effect of food on the pharmacokinetics of PA-824. The hypothesis to be tested in this study is that the rate and extent of absorption of two doses of PA-824 (50mg or 400 mg and 200mg) are the same after a high-calorie, high-fat meal as compared with after a minimum 10-hour fast.

For each of the two dose levels 16 subjects with approximately 8 men and 8 women, will be enrolled for a total of 32 subjects.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 32
• Est. completion date: January 2010
• Est. primary completion date: January 2010
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 19 Years to 50 Years

Eligibility

Inclusion Criteria:

1. Have the ability to understand the requirements of the study, have provided written informed consent (as evidenced by signature on an informed consent document approved by an IRB), and agree to abide by the study restrictions.

2. Be healthy non-tobacco/nicotine using (6-month minimum) adult subjects, 19 to 50 years of age, inclusive.

3. Be medically healthy subjects with clinically insignificant Screening results (among laboratory profiles, medical histories, ECGs, or physical exam), as deemed by the Principal Investigator.

4. Have a body mass index of 18 to 29.

5. Have negative urine test results for alcohol and drugs of abuse such as amphetamines, cannabinoids, and cocaine metabolites at both Screening and Check-in.

6. Agree to follow the requirements set forth in the protocol regarding pregnancy controls and donation of sperm, blood, or blood components.

Exclusion Criteria:

1. Any clinically significant (as deemed by the Principal Investigator) history, acute illness (resolved within 4 weeks of screening), or presence of cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal (including eating disorders), endocrine, metabolic, immunologic, dermatologic, neurologic, psychological, or psychiatric disease.

2. History of peptic ulcer disease, gastritis, esophagitis, or gastroesophageal reflux disease.

3. History of any cardiac abnormality (as deemed by the Principal Investigator).

4. Any clinically significant ECG abnormality at Screening (as deemed by the Principal Investigator and the Sponsor's Medical Monitor). Note: the following can be considered not clinically significant without consulting Sponsor's Medical Monitor:

• Sinus bradycardia with heart rate =50 beats per minute (sinus bradycardia with heart rate between 45 and 49, inclusive, is acceptable only in younger athletic subjects)

• 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

5. History of prolonged QT interval.

6. 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 or CHF or terminal cancer)

7. Resting pulse rate < 40 or > 100 bpm at Screening.

8. At Screening blood pressure greater than 140/90 mm Hg or below 95/65 mm Hg (supine, after a minimum 5-minute supine rest)

9. At either Screening or the pre-dose read before the first dose, a QTcB (Bazett's correction) >450ms for men and women, calculated from the average of triplicate reads collected at one sitting.

10. At either Screening or the pre-dose read before the first dose, a QTcF (Fridericia's correction) >450ms for men and women, calculated from the average of triplicate reads collected at one sitting.

11. History of hypokalemia or hypomagnesemia.

12. History or presence of alcoholism or drug abuse within the past 2 years (as deemed by the Principal Investigator).

13. Use of alcohol within 72 hours prior to dosing.

14. Significant history of drug and/or food allergies (as deemed by the Principal Investigator).

15. For women, subject is pregnant (positive test for serum HCG at Screening or Check-in), breastfeeding or planning to conceive a child within 1 week of cessation of treatment.

16. For males, planning to father a child within 12 weeks of cessation of treatment.

17. History of lens opacity or evidence of lens opacity on slit lamp ophthalmologic examination.

18. Any contraindication to the use of nitroimidazoles or prior treatment with PA-824 or OPC-67683.

19. Use of any systemic or topical prescription medication within 14 days prior to dosing or during the study, except hormonal contraceptives in women

20. Use of any systemic or over-the-counter medication including vitamins, herbal preparations, antacids, cough and cold remedies, etc., within 7 days prior to dosing or during the study.

21. Use of any drugs or substances within 30 days prior to dosing known to be strong inhibitors or inducers of cytochrome P450 enzymes (including quinidine, tyramine, ketoconazole, testosterone, quinine, gestodene, metyrapone, phenelzine, doxorubicin, troleandomycin, cyclobenzaprine, erythromycin, cocaine, furafylline, cimetidine, dextromethorphan, etc.) or known to prolong the QT interval (including amiodarone, bepridil chloroquine, chlorpromazine, cisapride, clarithromycin, disopyramide dofetilide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, methadone, pentamidine, pimozide, procainamide, quinidine, quinolones, sotalol, sparfloxacin, thioridazine,) or barbiturates, opiates, or phenothiazines.

22. Use of any therapeutic agents known to alter any major organ function (e.g., barbiturates, opiates, phenothiazines, cimetidine, etc.) within 30 days prior to dosing.

23. Consumption of products containing grapefruit within 10 days prior to dosing.

24. Any special dietary changes during the 30 days prior to dosing, as deemed by the Principal Investigator in consultation with the Sponsor Medical Monitor.

25. Any strenuous exercise within 7 days of Check-in, as deemed by the Principal Investigator in consultation with the Sponsor Medical Monitor.

26. Donation of whole blood or significant loss of blood within 56 days prior to dosing.

27. Plasma donation within 7 days prior to dosing

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

29. Any serum creatinine or BUN measure beyond the upper limit of the normal range at Screening or Check-in. Individual values may be discussed with the Sponsor Medical Monitor.

30. Hemoglobin < 12.0 g/dL at the screening and check-in visit.

31. Positive Screening test for HCV, HBV, or HIV.

32. Any other factor which suggests to the Principal Investigator that the subject should not participate in the study.

Related Conditions & MeSH terms

• Tuberculosis

Intervention

Drug:
• PA-824 200mg
Two single administrations of 200mg PA-824 each administered by four 50mg tablets, one administered in the fed state and one administered in the fasted state. The two administrations were separated by 8 days.
• PA-824 50mg
Two single administrations of 50mg PA-824 each administered by one 50mg tablet, one administered in the fed state and one administered in the fasted state. The two administrations were separated by 8 days.

Locations

Country	Name	City	State
United States	MDS Pharma Services (Celerion)	Lincoln	Nebraska

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	Time of the maximum drug concentration in hours [Tmax]	To compare the rate and extent of absorption as measured by Tmax of a single oral dose of PA-824 tablets (200 mg in Phase A and either 50 mg or 400 mg in Phase B) in healthy adult male and female subjects when PA-824 is administered after a high-calorie, high-fat meal and when it is administered after a minimum 10-hour fast. Tmax is obtained without interpolation.	mean through 36 hours after each dose with measurements at predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, and 36 hours post dose
Primary	Maximum observed drug concentration in ng/mL [Cmax]	To compare the rate and extent of absorption as measured by Cmax of a single oral dose of PA-824 tablets (200 mg in Phase A and either 50 mg or 400 mg in Phase B) in healthy adult male and female subjects when PA-824 is administered after a high-calorie, high-fat meal and when it is administered after a minimum 10-hour fast.	mean through 36 hours after each dose with measurements at predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, and 36 hours post dose
Primary	Area under the drug concentration-time curve in ng*hr/mL [AUC(0-t)]	To compare the rate and extent of absorption as measured by AUC(0-t) of a single oral dose of PA-824 tablets (200 mg in Phase A and either 50 mg or 400 mg in Phase B) in healthy adult male and female subjects when PA-824 is administered after a high-calorie, high-fat meal and when it is administered after a minimum 10-hour fast. AUC(0-t) is calculated using linear trapezoidal summation from time zero to time t, where t is the time of the last measurable concentration.	mean through 36 hours after each dose with measurements at predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, and 36 hours post dose
Primary	Area under the drug concentration-time curve from time zero to infinity in ng*hr/mL [AUC(0-inf)]	To compare the rate and extent of absorption as measured by AUC(0-inf) of a single oral dose of PA-824 tablets (200 mg in Phase A and either 50 mg or 400 mg in Phase B) in healthy adult male and female subjects when PA-824 is administered after a high-calorie, high-fat meal and when it is administered after a minimum 10-hour fast. AUC(0-inf) is calculated as AUC(0-t) + Ct/Kel.	mean through 36 hours after each dose with measurements at predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, and 36 hours post dose
Secondary	Ratio of AUC(0-t) to AUC(0-inf) [AUC(0-t)/ AUC(0-inf)]	To compare AUC(0-t)/ AUC(0-inf) of a single oral dose of PA-824 tablets (200 mg in Phase A and 50 mg or 400 mg in Phase B) in healthy adult male and female subjects when PA-824 is administered after a high-calorie, high-fat meal and when it is administered after a minimum 10-hour fast.	mean through 36 hours after each dose with measurements at predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, and 36 hours post dose
Secondary	Number of participants with adverse events	To compare the safety and tolerability as measured by the number of participants with adverse events after a single oral dose of PA-824 tablets (200 mg in Phase A and 50 mg or 400 mg in Phase B) in healthy adult male and female subjects when PA-824 is administered after a high-calorie, high-fat meal and when it is administered after a minimum 10-hour fast.	through the study Day 13, and through Day 103 for SAE and ophthalmologic events
Secondary	Elimination half-life in hours [t1/2]	To compare t1/2 of a single oral dose of PA-824 tablets (200 mg in Phase A and 50 mg or 400 mg in Phase B) in healthy adult male and female subjects when PA-824 is administered after a high-calorie, high-fat meal and when it is administered after a minimum 10-hour fast. T1/2 is calculated as ln (2)/Kel.	mean through 36 hours after each dose with measurements at predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, and 36 hours post dose
Secondary	Terminal elimination rate constant in 1/hour [Kel]	To compare Kel of a single oral dose of PA-824 tablets (200 mg in Phase A and 50 mg or 400 mg in Phase B) in healthy adult male and female subjects when PA-824 is administered after a high-calorie, high-fat meal and when it is administered after a minimum 10-hour fast. Kel is calculated by linear regression of the terminal linear portion of the log concentration vs. time curve, using at least 3 data points	mean through 36 hours after each dose with measurements at predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, and 36 hours post dose
Secondary	Oral clearance in L/hour [Cl/F]	To compare Cl/F of a single oral dose of PA-824 tablets (200 mg in Phase A and 50 mg or 400 mg in Phase B) in healthy adult male and female subjects when PA-824 is administered after a high-calorie, high-fat meal and when it is administered after a minimum 10-hour fast. Cl/F is calculated as Dose/AUC(0-inf).	mean through 36 hours after each dose with measurements at predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, and 36 hours post dose
Secondary	Volume of distribution following oral administration in L [Vd/F]	To compare Vd/F of a single oral dose of PA-824 tablets (200 mg in Phase A and 50 mg or 400 mg in Phase B) in healthy adult male and female subjects when PA-824 is administered after a high-calorie, high-fat meal and when it is administered after a minimum 10-hour fast. Vd/F is calculated as (CL/F)/Kel.	mean through 36 hours after each dose with measurements at predose, 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, and 36 hours post dose

External Links

•   Global Alliance for TB Drug Development website