Pharmacokinetics and PharmacoDynamics of GW685698 in Paedeatric Asthmatic Patients

Study Overview
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Brief Summary
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This study will investigate the effect of dosing with flutucasone furoate in asthmatic subjects aged 5-11 years of age. A randomized, two-way crossover, with placebo control, over a 14 day treatment period, it will investigate safety, tolerability, pharmacokinetics and serum cortisol levels.

Detailed Description
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This study will investigate the effect of dosing with fluticasone furoate 100 μg (micrograms) in asthmatic subjects aged 5-11 years of age. Fluticasone furoate is currently under development as the inhaled corticosteroid component of a combination product containing an inhaled corticosteroid and a long-acting beta-agonist. The study will be a randomized two-way crossover, with a placebo control. During each treatment period subjects will receive a daily dose via a novel dry powder inhaler for 14 days. Approximately 26 subjects will be recruited to this study, with the aim that 20 will complete the study. Safety, tolerability, pharmacokinetics and serum cortisol levels will be investigated.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Two-way Crossover 14-day Study to Investigate the Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of Repeat Dose Inhaled Fluticasone Furoate 100ug (Micrograms) in Children Aged 5-11 Years With Persistent Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: Fluticasone furoate
* Drug: Matching placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and pre-menarchial female subjects aged 5-11 years on the last planned treatment day are eligible for this study. Pre-menarchial females are defined as any female who has yet to begin menses and is considered Tanner Stage 2 or less. Diagnosis of asthma at least 6 months prior to screening. Patients must be controlled on their existing asthma treatment at screening as defined by a Childhood Asthma Control Test score of >19 and PEF (Peak Expiratory Flow) ≥80% predicted. Apart from asthma, eczema and rhinitis, subjects should be healthy and suffer from no other significant medical conditions. Subjects must be taking a stable regimen of a short acting beta-agonist inhaler on an as-need basis for at least 4 weeks prior to screening. Subjects must weigh at least 15 kg (kilograms). Subjects must demonstrate ability to accept and effectively use the fluticasone furoate devices using the demonstration kits provided to the site. Subjects and parents/guardians must be able to understand and comply with protocol requirements, instructions and protocol-stated restrictions. Parents/guardians must have the ability to read, write and record diary information collected throughout the study. They must also have the ability to manage study drug administration and PEF assessments. A signed and dated written informed consent from at least one parent/guardian, and accompanying informed assent from the subject prior to admission to the study. Exclusion Criteria: Subjects who have changed their asthma medication within 4 weeks of screening or subjects currently being treated with inhaled corticosteroids or have received such treatment within 4 weeks of screening. In addition, subjects currently receiving (or have received within 4 weeks of screening) any of the following asthma therapies: theophyllines, long-acting inhaled beta-agonists or oral beta-agonists. Any medical condition or circumstance making the volunteer unsuitable for participation in the study (e.g. history of life-threatening asthma). Any clinically relevant abnormality identified on the screening medical assessment, including asthma exacerbation requiring systemic corticosteroids (oral, intramuscular, intravenous) or emergency room attendance within 3 months or asthma exacerbation requiring hospitalization within 6 months prior to screening. Culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear that is not resolved within 4 weeks of screening and led to a change in asthma management or, in the opinion of the Investigator, is expected to affect the subject's asthma status or the subject's ability to participate in the study. Clinical visual evidence of oral candidiasis at screening. Parent/guardian has 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. Any adverse reaction including immediate or delayed hypersensitivity to any beta-2-agonist, sympathomimetic drug, or any intranasal, inhaled or systemic corticosteroid therapy. Known or suspected sensitivity to the constituents of the novel dry powder inhaler (i.e., lactose or magnesium stearate), for example, history of severe milk protein allergy. 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. Children who are wards of the state or government. Evidence of clinically significant abnormality in the 12-lead ECG (electrocardiogram) at screening.

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: COHORT 1 RANDOMISATION A<br>(8-11 years old) Repeat dose session: Fluticasone furoate 100µg; Day 1 and Day 14 = in house dosing; Day 2-13 = home dosing | Drug: Fluticasone furoate<br>* Novel dry powder inhaler: 100µg per blister One blister strip containing fluticasone furoate micronised drug blended with lactose and a second blister strip containing lactose and magnesium stearate.<br>|
| Placebo Comparator: COHORT 1 RANDOMISATION B<br>(8-11 years old) Repeat dose session: matching placebo; Day 1 and Day 14 = in house dosing; Days 2-13 = home dosing | Drug: Matching placebo<br>* Novel dry powder inhaler: One blister strip containing lactose and a second blister strip containing lactose and magnesium stearate.<br>|
| Active Comparator: COHORT 2 RANDOMISATION A<br>(5-7 years old) Repeat dose session: Fluticasone furoate 100µg; Day 1 and Day 14 = in house dosing; Days 2-13 = home dosing | Drug: Fluticasone furoate<br>* Novel dry powder inhaler: 100µg per blister One blister strip containing fluticasone furoate micronised drug blended with lactose and a second blister strip containing lactose and magnesium stearate.<br>|
| Placebo Comparator: COHORT 2 RANDOMISATION B<br>(5-7 years old) Repeat dose session: Matching placebo; Day 1 and Day 14 = in house dosing; Days 2-13 = home dosing | Drug: Matching placebo<br>* Novel dry powder inhaler: One blister strip containing lactose and a second blister strip containing lactose and magnesium stearate.<br>|

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 6)/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 44) | 
| 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 44) | 
| Reticulocyte and Red Blood Cell (RBC) Values at Day 14 of the Respective Treatment Period | Blood samples were collected for the measurement of reticulocyte and RBCs at Day 14 of the respective treatment period. | Day 14 of the respective treatment period (up to Study Day 44) | 
| 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 44) | 
| 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 44) | 
| 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 44) | 
| 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 44) | 
| 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 44) | 
| 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 44) | 
| Total Bilirubin, Creatinine, and Uric Acid Values at Day 14 of the Respective Treatment Period | Blood samples were collected for the measurement of total bilirubin, creatinine, and uric acid at Day 14 of the respective treatment period. | Day 14 of the respective treatment period (up to Study Day 44) | 
| 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 44) | 
| Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Baseline and Day 14 of the Respective Treatment Period | SBP and DBP were measured at Baseline and Day 14 of the respective treatment period. Baseline is defined as the pre-dose measurement at Day 1 for each period. | Baseline and Day 14 of the respective treatment period (up to Study Day 44) | 
| Heart Rate at Baseline and Day 14 of the Respective Treatment Period | Heart rate (HR) was measured at Baseline and Day 14 of the respective treatment period. Baseline is defined as the pre-dose measurement at Day 1 for each period. | Baseline and Day 14 of the respective treatment period (up to Study Day 44) | 
| Change From Baseline in the Indicated Electrocardiographic (ECG) Parameters at the Indicated Time Points on Day 14 of the Respective Treatment Period | PR, QRS, QT, QTcB, QTcF, and RR were measured at Baseline and Day 14 of the respective treatment period. Baseline is defined as the pre-dose measurement at Day 1 for each period. Change from Baseline was calculated as the value at Day 14 minus the Baseline value. QTcB is the QT duration corrected for heart rate by Bazett's formula. QTcF is the QT duration corrected for heart rate by Fridericia's formula. | Baseline and Day 14 of the respective treatment period (up to Study Day 44) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC(0-t) on Day 14 of the Respective Treatment Period | Area under the concentration-time (AUC(0-t)) curve from time zero (pre-dose) to the last time of quantifiable concentration of FF on Day 14 of the respective treatment period was measured. Samples were collected at the following times: pre-dose; 30 minutes, 1, 2, 4, 7, and 12 hours post-dose on Day 14 of the respective treatment period. Due to non-quantifiable values, it was not possible to derive AUC(0-12). | Day 14 of the respective treatment period | 
| Cmax on Day 14 of the Respective Treatment Period | Cmax is defined as the maximum observed concentration on Day 14 of the respective treatment period. Samples were collected at the following times: pre-dose; 30 minutes, 1, 2, 4, 7, and 12 hours post-dose on Day 14 of the respective treatment period. | Day 14 of the respective treatment period | 
| Tmax and t at Day 14 of the Respective Treatment Period | tmax is defined as the time to reach the observed maximum concentration, and t 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; 30 minutes, 1, 2, 4, 7, and 12 hours post-dose on Day 14 of the respective treatment period. | Day 14 of the respective treatment period | 
| Serum Cortisol Weighted Mean (0-12 Hours) on Day 14 of the Respective Treatment Period | Serum cortisol weighted mean was determined for each participant over the time period 0-12 hours on Day 14 of the respective treatment period. Samples were collected at the following times: pre-dose; 30 minutes, 1, 2, 4, 7, and 12 hours post-dose on Day 14 of the respective treatment period. | Day 14 of the respective treatment period | 
| Average Oropharyngeal Cross-sectional Area on Days 1 and 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. 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. | Days 1 and 14 of the respective treatment period | 
| Distance of Assessment on Days 1 and 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 each treatment period) using the mean of four measurements (pharyngograms), and the average oropharyngeal cross-sectional area was calculated. | Days 1 and 14 of the respective treatment period | 
| Oropharyngeal Volume on Days 1 and 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. | Days 1 and 14 of the respective treatment period | 
| Average Flow Rate and Peak Inspiratory Flow Rate (PIFR) 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. 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 | 
| Inhalation Time 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. 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 | 
| 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 | 
| 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 | 
| Total Emitted Dose (TED) on Days 1 and 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 1 and Day 14 of the respective treatment period | 
| Ex-throat Dose (ETD) and ETD <2 Microns on Days 1 and 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 1 and Day 14 of the respective treatment period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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inhalation profiles, pharmacokinetics, pharyngometry, asthma, pediatric subjects, GW685698, Fluticasone furoate, safety