A Phase 3 interventional study of fluticasone propionate inhalation solution and budesonide suspension in Asthma, sponsored by GlaxoSmithKline. Completed at 25 sites in China. Open to participants aged 17 Years to 70 Years. Per ClinicalTrials.gov, last updated 2018-10-11.
Sponsored by GlaxoSmithKline · Phase 3, Interventional, and Treatment
This is a multicentre, randomized, single-blind, active-controlled, parallel-group phase III local registration study for a treatment period of 12 weeks. This study aims to assess the effectiveness and safety of fluticasone propionate 1mg via nebulizer BID in treatment of Chinese adult and adolescent patients with severe persistent asthma for a treatment period of 12 weeks versus budesonide 2mg via nebulizer BID. The steady-state plasma pharmacokinetics of fluticasone propionate inhalation solution will also be assessed.
Male or female subjects between 17 to 70 (inclusive) years of age with severe persistent asthma meeting the inclusion criteria and having completed the screening period of 2 weeks will, in a proportion of 1:1, randomly receive fluticasone propionate 1mg via nebulizer BID or budesonide 2mg via nebulizer BID for a treatment period of 12 weeks. The clinic visit will be arranged at 2 weeks, 4 weeks, 8 weeks and 12 weeks during study treatment. If the subjects meet the criteria of pre-defined asthma control at treatment 4 weeks or 8 weeks, they will have one chance to be treated with the half dose of study drug. 2 weeks after completion of study treatment or after early withdrawal from study, the follow-up visit will be performed to assess the post-treatment adverse events. The primary endpoint is the mean change from baseline in morning peak expiratory flow (PEF) over the 12 week treatment period. Safety assessments include adverse events, vital signs, oral and oropharyngeal candidiasis, hematological, biochemical tests), 24-hour urinary cortisol and 12-lead ECG. The steady-state plasma pharmacokinetics of fluticasone propionate inhalation solution will also be assessed.
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Non-childbearing potential (i.e. physiologically incapable of becoming pregnant, including any female who is pre-menarchal, post-menopausal), or Child-bearing potential, has a negative urinary pregnancy test at screening and agrees to take contraceptive precautions (including abstinence) (referring to appendix 1: Highly Effective Methods For Avoidance Of Pregnancy In Women Of Childbearing Potential) which, in the opinion of the investigator are adequate to prevent pregnancy during the study.
Exclusion Criteria:
1 mg BID inhalation via nebulizer
Drug: fluticasone propionate inhalation solution
2 mg BID inhalation via nebulizer
Drug: budesonide suspension
1 mg BID inhalation for 12 weeks with one possible chance to change to 0.5 mg BID
2 mg BID inhalation for 12 weeks with one possible chance to change to 1 mg BID
Change From Baseline (Day 1 of Treatment Period/Visit 2) in Morning Peak Expiratory Flow (AM PEF) Over 12 Weeks in Intent-to-treat Population
The peak expiratory flow (PEF) is a person's maximum speed of expiration, A peak flow meter was issued to participants at Visit 1 to measure the morning PEF prior to study drug and rescue medication. The best of three attempts was recorded by the participants in the diary cards. Baseline value was the assessment at Visit 2. The raw and change from baseline in daily AM PEF averaged over the 12-week treatment period The mean value was considered missing if less than 4 days were recorded in the baseline week prior to randomization or if less than 4 days are recorded after randomization. Analysis was performed using analysis of covariance (ANCOVA) model. Abbreviations used in statistical analysis section: standard deviation (SD) and significance (sig)
Time frame: Baseline (Visit 2) and up to Week 12
Change From Baseline (Day 1 of Trt Period/Visit 2) in AM PEF Over 12 Weeks in Per Protocol Population
The peak expiratory flow (PEF) is a person's maximum speed of expiration, A peak flow meter was issued to participants at Visit 1 to measure the morning PEF prior to study drug and rescue medication. The best of three attempts was recorded by the participants in the diary cards. Baseline value was the assessment at Visit 2. The raw and change from baseline in daily AM PEF averaged over the 12-week treatment period The mean value was considered missing if less than 4 days were recorded in the baseline week prior to randomization or if less than 4 days are recorded after randomization. Analysis was performed using analysis of covariance (ANCOVA) model.
Time frame: Baseline (Visit 2) and up to Week 12
Mean Change of Evening PEF From Baseline Over 12 Weeks
The peak expiratory flow (PEF) is a person's maximum speed of expiration, A peak flow meter was issued to participants at Visit 1 to measure the evening PEF prior to study drug and rescue medication. The best of three attempts was recorded by the participants in the diary cards. Baseline value was the assessment at Visit 2. The raw and change from baseline in daily PM PEF averaged over the 12-weeks treatment period.
Time frame: Baseline (Visit 2) and up to Week 12
Mean Change in Percentage of Symptom-free 24-hour Periods From Baseline Over 12 Weeks
While calculating symptom-free 24-hour periods, a given 24-hour period was set to be "symptom free" only if the participant's responses to both the morning and evening assessments indicated no symptoms. The Baseline value was Visit 2 assessment and was derived from the last 7 days of the daily diary prior to the randomization. Change from Baseline was calculated as the difference between the value of the endpoint at the time point of interest and the baseline value. The value provided in outcome measure data is a consolidated value over Weeks 1 to 12.
Time frame: Baseline (Visit 2) and over 12 Weeks
Median Day-time and Night-time Symptom Scores Per Participant Over 12 Weeks
Participants recorded day-time symptom score every day in the morning and evening at bedtime before taking any rescue or study medication and before PEF measurement, using 6 point scale on Diary Card indicating 0 = No symptoms during the day and 5 =Symptoms so severe that participant could not go to work or perform normal daily activities. Night time symptoms were scored while waking in the morning on a scale of 0 (no symptoms) to 4 (severe). The value provided in outcome measure data is a consolidated value over Weeks 1 to 12.
Time frame: Over 12 Weeks
Mean Change in Percentage of Rescue-free 24-hour Periods From Baseline Over 12 Weeks
While calculating rescue-free 24-hour periods, the 24-hour period was only set to be "rescue free" if responses to both the morning and evening, assessments indicated no use of rescue medication. If there were symptoms in either the morning or the evening then that 24-hour period was set to as "not symptom free". Similarly, if there was rescue medication use in either the morning or the evening, then that 24-hour period was set to as "not rescue free". The Baseline value was Visit 2 assessment and was derived from the last 7 days of the daily diary prior to the randomization. The value provided in outcome measure data is a consolidated value over Weeks 1 to 12.
Time frame: Baseline and over 12 weeks
Median Number of Times Rescue Medication Use Over 12 Weeks
Participants recorded the number of inhalations of rescue salbutamol inhalation aerosol used during the day and night. The baseline value was Visit 2 assessment and was derived from the last 7 days of the daily diary prior to the randomization. The analysis only included participants who had at least 2 days of non-missing numbers of times rescue medication (including zero) after randomization.
Time frame: Up to week 12
Change of Clinical Lung Function Measurement Forced Expiratory Volume in One Second (FEV1) From Baseline Over 12 Weeks
FEV1 as a measure of lung function assessment was measured at Week 2, 4, 8 and 12. FEV1 measures were performed electronically by spirometry. The highest of three technically acceptable measurements was recorded. FEV1 was measured prior to study drug administration and any rescue salbutamol use. Baseline value was the assessment at Visit 2.Change from baseline was calculated as the value at the specific time point minus baseline value.
Time frame: Baseline and at Week 2, 4, 8 and 12
Steady-state Plasma Pharmacokinetics of Fluticasone Propionate Inhalation Solution- Time to Maximum Observed Plasma Concentration (Tmax)
Tmax is defined as the time to maximum observed plasma concentration. Blood Pharmacokinetic (PK) samples were taken on Visit 3 (Day 14±2) pre-dose, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h and 12h post dose from participants. Blood sample for PK analysis, obtained within 72 hours of the last dose.
Time frame: Pre-dose, 0.5 hour (h), 1h, 2h, 3h, 4h, 6h, 8h and 12h post dose at Week 2
Steady-state Plasma Pharmacokinetics of Fluticasone Propionate Inhalation Solution-maximum Observed Plasma Concentration (Cmax)
Cmax was defined as maximum observed plasma concentration. Blood PK samples were taken on Visit 3 (Day 14±2) pre-dose, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h and 12h post dose from participants. Blood sample for PK analysis, obtained within 72 hours of last dose.
Time frame: Pre-dose, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h and 12h post dose at Week 2
Steady-state Plasma Pharmacokinetics of Fluticasone Propionate Inhalation Solution-area Under the Plasma Concentration-time Curve for the Dose Interval [AUC (0-τ)]
AUC (0-τ) was defined as the area under the plasma concentration-time curve for the dose interval. Blood PK samples were taken on Visit 3 (Day 14±2) pre-dose, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h and 12h post dose from participants. Blood sample for PK analysis, obtained within 72 hours of last dose.
Time frame: Pre-dose, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h and 12h post dose at Week 2
A total of 317 Chinese adults and adolescents aged \>= 17 years and \<= 70 years with severe persistent asthma were planned to be enrolled in study. This study was conducted from 27-September-2012 to 7-November-2013.
| Milestone | FP 1 mg BID | BUD 2 mg BID |
|---|---|---|
| Started | 158 | 157 |
| Completed | 123 | 130 |
| Not completed | 35 | 27 |
| Withdrew: Adverse event | 11 | 4 |
| Withdrew: Lack of efficacy | 3 | 1 |
| Withdrew: Protocol violation | 1 | 3 |
| Withdrew: Protocol defined stopping criteria | 8 | 10 |
| Withdrew: Lost to follow-up | 1 | 1 |
| Withdrew: Investigator discretion | 2 | 0 |
| Withdrew: Withdrawal by subject | 9 | 8 |
The peak expiratory flow (PEF) is a person's maximum speed of expiration, A peak flow meter was issued to participants at Visit 1 to measure the morning PEF prior to study drug and rescue medication. The best of three attempts was recorded by the participants in the diary cards. Baseline value was the assessment at Visit 2. The raw and change from baseline in daily AM PEF averaged over the 12-week treatment period The mean value was considered missing if less than 4 days were recorded in the baseline week prior to randomization or if less than 4 days are recorded after randomization. Analysis was performed using analysis of covariance (ANCOVA) model. Abbreviations used in statistical analysis section: standard deviation (SD) and significance (sig)
| Litres/Minute | FP 1 mg BID | BUD 2 mg BID |
|---|---|---|
| Change From Baseline (Day 1 of Treatment Period/Visit 2) in Morning Peak Expiratory Flow (AM PEF) Over 12 Weeks in Intent-to-treat Population | 12.71 ± 3.677 | 14.51 ± 3.714 |
The peak expiratory flow (PEF) is a person's maximum speed of expiration, A peak flow meter was issued to participants at Visit 1 to measure the morning PEF prior to study drug and rescue medication. The best of three attempts was recorded by the participants in the diary cards. Baseline value was the assessment at Visit 2. The raw and change from baseline in daily AM PEF averaged over the 12-week treatment period The mean value was considered missing if less than 4 days were recorded in the baseline week prior to randomization or if less than 4 days are recorded after randomization. Analysis was performed using analysis of covariance (ANCOVA) model.
| Litres/Minute | FP 1 mg BID | BUD 2 mg BID |
|---|---|---|
| Change From Baseline (Day 1 of Trt Period/Visit 2) in AM PEF Over 12 Weeks in Per Protocol Population | 13.50 ± 3.806 | 15.78 ± 3.750 |
The peak expiratory flow (PEF) is a person's maximum speed of expiration, A peak flow meter was issued to participants at Visit 1 to measure the evening PEF prior to study drug and rescue medication. The best of three attempts was recorded by the participants in the diary cards. Baseline value was the assessment at Visit 2. The raw and change from baseline in daily PM PEF averaged over the 12-weeks treatment period.
| Litres/Minute | FP 1 mg BID | BUD 2 mg BID |
|---|---|---|
| Mean Change of Evening PEF From Baseline Over 12 Weeks | 12.39 ± 3.469 | 15.16 ± 3.504 |
While calculating symptom-free 24-hour periods, a given 24-hour period was set to be "symptom free" only if the participant's responses to both the morning and evening assessments indicated no symptoms. The Baseline value was Visit 2 assessment and was derived from the last 7 days of the daily diary prior to the randomization. Change from Baseline was calculated as the difference between the value of the endpoint at the time point of interest and the baseline value. The value provided in outcome measure data is a consolidated value over Weeks 1 to 12.
| Percentage of symptom-free 24-hour | FP 1 mg BID | BUD 2 mg BID |
|---|---|---|
| Mean Change in Percentage of Symptom-free 24-hour Periods From Baseline Over 12 Weeks | 21.77 ± 2.340 | 21.15 ± 2.364 |
Participants recorded day-time symptom score every day in the morning and evening at bedtime before taking any rescue or study medication and before PEF measurement, using 6 point scale on Diary Card indicating 0 = No symptoms during the day and 5 =Symptoms so severe that participant could not go to work or perform normal daily activities. Night time symptoms were scored while waking in the morning on a scale of 0 (no symptoms) to 4 (severe). The value provided in outcome measure data is a consolidated value over Weeks 1 to 12.
| Score on Scale | FP 1 mg BID | BUD 2 mg BID |
|---|---|---|
| Median day-time symptom score | 1.0 (0 to 4) | 1.0 (0 to 4) |
| Median night-time symptom score | 1.0 (0 to 2) | 1.0 (0 to 3) |
While calculating rescue-free 24-hour periods, the 24-hour period was only set to be "rescue free" if responses to both the morning and evening, assessments indicated no use of rescue medication. If there were symptoms in either the morning or the evening then that 24-hour period was set to as "not symptom free". Similarly, if there was rescue medication use in either the morning or the evening, then that 24-hour period was set to as "not rescue free". The Baseline value was Visit 2 assessment and was derived from the last 7 days of the daily diary prior to the randomization. The value provided in outcome measure data is a consolidated value over Weeks 1 to 12.
| Percentage of rescue -free 24-hours | FP 1 mg BID | BUD 2 mg BID |
|---|---|---|
| Mean Change in Percentage of Rescue-free 24-hour Periods From Baseline Over 12 Weeks | 19.27 ± 2.595 | 24.01 ± 2.612 |
Participants recorded the number of inhalations of rescue salbutamol inhalation aerosol used during the day and night. The baseline value was Visit 2 assessment and was derived from the last 7 days of the daily diary prior to the randomization. The analysis only included participants who had at least 2 days of non-missing numbers of times rescue medication (including zero) after randomization.
| Number of Inhalations | FP 1 mg BID | BUD 2 mg BID |
|---|---|---|
| Median Number of Times Rescue Medication Use Over 12 Weeks | 0.0 (0 to 7) | 0.0 (0 to 4) |
FEV1 as a measure of lung function assessment was measured at Week 2, 4, 8 and 12. FEV1 measures were performed electronically by spirometry. The highest of three technically acceptable measurements was recorded. FEV1 was measured prior to study drug administration and any rescue salbutamol use. Baseline value was the assessment at Visit 2.Change from baseline was calculated as the value at the specific time point minus baseline value.
| Litres | FP 1 mg BID | BUD 2 mg BID |
|---|---|---|
| Week 2 | 0.122 ± 0.0283 | 0.161 ± 0.0281 |
| Week 4 | 0.187 ± 0.0333 | 0.195 ± 0.0328 |
| Week 8 | 0.175 ± 0.0314 | 0.201 ± 0.0309 |
| Week 12 | 0.217 ± 0.0342 | 0.200 ± 0.0336 |
Tmax is defined as the time to maximum observed plasma concentration. Blood Pharmacokinetic (PK) samples were taken on Visit 3 (Day 14±2) pre-dose, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h and 12h post dose from participants. Blood sample for PK analysis, obtained within 72 hours of the last dose.
| Hour | FP 1 mg BID |
|---|---|
| Steady-state Plasma Pharmacokinetics of Fluticasone Propionate Inhalation Solution- Time to Maximum Observed Plasma Concentration (Tmax) | 0.905 ± 59.9 |
Cmax was defined as maximum observed plasma concentration. Blood PK samples were taken on Visit 3 (Day 14±2) pre-dose, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h and 12h post dose from participants. Blood sample for PK analysis, obtained within 72 hours of last dose.
| picogram per milliliter (pg/mL) | FP 1 mg BID |
|---|---|
| Steady-state Plasma Pharmacokinetics of Fluticasone Propionate Inhalation Solution-maximum Observed Plasma Concentration (Cmax) | 59.24 ± 115.0 |
AUC (0-τ) was defined as the area under the plasma concentration-time curve for the dose interval. Blood PK samples were taken on Visit 3 (Day 14±2) pre-dose, 0.5h, 1h, 2h, 3h, 4h, 6h, 8h and 12h post dose from participants. Blood sample for PK analysis, obtained within 72 hours of last dose.
| Picogram hours per milliliter (pg*h/mL) | FP 1 mg BID |
|---|---|
| Steady-state Plasma Pharmacokinetics of Fluticasone Propionate Inhalation Solution-area Under the Plasma Concentration-time Curve for the Dose Interval [AUC (0-τ)] | 403.0958 ± 70.5 |
Collected over Up to Week 12. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| FP 1 mg BID | 1/158 (0.6%) | 4/158 (2.5%) | 23/158 (14.6%) |
| BUD 2 mg BID | 0/157 (0%) | 2/157 (1.3%) | 15/157 (9.6%) |
| Event | FP 1 mg BID | BUD 2 mg BID |
|---|---|---|
| AsthmaRespiratory, thoracic and mediastinal disorders | 2/158 | 2/157 |
| InfectionInfections and infestations | 1/158 | 1/157 |
| Lung infectionInfections and infestations | 0/158 | 1/157 |
| SpondylolisthesisMusculoskeletal and connective tissue disorders | 1/158 | 0/157 |
| Nephrotic syndromeRenal and urinary disorders | 1/158 | 0/157 |
| Event | FP 1 mg BID | BUD 2 mg BID |
|---|---|---|
| NasopharyngitisInfections and infestations | 13/158 | 10/157 |
| Upper respiratory tract infectionInfections and infestations | 10/158 | 5/157 |
The analysis was performed on intent-to-treat population. This population comprised of all participants randomized to treatment and who received at least one dose of study medication. Only the participants present at the indicated time point were analyzed.
| Age, Continuous(Years) | FP 1 mg BID | BUD 2 mg BID | Total |
|---|---|---|---|
| Mean | 51.7 ± 9.84 | 51.1 ± 6.65 | 51.4 ± 9.74 |
| Sex: Female, Male(Participants) | FP 1 mg BID | BUD 2 mg BID | Total |
|---|---|---|---|
| Female | 77 | 71 | 148 |
| Male | 81 | 86 | 167 |
| Region of Enrollment(Participants) | FP 1 mg BID | BUD 2 mg BID | Total |
|---|---|---|---|
| China | 158 | 157 | 315 |
Plan to share: Yes — IPD for this study will be made available via the Clinical Study Data Request site.
Supporting information: Study protocol, Sap, Icf, Csr
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GlaxoSmithKline