To Investigate the Pharmacokinetics and Safety of Fluticasone Furoate (FF)/ Umeclidinium (UMEC) Combination Compared With FF and UMEC Monotherapies in Adult Healthy Volunteers Using a Dry Powder Inhaler (DPI)

NCT01725685 | Completed Phase 1

• 1 other identifier: 116524
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

This will be a randomized, double-blind, single-dose, three-period balanced crossover study in adult healthy subjects. Each of the 18 subjects will be randomized to receive a treatment sequence consisting of each of the three treatments (FF 400 microgram (mcg), UMEC 500 mcg and FF 400 mcg/UMEC 500 mcg), in three consecutive periods, with a wash-out period of 7 to 10 days between the periods. The study will include a Screening period (28 days prior to first dose), Treatment period (3 single dose periods separated by two 7 to 10 days washout periods) and Follow-up period (7 to 14 days post last dose). The pharmacokinetic (PK) and safety assessments will be performed during the study at fixed timepoints.

Conditions

Asthma

Keywords

healthy volunteers; Umeclidinium; tolerability; Safety; Fluticasone Furoate; Pharmacokinetics

Outcome Measures

Primary Outcomes (14)

• Maximum observed plasma concentration (Cmax) in plasma for FF and UMEC

  The PK parameter Cmax will be calculated for FF/UMEC in combination and as monotherapies

  Period 1, 2 and 3: Day 1 (pre-dose, 5 minutes [mins], 15 mins, 30 mins, 45 mins, 1 hour (h), 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 16 h) and Day 2 (24 h)

• Area under the concentration-time curve (AUC(0-t)), where t is time of last measurable concentration in plasma for FF and UMEC

  The PK parameter AUC(0-t) will be calculated for will be calculated for FF/UMEC in combination and as monotherapies

  Period 1, 2 and 3: Day 1 (pre-dose, 5 mins, 15 mins, 30 mins, 45 mins, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 16 h) and Day 2 (24 h)

• Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time [AUC(0-inf)] in plasma for FF and UMEC, if data permits

  The PK parameter AUC(0-inf) will be calculated for will be calculated for FF/UMEC in combination and as monotherapies

  Period 1, 2 and 3: Day 1 (pre-dose, 5 mins, 15 mins, 30 mins, 45 mins, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 16 h) and Day 2 (24 h)

• Time of maximum observed concentration (tmax) in plasma for FF and UMEC

  The FF and UMEC PK parameter in plasma will be calculated to compare the PK of FF/UMEC in combination with FF and UMEC monotherapies

  Period 1, 2 and 3: Day 1 (pre-dose, 5 mins, 15 mins, 30 mins, 45 mins, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 16 h) and Day 2 (24 h)

• Time of last measurable concentration (tlast) in plasma for FF and UMEC

  The FF and UMEC PK parameter in plasma will be calculated to compare the PK of FF/UMEC in combination with FF and UMEC monotherapies

  Period 1, 2 and 3: Day 1 (pre-dose, 5 mins, 15 mins, 30 mins, 45 mins, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 16 h) and Day 2 (24 h)

• Plasma elimination half life (t½) in plasma for FF and UMEC, if data permits

  The FF and UMEC PK parameter in plasma will be calculated to compare the PK of FF/UMEC in combination with FF and UMEC monotherapies

  Period 1, 2 and 3: Day 1 (pre-dose, 5 mins, 15 mins, 30 mins, 45 mins, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 16 h) and Day 2 (24 h)

• Elimination rate constant (Lambda z) in plasma for FF and UMEC, if data permits

  The FF and UMEC PK parameter in plasma will be calculated to compare the PK of FF/UMEC in combination with FF and UMEC monotherapies

  Period 1, 2 and 3: Day 1 (pre-dose, 5 mins, 15 mins, 30 mins, 45 mins, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 16 h) and Day 2 (24 h)

• Apparent clearance (CL/F) in plasma for FF and UMEC, if data permits

  The FF and UMEC PK parameter in plasma will be calculated to compare the PK of FF/UMEC in combination with FF and UMEC monotherapies

  Period 1, 2 and 3: Day 1 (pre-dose, 5 mins, 15 mins, 30 mins, 45 mins, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 16 h) and Day 2 (24 h)

• Apparent volume of distribution (V/F) in plasma for FF and UMEC, if data permits

  The FF and UMEC PK parameter in plasma will be calculated to compare the PK of FF/UMEC in combination with FF and UMEC monotherapies

  Period 1, 2 and 3: Day 1 (pre-dose, 5 mins, 15 mins, 30 mins, 45 mins, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 16 h) and Day 2 (24 h)

• Cumulative amount excreted drug in urine (Ae) for UMEC

  The UMEC PK parameter in urine will be calculated to compare the PK of UMEC when co-administered with FF; with UMEC as a monotherapy

  Period 1, 2 and 3: Day 1 (pre-dose, 0-6 h, 0-8 h, 0-12 h, 0-16 h) and Day 2(0-24 h)

• Percent of dose excreted (% Fe) in urine for UMEC

  The UMEC PK parameter in urine will be calculated to compare the PK of UMEC when co-administered with FF; with UMEC as a monotherapy

  Period 1, 2 and 3: Day 1 (pre-dose, 0-6 h, 0-8 h, 0-12 h, 0-16 h) and Day 2 (0-24 h)

• Urine half life (urine t½) for UMEC, if data permits

  The UMEC PK parameter in urine will be calculated to compare the PK of UMEC when co-administered with FF; with UMEC as a monotherapy

  Period 1, 2 and 3: Day 1 (pre-dose, 0-6 h, 0-8 h, 0-12 h, 0-16 h) and Day 2 (0-24 h)

• Renal clearance (CLr) in urine for UMEC, if data permits

  The UMEC PK parameter in urine will be calculated to compare the PK of UMEC when co-administered with FF; with UMEC as a monotherapy

  Period 1, 2 and 3: Day 1 (pre-dose, 0-6 h, 6-8 h, 8-12 h, 12-16 h) and Day 2(16-24 h)

• Area under the concentration-time curve from time zero (pre-dose) to the time at which AUC is calculable for all subjects (AUC(0-t')), where t' is the time at which AUC is calculable for all the subjects

  The PK parameter AUC(0-t') will be calculated for will be calculated for FF/UMEC in combination and as monotherapies

  Period 1, 2 and 3: Day 1 (pre-dose, 5 mins, 15 mins, 30 mins, 45 mins, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h, 8 h, 12 h, and 16 h) and Day 2 (24 h)

Secondary Outcomes (5)

• Clinical Safety data assessed as number of adverse events (AE) in each treatment group

  Period 1 Day 1 dose to Follow up visit

• Clinical laboratory measurements for each treatment group

  Period 1, 2 and 3: Baseline (Day -1) and Day 2

• Systolic and diastolic blood pressure for each treatment group

  Baseline (Day 1 pre-dose) and Day 2 of each treatment period; and Follow-up Visit

• Heart rate for each treatment group

  Baseline (Day 1 pre-dose) and Day 2 of each treatment period; and Follow-up Visit

• 12-lead electrocardiogram (ECG) for each treatment group

  Baseline (Day 1 pre-dose) and Day 2 of each treatment period; and Follow-up Visit

Study Arms (3)

Treatment A - FF 400 microgram (mcg)

EXPERIMENTAL

Subjects will be randomized to single dose of FF 400 mcg in either of the three treatment period, which is separated by a wash-out period of 7 to 10 days.

Drug: FF 400 mcg

Treatment B - UMEC 500 mcg

EXPERIMENTAL

Subjects will be randomized to single dose of UMEC 125 mcg in either of the three treatment period, which is separated by a wash-out period of 7 to 10 days.

Drug: UMEC 500 mcg

Treatment C - FF/UMEC 400/500 mcg

EXPERIMENTAL

Subjects will be randomized to single dose of FF/UMEC 100/125 mcg in either of the three treatment period, which is separated by a wash-out period of 7 to 10 days.

Drug: FF/UMEC 400/500 mcg

Interventions

FF 400 mcg DRUG

FF will be available as 100 mcg strength administered as 4 inhalations from a DPI

Treatment A - FF 400 microgram (mcg)

UMEC 500 mcg DRUG

UMEC will be available as 125 mcg strength administered as 4 inhalations from a DPI

Treatment B - UMEC 500 mcg

FF/UMEC 400/500 mcg DRUG

FF/UMEC will be available as 100/125 mcg strength administered as 4 inhalations from a DPI

Treatment C - FF/UMEC 400/500 mcg

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring.
• A subject with a clinical abnormality or laboratory parameters outside the reference range for the population being studied may be included only if the Investigator and the GlaxoSmithKline (GSK) Medical Monitor agree that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
• Male or female between 18 and 65 years of age inclusive, at the time of signing the informed consent.
• A female subject is eligible to participate if she is of: Child-bearing potential and is abstinent or agrees to use the contraception methods listed in Protocol 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 the follow up visit (i.e. until after the follow up visit is complete; Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \> 40 million international units (MlU)/milliliter (ml) and estradiol \<40 picograms (pg)/ml (\<147 pmol/L) is confirmatory\] Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use the contraception methods listed in Protocol if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status prior to study enrollment. For most forms of HRT, at least 2 to 4 weeks should 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.
• Women who are confirmed postmenopausal or permanently sterilized (e.g. tubal occlusion, tubal ligation, hysterectomy, bilateral salpingectomy).
• Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods listed in Protocol. This criterion must be followed from the time of the first dose of study medication until the follow up visit.
• Alanine aminotransferase (ALT), alkaline phosphatase and bilirubin \<=1.5xupper limit of normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
• Average QT duration corrected for heart rate by Fridericia's formula (QTcF) \< 450 miliseconds (msec).
• Body mass index (BMI) within the range 19 to 33 kilogram (kg)/meter square (m2) (inclusive).
• Subjects who are current non-smokers who have not used any tobacco products in the 6-month period preceding the screening visit and have a pack history of ≤10 pack years.\[number of pack years = (number of cigarettes per day /20) x number of years smoked\]

You may not qualify if:

• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities.
• A positive pre-study drug/alcohol screen.
• A positive test for human Immunodeficiency virus (HIV) antibody.
• History of regular alcohol consumption within 6 months of the study defined as: an average weekly intake of \>14 drinks for males or \>7 drinks for females. One drink is equivalent to 12 g of alcohol: 12 ounces (360 mililitre \[mL\]) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.
• 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: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
• Exposure to more than four new chemical entities within 12 months prior to the first dosing day.
• Unable to refrain from the 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.
• 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.
• Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period.
• Pregnant females as determined by positive serum or urine hCG test at screening or prior to dosing.
• Lactating females.
• Unwillingness or inability to follow the procedures outlined in the protocol.
• Subject is mentally or legally incapacitated.
• History of sensitivity to heparin or heparin-induced thrombocytopenia.

Sponsors & Collaborators

• GlaxoSmithKline: lead
• Parexel: collaborator

Study Sites (1)

GSK Investigational Site

Baltimore, Maryland, 21225, United States

Location

Related Publications (1)

• Yang S, Lee L, Mallett S, Ayer J, Wolstenholme A, Pascoe S. A randomized, crossover study to investigate the pharmacokinetics and safety of inhaled fluticasone furoate and umeclidinium, administered separately and in combination via dry powder inhaler in healthy adult volunteers. Adv Ther. 2015 Feb;32(2):157-71. doi: 10.1007/s12325-015-0184-6. Epub 2015 Feb 21.

  PMID: 25700806 DERIVED

Related Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.
• Results for study 116524 can be found on the GSK Clinical Study Register.

MeSH Terms

Conditions

Asthma

Condition Hierarchy (Ancestors)

Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 1, 2012
• First Posted: November 14, 2012
• Study Start: November 8, 2012
• Primary Completion: January 2, 2013
• Study Completion: January 2, 2013
• Last Updated: June 9, 2017

Record last verified: 2017-06

Data Sharing

• IPD Sharing: Will share

Locations

US (1)