A Drug Interaction Study With Fluticasone Furoate/GW642444 Inhalation Powder and Ketoconazole

Condition(s) targeted: Asthma

Intervention: ketoconazole (placebo to match) (Drug); FF / GW642444 (Drug); ketoconazole (Drug)

Phase: Phase 1

Status: Recruiting

Sponsored by: GlaxoSmithKline

Official(s) and/or principal investigator(s):
GSK Clinical Trials, Study Director, Affiliation: GlaxoSmithKline

Overall contact:
US GSK Clinical Trials Call Center, Phone: 877-379-3718

A randomized two-way crossover study to determine whether concomitant administration of CYP P450 3A4 inhibitor ketoconazole and fluticasone furoate/GW642444M combination significantly increases the systemic effects and exposure to repeat dose fluticasone furoate and/or GW642444 in healthy subjects. Key assessments will include blood potassium, heart rate, blood pressure, QTc, serum cortisol and pharmacokinetic parameters, and safety including vital signs, ECGs, adverse event monitoring and laboratory safety tests, including blood glucose

Official title: A Double-blind, Randomized, Placebo-controlled, Repeat Dose, 2-way Crossover Drug Interaction Study to Investigate the Pharmacokinetic and Pharmacodynamic Effects Following Administration of Fluticasone Furoate/GW642444M Inhalation Powder With Ketoconazole

Study design: Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator)

Primary outcome:

Weighted mean serum cortisol (0-24 hours) on Day 11.

Maximum heart rate (0-4 hours) and minimum blood potassium level (0-4 hours) on the morning of Day 11

Secondary outcome:

Minimum diastolic blood pressure (0-4 hours), maximum systolic blood pressure (0-4 hours) and maximum QTcF (0-4 hours) on the morning of Day 11

Fluticasone furoate and GW642444 pharmacokinetics (AUC(0-t), AUC(0-24), Cmax, tmax) on Day 5 and 11

Reported adverse events

12-lead ECG and clinical laboratory data and maximum heart rate (0-4 hours) maximum QTc (0-4 hours) and minimum blood potassium and blood glucose levels (0-4 hours) on the morning of Day 5.

Detailed description: This will be a single centre, randomized, double-blind (with respect to ketoconazole), two-way cross-over study in healthy male and female subjects. Subjects will attend for a screening visit within 28 days prior to the first treatment period. There will be two study periods, each consisting of 14 days. Ketoconazole or matching placebo will be administered for 11 days with fluticasone furoate/GW642444M inhalation powder co-administered on Days

5-11. During each period subjects will be required to report to the unit on Day - 1 and will

remain there until 1 hour post-dosing with ketoconazole or placebo on Day 1. Subjects will return to the unit on the mornings of Day 2 to Day 4 for dosing with ketoconazole or placebo. Subjects will then return on the evening of Day 4 and leave the unit on the morning of Day 6 (2 nights). Subjects will return to the unit on the mornings of Day 7 to Day 10 for dosing and pre-fluticasone furoate/GW642444M dose safety assessments. Subjects will return on the evening of Day 10 and leave the unit on the morning of Day 12 (2 nights). Subjects will make two outpatient visits, one in the evening on Day 12 and one in the morning on Day 13, to complete a few study related procedures. The two treatment periods will be separated by a washout of at least 7 days and no more than 14 days. Pharmacodynamic profiles for potassium, heart rate, QTc, blood pressure and serum cortisol will be taken on Day 11 with fluticasone furoate and GW642444 pharmacokinetic profiles on Days 5 and 11. Safety assessments will include vital signs, ECGs, adverse event monitoring and laboratory safety tests, plus blood glucose and blood potassium profiles on Day 5.

Minimum age: 18 Years. Maximum age: 64 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

1. Healthy male or female between 18 and 64 years of age inclusive

2. A female subject is eligible to participate if she is of:

- Non-childbearing potential defined as pre-menopausal females with a documented

tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MlU/ml and estradiol < 40 pg/ml (<140 pmol/L) is confirmatory]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods in Section 8. 1 if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.

- Child-bearing potential and agrees to use one of the contraception methods

listed in Section 8. 1 for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until completion of the follow-up visit.

3. Body mass index within range of 18. 5-29. 0 kg/m2 inclusive.

4. Subjects who are current non-smokers, who have not used any tobacco products in the 12 month period preceding the screening visit, and have a pack history of 5. AST, ALT, alkaline phosphatase and bilirubin 1. 5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).

6. No significant abnormality on 12-lead ECG at screening, including the following specific requirements:

- QTcF < 450 msec

7. No clinically significant abnormality on the Holter ECG at screening.

8. FEV1 >/= 85% predicted at screening.

9. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

10. Able to satisfactorily use the dry powder inhaler.

Exclusion Criteria:

1. As a result of medical interview, physical examination or screening investigations, the principal investigator or delegate physician deems the subject unsuitable for the study. Subjects must not have a systolic blood pressure above 145 mmHg or a diastolic pressure above 85 mmHg unless the Investigator confirms that it is satisfactory for their age.

2. The subject has any history of breathing problems in adult life (i. e. history of asthmatic symptomatology).

3. Pregnant females as determined by positive serum hCG test at screening or by positive serum/urine hCG test prior to dosing.

4. Lactating females.

5. The subject has been treated for or diagnosed with depression within six months of screening or has a history of significant psychiatric illness.

6. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).

7. Subjects who have suffered a lower respiratory tract infection within 4 weeks of the screening visit.

8. History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation.

9. Any adverse reaction including immediate or delayed hypersensitivity to any beta-agonist, sympathomimetic drug, or any intranasal, inhaled or systemic corticosteroid therapy. Known or suspected sensitivity to the constituents of the new powder inhaler (ie lactose or magnesium stearate)

10. History of milk protein allergy.

11. Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety.

12. The subject has taken oral corticosteroids less than 8 weeks before the screening visit.

13. The subject has taken inhaled, intranasal or topical steroids less than 4 weeks before the screening visit.

14. History of alcohol/drug abuse or dependence within 12 months of the study. Abuse of alcohol defined as an average weekly intake of greater than 21 units or an average daily intake of greater than 3 units (males) or defined as an average weekly intake of greater than 14 units or an average daily intake of greater than 2 units (females).

15. The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 3 months, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).

16. Exposure to more than four new chemical entities within 12 months prior to the first dosing day.

17. Where participation in the study would result in donation of blood or blood products in excess of 500 mL within 3 months of the start of the trial.

18. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.

19. The subject has tested positive for HIV antibodies.

20. A positive pre-study urine drug screen or when randomly tested during the study.

21. Positive carbon monoxide (CO) or alcohol breath test at screening or on admission to the Unit.

22. Consumption of seville oranges, pomelos (members of the grapefruit family) or grapefruit juice from 7 days prior to the first dose of study medication.

23. Unwillingness or inability to follow the procedures outlined in the protocol.

24. Subject is mentally or legally incapacitated.

US GSK Clinical Trials Call Center, Phone: 877-379-3718

GSK Investigational Site, London NW10 7EW, United Kingdom; Recruiting
Steve Warrington, Principal Investigator

Starting date: July 2010
Last updated: July 16, 2010