Asthma
Conditions
Keywords
Inhalation, Pharmacodynamic, Patients,
Brief summary
A randomised, double-blind, double-dummy, multi-site, phase III, single dose, 4-way cross-over pharmacodynamic study evaluating the efficacy of Bricanyl Turbuhaler M3 compared to Bricanyl Turbuhaler M2 by studying the protective effect on methacholine induced bronchoconstriction in patients with stable, mild to moderate asthma
Detailed description
The study will include female and male patients, between 18 and 65 years old, with stable, mild to moderate asthma who are on short acting β2-agonist (SABA) alone, on low dose inhaled corticosteroid (ICS) (200-400 µg budesonide or corresponding) or on a combination of low dose ICS and long acting β2-agonists (LABA). Approximately 60 patients will be randomised in order to have 49 completed. The primary objective is to demonstrate therapeutic equivalence between Bricanyl Turbuhaler M3 and Bricanyl Turbuhaler M2 using bronchoprotective effect. Outcome measure: PC20 (Methacholine provocative concentration causing a 20% drop in FEV1). The safety objective is to compare safety of Bricanyl Turbuhaler M2 and Bricanyl Turbuhaler M3. Outcome measure Adverse Events/Serious. Study period Q1 2015 - Q1 2016.
Interventions
DRUGTerbutaline sulphate
Bricanyl Turbuhaler M2
DRUGPlacebo for terbutaline sulphate
Placebo Turbuhaler M2
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
- Female and male aged 18 and 65 years. * At least 6 months of documented clinical diagnosis of asthma as defined by GINA 2012 or American Thoracic Society (Expert Panel Report 3 2007) prior to visit 1 * Stable asthmatics on SABA alone, on low dose ICS (200-400 µg budesonide corresponding) or on fixed combination of low ICS/LABA * At the enrolment visit 1a, the visit baseline FEV1 must be ≥80 % of that predicted normal (NHANES III). For LABA patients the visit baseline FEV1 must be ≥80 % of that predicted normal (NHANES III) at both visit 1a and visit 1b. If not, the patient will be withdrawn from the study * At the enrolment visits 1a or 1b (LABA patients only) and at the end of run-in period, visit 2, eligible patients should demonstrate an airway responsiveness to methacholine PC20 \<8 mg/mL. If not, the patient will be withdrawn from the study * Capable of using Turbuhaler inhalation device as judged by investigator.
Exclusion criteria
Diagnosed with COPD or history of cystic fibrosis, bronchiectasis or other respiratory diseases * Pregnancy, breast-feeding, lactation, or planned pregnancy during the study. Fertile women not using acceptable contraceptive measures * Conditions which could alter airway reactivity to methacholine (e.g. pneumonia, upper respiratory tract infection, viral bronchitis and/or sinobronchitis) within past six weeks * Exacerbation due to asthma or change in asthma medication during the last 3 months prior to enrolment * Night time awakenings due to asthma symptoms on 2 consecutive nights during the last 4 weeks prior to enrolment * Smokers 6 months prior to the study start or with a history of smoking of more than 10 pack years (e.g. 20 cigarettes/day for at least 10 years, or 10 cigarettes/day for at least 20 years, or equal).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Provocative Concentration of Methacholine Which Produces a 20% Fall in FEV1 (PC20) | 4 cross-over treatments (<1 day each) with 2-10 days between treatment washout periods |
Countries
Canada, Netherlands, Sweden
Participant flow
Recruitment details
Patients with stable, mild to moderate asthma were enrolled. The first subject entered study on March 10, 2015 and the last subject completed study on November 5, 2015. Subjects were recuited from Site 1001 and 1002 in Canada, Site 7201 in Sweden, and Site 5001 in Netherlands.
Pre-assignment details
Of the 95 patients enrolled 34 were screen failures mainly due to not fulfilling specific randomization criteria on stability in asthma or sensitivity to methacholine challenge; 1 was withdrawal by subject; 72 entered run in period. A total of 60 patients were randomized to the 4 single-dose treatments with terbutaline in a crossover design.
Participants by arm
| Arm | Count |
|---|---|
| Overall Total number of participants in the Full analysis set | 60 |
| Total | 60 |
Baseline characteristics
| Characteristic | Overall |
|---|---|
| Age, Continuous | 31.1 Years STANDARD_DEVIATION 12.19 |
| Gender Female | 40 Participants |
| Gender Male | 20 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants |
| Race/Ethnicity, Customized White | 57 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 12 / 60 | 10 / 60 | 7 / 60 | 13 / 60 |
| serious Total, serious adverse events | 0 / 60 | 0 / 60 | 0 / 60 | 0 / 60 |
Outcome results
Primary
Provocative Concentration of Methacholine Which Produces a 20% Fall in FEV1 (PC20)
Time frame: 4 cross-over treatments (<1 day each) with 2-10 days between treatment washout periods
Population: Efficacy analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| M3 1.5 mg | Provocative Concentration of Methacholine Which Produces a 20% Fall in FEV1 (PC20) | 17.70 mg/mL |
| M3 0.5 mg | Provocative Concentration of Methacholine Which Produces a 20% Fall in FEV1 (PC20) | 9.88 mg/mL |
| M2 1.5 mg | Provocative Concentration of Methacholine Which Produces a 20% Fall in FEV1 (PC20) | 20.10 mg/mL |
| M2 0.5 mg | Provocative Concentration of Methacholine Which Produces a 20% Fall in FEV1 (PC20) | 10.78 mg/mL |
Comparison: A linear mixed effect model based on restricted maximum likelihood analysis is used to estimate the treatment effect. PC20 in natural log scale is the response variable, treatment and period are the fixed effects, and patient within sequence is a random effect.p-value: <0.00195% CI: [1.52, 2.29]Mixed Models Analysis
Comparison: A linear mixed effect model based on restricted maximum likelihood analysis is used to estimate the treatment effect. PC20 in natural log scale is the response variable, treatment and period are the fixed effects, and patient within sequence is a random effect.p-value: <0.00195% CI: [1.46, 2.2]Mixed Models Analysis
Comparison: A linear mixed effect model based on restricted maximum likelihood analysis is used to estimate the treatment effect. PC20 in natural log scale is the response variable, treatment and period are the fixed effects, and patient within sequence is a random effect.95% CI: [0.75, 1.13]Mixed Models Analysis
Comparison: A linear mixed effect model based on restricted maximum likelihood analysis is used to estimate the treatment effect. PC20 in natural log scale is the response variable, treatment and period are the fixed effects, and patient within sequence is a random effect.95% CI: [0.72, 1.08]Mixed Models Analysis