Asthma
Conditions
Keywords
Fluticasone Furoate, FF Inhalation Powder, morning dosing, evening dosing, efficacy, FEV1
Brief summary
This study will investigate the effects of altering the time of day of dosing (morning or evening) with Fluticasone Furoate 100 (FF 100) micrograms (mcg) once daily administered via a dry powder inhaler (DPI) in subjects with persistent bronchial asthma. This is a repeat-dose, double-blind, randomized, placebo-controlled, three-way crossover study to compare the effect of morning (AM) and evening (PM) dosing with FF 100 on lung function. Twenty-four male and female subjects with persistent bronchial asthma will be enrolled to ensure twenty evaluable subjects. The three treatments will be FF 100 AM (with placebo PM), FF 100 PM (with placebo AM) and matching placebo (AM and PM). All treatments will be administered for 14 (+/-2) days with 14 day run-in and 14 to 21 day washout periods. The total duration of the study will be approximately 13 to18 weeks for each subject.
Interventions
Inhalation powder 100 microgram per blister strip to be administered via dry powder inhaler either in the morning (AM dose with FF and PM dose with +/-2 days).
DRUGPlacebo
Placebo in single strip to be administered via dry powder inhaler in the morning and evening for 14 days (+/- 2 days).
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Subjects with a documented history of persistent asthma, with the exclusion of other significant pulmonary diseases (pneumonia, pneumothorax, atelectasis, pulmonary fibrotic disease, bronchopulmonary dysplasia, chronic bronchitis, emphysema, chronic obstructive pulmonary disease, or other respiratory abnormalities other than asthma). * Male or female between 18 and 70 years of age inclusive, at the time of signing the informed consent. * A female subject is eligible to participate if she is: * Of non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy or postmenopausal defined as 12 months of spontaneous amenorrhea. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use contraception method, if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2 to 4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method. * Child-bearing potential with negative pregnancy test as determined by serum human chorionic gonadotropin (hCG) test at screening and serum or urine hCG test prior to dosing and agrees to use one of the contraception methods for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until completion of the follow up visit or has only same-sex partners, when this is her preferred and usual lifestyle. * All subjects must either be clinically stable on a low to mid dose inhaled corticosteroid (ICS) (with or without a short acting beta-2 receptor agonist \[SABA\]) such as Fluticasone Propionate (FP) 100 to250 mcg twice-daily (total daily dose 200 to 500 mcg) or equivalent, for at least 4 weeks preceding the screening visit or be clinically stable on a low dose ICS/ long acting beta-2 receptor agonist (LABA) combination, such as SERETIDE/ADVAIR 100/50 twice- daily or equivalent (administered either in combination or from separate inhalers), for at least 4 weeks preceding the screening visit. Higher ICS/LABA doses (i.e. equivalent to SERETIDE/ADVAIR 250/50 or 500/50) would not be acceptable. Subjects must refrain from using their LABA for at least 24 hour (h) prior to the screening visit * Subjects with a screening pre-bronchodilator FEV1 \>= 60 percent of predicted. Predicted values will be based upon National Health and Nutrition Examination Survey (NHANES III). * During the screening visit, subjects must demonstrate the presence of reversible airway disease, defined as an increase in FEV1 of \>= 12.0 percent over baseline and an absolute change of \>= 200 mL within 60 minutes following 4 inhalations of albuterol/salbutamol inhalation aerosol (or equivalent nebulized treatment with albuterol/salbutamol solution). * All subjects must be able to replace all their current asthma treatments with albuterol/salbutamol aerosol inhaler at screening for use as needed for the run-in period and throughout the duration of the study. Subjects on LABAs must also withhold this for at least 24 h prior to the screening visit. Subjects will therefore be on SABA alone for the duration of the study, and on SABA and FF during the FF treatment periods. Subjects must be able to withhold albuterol/salbutamol for at least 6 h prior to screening and study visits. * Subjects who are current non-smokers and who have a pack history of \<= 10 pack years. A subject may not have used inhaled tobacco products within the past 3 months (i.e., cigarettes, cigars or pipe tobacco). * Body weight \>= 50 kilograms (kg) and Body Mass Index (BMI) within the range 19.0 to29.9 kg/meter\^2 (inclusive) * Based on single or averaged QT duration corrected for heart rate by Fridericia's formula (QTcF) values of triplicate electrocardiograms (ECGs) obtained over a brief recording period: QTcF \< 450 millisecond (msec); or QTcF \< 480 msec in subjects with Bundle Branch Block. * Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) \< 2x Upper limit of normal (ULN), alkaline phosphatase and bilirubin \<= 1.5xULN (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35 percent). * Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. * Able to satisfactorily use the DPI Inclusion Criteria for Randomisation to Treatment * Evening pre-dose FEV1 of \>=60 percent of their predicted normal at Day 1 * Daily diary compliance defined as completion of all AM daily diary data on \>=4 of the last 7 consecutive days of the Run-in Period (not including the date of randomisation) and completion of all PM daily diary data on \>=4 of the last 7 consecutive days of the Run-in Period (not including the date of randomisation)
Exclusion criteria
* A history of life-threatening asthma, defined as an asthma episode that required intubation and/or was associated with hypercapnia, respiratory arrest or hypoxic seizures within the last 5 years. * 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. * Any asthma exacerbation requiring oral corticosteroids within 12 weeks of screening or that resulted in overnight hospitalization requiring additional treatment for asthma within 6 months prior to screening. * A subject has any clinically significant, uncontrolled condition or disease state that, in the opinion of the investigator, would put the safety of the subject at risk through study participation or would confound the interpretation of the efficacy results if the condition/disease exacerbated during the study. The list of additional excluded conditions/diseases includes, but is not limited to the following: congestive heart failure, known aortic aneurysm, clinically significant coronary heart disease, clinically significant cardiac arrhythmia, stroke within 3 months of Visit 1, uncontrolled hypertension, recent or poorly controlled peptic ulcer, hematologic, hepatic, or renal disease (with the exception of Gilbert's syndrome or asymptomatic gallstones), immunologic compromise, current malignancy, tuberculosis (current or untreated), Cushing's disease, Addison's disease, uncontrolled diabetes mellitus, uncontrolled thyroid disorder, recent history of drug or alcohol abuse. * 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 DPI (i.e. lactose). * History of severe milk protein allergy. * 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 GlaxoSmithKline (GSK) Medical Monitor, contraindicates their participation. * Use of prescription or non-prescription drugs including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety. * Subjects who have taken oral steroids within 12 weeks of the screening visit. * History of regular alcohol consumption within 6 months of the study defined as Abuse of alcohol defined as an average weekly intake of greater than 21 units or an average daily intake of greater than 3 units (males) or defined as an average weekly intake of greater than 14 units or an average daily intake of greater than 2 units (females). One unit is equivalent to a 285 mL glass of full strength beer or 425 mL schooner of light beer or 1 (30 mL) measure of spirits or 1 glass (100 mL) of wine.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Weighted Mean Forced Expiratory Volume in 1 Second (FEV1) Measured Over 24 Hours at Day 14 of Each Treatment Period | 24 hours post-PM dose on Day 14 of each treatment period (up to Study Day 105) | FEV1 is a measure of lung function and the maximal amount of air that can be forcefully exhaled in one second. FEV1 was measured using site equipment (KoKo Pneumotach Spirometer). Weighted mean FEV1 was calculated using the Day 14 24-hour serial FEV1 measurements taken at 3, 6, 9, 12, 15, 18, 21, and 24 hours post-dose (measured in the evening of Day 15). At each time point, the highest of three technically acceptable measurements was recorded. FEV1 weighted mean was analyzed using a mixed effects analysis of a covariance model with fixed effect terms for treatment and period, participant Baseline, period Baseline, gender, and age as covariates, and participant as a random effect. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pre-treatment AM and PM Trough FEV1 on Day 14 of Each Treatment Period | Day 14 of each treatment period (up to Study Day 105) | FEV1 is a measure of lung function and the maximal amount of air that can be forcefully exhaled in one second. FEV1 was measured using site equipment (KoKo Pneumotach Spirometer). FEV1 PM trough FEV1 values were the values taken pre-treatment on Day 14, and AM trough FEV1 values were the values taken pre-treatment on Day 15 in each treatment period; thus, there is only one value (pre-treatment record) per period for AM and PM trough. |
| Number of Participants With Any Adverse Event (AE) | Up to 18 weeks | An AE is defined as any untoward medical occurrence in a participant or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AEs were collected from the start of dosing with investigational product and until follow-up. |
| Peak Expiratory Flow (PEF) | Up to 18 weeks | PEF is a measure of lung function and is defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated. AM and PM pre-treatment PEF was measured throughout the study for the purposes of monitoring participants' asthma stability, and was measured from the start of the Run-in Period until completion of Treatment Period 3 (including during the washout periods), prior to study medication and/or any rescue albuterol/salbutamol inhalation aerosol use. The data collected were only assessed by the Investigator on an individual basis during the study and were not formally summarized or statistically analyzed; consequently, data are not reported. |
Countries
Australia
Participant flow
Recruitment details
Participants meeting eligibility criteria at the Screening visit entered a 2-week Run-in Period for Baseline safety evaluations and to obtain measures of asthma status.
Pre-assignment details
Participants meeting randomization criteria were enrolled in the study for 13-18 weeks: three 14-day treatment periods separated by a 14- to 21-day washout period, followed by a follow-up visit within 7-14 days of the last dose.
Participants by arm
| Arm | Count |
|---|---|
| FF 100 µg AM/FF 100 µg PM/Placebo Participants received 3 treatments (A, B, and C) in either of the six sequences: ABC , ACB, BAC, BCA, CAB, or CBA. During treatment A participants received fluticasone furoate (FF) 100 micrograms (100 µg) in the morning (AM) at approximately 09:00 and received placebo in the evening (PM) at approximately 21:00 for 14 days (+/-2 days) via a dry powder inhaler (DPI), during treatment B: participants received placebo in the AM and FF 100 µg in the PM for 14 days (+/-2 days) via a DPI during treatment C: participants received placebo via a DPI for 14 days (+/-2 days) in the AM and PM. In addition, all participants were provided with albuterol/salbutamol aerosol to be used as rescue medication as needed. | 28 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Treatment Period 1 (14 Days) | Met Protocol-defined Stopping Criteria | 0 | 0 | 0 | 1 | 2 | 1 |
| Treatment Period 1 (14 Days) | Withdrawal by Subject | 0 | 1 | 0 | 1 | 0 | 0 |
| Treatment Period 3 (14 Days) | Met Protocol-defined Stopping Criteria | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | FF 100 µg AM/FF 100 µg PM/Placebo |
|---|---|
| Age, Continuous | 31.7 Years STANDARD_DEVIATION 10.99 |
| Gender Female | 15 Participants |
| Gender Male | 13 Participants |
| Race/Ethnicity, Customized African American/African Heritage | 1 Participants |
| Race/Ethnicity, Customized Asian - Central/South Asian Heritage | 2 Participants |
| Race/Ethnicity, Customized Asian - South East Asian Heritage | 1 Participants |
| Race/Ethnicity, Customized Mixed Race | 2 Participants |
| Race/Ethnicity, Customized White - Mixed Race | 1 Participants |
| Race/Ethnicity, Customized White - White/Caucasian/European Heritage | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 18 / 23 | 18 / 24 | 16 / 25 |
| serious Total, serious adverse events | 0 / 23 | 0 / 24 | 0 / 25 |
Outcome results
Primary
Weighted Mean Forced Expiratory Volume in 1 Second (FEV1) Measured Over 24 Hours at Day 14 of Each Treatment Period
FEV1 is a measure of lung function and the maximal amount of air that can be forcefully exhaled in one second. FEV1 was measured using site equipment (KoKo Pneumotach Spirometer). Weighted mean FEV1 was calculated using the Day 14 24-hour serial FEV1 measurements taken at 3, 6, 9, 12, 15, 18, 21, and 24 hours post-dose (measured in the evening of Day 15). At each time point, the highest of three technically acceptable measurements was recorded. FEV1 weighted mean was analyzed using a mixed effects analysis of a covariance model with fixed effect terms for treatment and period, participant Baseline, period Baseline, gender, and age as covariates, and participant as a random effect.
Time frame: 24 hours post-PM dose on Day 14 of each treatment period (up to Study Day 105)
Population: Intent-to-Treat (ITT) Population: all participants randomized to treatment who received at least one dose of study medication, and had at least one Baseline and post-dose FEV1 measurement performed. Only those participants with non-missing covariates and a post-Baseline FEV1 measurement were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| FF 100 µg AM | Weighted Mean Forced Expiratory Volume in 1 Second (FEV1) Measured Over 24 Hours at Day 14 of Each Treatment Period | 3.303 Liters | Standard Error 0.0589 |
| FF 100 µg PM | Weighted Mean Forced Expiratory Volume in 1 Second (FEV1) Measured Over 24 Hours at Day 14 of Each Treatment Period | 3.332 Liters | Standard Error 0.0584 |
| Placebo | Weighted Mean Forced Expiratory Volume in 1 Second (FEV1) Measured Over 24 Hours at Day 14 of Each Treatment Period | 3.227 Liters | Standard Error 0.0585 |
90% CI: [0.001, 0.152]
90% CI: [0.029, 0.18]
90% CI: [-0.102, 0.045]
Secondary
Number of Participants With Any Adverse Event (AE)
An AE is defined as any untoward medical occurrence in a participant or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AEs were collected from the start of dosing with investigational product and until follow-up.
Time frame: Up to 18 weeks
Population: All Subjects Population: all participants who received at least one dose of study medication
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FF 100 µg AM | Number of Participants With Any Adverse Event (AE) | 18 Participants |
| FF 100 µg PM | Number of Participants With Any Adverse Event (AE) | 18 Participants |
| Placebo | Number of Participants With Any Adverse Event (AE) | 16 Participants |
Secondary
Peak Expiratory Flow (PEF)
PEF is a measure of lung function and is defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated. AM and PM pre-treatment PEF was measured throughout the study for the purposes of monitoring participants' asthma stability, and was measured from the start of the Run-in Period until completion of Treatment Period 3 (including during the washout periods), prior to study medication and/or any rescue albuterol/salbutamol inhalation aerosol use. The data collected were only assessed by the Investigator on an individual basis during the study and were not formally summarized or statistically analyzed; consequently, data are not reported.
Time frame: Up to 18 weeks
Secondary
Pre-treatment AM and PM Trough FEV1 on Day 14 of Each Treatment Period
FEV1 is a measure of lung function and the maximal amount of air that can be forcefully exhaled in one second. FEV1 was measured using site equipment (KoKo Pneumotach Spirometer). FEV1 PM trough FEV1 values were the values taken pre-treatment on Day 14, and AM trough FEV1 values were the values taken pre-treatment on Day 15 in each treatment period; thus, there is only one value (pre-treatment record) per period for AM and PM trough.
Time frame: Day 14 of each treatment period (up to Study Day 105)
Population: Intent-to-Treat (ITT) Population: all participants randomized to treatment who received at least one dose of study medication, and had at least one Baseline and post-dose FEV1 measurement performed. Only those participants available at the specified time points were analyzed
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| FF 100 µg AM | Pre-treatment AM and PM Trough FEV1 on Day 14 of Each Treatment Period | AM Trough FEV1 | 3.299 Liters | Standard Error 0.0707 |
| FF 100 µg AM | Pre-treatment AM and PM Trough FEV1 on Day 14 of Each Treatment Period | PM Trough FEV1 | 3.236 Liters | Standard Error 0.0607 |
| FF 100 µg PM | Pre-treatment AM and PM Trough FEV1 on Day 14 of Each Treatment Period | AM Trough FEV1 | 3.359 Liters | Standard Error 0.0702 |
| FF 100 µg PM | Pre-treatment AM and PM Trough FEV1 on Day 14 of Each Treatment Period | PM Trough FEV1 | 3.290 Liters | Standard Error 0.0598 |
| Placebo | Pre-treatment AM and PM Trough FEV1 on Day 14 of Each Treatment Period | AM Trough FEV1 | 3.286 Liters | Standard Error 0.0703 |
| Placebo | Pre-treatment AM and PM Trough FEV1 on Day 14 of Each Treatment Period | PM Trough FEV1 | 3.177 Liters | Standard Error 0.06 |