Pharmacokinetics and Pharacodynamics of GW642444 in Paedetric Subjects

Asthma Clinical Trial

Official title:

A Randomized, Double-blind, Placebo-controlled, Two-way Crossover 7-day Study to Investigate the Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of Repeat Dose Inhaled GW642444 25 μg (Micrograms) in Children Aged 5-11 Years With Persistent Asthma.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01453296
• Other study ID #: 112776
• Status: Completed
• Phase: Phase 2
• First received: September 1, 2011
• Last updated: August 15, 2013
• Start date: August 2010
• Est. completion date: April 2011

Study information

• Verified date: June 2013
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This study will investigate the effect of dosing paedeatric asthmatic subjects with GW642444, an orally inhaled long-acting agonist of the β2-adrenoceptor.

Description:

This study will investigate the effect of dosing with 25 μg GW642444, an orally inhaled long-acting agonist of the β2-adrenoceptor, in asthmatic subjects aged 5 to 11. GW642444 is currently under development as the long-acting beta-agonist component of a combination product containing an inhaled corticosteroid and a longacting beta-agonist.

Subjects will receive a single dose via a novel dry powder inhaler, then 7 days once-daily repeat dosing following a washout period. The study will be a randomized two-way crossover, with a placebo control. Approximately 26 subjects will be recruited to this study, with the aim that 20 will complete the study. Safety, tolerability, pharmacokinetics and glucose and potassium levels will be investigated.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 28
• Est. completion date: April 2011
• Est. primary completion date: April 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 5 Years to 11 Years

Eligibility

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) >75 % predicted.

• Subjects must be taking a stable regimen of fluticasone propionate (=200 µg (micrograms) twice daily or equivalent) and short acting beta-agonist inhaler on an as-need basis for at least 4 weeks prior to screening.

• Apart from asthma, eczema and rhinitis, subjects should be healthy and suffer from no other significant medical conditions.

• Subjects must weigh at least 15 kg (kilograms).

• Subjects must demonstrate ability to accept and effectively use the GW642444 device using the demonstration kits provided to the site.

• The subject and parent or 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 also have the ability to manage study drug administration and PEF assessments.

• At least one parent or 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.

Exclusion Criteria:

• Subjects currently receiving (or have received within 4 weeks of screening) any of the following asthma therapies: theophyllines, long-acting inhaled beta-agonists, oral beta-agonist.

• Subjects who have changed their asthma medication within 4 weeks of screening.

• Clinical visual evidence of oral candidiasis at screening.

• Any clinically relevant abnormality identified on the screening medical assessment

• Any medical condition or circumstance making the subject unsuitable for participation in the study (e.g. history of life-threatening asthma)

• 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 the screening visit.

• Culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract which is not resolved within 4 weeks of the screening visit.

• Any adverse reaction including immediate or delayed hypersensitivity to any betaagonist 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.

• The parent or guardian has history of psychiatric disease, intellectual deficiency, substance abuse, or other condition (e.g., inability to read, comprehend or write) which will limit the validity of consent to participate in this study.

• 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

Study Design

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Asthma

Intervention

Drug:
• GW642444
GW642444 25 µg; Novel dry powder inhaler
• Placebo
Matching placebo; Novel dry powder inhaler

Locations

Country	Name	City	State
United States	GSK Investigational Site	Cypress	California
United States	GSK Investigational Site	Denver	Colorado
United States	GSK Investigational Site	Huntington Beach	California
United States	GSK Investigational Site	Medford	Oregon
United States	GSK Investigational Site	Normal	Illinois

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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 AE/SAE module for a complete list of AEs and SAEs.	From the start of study medication until Week 11 (Visit 8)/Early Withdrawal	No
Primary	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. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.	Day 14 of the respective treatment period (up to Study Day 49)	No
Primary	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. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.	Day 14 of the respective treatment period (up to Study Day 49)	No
Primary	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. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.	Day 14 of the respective treatment period (up to Study Day 49)	No
Primary	Hematocrit Value 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). Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.	Day 14 of the respective treatment period (up to Study Day 49)	No
Primary	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. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.	Day 14 of the respective treatment period (up to Study Day 49)	No
Primary	Mean Corpuscle Hemoglobin (MCH) Value 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. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.	Day 14 of the respective treatment period (up to Study Day 49)	No
Primary	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. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.	Day 14 of the respective treatment period (up to Study Day 49)	No
Primary	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. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.	Day 14 of the respective treatment period (up to Study Day 49)	No
Primary	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. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.	Day 14 of the respective treatment period (up to Study Day 49)	No
Primary	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. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.	Day 14 of the respective treatment period (up to Study Day 49)	No
Primary	Peak Expiratory Flow on Day 1, Day 8, 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 pre-dose measurement at Day 1 for the respective period. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg (n=28).	Day 1, Day 8, and Day 14 of the respective treatment period (up to Study Day 49)	No
Primary	Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Day 1, Day 8, and Day 14 of the Respective Treatment Period	SBP and DBP were measured at Day 1, Day 8, and Day 14 of the respective treatment period. PD=post-dose. Baseline is defined as the pre-dose measurement at Day 1 for the respective period. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg (n=28).	Day 1, Day 8, and Day 14 of the respective treatment period (up to Study Day 49)	No
Primary	Maximum Heart Rate at Day 1 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. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg (n=28).	Day 1 and Day 14 of the respective treatment period (up to Study Day 49)	No
Primary	Weighted Mean Heart Rate at Day 1 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. 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 times were used for these observations. For 0-8 hr parameters, treatment, period, participant Baseline, and period Baseline were fitted as fixed effects, and participant was fitted as a random effect. For 0-2 hr parameters, 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. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg (n=28).	Day 1 and Day 14 of the respective treatment period (up to Study Day 49)	No
Primary	Maximum QTcF at Day 1 and Day 14 of the Respective Treatment Period	The electrocardiographic (ECG) parameter QT duration corrected using Fridericia's formula (QTcF) was measured at Day 1 and Day 14 of the respective treatment period. hr=hour. For 0-8 hr parameters, treatment, period, participant Baseline, and period Baseline were fitted as fixed effects, and participant was fitted as a random effect. For 0-2 hr parameters, 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. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg (n=28).	Day 1 and Day 14 of the respective treatment period (up to Study Day 49)	No
Primary	Weighted Mean QTcF at Day 1 and Day 14 of the Respective Treatment Period	The electrocardiographic (ECG) parameter QT duration corrected using Fridericia's formula (QTcF) was measured at Day 1 and Day 14 of the respective treatment period. hr=hour. Actual relative times were used for the calculation except where actual times were missing. If any actual times were missing, planned relative times were used for these observations. For 0-8 hr parameters, treatment, period, participant Baseline, and period Baseline were fitted as fixed effects, and participant was fitted as a random effect. For 0-2 hr parameters, 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. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg (n=28).	Day 1 and Day 14 of the respective treatment period (up to Study Day 49)	No
Secondary	AUC(0-t) and AUC(0-8) 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 8 hours AUC(0-8) 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, 4, 6, and 8 hours post-dose for participants who were >=20 kilograms and pre-dose; 10 min and 30 min post-dose; and 1, 2, and 4 hours post-dose for participants who were <=20 kilograms on Day 14 of the respective treatment period. Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects everyone in the Pharmacokinetic Population.	Day 14 of the respective treatment period (up to Study Day 49)	No
Secondary	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; 10 minutes (min) and 30 min post-dose; and 1, 2, 4, 6, and 8 hours post-dose for participants who were >=20 kilograms and pre-dose; 10 min and 30 min post-dose; and 1, 2, and 4 hours post-dose for participants who were <=20 kilograms on Day 14 of the respective treatment period.	Day 14 of the respective treatment period (up to Study Day 49)	No
Secondary	Tmax, t1/2, and t at Day 14 of the Respective Treatment Period	tmax is defined as the time to reach the observed maximum concentration, t1/2 is defined as the time required to reduce the plasma concentration to one half its initial value, 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; 10 minutes (min) and 30 min post-dose; and 1, 2, 4, 6, and 8 hours post-dose for participants who were >=20 kilograms and pre-dose; 10 min and 30 min post-dose; and 1, 2, and 4 hours post-dose for participants who were <=20 kilograms on Day 14 of the respective treatment period.	Day 14 of the respective treatment period (up to Study Day 49)	No
Secondary	Blood Glucose and Potassium 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, 4, 6, and 8 hours post-dose for participants who were >=20 kilograms and pre-dose; 10 min and 30 min post-dose; and 1, 2, and 4 hours post-dose for participants who were <=20 kilograms on Day 14 of the respective treatment period. . 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 times were used for these observations. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg. 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 49)	No
Secondary	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 49)	No
Secondary	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 49)	No
Secondary	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 (centimeters cubed [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 49)	No
Secondary	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. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.	Day 1 and Day 14 of the respective treatment period (up to Study Day 49)	No
Secondary	Inhalation Time 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. 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. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.	Day 1 and Day 14 of the respective treatment period (up to Study Day 49)	No
Secondary	Inhaled Volume 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. 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. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.	Day 1 and Day 14 of the respective treatment period (up to Study Day 49)	No
Secondary	Peak Pressure Drop 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. 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. Subject 2308 received VI 25 µg in both treatment periods, and contributed twice to the summary of VI 25 µg.	Day 1 and Day 14 of the respective treatment period (up to Study Day 49)	No
Secondary	Total Emitted Dose (TED) on Day 1 and 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 1 and Day 14 of the respective treatment period (up to Study Day 49)	No
Secondary	Ex-throat Dose (ETD) and ETD <2 Microns on Day 1 and 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 1 and Day 14 of the respective treatment period (up to Study Day 49)	No