A Study to Assess the Systemic Exposure, Systemic Pharmacodynamics and Safety and Tolerability of FluticasoneFuroate, Umeclidinium and Vilanterol in Healthy Subjects

This study has been completed.
Sponsor:
Collaborator:
Parexel
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01691547
First received: September 20, 2012
Last updated: May 9, 2013
Last verified: May 2013
  Purpose

This is a double-blind, single dose (four inhalations), four-way cross over study in healthy subjects that will assess the systemic pharmacokinetics (PK) and systemic pharmacodynamics (PD) of Fluticasone Furoate, (FF), Umeclidinium, (UMEC) and Vilanterol (VI). Study drug will be delivered through a novel single-step activation dry powder inhaler (NDPI) which has a two strip configuration. The NDPI will be configured with different combinations of each compound and also a new blend of UMEC/VI inhalation powder within a single strip of the NDPI device. Study drug will be administered through the inhaled route to healthy subjects in single doses (four inhalations). Each subject will receive treatment in a randomized order Treatment A FF (400 microgram [µg]) and UMEC (500 µg)/VI (100 µg), Treatment B UMEC (500 µg) and VI (100 µg), Treatment C FF (400 µg) and VI (100 µg) and Treatment D FF (400 µg) and UMEC (500 µg) over four treatment periods. Each treatment period will be separated by a washout of 7 to 21 days. After the four treatment periods, a follow up visit will take place 7 to 21 days following the final dose of study medication and the maximum duration a subject will be involved in the study is eighteen weeks.

Pharmacokinetics will be assessed by the measurement of plasma and urine concentrations of FF, UMEC and VI. Safety and PD will be monitored using blood glucose, serum potassium, heart rate, 12-lead ECGs and clinical laboratory tests. Plasma samples for PK will be collected throughout the study, urine, blood glucose, serum potassium, heart rate, 12-lead ECGs and clinical laboratory tests will be assessed on Day 1 only. AEs will be assessed throughout the study.


Condition Intervention Phase
Pulmonary Disease, Chronic Obstructive
Drug: UMEC /VI
Drug: UMEC
Drug: VI
Drug: FF
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Official Title: A Randomized, Double-blind, Single Dose, Four Way Cross-over Study to Assess the Systemic Exposure, Systemic Pharmacodynamics and Safety and Tolerability of FluticasoneFuroate, Umeclidinium and Vilanterol Following Single Inhaled Doses of Umeclidinium/Vilanterol Blend + Fluticasone Furoate, Umeclidinium + Vilanterol, Fluticasone Furoate + Vilanterol and Fluticasone Furoate + Umeclidinium in Healthy Subjects

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • AUC and Cmax, for each of the treatment groups FF/UMEC/VI, UMEC/VI and FF/VI [ Time Frame: 3 days of each treatment period. ] [ Designated as safety issue: No ]
    The PK parameters and plasma concentrations: area under the concentration time-curve (AUC) from time zero to infinity (AUC(0-inf)) or AUC from time zero to last time of quantifiable concentration AUC(0-t') and maximum observed plasma concentration (Cmax) will be derived for each treatment group following single inhaled doses (four inhalations) of FF/UMEC/VI, UMEC/VI and FF/VI using the following treatment ratios: FF:FF/UMEC/VI versus FF/VI, UMEC:FF/UMEC/VI versus UMEC/VI, VI: FF/UMEC/VI versus UMEC/VI and VI: FF/UMEC/VI versus FF/VI.


Secondary Outcome Measures:
  • AUC(0-inf) or AUC(0-t') and Cmax for FF/UMEC/VI and FF/UMEC [ Time Frame: 3 days of each treatment period in which FF+UMEC/VI or FF+UMEC were administered. ] [ Designated as safety issue: No ]
    The PK parameters will be derived for FF and UMEC and VI following single inhaled doses (four inhalations) of FF/UMEC/VI and FF/UMEC using the following treatment ratios: UMEC:FF/UMEC/VI versus FF/UMEC and FF:FF/UMEC/VI versus FF/UMEC.

  • Plasma PK parameters: tmax, AUC(0-t), t (last), t1/2, λz, CL/F and V/F for individual component of each treatment group (FF/UMEC/VI, UMEC/VI, FF/VI and FF/UMEC) [ Time Frame: 3 days of each treatment period. ] [ Designated as safety issue: No ]
    The plasma PK parameters: time to Cmax (tmax), AUC(0-t), time of last measurable concentration (tlast), and terminal phase half-life (t1/2), elimination rate constant (λz), apparent clearance (CL/F) and apparent volume of distribution (V/F) (data permitting) will be derived for FF and UEMC and VI following single inhaled doses (four inhalations) of FF/UMEC/VI, UMEC/VI, FF/VI and FF/UMEC.

  • Urine pharmacokinetic parameters: Ae6, Ae10, Ae14, Ae18. Ae24, Ae36, Fe6, Fe10, Fe14, Fe 18, Fe24 and Fe36; urine t1/2 and CLr for UMEC following each treatment group (FF/UMEC/VI, UMEC/VI, and FF/UMEC) [ Time Frame: Day 1 of each treatment period in which UMEC (single or blended) was administered. ] [ Designated as safety issue: No ]
    Urine pharmacokinetic parameters: cumulative amount excreted (Ae) in the time interval Ae6, Ae10, Ae14, Ae18, Ae24, Ae36, percent of dose excreted (þ) in the time interval Fe6, Fe10, Fe14, Fe 18, Fe24 and Fe36; urine half life (urine t1/2) and renal clearance CLr (data permitting) will be assessed for UMEC following single inhaled doses (four inhalations) of FF/UMEC/VI, UMEC/VI and FF/UMEC

  • Maximum and weighted mean change from Baseline supine heart rate (0-4 hour (h)) [ Time Frame: 3 days of each treatment period. ] [ Designated as safety issue: No ]
    The heart rate of the subjects will be measured following single inhaled doses (four inhalations) of FF/UMEC/VI, UMEC/VI, FF/VI and FF/UMEC. Change from Baseline will be calculated as supine heart rate (0-4 h) minus supine heart rate (0-4 h) at Baseline.

  • Minimum and weighted mean change from Baseline serum potassium (0-4 h) [ Time Frame: 3 days of each treatment period. ] [ Designated as safety issue: No ]
    The serum potassium of the subjects will be measured following single inhaled doses (four inhalations) of FF/UMEC/VI, UMEC/VI, FF/VI and FF/UMEC. Change from Baseline will be calculated as serum potassium (0-4 h) minus serum potassium (0-4 h) at Baseline.

  • Maximum and weighted mean change from Baseline serum glucose (0-4 h) [ Time Frame: 3 days of each treatment period. ] [ Designated as safety issue: No ]
    The blood glucose of the subjects will be measured following single inhaled doses (four inhalations) of FF/UMEC/VI, UMEC/VI, FF/VI and FF/UMEC. Change from Baseline will be calculated as blood glucose (0-4 h) minus blood glucose (0-4 h) at Baseline.

  • Safety and tolerability of FF, UMEC and VI [ Time Frame: 18 weeks ] [ Designated as safety issue: No ]
    Safety and tolerability parameters include AEs, ECG, vital signs (pulse rate and systolic and diastolic blood pressure) and laboratory assessments include clinical biochemistry and hematological parameters.


Enrollment: 44
Study Start Date: December 2012
Study Completion Date: March 2013
Primary Completion Date: March 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: UMEC/VI+FF
UMEC (500 µg)/VI(100 µg) (blended together) and FF (400 µg) will be administered as single dose (4 inhalations); as dry powder in NDPI device once in 7 days in one of the 4 Treatment Periods of the study.
Drug: UMEC /VI
Umeclidinium is an inhaled long-acting muscarinic antagonist (LAMA) and vilanterol is a long-acting beta2 agonist (LABA). UMEC/VI (blended together) will be available as dry powder in the dose of 125 µg /25 µg per inhalation.
Drug: FF
Fluticasone Furoate is a novel inhaled corticosteroid (ICS). FF will be available as dry powder in the dose of 100 µg per inhalation.
Experimental: UMEC+VI
UMEC (500 µg) and VI (100 µg) will be administered as single dose (4 inhalations); as dry powder in NDPI device once in 7 days in one of the 4 Treatment Periods of the study.
Drug: UMEC
Umeclidinium is an inhaled long-acting muscarinic antagonist (LAMA). UMEC will be available as dry powder in the dose of 125 µg per inhalation.
Drug: VI
Vilanterol is a long-acting beta2 agonist (LABA). VI will be available as dry powder in the dose of 25 µg per inhalation.
Experimental: FF+VI
FF (400 µg) and VI (100 µg) will be administered as single dose (4 inhalations); as dry powder in NDPI device once in 7 days in one of the 4 Treatment Periods of the study.
Drug: VI
Vilanterol is a long-acting beta2 agonist (LABA). VI will be available as dry powder in the dose of 25 µg per inhalation.
Drug: FF
Fluticasone Furoate is a novel inhaled corticosteroid (ICS). FF will be available as dry powder in the dose of 100 µg per inhalation.
Experimental: FF+UMEC
FF (400 µg) and UMEC (500 µg) will be administered as single dose (4 inhalations); as dry powder in NDPI device once in 7 days in one of the 4 Treatment Periods of the study.
Drug: UMEC
Umeclidinium is an inhaled long-acting muscarinic antagonist (LAMA). UMEC will be available as dry powder in the dose of 125 µg per inhalation.
Drug: FF
Fluticasone Furoate is a novel inhaled corticosteroid (ICS). FF will be available as dry powder in the dose of 100 µg per inhalation.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Healthy as determined by a responsible and experienced physician, based on a medical evaluation
  • Male or female between 18 and 65 years of age
  • Body Mass Index (BMI) within the range 19.0 - 33.0 kilogram (kg)/meters (m)^2 (inclusive)
  • Average QT interval corrected using Fridericia's (QTcF) formula < 450 millisecond (msec)
  • Forced Expiratory Volume in 1 second (FEV1) >=80% predicted and a FEV1/Forced Vital Capacity (FVC) ratio >=0.7
  • Subjects who are current non-smokers who have not used any tobacco products in the 6-month period preceding the screening visit
  • Alanine transaminase (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%)
  • A female subject is eligible to participate if she is confirmed postmenopausal or permanently sterilized; or if she is of child-bearing potential and is abstinent or agrees to use contraception prior to start of dosing until the follow up visit
  • Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form

Exclusion Criteria:

  • A supine mean heart rate outside the range 40-90 beats per minute (bpm) at screening.
  • History of respiratory disease (i.e. history of asthmatic symptoms) in the last 10 years.
  • A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening or a positive test for human immunodeficiency virus (HIV) antibody.
  • Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) or a 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.
  • A positive pre-study drug/alcohol screen
  • 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) or has had exposure to more than four new chemical entities within 12 months prior to the first dosing day.
  • Lactating or pregnant females as determined by positive serum or urine human chorionic gonadotropin (hCG) test at screening or prior to dosing.
  • 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 Glaxo SmithKline (GSK) Medical Monitor the medication will not interfere with the study procedures or compromise subject safety. Or the subject is unable to refrain from consumption of red wine, seville oranges, grapefruit or grapefruit juice and pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices from 7 days prior to the first dose of study medication and for the duration of the study.
  • 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.
  • Unwillingness or inability to follow the procedures outlined in the protocol
  • Subject is mentally or legally incapacitated
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01691547

Sponsors and Collaborators
GlaxoSmithKline
Parexel
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01691547     History of Changes
Other Study ID Numbers: 116415
Study First Received: September 20, 2012
Last Updated: May 9, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by GlaxoSmithKline:
GW642444 (Vilanterol)
pharmacokinetics
pharmacodynamics
GSK573719 (Umeclidinium)
healthy subjects
GW685698 (Fluticasone Furoate)

Additional relevant MeSH terms:
Chronic Disease
Lung Diseases
Pulmonary Disease, Chronic Obstructive
Disease Attributes
Pathologic Processes
Respiratory Tract Diseases
Lung Diseases, Obstructive
Muscarinic Antagonists
Fluticasone
Cholinergic Antagonists
Cholinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Anti-Inflammatory Agents
Therapeutic Uses
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Anti-Asthmatic Agents
Respiratory System Agents
Dermatologic Agents
Anti-Allergic Agents

ClinicalTrials.gov processed this record on August 21, 2014