Inhaled Fluticasone Furoate/Vilanterol Safety and Tolerability, PK and PD Study

Study Overview
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Brief Summary
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This study will investigate the safety and tolerability, pharmacokinetics, and pharmacodynamics of fluticasone furoate/vilanterol (FF/VI) 100/25mcg administered using the novel dry powder inhaler in children aged 5 to 11 years with persistent asthma.

Detailed Description
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This study will investigate the safety and tolerability, pharmacokinetics, and pharmacodynamics of fluticasone furoate/vilanterol (FF/VI) 100/25mcg administered using the novel dry powder inhaler in children aged 5 to 11 years with persistent asthma. Fluticasone furoate (FF, GW685698) is a novel once daily inhaled corticosteroid (ICS) and vilanterol (VI, GW642444) is an inhaled once daily long-acting beta2 agonist (LABA). FF/VI is a novel ICS/LABA combination with once-daily dosing being developed for the treatment of asthma in adults, adolescents, and children of 5 years and above. This study will be a randomized, double-blind, repeat dose, two period crossover study, with FF as the control. During each of two treatment periods subjects will receive either FF/VI 100/25 micrograms (mcg) or FF 100 mcg daily on 14 consecutive mornings via the novel dry powder inhaler. Approximately 26 subjects will be recruited into this study, with a target of 20 completed subjects. Safety, tolerability, pharmacokinetics and glucose , potassium and cortisol levels will be investigated.

Official Title
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A Randomized, Double-blind, Repeat Dose, Two Period Crossover Study to Evaluate the Safety and Tolerability, Pharmacokinetics, and Pharmacodynamics of Inhaled Fluticasone Furoate/Vilanterol 100/25 Micrograms in Children Aged 5 to 11 Years With Persistent Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: Fluticasone Furoate
* Drug: Fluticasone Furoate/Vilanterol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy as determined by a study physician, based medical history, physical examination, laboratory testing, and electrocardiogram (ECG); with no significant medical condition apart from asthma, eczema, or rhinitis. A subject with a clinical abnormality or laboratory parameters outside the reference range for this study may be included if the Investigator and GSK Medical Monitor agree the finding is unlikely to introduce additional risk factors or interfere with the study procedures. Male and pre-menarchial female subjects aged 5 to less than 12 years on the last planned treatment day are eligible for this study. Pre-menarchial females are defined as any female who has not begun menses and is considered Tanner Stage 2 or less. Diagnosis of asthma at least 6 months prior to screening. Stable asthma therapy (fluticasone propionate, total daily dose less than or equal to 400 microgram or equivalent) and short acting beta-agonist (SABA) inhaler for at least 4 weeks prior to screening. Subjects must be controlled on their existing asthma treatment at screening, which will be continued during the run-in, washout and run-out periods (but not during active treatment periods). Control is defined as a Childhood Asthma Control Test score of >19 and (Peak Expiratory Flow) PEF more than 75 percent predicted. Subjects must demonstrate an ability to accept and effectively use a demonstration inhaler from the demonstration kits provided. Subjects must weigh at least 20 kilograms. The subject and parent/guardian are able to understand and comply with protocol requirements, instructions, and protocol stated restrictions. The parent or guardian must have the ability to read, write, and record diary information collected throughout the study. The parent or guardian must have the ability to manage study drug administration and PEF assessments. At least one parent/guardian has signed and dated the written informed consent prior to admission to the study. This will be accompanied by informed assent from the subject for children aged 7 to 11 years. Exclusion Criteria: Subjects with a history of life-threatening asthma, an asthma exacerbation requiring systemic corticosteroids or Emergency Room attendance (within 3 months) or requiring hospitalization (within 6 months) prior to screening. Subjects with any medical condition or circumstance making the volunteer unsuitable for participation in the study. Culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus, or middle ear, not resolved within 4 weeks of screening leading to a change in asthma management; or, in the opinion of the investigator, is likely to affect the subject's asthma status or ability to participate in the study. Clinical visual evidence of oral candidiasis at screening. Subjects currently receiving (or have received within 4 weeks of screening) asthma therapies including theophyllines, long-acting inhaled beta-agonists, oral beta-agonists, or who have changed their asthma medication within 4 weeks of screening. Significant abnormality of rate, interval, conduction or rhythm in the 12-lead ECG (electrocardiogram), determined by the investigator in conjunction with the age and gender of the child and the assessment provided by the remote analysis service. QTcF (QT interval corrected for heart rate using Fridericia's formula) more than 450 milliseconds or an ECG not suitable for QT measurement (e.g. poorly defined termination of the T wave). Aspartarte aminotransferase, Alanine aminotransferase, alkaline phosphatase and bilirubin more than 1.5 times Upper Limit of Normal (ULN) (isolated bilirubin more than 1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin less than 35 percent). A known or suspected sensitivity to any constituents of the novel dry powder inhaler (i.e. lactose or magnesium stearate) (e.g. history of severe milk protein allergy) Any adverse reaction including immediate or delayed hypersensitivity to any beta-2-agonist, sympathomimetic drug, or any intranasal, inhaled or systemic corticosteroid therapy. Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days 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. Consumption of red wine, seville oranges, grapefruit or grapefruit juice, and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices from 7 days prior to the first dose of study medication. The subject has participated in a clinical trial and has received an investigational product within 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. Where participation in the study would result in donation of blood or blood products in excess of the lesser of 50 millilitres (mL) or 3mL per kilogram within a 56 day period. Parent/guardian has a history of psychiatric disease, intellectual deficiency, substance abuse, or other condition (e.g. inability to read, comprehend and write) which will limit the validity of consent to participate in this study. Unwillingness or inability of the subject or parent/guardian to follow the procedures outlined in the protocol. Subject who is mentally or legally incapacitated. Children who are wards of the state or government. A subject will not be eligible for this study if he/she is an immediate family member of the participating investigator, sub-investigator, study coordinator, or employee of the participating investigator.

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 11 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Fluticasone Furoate<br>One of two study treatments subjects will receive. Given to allow comparison of FF exposure in combination versus as mono therapy. | Drug: Fluticasone Furoate<br>* 100mcg delivered via a novel dry powder inhaler on days 1-14 of one study treatment period.<br>* Other names: FF;|
| Experimental: Fluticasone Furoate/Vilanterol<br>One of two study treatments subjects will receive. FF/VI combined is being tested and compared to fluticasone furoate. | Drug: Fluticasone Furoate/Vilanterol<br>* 100/25 mcg delivered via a novel dry powder inhaler on days 1-14 of one study treatment period.<br>* Other names: FF/VI;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Any Adverse Event (AE) or Any Serious Adverse Event (SAE) During the Treatment Period | An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect. Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in other situations. Refer to the General Adverse AE/SAE module for a complete list of AEs and SAEs. | From the start of study medication until Week 11 (Visit 9)/Early Withdrawal | 
| Basophil, Eosinophil, Lymphocyte, Monocyte, Total Neutrophil, Platelet, and White Blood Cell Count Values at Day 14 of the Respective Treatment Period | Blood samples were collected for the measurement of basophils, eosinophils, lymphocytes, monocytes, total neutrophils, platelets, and white blood cell (WBC) count at Day 14 of the respective treatment period. | Day 14 of the respective treatment period (up to Study Day 63) | 
| Hemoglobin and Mean Corpuscle Hemoglobin Concentration (MCHC) Values at Day 14 of the Respective Treatment Period | Blood samples were collected for the measurement of hemoglobin and MCHC at Day 14 of the respective treatment period. | Day 14 of the respective treatment period (up to Study Day 63) | 
| Reticulocyte and Red Blood Cell (RBC) Values at Day 14 of the Respective Treatment Period | Blood samples were collected for the measurement of reticulocytes and RBCs at Day 14 of the respective treatment period. | Day 14 of the respective treatment period (up to Study Day 63) | 
| Hematocrit Values at Day 14 of the Respective Treatment Period | Blood samples were collected for the measurement of hematocrit at Day 14 of the respective treatment period. Hematocrit is a measure of the percentage of the volume of the whole blood that is composed of red blood cells, as determined by separation of red blood cells from the plasma (usually by centrifugation). | Day 14 of the respective treatment period (up to Study Day 63) | 
| Mean Corpuscle Volume (MCV) Value at Day 14 of the Respective Treatment Period | Blood samples were collected for the measurement of MCV at Day 14 of the respective treatment period. | Day 14 of the respective treatment period (up to Study Day 63) | 
| Mean Corpuscle Hemoglobin (MCH) Values at Day 14 of the Respective Treatment Period | Blood samples were collected for the measurement of MCH at Day 14 of the respective treatment period. | Day 14 of the respective treatment period (up to Study Day 63) | 
| Alanine Amino Transferase (ALT), Alkaline Phosphatase (ALP), Aspartate Amino Transferase (AST), and Gamma Glutamyl Transferase (GGT) Values at Day 14 of the Respective Treatment Period | Blood samples were collected for the measurement of ALT, ALP, AST, and GGT at Day 14 of the respective treatment period. | Day 14 of the respective treatment period (up to Study Day 63) | 
| Albumin and Total Protein Values at Day 14 of the Respective Treatment Period | Blood samples were collected for the measurement of albumin and total protein at Day 14 of the respective treatment period. | Day 14 of the respective treatment period (up to Study Day 63) | 
| Calcium, Chloride, Carbon Dioxide (CO2) Content/Bicarbonate, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen (BUN) Values at Day 14 of the Respective Treatment Period | Blood samples were collected for the measurement of calcium, chloride, carbon dioxide content/bicarbonate (CO2/BI), glucose, potassium, sodium, and urea/BUN at Day 14 of the respective treatment period. | Day 14 of the respective treatment period (up to Study Day 63) | 
| Total Bilirubin, Direct Bilirubin, Creatinine, and Uric Acid Values at Day 14 of the Respective Treatment Period | Blood samples were collected for the measurement of total bilirubin, direct bilirubin, creatinine, and uric acid at Day 14 of the respective treatment period. | Day 14 of the respective treatment period (up to Study Day 63) | 
| Peak Expiratory Flow on Day 1 and Day 14 of the Respective Treatment Period | Peak Expiratory Flow (PEF) is defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated. PEF is calculated as the maximum of three readings taken at each timepoint for each participant. Baseline is defined as the maximum pre-dose measurement at Day 1 for each period. | Day 1 and Day 14 of the respective treatment period (up to Study Day 63) | 
| Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1 and Day 14 of the Respective Treatment Period | SBP and DBP were measured at Day 1 and Day 14 of the respective treatment period. Baseline is defined as the pre-dose measurement at Day 1. Change from Baseline was calculated as the Day 14 value minus the Baseline value. | Day 1 and Day 14 of the respective treatment period (up to Study Day 63) | 
| Change From Baseline in Heart Rate at Day1 and Day 14 of the Respective Treatment Period | Heart rate (HR) was measured at Day 1 and Day 14 of the respective treatment period. hr=hour. Baseline is defined as the pre-dose measurement at Day 1. Change from Baseline was calculated as the Day 14 value minus the Baseline value. Treatment, period, day (1 and 14), participant Baseline, period Baseline, and treatment*day interaction were fitted as fixed effects, and participant was fitted as a random effect. | Day 1 and Day 14 of the respective treatment period (up to Study Day 63) | 
| Maximum QTcF at Day 1 and Day 14 of the Respective Treatment Period | QTcF is the QT domain corrected for heart rate by Fridericia's formula. Treatment, period, day (1 and 14), participant Baseline, period Baseline, and treatment*day interaction were fitted as fixed effects, and participant was fitted as a random effect. | Day 1 and Day 14 of the respective treatment period (up to Study Day 63) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC(0-t) and AUC(0-4) of FF on Day 14 of the Respective Treatment Period | Area under the concentration-time (AUC) curve from time zero (pre-dose) to the last time AUC(0-t) and from time zero to 4 hours AUC(0-4) of quantifiable concentration of FF on Day 14 of the respective treatment period was measured. Samples were collected at the following times: pre-dose; 10 minutes (min) and 30 min post-dose; and 1, 2, and 4 hours post-dose. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the PK Population. | Day 14 of the respective treatment period (up to Study Day 63) | 
| Cmax of FF on Day 14 of the Respective Treatment Period | Cmax is defined as the maximum observed concentration of FF on Day 14 of the respective treatment period. Samples were collected at the following times: pre-dose; 10 minutes (min) and 30 min post-dose; and 1, 2, and 4 hours post-dose. | Day 14 of the respective treatment period (up to Study Day 63) | 
| Tmax and Tlast of FF on Day 14 of the Respective Treatment Period | tmax is defined as the time to reach the observed maximum concentration, and tlast is defined as the time of the last observed quantifiable concentration on Day 14 of the respective treatment period. Samples were collected at the following times: pre-dose; 10 minutes (min) and 30 min post-dose; and 1, 2, and 4 hours post-dose. | Day 14 of the respective treatment period (up to Study Day 63) | 
| AUC(0-t) and AUC(0-4) of VI on Day 14 of the Respective Treatment Period | Area under the concentration-time (AUC) curve from time zero (pre-dose) to the last time AUC(0-t) and from time zero to 4 hours AUC(0-4) of quantifiable concentration of VI on Day 14 of the respective treatment period was measured. Samples were collected at the following times: pre-dose; 10 minutes (min) and 30 min post-dose; and 1, 2, and 4 hours post-dose. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the VI PK Population. | Day 14 of the respective treatment period (up to Study Day 63) | 
| Cmax of VI on Day 14 of the Respective Treatment Period | Cmax is defined as the maximum observed concentration of VI on Day 14 of the respective treatment period. Samples were collected at the following times: pre-dose; 10 minutes (min) and 30 min post-dose; and 1, 2, and 4 hours post-dose. | Day 14 of the respective treatment period (up to Study Day 63) | 
| Tmax and Tlast of VI on Day 1 of the Respective Treatment Period | tmax is defined as the time to reach the observed maximum VI concentration, and tlast is defined as the time of the last observed quantifiable VI concentration on Day 14 of the respective treatment period. Samples were collected at the following times: pre-dose; 10 minutes (min) and 30 min post-dose; and 1, 2, and 4 hours post-dose. | Day 14 of the respective treatment period (up to Study Day 63) | 
| Blood Glucose and Potassium Values on Day 14 of the Respective Treatment Period | Blood glucose and potassium values were measured on Day 14 of the respective treatment period. Samples were collected at the following times: pre-dose; 10 minutes (min) and 30 min post-dose; and 1, 2, and 4 hours post-dose. Weighted means were derived using the linear trapezoidal rule. Actual relative times were used for the calculation except where actual times were missing. If any actual times were missing, planned relative time were used for these observations. Treatment and period were fitted as fixed effects and participant was fitted as a random effect. | Day 14 of the respective treatment period (up to Study Day 63) | 
| Serum Cortisol (SC) Weighted Mean (0-12 Hours) on Day 14 of the Respective Treatment Period | SC weighted mean was determined for each participant over the time period of 0-12 hours on Day 14 of the respective treatment period. SC weighted mean was derived by dividing the area under the concentration-time curve (AUC; defined as thearea under the concentration-time curve from time zero up to 24 hours) by the sample collection time interval. The sample collection time interval is defined as the difference between the time of the last cortisol sample and the time of the first cortisol sample. Samples were collected at the following time points: 0 (first blood draw/pre-dose); 2, 4, 8, and 12 hours (relative to the 0 time point). Weighted means were derived using the linear trapezoidal rule. Actual relative times were used for the calculation except where actual times were missing. If any actual times were missing, planned relative time were used for these observations. Treatment and period were fitted as fixed effects and participant was fitted as a random effect. | Day 14 of the respective treatment period (up to Study Day 63) | 
| Average Oropharyngeal Cross-sectional Area on Day 1 and Day 14 of the Respective Treatment Period | During the pharyngometry assessment, participants inhaled through a wavetube, which had a mouthpiece with the same dimensions as the mouthpiece on the dry powder inhaler used for the study. This technique was used to measure the size of the throat and mouth (oropharynx) in the form of pharyngograms. Pharyngometry data were recorded for each day (Day 1 and Day 14 of the respective treatment period) using the mean of four measurements (pharyngograms), and the average oropharyngeal cross-sectional area was calculated. | Day 1 and Day 14 of the respective treatment period (up to Study Day X) | 
| Distance of Assessment on Day 1 and Day 14 of the Respective Treatment Period | During the pharyngometry assessment, participants inhaled through a wavetube, which had a mouthpiece with the same dimensions as the mouthpiece on the dry powder inhaler used for this study. This technique was used to measure the size of the throat and mouth (oropharynx) in the form of pharyngograms. Distance of assessment is defined as the distance (length measured in centimeters [cm]) estimated to be from the lips to the larynx. Pharyngometry data were recorded for each day (Days 1 and 14 of the respective treatment period) using the mean of four measurements (pharyngograms), and the average oropharyngeal cross-sectional area was calculated. | Day 1 and Day 14 of the respective treatment period (up to Study Day 63) | 
| Oropharyngeal Volume on Day 1 and Day 14 of the Respective Treatment Period | During the pharyngometry assessment, participants inhaled through a wavetube, which had a mouthpiece with the same dimensions as the mouthpiece on the dry powder inhaler used for this study. This technique was used to measure the size of the throat and mouth (oropharynx) in the form of pharyngograms. Oropharyngeal volume is defined as the volume (cm^3) of the mouth and throat estimated to be from the lips to the larynx. Pharyngometry data were recorded for each day (Days 1 and 14 of the respective treatment period) using the mean of four measurements (pharyngograms), and the average oropharyngeal cross-sectional area was calculated. | Day 1 and Day 14 of the respective treatment period (up to Study Day 63) | 
| Average Flow Rate and Peak Inspiratory Flow Rate (PIFR) on Day 1 and Day 14 of the Respective Treatment Period | During the inhalation profile assessment, participants inhaled through a mouthpiece from a device with a similar resistance to the dry powder inhaler used for this study. Average flow rate is defined as the average inspiratory flow rate (Liters [L]/min) across the inhalation profile when inhaling across the resistance of the inhaler. PIFR is defined as the Peak Inspiratory Flow Rate (L/min) of the inhalation profile when inhaling across the resistance of the inhaler.The pressure drop during the inhalation was measured, and the inhalation profiles (pressure drop versus time profile) of the participants were obtained. The mean of the two inhalation profile measurements was used for each day (Days 1 and 14 of the respective treatment period), and the average flow rate and PIFR were determined. | Day 1 and Day 14 of the respective treatment period (up to Study Day 63) | 
| Inhalation Time on Days 1 and 14 of of the Respective Treatment Period | During the inhalation profile assessment, participants inhaled through a mouthpiece from a device with a similar resistance to the dry powder inhaler used for this study. Inhalation time is defined as the duration of the inhalation(s) when inhaling across the resistance of the inhaler. The pressure drop during the inhalation was measured, and the inhalation profiles (pressure drop versus time profile) of the participants were obtained. The mean of the two inhalation profile measurements was used for each day (Days 1 and 14 of the respective treatment period), and the inhalation time was determined. | Day 1 and Day 14 of the respective treatment period (up to Study Day 63) | 
| Inhaled Volume on Days 1 and 14 of the Respective Treatment Period | During the inhalation profile assessment, participants inhaled through a mouthpiece from a device with a similar resistance to the dry powder inhaler used for this study. Inhaled volume is defined as the volume of air (Liters) inhaled during the inhalation across the resistance of the inhaler. The pressure drop during the inhalation was measured, and the inhalation profiles (pressure drop versus time profile) of the participants were obtained. The mean of the two inhalation profile measurements was used for each day (Days 1 and 14 of the respective treatment period), and the inhalaled volume was determined. | Day 1 and Day 14 of the respective treatment period (up to Study Day 63) | 
| Peak Pressure Drop on Days 1 and 14 of the Respective Treatment Period | During the inhalation profile assessment, participants inhaled through a mouthpiece from a device with a similar resistance to the dry powder inhaler used for this study. Peak pressure drop is defined as the maximum pressure drop (kilopascal [kPa]) achieved during inhalation across the resistance of the inhaler. The pressure drop during the inhalation was measured, and the inhalation profiles (pressure drop versus time profile) of the participants were obtained. The mean of the two inhalation profile measurements was calculated for each day (Days 1 and 14 of the respective treatment period), and used for subsequent modeling and prediction of dose emission attributes. | Day 1 and Day 14 of the respective treatment period (up to Study Day 63) | 
| Total Emitted Dose (TED) on Day 14 of the Respective Treatment Period | The total emitted dose (TED) is defined as the mass (micrograms) of the nominal dose that passes beyond the throat. The recorded inhalation profiles of the participants and the mouth-throat (oropharyngeal) models of the sizes that approximated to pharyngometry measurements of the participants were used in conjunction with the electronic Lung (eLung) for in vitro assessment. The eLung is a breathing simulator that replicates the selected inhalation profile with an active inhaler placed at the lips end of the selected ororpharyngeal model. After the dose is emitted from the inhaler, the analysis and assay of throat deposition and material passing beyond the throat was used to derive the nominal, minimum, and maximum predicted total emitted dose. | Day 14 of the respective treatment period (up to Study Day 63) | 
| Ex-throat Dose (ETD) and ETD <2 Microns on Day 14 of the Respective Treatment Period | The ex-throat dose (ETD) and the nominal ETD is the mass (micrograms) of active investigational material that passes beyond the throat, nominal being the mean. The recorded inhalation profiles of the participants and the mouth-throat (oropharyngeal) models of the sizes that approximated to pharyngometry measurements of the participants were used in conjunction with the electronic Lung (eLung) for in vitro assessment. The eLung is a breathing simulator that replicates the selected inhalation profile with an active inhaler placed at the lips end of the selected ororpharyngeal model. After the dose is emitted from the inhaler, the analysis and assay of throat deposition and material passing beyond the throat was used to derive the nominal, minimum, and maximum predicted ETD and ETD <2 microns. | Day 14 of the respective treatment period (up to Study Day 63) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pediatric ages 5 to 11 years