Asthma
Conditions
Brief summary
This is a Phase IIa, multicentre, single dose, randomised, double blind, controlled, 2 way cross-over study to evaluate the potential for bronchoconstriction of the new HFA-152a propellant (single dose) versus the marketed HFA-134a propellant (single dose) in adults with mild asthma. HFA=Hydrofluoroalkane
Interventions
DRUGPlacebo 152a
Placebo pressurised metered-dose inhaler (pMDI) formulated with the 152a propellant
DRUGPlacebo 134a
Placebo pressurised metered-dose inhaler (pMDI) formulated with the 134a propellant
Sponsors
Chiesi Farmaceutici S.p.A.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Subject's written informed consent obtained prior to any study related procedure. 2. Gender and age: Male or female adults aged from 18 to 75 years old (inclusive). 3. Diagnosis of asthma: documented established diagnosis of mild asthma for at least 6 months according to Step 1 of the Global Initiative for Asthma (GINA) 2021 guidelines. 4. Lung function: subjects with a pre-bronchodilator forced expiratory volume in 1 second (FEV1) ≥60% of the predicted normal value and ≥1.5 L at screening and prior to randomisation, after appropriate wash-out from bronchodilators. 5. Documented excessive variability in lung function. 6. Current asthma therapy: as needed low-dose inhaled corticosteroids (ICS)-formoterol, as needed short-acting β2-agonists (SABA), or low-dose ICS whenever SABA was taken taken not more than twice a week (2 events) in the 4 weeks prior to screening or in the 6 weeks prior to randomisation. 7. Asthma control: controlled or partly controlled based on an Asthma Control Questionnaire© (ACQ-5) score \<1.5 at screening and prior to randomisation. 8. Ability to use the inhalers. 9. Ability to comply with the protocol. 10: Female subjects of non-childbearing potential (defined as physiologically incapable of becoming pregnant (i.e. postmenopausal or permanently sterile) and Female subjects of childbearing potential, who accepts the use of highly effective contraceptive methods during the study or with non-fertile male partners. 11\. Male subjects fulfilling one of the following criteria: 1. Fertile male subjects with pregnant or non-pregnant women of childbearing potential (WOCBP) partners: they must be willing to use male condom from the signature of the Informed Consent Form (ICF) and until the follow-up visit/call, or; 2. Non-fertile male subjects (contraception is not required in this case), or; 3. Fertile male subjects with women of non-childbearing potential (WONCBP) partner (contraception is not required in this case).
Exclusion criteria
1. History of at risk asthma. 2. Recent exacerbation. 3. Asthma requiring use of biologics. 4. Respiratory disorders other than asthma. 5. Lung cancer or history of lung cancer. 6. Lung resection. 7. Lower respiratory tract infection. 8. Documented coronavirus disease 2019 (COVID-19) diagnosis. 9. Smoking status: current smoker, or ex-smoker with a smoking history of ≥10 pack-years. 10. Cancer or history of cancer (other than lung cancer);subject with active cancer or a history of cancer with less than 5 years disease-free survival time. 11. Cardiovascular diseases: subjects who have known and clinically significant (CS) cardiovascular conditions. 12. Electrocardiogram (ECG) criteria: any CS abnormal 12-lead ECG that, in the Investigator's opinion, would affect safety evaluations or place the subject at risk. 13. Central nervous system disorders: subjects with a history of symptoms or significant neurological disease. 14. Other concurrent diseases: subjects with historical or current evidence of uncontrolled concurrent disease such as, but not limited to, hyperthyroidism, diabetes mellitus or other endocrine disease, haematological disease, autoimmune disorders (e.g. rheumatoid arthritis), gastrointestinal disorders (e.g. poorly controlled peptic ulcer, gastroesophageal reflux disease), significant renal impairment or other disease or condition that might, in the judgement of the Investigator, place the subject at undue risk or potentially compromise the results or interpretations of the study. 15. Laboratory abnormalities: subjects with CS laboratory abnormalities indicating a significant or unstable concomitant disease. 16. Alcohol/drug abuse. 17. Participation to investigational trial: subjects who have received any investigational drug within the 30 days (60 days for biologics) prior to screening. 16\. Hypersensitivity: history of hypersensitivity to any of the study medications components. 17.Subjects mentally or legally incapacitated. 18. Recent eye surgery or any condition where raised intracranial pressure (caused by forceful exhalation) would be harmful. 19\. For female subjects only: pregnant or lactating women, where pregnancy is defined as the state of a female after conception and until termination of the gestation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety: Relative Change From Baseline* in Forced Expiratory Volume in 1 s (FEV1) -- 15 Min Post-dose | At 15 min post-dose after T1. | Safety: Relative change from baseline\* in forced expiratory volume in 1 s (FEV1) at the 15 min post-dose time point. Results are presented as adjusted mean and 95% confidence interval (CI.) The potential of the test propellant (HFA-152a vs HFA-134a) for bronchoconstriction was evaluated using centralised spirometry assessments performed during treatment period 1 (TP1) and treatment period 2 (TP2). T0 was defined as the moment when the first inhalation took place, and was used to calculate the pre-dose time points. T1 was defined as the moment when the last inhalation took place, and was used to calculate the post-dose time points. \*The baseline FEV1 values were the mean of the two pre-dose assessments (i.e., performed at 45 min and 15 min before T0). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety: Absolute Change From Baseline* in FEV1 -- All Time Points Post Dose | At 5 min, 15 min, 30 min, 1 h, 1 h 30 min, and 3 h after T1. | Safety: Absolute change from baseline\* in FEV1 at all post-dose time points. Results are presented as adjusted mean and 95% CI. The potential of the test propellant (HFA-152a vs HFA-134a) for bronchoconstriction was evaluated using centralised spirometry assessments performed during treatment period 1 (TP1) and treatment period 2 (TP2). T0 was defined as the moment when the first inhalation took place, and was used to calculate the pre-dose time points. T1 was defined as the moment when the last inhalation took place, and was used to calculate the post-dose time points. The baseline FEV1 values were the mean of the two pre-dose assessments (i.e., performed at 45 min and 15 min before T0). |
| Safety: Subjects With a Relative Change From Baseline* in FEV1 <-15% -- All Post-dose Time Points | At 5 min, 15 min, 30 min, 1 h, 1 h 30 min, and 3 h after T1. | Safety: Number and percentage of subjects with a relative change from baseline\* in FEV1 at each post-dose time point \<-15%. The baseline FEV1 values were the mean of the two pre-dose assessments (i.e., performed at 45 min and 15 min before T0). |
| Safety: Change From Baseline* in FEV1 Area Under the Concentration-time Curve From Time Zero to 3 Hours (AUC0-3h) | At 3 h post-dose. | Change from baseline\* in FEV1 area under the concentration-time curve from time zero to 3 hours (AUC0-3h). Results show the change from baseline in FEV1 AUC(0-3h) corrected for Time, in litres The potential of the test propellant (HFA-152a vs HFA-134a) for bronchoconstriction was evaluated using centralised spirometry assessments performed during treatment period 1 (TP1) and treatment period 2 (TP2). T0 was defined as the moment when the first inhalation took place, and was used to calculate the pre-dose time points. T1 was defined as the moment when the last inhalation took place, and was used to calculate the post-dose time points. \*The baseline FEV1 values were the mean of the two pre-dose assessments (i.e., performed at 45 min and 15 min before T0). |
| Safety: Relative Change From Baseline* in Peak Expiratory Flow (PEF) -- All Post-dose Time Points | At 5 min, 15 min, 30 min, 1 h, 1 h 30 min, and 3 h after T1. | Safety: Relative change from baseline\* in peak expiratory flow (PEF) at all post-dose time points. The potential of the test propellant (HFA-152a vs HFA-134a) for bronchoconstriction was evaluated using centralised spirometry assessments performed during treatment period 1 (TP1) and treatment period 2 (TP2). T0 was defined as the moment when the first inhalation took place, and was used to calculate the pre-dose time points. T1 was defined as the moment when the last inhalation took place, and was used to calculate the post-dose time points. The baseline PEF values were the mean of the two pre-dose assessments (i.e., performed at 45 min and 15 min before T0). |
| Safety: Absolute Change From Baseline* in PEF -- All Post-dose Time Points | At 5 min, 15 min, 30 min, 1 h, 1 h 30 min, and 3 h after T1. | Safety: Absolute change from baseline\* in PEF at all post-dose time points. The potential of the test propellant (HFA-152a vs HFA-134a) for bronchoconstriction was evaluated using centralised spirometry assessments performed during treatment period 1 (TP1) and treatment period 2 (TP2). T0 was defined as the moment when the first inhalation took place, and was used to calculate the pre-dose time points. T1 was defined as the moment when the last inhalation took place, and was used to calculate the post-dose time points. The baseline PEF values were the mean of the two pre-dose assessments (i.e., performed at 45 min and 15 min before T0). |
| Safety: Subjects With Use of Rescue Medication -- 3 h Post Dose | 3 h post-dose. | Number and percentage of subjects with use of rescue medication in the 3 h post dose. |
| Safety: Safety: Relative Change From Baseline* in FEV1 -- All Other Post-dose Time Points | At 5 min, 30 min, 1 h, 1 h 30 min, and 3 h after T1. | Safety: Relative change from baseline\* in FEV1 at all the other post-dose time points (5 min, 30 min, 1 h, 1 h 30 min, and 3 h after T1). Results are presented as adjusted mean and 95% CI. The potential of the test propellant (HFA-152a vs HFA-134a) for bronchoconstriction was evaluated using centralised spirometry assessments performed during treatment period 1 (TP1) and treatment period 2 (TP2). T0 was defined as the moment when the first inhalation took place, and was used to calculate the pre-dose time points. T1 was defined as the moment when the last inhalation took place, and was used to calculate the post-dose time points. \*The baseline FEV1 values were the mean of the two pre-dose assessments (i.e., performed at 45 min and 15 min before T0). |
| Safety and Tolerability: Vital Signs -- Systolic Blood Pressure | At 45 min, 1.75 h, 2.75 h post dose. | Safety and tolerability: Mean change from baseline in the Vital Signs -- Systolic Blood Pressure |
| Safety and Tolerability: ECG Parameter -- Heart Rate | At 45 min, 1.75 h, 2.75 h post dose. | Safety and tolerability: Mean change from baseline in the ECG parameter -- Heart rate |
| Safety and Tolerability: ECG Parameter -- PR Interval | At 45 min, 1.75 h, 2.75 h post dose. | Safety and tolerability: Mean change from baseline in the ECG parameter -- PR interval. |
| Safety and Tolerability: ECG Parameter -- QRS | At 45 min, 1.75 h, 2.75 h post dose. | Safety and tolerability: Mean change from baseline in the ECG parameter -- QRS interval. |
| Safety and Tolerability: ECG Parameter -- QTcF Interval | At 45 min, 1.75 h, 2.75 h post dose. | Safety and tolerability: Mean change from baseline in the ECG parameter -- QTcF interval. |
| Safety and Tolerability: Vital Signs -- Diastolic Blood Pressure | At 45 min, 1.75 h, 2.75 h post dose. | Safety and tolerability: Mean change from baseline in the Vital Signs -- Diastolic Blood Pressure |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| HFA-152a Followed by HFA-134a HFA-152a and HFA-134a propellant via pressurised metered-dose inhaler (pMDI):
Administration: Single-dose administration.
Placebo HFA-152a and Placebo HFA-134a: Placebo pMDI formulated with the propellant HFA-152a/ HFA-134a.
In this study arm, HFA-152a was used during period 1 and HFA-134a was used during period 2. | 14 |
| HFA-134a Followed by HFA-152a HFA-134a and HFA-152a propellant via pressurised metered-dose inhaler (pMDI):
Administration: Single-dose administration.
Placebo HFA-134a and Placebo HFA-152a: Placebo pMDI formulated with the propellant HFA-134a/HFA-152a.
In this study arm, HFA-134a was used during period 1 and HFA-152a was used during period 2. | 11 |
| Total | 25 |
Baseline characteristics
| Characteristic | HFA-152a Followed by HFA-134a | HFA-134a Followed by HFA-152a | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 0 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 11 Participants | 23 Participants |
| Age, Continuous | 44.5 years STANDARD_DEVIATION 16.1 | 38.9 years STANDARD_DEVIATION 13.3 | 42.0 years STANDARD_DEVIATION 14.9 |
| Asthma Control Questionnaire 5 (ACQ-5) total score at screening | 0.43 score | 0.38 score | 0.41 score |
| Asthma Control Questionnaire 5 (ACQ-5) total score on Day 1, pre-dose | 0.33 score | 0.29 score | 0.31 score |
| Asthma medication at study entry As needed short-acting β2-agonists (SABA) | 12 Participants | 11 Participants | 23 Participants |
| Asthma medication at study entry Low-dose inhaled corticosteroids (ICS) whenever SABA was taken | 2 Participants | 0 Participants | 2 Participants |
| Body mass index | 28.74 kg/m^2 STANDARD_DEVIATION 4.22 | 26.17 kg/m^2 STANDARD_DEVIATION 3.08 | 27.61 kg/m^2 STANDARD_DEVIATION 3.91 |
| Duration of smoking | 3.5 years | 5.3 years | 4.7 years |
| Height | 171.22 cm STANDARD_DEVIATION 7.82 | 171.70 cm STANDARD_DEVIATION 8.34 | 171.43 cm STANDARD_DEVIATION 7.89 |
| Number of exacerbations in the previous 12 months | 0.14 Number of exacerbations | 0.00 Number of exacerbations | 0.08 Number of exacerbations |
| Number of pack-years | 2.00 pack-years | 1.58 pack-years | 1.72 pack-years |
| Number of participants with exacerbations (0 or 1) in the previous 12 months, 0 (no exacerbation) | 12 Participants | 11 Participants | 23 Participants |
| Number of participants with exacerbations (0 or 1) in the previous 12 months, 1 (one exacerbation) | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 11 Participants | 9 Participants | 20 Participants |
| Region of Enrollment United Kingdom | 14 participants | 11 participants | 25 participants |
| Sex: Female, Male Female | 5 Participants | 5 Participants | 10 Participants |
| Sex: Female, Male Male | 9 Participants | 6 Participants | 15 Participants |
| Smoking status at screening Ex-smoker | 2 Participants | 4 Participants | 6 Participants |
| Smoking status at screening Non-smoker | 12 Participants | 7 Participants | 19 Participants |
| Time since first asthma diagnosis | 33.50 years | 29.41 years | 31.70 years |
| Time since the last exacerbation | 194.03 months | 212.40 months | 197.09 months |
| Weight | 84.25 kg STANDARD_DEVIATION 13.34 | 77.11 kg STANDARD_DEVIATION 10.47 | 81.11 kg STANDARD_DEVIATION 12.46 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 25 |
| other Total, other adverse events | 1 / 25 | 3 / 25 |
| serious Total, serious adverse events | 0 / 25 | 0 / 25 |
Outcome results
Primary
Safety: Relative Change From Baseline* in Forced Expiratory Volume in 1 s (FEV1) -- 15 Min Post-dose
Safety: Relative change from baseline\* in forced expiratory volume in 1 s (FEV1) at the 15 min post-dose time point. Results are presented as adjusted mean and 95% confidence interval (CI.) The potential of the test propellant (HFA-152a vs HFA-134a) for bronchoconstriction was evaluated using centralised spirometry assessments performed during treatment period 1 (TP1) and treatment period 2 (TP2). T0 was defined as the moment when the first inhalation took place, and was used to calculate the pre-dose time points. T1 was defined as the moment when the last inhalation took place, and was used to calculate the post-dose time points. \*The baseline FEV1 values were the mean of the two pre-dose assessments (i.e., performed at 45 min and 15 min before T0).
Time frame: At 15 min post-dose after T1.
Population: Safety set was used: includes all subjects who were randomised and received at least one dose of study drug (HFA-152a or HFA-134a).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Test | Safety: Relative Change From Baseline* in Forced Expiratory Volume in 1 s (FEV1) -- 15 Min Post-dose | 2.12 percent change |
| Reference | Safety: Relative Change From Baseline* in Forced Expiratory Volume in 1 s (FEV1) -- 15 Min Post-dose | 0.26 percent change |
Comparison: Statistical analysis performed on the data at 15 min post-dose timepoint.~Statistical analysis was performed by means of Analysis of Covariance (ANCOVA) model including treatment group, subject, and period as fixed effects and FEV1 baseline as covariate.p-value: 0.11395% CI: [-0.48, 4.2]ANCOVA
Secondary
Safety: Absolute Change From Baseline* in FEV1 -- All Time Points Post Dose
Safety: Absolute change from baseline\* in FEV1 at all post-dose time points. Results are presented as adjusted mean and 95% CI. The potential of the test propellant (HFA-152a vs HFA-134a) for bronchoconstriction was evaluated using centralised spirometry assessments performed during treatment period 1 (TP1) and treatment period 2 (TP2). T0 was defined as the moment when the first inhalation took place, and was used to calculate the pre-dose time points. T1 was defined as the moment when the last inhalation took place, and was used to calculate the post-dose time points. The baseline FEV1 values were the mean of the two pre-dose assessments (i.e., performed at 45 min and 15 min before T0).
Time frame: At 5 min, 15 min, 30 min, 1 h, 1 h 30 min, and 3 h after T1.
Population: Safety set was used: includes all subjects who were randomised and received at least one dose of study drug (HFA-152a or HFA-134a).
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Test | Safety: Absolute Change From Baseline* in FEV1 -- All Time Points Post Dose | 30 min post-dose | 0.054 Liter |
| Test | Safety: Absolute Change From Baseline* in FEV1 -- All Time Points Post Dose | 3 h post-dose | 0.059 Liter |
| Test | Safety: Absolute Change From Baseline* in FEV1 -- All Time Points Post Dose | 1 h post-dose | 0.045 Liter |
| Test | Safety: Absolute Change From Baseline* in FEV1 -- All Time Points Post Dose | 1.5 h post-dose | 0.087 Liter |
| Test | Safety: Absolute Change From Baseline* in FEV1 -- All Time Points Post Dose | 15 min post-dose | 0.066 Liter |
| Test | Safety: Absolute Change From Baseline* in FEV1 -- All Time Points Post Dose | 5 min post-dose | 0.008 Liter |
| Reference | Safety: Absolute Change From Baseline* in FEV1 -- All Time Points Post Dose | 3 h post-dose | 0.082 Liter |
| Reference | Safety: Absolute Change From Baseline* in FEV1 -- All Time Points Post Dose | 5 min post-dose | -0.006 Liter |
| Reference | Safety: Absolute Change From Baseline* in FEV1 -- All Time Points Post Dose | 15 min post-dose | 0.005 Liter |
| Reference | Safety: Absolute Change From Baseline* in FEV1 -- All Time Points Post Dose | 30 min post-dose | 0.049 Liter |
| Reference | Safety: Absolute Change From Baseline* in FEV1 -- All Time Points Post Dose | 1.5 h post-dose | 0.090 Liter |
| Reference | Safety: Absolute Change From Baseline* in FEV1 -- All Time Points Post Dose | 1 h post-dose | 0.056 Liter |
Comparison: Statistical analysis performed on the data at 5 min post-dose timepoint.~Statistical analysis was performed by means of Analysis of Covariance (ANCOVA) model including treatment group, subject and period as fixed effects and FEV1 baseline as covariate.p-value: 0.51995% CI: [-0.032, 0.061]ANCOVA
Comparison: Statistical analysis performed on the data at 15 min post-dose timepoint.~Statistical analysis was performed by means of Analysis of Covariance (ANCOVA) model including treatment group, subject and period as fixed effects and FEV1 baseline as covariate.p-value: 0.08595% CI: [-0.009, 0.13]ANCOVA
Comparison: Statistical analysis performed on the data at 30 min post-dose timepoint.~Statistical analysis was performed by means of Analysis of Covariance (ANCOVA) model including treatment group, subject and period as fixed effects and FEV1 baseline as covariate.p-value: 0.85895% CI: [-0.045, 0.054]ANCOVA
Comparison: Statistical analysis performed on the data at 1 h post-dose timepoint.~Statistical analysis was performed by means of Analysis of Covariance (ANCOVA) model including treatment group, subject and period as fixed effects and FEV1 baseline as covariate.p-value: 0.63295% CI: [-0.058, 0.036]ANCOVA
Comparison: Statistical analysis performed on the data at 1.5 h post-dose timepoint.~Statistical analysis was performed by means of Analysis of Covariance (ANCOVA) model including treatment group, subject and period as fixed effects and FEV1 baseline as covariate.p-value: 0.84695% CI: [-0.038, 0.031]ANCOVA
Comparison: Statistical analysis performed on the data at 3 h post-dose timepoint.~Statistical analysis was performed by means of Analysis of Covariance (ANCOVA) model including treatment group, subject and period as fixed effects and FEV1 baseline as covariate.p-value: 0.28295% CI: [-0.068, 0.021]ANCOVA
Secondary
Safety: Absolute Change From Baseline* in PEF -- All Post-dose Time Points
Safety: Absolute change from baseline\* in PEF at all post-dose time points. The potential of the test propellant (HFA-152a vs HFA-134a) for bronchoconstriction was evaluated using centralised spirometry assessments performed during treatment period 1 (TP1) and treatment period 2 (TP2). T0 was defined as the moment when the first inhalation took place, and was used to calculate the pre-dose time points. T1 was defined as the moment when the last inhalation took place, and was used to calculate the post-dose time points. The baseline PEF values were the mean of the two pre-dose assessments (i.e., performed at 45 min and 15 min before T0).
Time frame: At 5 min, 15 min, 30 min, 1 h, 1 h 30 min, and 3 h after T1.
Population: Safety set was used: includes all subjects who were randomised and received at least one dose of study drug (HFA-152a or HFA-134a).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Test | Safety: Absolute Change From Baseline* in PEF -- All Post-dose Time Points | 1 h post-dose | 0.0 Litres/min | Standard Deviation 20 |
| Test | Safety: Absolute Change From Baseline* in PEF -- All Post-dose Time Points | 5 min post-dose | -8.4 Litres/min | Standard Deviation 16.5 |
| Test | Safety: Absolute Change From Baseline* in PEF -- All Post-dose Time Points | 1 h 30 min post-dose | 9.9 Litres/min | Standard Deviation 23.4 |
| Test | Safety: Absolute Change From Baseline* in PEF -- All Post-dose Time Points | 30 min post-dose | -0.8 Litres/min | Standard Deviation 20.2 |
| Test | Safety: Absolute Change From Baseline* in PEF -- All Post-dose Time Points | 3 h post-dose | 4.4 Litres/min | Standard Deviation 17.9 |
| Test | Safety: Absolute Change From Baseline* in PEF -- All Post-dose Time Points | 15 min post-dose | -2.0 Litres/min | Standard Deviation 20.2 |
| Reference | Safety: Absolute Change From Baseline* in PEF -- All Post-dose Time Points | 3 h post-dose | 6.5 Litres/min | Standard Deviation 24.4 |
| Reference | Safety: Absolute Change From Baseline* in PEF -- All Post-dose Time Points | 15 min post-dose | -14.5 Litres/min | Standard Deviation 21.5 |
| Reference | Safety: Absolute Change From Baseline* in PEF -- All Post-dose Time Points | 30 min post-dose | -2.1 Litres/min | Standard Deviation 17.3 |
| Reference | Safety: Absolute Change From Baseline* in PEF -- All Post-dose Time Points | 1 h post-dose | -0.3 Litres/min | Standard Deviation 24.5 |
| Reference | Safety: Absolute Change From Baseline* in PEF -- All Post-dose Time Points | 1 h 30 min post-dose | 3.9 Litres/min | Standard Deviation 29.5 |
| Reference | Safety: Absolute Change From Baseline* in PEF -- All Post-dose Time Points | 5 min post-dose | -12.5 Litres/min | Standard Deviation 20.8 |
Secondary
Safety and Tolerability: ECG Parameter -- Heart Rate
Safety and tolerability: Mean change from baseline in the ECG parameter -- Heart rate
Time frame: At 45 min, 1.75 h, 2.75 h post dose.
Population: Safety set was used: includes all subjects who were randomised and received at least one dose of study drug (HFA-152a or HFA-134a).
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Test | Safety and Tolerability: ECG Parameter -- Heart Rate | Baseline (actual value) | 59.4 beats/min |
| Test | Safety and Tolerability: ECG Parameter -- Heart Rate | 45 min post dose (change from baseline) | -3.6 beats/min |
| Test | Safety and Tolerability: ECG Parameter -- Heart Rate | 1.75 h post dose (change from baseline) | -3.4 beats/min |
| Test | Safety and Tolerability: ECG Parameter -- Heart Rate | 2.75 h post dose (change from baseline) | 5.0 beats/min |
| Reference | Safety and Tolerability: ECG Parameter -- Heart Rate | 2.75 h post dose (change from baseline) | 5.6 beats/min |
| Reference | Safety and Tolerability: ECG Parameter -- Heart Rate | Baseline (actual value) | 59.0 beats/min |
| Reference | Safety and Tolerability: ECG Parameter -- Heart Rate | 1.75 h post dose (change from baseline) | -3.3 beats/min |
| Reference | Safety and Tolerability: ECG Parameter -- Heart Rate | 45 min post dose (change from baseline) | -1.9 beats/min |
Secondary
Safety and Tolerability: ECG Parameter -- PR Interval
Safety and tolerability: Mean change from baseline in the ECG parameter -- PR interval.
Time frame: At 45 min, 1.75 h, 2.75 h post dose.
Population: Safety set was used: includes all subjects who were randomised and received at least one dose of study drug (HFA-152a or HFA-134a).
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Test | Safety and Tolerability: ECG Parameter -- PR Interval | Baseline (actual value) | 154.8 msec |
| Test | Safety and Tolerability: ECG Parameter -- PR Interval | 45 min post dose (change from baseline) | -2.3 msec |
| Test | Safety and Tolerability: ECG Parameter -- PR Interval | 1.75 h post dose (change from baseline) | -3.0 msec |
| Test | Safety and Tolerability: ECG Parameter -- PR Interval | 2.75 h post dose (change from baseline) | 1.7 msec |
| Reference | Safety and Tolerability: ECG Parameter -- PR Interval | 2.75 h post dose (change from baseline) | -0.3 msec |
| Reference | Safety and Tolerability: ECG Parameter -- PR Interval | Baseline (actual value) | 154.2 msec |
| Reference | Safety and Tolerability: ECG Parameter -- PR Interval | 1.75 h post dose (change from baseline) | -0.9 msec |
| Reference | Safety and Tolerability: ECG Parameter -- PR Interval | 45 min post dose (change from baseline) | 0.4 msec |
Secondary
Safety and Tolerability: ECG Parameter -- QRS
Safety and tolerability: Mean change from baseline in the ECG parameter -- QRS interval.
Time frame: At 45 min, 1.75 h, 2.75 h post dose.
Population: Safety set was used: includes all subjects who were randomised and received at least one dose of study drug (HFA-152a or HFA-134a).
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Test | Safety and Tolerability: ECG Parameter -- QRS | Baseline (actual value) | 96.6 msec |
| Test | Safety and Tolerability: ECG Parameter -- QRS | 45 min post dose (change from baseline) | 0.2 msec |
| Test | Safety and Tolerability: ECG Parameter -- QRS | 1.75 h post dose (change from baseline) | 1.6 msec |
| Test | Safety and Tolerability: ECG Parameter -- QRS | 2.75 h post dose (change from baseline) | 1.4 msec |
| Reference | Safety and Tolerability: ECG Parameter -- QRS | 2.75 h post dose (change from baseline) | 0.8 msec |
| Reference | Safety and Tolerability: ECG Parameter -- QRS | Baseline (actual value) | 96.8 msec |
| Reference | Safety and Tolerability: ECG Parameter -- QRS | 1.75 h post dose (change from baseline) | 0.8 msec |
| Reference | Safety and Tolerability: ECG Parameter -- QRS | 45 min post dose (change from baseline) | 0.7 msec |
Secondary
Safety and Tolerability: ECG Parameter -- QTcF Interval
Safety and tolerability: Mean change from baseline in the ECG parameter -- QTcF interval.
Time frame: At 45 min, 1.75 h, 2.75 h post dose.
Population: Safety set was used: includes all subjects who were randomised and received at least one dose of study drug (HFA-152a or HFA-134a).
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Test | Safety and Tolerability: ECG Parameter -- QTcF Interval | Baseline (actual value) | 408.4 msec |
| Test | Safety and Tolerability: ECG Parameter -- QTcF Interval | 45 min post dose (change from baseline) | 0.8 msec |
| Test | Safety and Tolerability: ECG Parameter -- QTcF Interval | 1.75 h post dose (change from baseline) | 4.6 msec |
| Test | Safety and Tolerability: ECG Parameter -- QTcF Interval | 2.75 h post dose (change from baseline) | 5.7 msec |
| Reference | Safety and Tolerability: ECG Parameter -- QTcF Interval | 2.75 h post dose (change from baseline) | 1.5 msec |
| Reference | Safety and Tolerability: ECG Parameter -- QTcF Interval | Baseline (actual value) | 409.0 msec |
| Reference | Safety and Tolerability: ECG Parameter -- QTcF Interval | 1.75 h post dose (change from baseline) | -0.1 msec |
| Reference | Safety and Tolerability: ECG Parameter -- QTcF Interval | 45 min post dose (change from baseline) | 0.1 msec |
Secondary
Safety and Tolerability: Vital Signs -- Diastolic Blood Pressure
Safety and tolerability: Mean change from baseline in the Vital Signs -- Diastolic Blood Pressure
Time frame: At 45 min, 1.75 h, 2.75 h post dose.
Population: Safety set was used: includes all subjects who were randomised and received at least one dose of study drug (HFA-152a or HFA-134a).
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Test | Safety and Tolerability: Vital Signs -- Diastolic Blood Pressure | Baseline (actual value) | 71.5 mmHg |
| Test | Safety and Tolerability: Vital Signs -- Diastolic Blood Pressure | 45 min post dose (change from baseline) | 1.4 mmHg |
| Test | Safety and Tolerability: Vital Signs -- Diastolic Blood Pressure | 1.75 h post dose (change from baseline) | 2.8 mmHg |
| Test | Safety and Tolerability: Vital Signs -- Diastolic Blood Pressure | 2.75 h post dose (change from baseline) | -1.8 mmHg |
| Reference | Safety and Tolerability: Vital Signs -- Diastolic Blood Pressure | 2.75 h post dose (change from baseline) | -2.7 mmHg |
| Reference | Safety and Tolerability: Vital Signs -- Diastolic Blood Pressure | Baseline (actual value) | 72.5 mmHg |
| Reference | Safety and Tolerability: Vital Signs -- Diastolic Blood Pressure | 1.75 h post dose (change from baseline) | 1.2 mmHg |
| Reference | Safety and Tolerability: Vital Signs -- Diastolic Blood Pressure | 45 min post dose (change from baseline) | 0.7 mmHg |
Secondary
Safety and Tolerability: Vital Signs -- Systolic Blood Pressure
Safety and tolerability: Mean change from baseline in the Vital Signs -- Systolic Blood Pressure
Time frame: At 45 min, 1.75 h, 2.75 h post dose.
Population: Safety set was used: includes all subjects who were randomised and received at least one dose of study drug (HFA-152a or HFA-134a).
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Test | Safety and Tolerability: Vital Signs -- Systolic Blood Pressure | Baseline (actual value) | 117.4 mmHg |
| Test | Safety and Tolerability: Vital Signs -- Systolic Blood Pressure | 45 min post dose (change from baseline) | 2.3 mmHg |
| Test | Safety and Tolerability: Vital Signs -- Systolic Blood Pressure | 1.75 h post dose (change from baseline) | 4.9 mmHg |
| Test | Safety and Tolerability: Vital Signs -- Systolic Blood Pressure | 2.75 h post dose (change from baseline) | 1.0 mmHg |
| Reference | Safety and Tolerability: Vital Signs -- Systolic Blood Pressure | 2.75 h post dose (change from baseline) | 2.0 mmHg |
| Reference | Safety and Tolerability: Vital Signs -- Systolic Blood Pressure | Baseline (actual value) | 115.8 mmHg |
| Reference | Safety and Tolerability: Vital Signs -- Systolic Blood Pressure | 1.75 h post dose (change from baseline) | 2.5 mmHg |
| Reference | Safety and Tolerability: Vital Signs -- Systolic Blood Pressure | 45 min post dose (change from baseline) | 1.3 mmHg |
Secondary
Safety: Change From Baseline* in FEV1 Area Under the Concentration-time Curve From Time Zero to 3 Hours (AUC0-3h)
Change from baseline\* in FEV1 area under the concentration-time curve from time zero to 3 hours (AUC0-3h). Results show the change from baseline in FEV1 AUC(0-3h) corrected for Time, in litres The potential of the test propellant (HFA-152a vs HFA-134a) for bronchoconstriction was evaluated using centralised spirometry assessments performed during treatment period 1 (TP1) and treatment period 2 (TP2). T0 was defined as the moment when the first inhalation took place, and was used to calculate the pre-dose time points. T1 was defined as the moment when the last inhalation took place, and was used to calculate the post-dose time points. \*The baseline FEV1 values were the mean of the two pre-dose assessments (i.e., performed at 45 min and 15 min before T0).
Time frame: At 3 h post-dose.
Population: Safety set was used: includes all subjects who were randomised and received at least one dose of study drug (HFA-152a or HFA-134a).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Test | Safety: Change From Baseline* in FEV1 Area Under the Concentration-time Curve From Time Zero to 3 Hours (AUC0-3h) | 0.055 Litres | Standard Deviation 0.088 |
| Reference | Safety: Change From Baseline* in FEV1 Area Under the Concentration-time Curve From Time Zero to 3 Hours (AUC0-3h) | 0.068 Litres | Standard Deviation 0.081 |
Secondary
Safety: Relative Change From Baseline* in Peak Expiratory Flow (PEF) -- All Post-dose Time Points
Safety: Relative change from baseline\* in peak expiratory flow (PEF) at all post-dose time points. The potential of the test propellant (HFA-152a vs HFA-134a) for bronchoconstriction was evaluated using centralised spirometry assessments performed during treatment period 1 (TP1) and treatment period 2 (TP2). T0 was defined as the moment when the first inhalation took place, and was used to calculate the pre-dose time points. T1 was defined as the moment when the last inhalation took place, and was used to calculate the post-dose time points. The baseline PEF values were the mean of the two pre-dose assessments (i.e., performed at 45 min and 15 min before T0).
Time frame: At 5 min, 15 min, 30 min, 1 h, 1 h 30 min, and 3 h after T1.
Population: Safety set was used: includes all subjects who were randomised and received at least one dose of study drug (HFA-152a or HFA-134a).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Test | Safety: Relative Change From Baseline* in Peak Expiratory Flow (PEF) -- All Post-dose Time Points | 15 min post-dose | -0.62 percent change | Standard Deviation 4.31 |
| Test | Safety: Relative Change From Baseline* in Peak Expiratory Flow (PEF) -- All Post-dose Time Points | 1 h post-dose | -0.12 percent change | Standard Deviation 3.95 |
| Test | Safety: Relative Change From Baseline* in Peak Expiratory Flow (PEF) -- All Post-dose Time Points | 30 min post-dose | -0.19 percent change | Standard Deviation 3.88 |
| Test | Safety: Relative Change From Baseline* in Peak Expiratory Flow (PEF) -- All Post-dose Time Points | 1 h 30 min post-dose | 1.96 percent change | Standard Deviation 4.75 |
| Test | Safety: Relative Change From Baseline* in Peak Expiratory Flow (PEF) -- All Post-dose Time Points | 3 h post-dose | 1.08 percent change | Standard Deviation 3.57 |
| Test | Safety: Relative Change From Baseline* in Peak Expiratory Flow (PEF) -- All Post-dose Time Points | 5 min post-dose | -1.85 percent change | Standard Deviation 3.74 |
| Reference | Safety: Relative Change From Baseline* in Peak Expiratory Flow (PEF) -- All Post-dose Time Points | 3 h post-dose | 1.62 percent change | Standard Deviation 4.77 |
| Reference | Safety: Relative Change From Baseline* in Peak Expiratory Flow (PEF) -- All Post-dose Time Points | 30 min post-dose | -0.28 percent change | Standard Deviation 3.2 |
| Reference | Safety: Relative Change From Baseline* in Peak Expiratory Flow (PEF) -- All Post-dose Time Points | 1 h 30 min post-dose | 1.14 percent change | Standard Deviation 5.43 |
| Reference | Safety: Relative Change From Baseline* in Peak Expiratory Flow (PEF) -- All Post-dose Time Points | 15 min post-dose | -2.64 percent change | Standard Deviation 4.35 |
| Reference | Safety: Relative Change From Baseline* in Peak Expiratory Flow (PEF) -- All Post-dose Time Points | 5 min post-dose | -2.35 percent change | Standard Deviation 3.69 |
| Reference | Safety: Relative Change From Baseline* in Peak Expiratory Flow (PEF) -- All Post-dose Time Points | 1 h post-dose | 0.11 percent change | Standard Deviation 4.82 |
Secondary
Safety: Safety: Relative Change From Baseline* in FEV1 -- All Other Post-dose Time Points
Safety: Relative change from baseline\* in FEV1 at all the other post-dose time points (5 min, 30 min, 1 h, 1 h 30 min, and 3 h after T1). Results are presented as adjusted mean and 95% CI. The potential of the test propellant (HFA-152a vs HFA-134a) for bronchoconstriction was evaluated using centralised spirometry assessments performed during treatment period 1 (TP1) and treatment period 2 (TP2). T0 was defined as the moment when the first inhalation took place, and was used to calculate the pre-dose time points. T1 was defined as the moment when the last inhalation took place, and was used to calculate the post-dose time points. \*The baseline FEV1 values were the mean of the two pre-dose assessments (i.e., performed at 45 min and 15 min before T0).
Time frame: At 5 min, 30 min, 1 h, 1 h 30 min, and 3 h after T1.
Population: Safety set was used: includes all subjects who were randomised and received at least one dose of study drug (HFA-152a or HFA-134a).
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Test | Safety: Safety: Relative Change From Baseline* in FEV1 -- All Other Post-dose Time Points | 5 min post-dose | 0.25 percent change |
| Test | Safety: Safety: Relative Change From Baseline* in FEV1 -- All Other Post-dose Time Points | 30 min post-dose | 1.73 percent change |
| Test | Safety: Safety: Relative Change From Baseline* in FEV1 -- All Other Post-dose Time Points | 1 h post-dose | 1.32 percent change |
| Test | Safety: Safety: Relative Change From Baseline* in FEV1 -- All Other Post-dose Time Points | 1.5 h post-dose | 2.73 percent change |
| Test | Safety: Safety: Relative Change From Baseline* in FEV1 -- All Other Post-dose Time Points | 3 h post-dose | 1.91 percent change |
| Reference | Safety: Safety: Relative Change From Baseline* in FEV1 -- All Other Post-dose Time Points | 3 h post-dose | 2.59 percent change |
| Reference | Safety: Safety: Relative Change From Baseline* in FEV1 -- All Other Post-dose Time Points | 1.5 h post-dose | 2.86 percent change |
| Reference | Safety: Safety: Relative Change From Baseline* in FEV1 -- All Other Post-dose Time Points | 5 min post-dose | -0.32 percent change |
| Reference | Safety: Safety: Relative Change From Baseline* in FEV1 -- All Other Post-dose Time Points | 1 h post-dose | 1.72 percent change |
| Reference | Safety: Safety: Relative Change From Baseline* in FEV1 -- All Other Post-dose Time Points | 30 min post-dose | 1.50 percent change |
Comparison: Statistical analysis performed on the data at 5 min post-dose timepoint.~Statistical analysis was performed by means of Analysis of Covariance (ANCOVA) model including treatment group, subject, and period as fixed effects and FEV1 baseline as covariate.p-value: 0.48395% CI: [-1.1, 2.25]ANCOVA
Comparison: Statistical analysis performed on the data at 30 min post-dose timepoint.~Statistical analysis was performed by means of Analysis of Covariance (ANCOVA) model including treatment group, subject, and period as fixed effects and FEV1 baseline as covariate.p-value: 0.78295% CI: [-1.45, 1.9]ANCOVA
Comparison: Statistical analysis performed on the data at 1 h post-dose timepoint.~Statistical analysis was performed by means of Analysis of Covariance (ANCOVA) model including treatment group, subject, and period as fixed effects and FEV1 baseline as covariate.p-value: 0.59995% CI: [-1.97, 1.16]ANCOVA
Comparison: Statistical analysis performed on the data at 1.5 h post-dose timepoint.~Statistical analysis was performed by means of Analysis of Covariance (ANCOVA) model including treatment group, subject, and period as fixed effects and FEV1 baseline as covariate.p-value: 0.81595% CI: [-1.24, 0.99]ANCOVA
Comparison: Statistical analysis performed on the data at 3 h post-dose timepoint.~Statistical analysis was performed by means of Analysis of Covariance (ANCOVA) model including treatment group, subject, and period as fixed effects and FEV1 baseline as covariate.p-value: 0.29495% CI: [-2.01, 0.64]ANCOVA
Secondary
Safety: Subjects With a Relative Change From Baseline* in FEV1 <-15% -- All Post-dose Time Points
Safety: Number and percentage of subjects with a relative change from baseline\* in FEV1 at each post-dose time point \<-15%. The baseline FEV1 values were the mean of the two pre-dose assessments (i.e., performed at 45 min and 15 min before T0).
Time frame: At 5 min, 15 min, 30 min, 1 h, 1 h 30 min, and 3 h after T1.
Population: Safety set was used: includes all subjects who were randomised and received at least one dose of study drug (HFA-152a or HFA-134a).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Test | Safety: Subjects With a Relative Change From Baseline* in FEV1 <-15% -- All Post-dose Time Points | 5 min post-dose | 0 Participants |
| Test | Safety: Subjects With a Relative Change From Baseline* in FEV1 <-15% -- All Post-dose Time Points | 15 min post-dose | 0 Participants |
| Test | Safety: Subjects With a Relative Change From Baseline* in FEV1 <-15% -- All Post-dose Time Points | 30 min post-dose | 0 Participants |
| Test | Safety: Subjects With a Relative Change From Baseline* in FEV1 <-15% -- All Post-dose Time Points | 1 h post-dose | 0 Participants |
| Test | Safety: Subjects With a Relative Change From Baseline* in FEV1 <-15% -- All Post-dose Time Points | 1 h 30 min post-dose | 0 Participants |
| Test | Safety: Subjects With a Relative Change From Baseline* in FEV1 <-15% -- All Post-dose Time Points | 3 h post-dose | 0 Participants |
| Reference | Safety: Subjects With a Relative Change From Baseline* in FEV1 <-15% -- All Post-dose Time Points | 1 h 30 min post-dose | 0 Participants |
| Reference | Safety: Subjects With a Relative Change From Baseline* in FEV1 <-15% -- All Post-dose Time Points | 5 min post-dose | 0 Participants |
| Reference | Safety: Subjects With a Relative Change From Baseline* in FEV1 <-15% -- All Post-dose Time Points | 1 h post-dose | 0 Participants |
| Reference | Safety: Subjects With a Relative Change From Baseline* in FEV1 <-15% -- All Post-dose Time Points | 15 min post-dose | 0 Participants |
| Reference | Safety: Subjects With a Relative Change From Baseline* in FEV1 <-15% -- All Post-dose Time Points | 3 h post-dose | 0 Participants |
| Reference | Safety: Subjects With a Relative Change From Baseline* in FEV1 <-15% -- All Post-dose Time Points | 30 min post-dose | 0 Participants |
Secondary
Safety: Subjects With Use of Rescue Medication -- 3 h Post Dose
Number and percentage of subjects with use of rescue medication in the 3 h post dose.
Time frame: 3 h post-dose.
Population: Safety set was used: includes all subjects who were randomised and received at least one dose of study drug (HFA-152a or HFA-134a).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Test | Safety: Subjects With Use of Rescue Medication -- 3 h Post Dose | 0 Participants |
| Reference | Safety: Subjects With Use of Rescue Medication -- 3 h Post Dose | 0 Participants |