Asthma
Conditions
Keywords
Asthma, Beclomethasone Dipropionate, Beclometasone dipropionate/Formoterol fumarate, Inhaled Corticosteroids, CHF 1535 pMDI, CHF 718 pMDI
Brief summary
Compare the superiority of CHF 1535 versus CHF 718 in subjects with asthma who are on medium or high dose inhaled corticosteroids.
Detailed description
This was a phase III, multicenter, randomized, double-blind active controlled 2-arm parallel group to compare superiority of CHF 1535 pressurised metered dose inhaler (pMDI) compared with CHF 718 pMDI, in subjects with asthma on medium or high dose inhaled corticosteroids, with regard to change from baseline in forced expiratory volume in the first second (FEV1) Area under the Curve Calculated Between Time 0 and 12 Hours (AUC0-12h) at Week 12. After screening, eligible subjects entered a 2-week run-in period using CHF 718 (BDP) pMDI 100µg, followed by a 12-week double-blind, treatment period. Screened subjects who were on a medium dose inhaled corticosteroid (ICS) or medium dose ICS-long-acting β2-adrenergic receptor agonists (LABA) prior to the study, received CHF 718 pMDI 100µg 2 inhalations twice daily (BID) i.e. total daily dose (TDD) 400µg) during the 2-week run in period. Screened subjects who were on a high dose ICS prior to the study received CHF 718 pMDI 100µg 4 inhalations BID (TDD 800µg) during the 2-week run in period. Following the run-in period, eligible subjects were randomized to one of two study drug arms (using a 1:1 allocation ratio) for 12 weeks. A total of 6 clinic visits (V), (V0-V5) and a follow-up call (V6) were performed during the study. During the study, daily symptoms, rescue medication use, and compliance with the study drug were recorded via a subject-specific electronic diary (eDiary). Concomitant medications and adverse events (AEs) were assessed and recorded throughout the study. Vital signs measurements, physical exam, 12-lead electrocardiogram (ECG), peak expiratory flow (PEF), and spirometry measurements, including serial spirometry were performed and recorded. Symptoms were assessed using disease specific questionnaires. Routine hematology, blood chemistry, and urine pregnancy testing were performed before enrolment and at the end of study. CHF 1535 pMDI = 200/6 μg pressurised metered dose inhaler (fixed combination of extrafine beclomethasone dipropionate \[BDP\] plus formoterol fumarate \[FF\]). CHF 718 pMDI = 100 μg pressurised metered dose inhaler (extrafine beclomethasone dipropionate \[BDP\]).
Interventions
Available in pressurized inhalation solution BDP/FF 200/6 µg
DRUGBeclomethasone Dipropionate
Available in pressurized inhalation solution BDP 100 µg
Sponsors
Chiesi Farmaceutici S.p.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
The blinded roles were participant, investigator, care provider, monitor, data analyst, and assessor.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
(IC): 1. Informed consent: A signed and dated written informed consent obtained prior to any study-related procedures. 2. Sex and age: Male or female aged ≥18 and ≤75 years. 3. Diagnosis of asthma: A documented history of asthma for at least 1 year, with onset before age 40 4. Stable asthma therapy: Use of medium-dose ICS with or without a LABA or high-dose ICS alone for 3 months (at a stable dose for at least 4 weeks prior to screening). 5. Lung function: Subjects with a pre-bronchodilator FEV1 ≥40% and ≤85% of predicted, after appropriate washout from bronchodilators, at the screening and randomization visits. In addition, the absolute value of the first pre-dose FEV1 at randomization (V2) must be at least 80% of the pre-bronchodilator value attained at screening. 6. Reversibility post-bronchodilator: Subjects with a positive reversibility to bronchodilator at screening, defined as an increase in FEV1 \> 12% and \> 200mL compared to baseline within 30 minutes after 4 inhalations of albuterol hydrofluoroalkane (HFA) pMDI 90µg/actuation. Note for IC#5 and IC#6: In case the reversibility and/or quality threshold is not met at screening, the test can be performed once before randomization. 7. Female subjects: a. Women of childbearing potential (WOCBP) fulfilling one of the following criteria: i. WOCBP with fertile male partners: they and/or their partner must be willing to use a highly effective birth control method from the signing of the informed consent form and until the follow-up contact or ii. WOCBP with non-fertile male partners (contraception is not required in this case). b. Female subjects of non-childbearing potential defined as physiologically incapable of becoming pregnant (i.e. post-menopausal or permanently sterile as per definitions given in Appendix 2). Tubal ligation or partial surgical interventions are not acceptable. If indicated, as per investigator's request, post-menopausal status may be confirmed by follicle-stimulating hormone levels (according to local laboratory ranges). 8. Cooperative attitude and ability to demonstrate correct use of the pMDI inhalers and eDiary/peak flow meter.
Exclusion criteria
1. Pregnancy or lactation: where pregnancy is defined as the state of a female after conception and until termination of the gestation, confirmed by a positive pregnancy test (serum and urine pregnancy test to be performed at screening visit and urine pregnancy test to be performed prior to randomization). 2. Poor compliance with run-in medication or eDiary completion \<50% before randomization. 3. History of "at risk" asthma: History of near-fatal asthma or of a past hospitalization for asthma in intensive care unit which, in the judgement of the investigator, may place the subject at undue risk. 4. Recent asthma exacerbation: Hospitalization, emergency room admission or use of systemic corticosteroids for an asthma exacerbation in the 4 weeks prior to screening visit or during the run-in period. 5. Unresolved respiratory tract infection (RTI) in the 4 weeks prior to the screening visit or during run-in period. Documented coronavirus disease 2019 (COVID-19) diagnosis within the last 8 weeks or complications from this disease, which have not resolved within 14 days prior to screening. 6. Unstable ICS dose during the 4 weeks prior to screening visit, including any change in dose, schedule, or formulation. 7. Use of systemic corticosteroid medication in the 4 weeks prior to screening or slow-release corticosteroids in the 12 weeks before screening. 8. Respiratory disorders other than asthma: History of a diagnosis of cystic fibrosis, bronchiectasis, Chronic Obstructive Pulmonary Disease (COPD), (as defined by the current Global Initiative for Chronic Obstructive Lung Disease \[GOLD\] Report), alpha-1 antitrypsin deficiency, or any other significant lung disease which may interfere with study evaluations. 9. Smoking status: Current smokers or ex-smokers with total cumulative exposure equal to or more than 10 pack-years or having stopped smoking within one year prior to screening visit. 10. E-cigarette status: Current e-cigarettes users at the time of the screening visit. 11. Cannabis usage: Current use of inhaled or oral cannabis products (e.g. marijuana). 12. Substance abuse: Subjects with a history of alcohol or substance/drug abuse within 12 months prior to screening. 13. Cardiovascular diseases: Subjects who have clinically significant cardiovascular condition such as, but not limited to, unstable ischemic heart disease, New York Heart Association (NYHA) Class III/IV heart failure, acute ischemic heart disease within one year prior to study entry, known history of atrial fibrillation or history of sustained and non-sustained cardiac arrhythmias diagnosed within the last 6 months prior to screening, not controlled with a rate control strategy. Note: Subjects with Permanent Atrial Fibrillation (for at least 6 months) with a resting ventricular rate \<100/min, controlled with a rate control strategy (i.e., selective β-blocker, calcium channel blocker, pacemaker placement, digoxin, or ablation therapy) can be considered for the enrollment. 14. ECG criteria: An abnormal and clinically significant 12-lead electrocardiogram (ECG) which may impact the safety of the subject according to Investigator's judgement. In terms of the QTcF, subjects with QTcF \>450ms for males or QTcF \>470ms for females at screening or at randomization visits (criterion not applicable for subject with pacemaker or permanent atrial fibrillation). 15. Other medical conditions: Other active severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study. 16. Vaccination: Subjects having received a vaccination within 2 weeks prior to screening or during the run-in period. 17. Subjects' wellbeing: Subjects mentally or legally incapacitated, including but not limited to subjects who are institutionalized or incarcerated. 18. Hypersensitivity: Subjects with known intolerance, hypersensitivity or contraindication to treatment with ß2-agonists, ICS, or propellant gases/excipients. 19. Surgery: Subjects with major surgery in the 3 months prior to the screening visit or planned surgery during the study. 20. Additional treatment: Subjects treated with non-potassium sparing diuretics (unless administered as a fixed-dose combination with a potassium conserving drug or changed to potassium sparing before the screening), non-selective beta-blocking drugs, quinidine, quinidine-like anti-arrhythmic, or any medication with a QTc prolongation potential or a history of QTc prolongation. 21. Subjects treated with monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants. 22. Subjects with concomitant immunosuppressive therapy, use of oral or injected corticosteroids, anti-immunoglobulin E (IgE), anti-IL5 or other monoclonal or polyclonal antibodies within 12 weeks prior to screening. 23. Subjects who are receiving any therapy that could interfere with the study drugs according to investigator's opinion. 24. Participating in other investigational trial: Subjects who have received an investigational drug within 1 month or 5 half-lives (whichever is greater) prior to screening visit, or have been previously randomized in this trial, or are currently participating in another clinical trial. 25. Spacer: The need to use a spacer for correct self-administration of a pMDI.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 1_Change From Baseline in FEV1 AUC0-12h Normalised by Time at Week 12 | Baseline (pre-dose on Week 0) and Week 12. | The pre-dose FEV1 at baseline (i.e. pre-dose on Week 0 \[Visit 2\]) and the FEV1 AUC0-12h normalised by time at Week 12 (Visit 5) are presented by treatment group in the ITT population, as change from baseline. AUC0=12h Area under the curve calculated between time 0 and 12 hours |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 2_Change From Baseline in Peak FEV1 Within the First 3 Hours Post-dose at Week 12 | Baseline (pre-dose on Week 0) and Week 12. | The peak FEV1 at baseline (i.e. pre-dose on Week 0 \[V2\]) and the peak FEV1 within the first 3 hours post-dose at Week 12 (V5) are presented by treatment group in the ITT population, as change from baseline. FEV1=Forced Expiratory Volume in the First Second |
| 3_Change From Baseline in FEV1 AUC0-12h Normalised by Time at Week 0 | Baseline (pre-dose on Week 0) and Week 12. | The pre-dose FEV1 at baseline (i.e. pre-dose on Week 0 \[V2\]) and the FEV1 AUC0-12h normalised by time at Week 0 (V2, post-dose) are presented by treatment group in the ITT population, as change from baseline. |
| 4_Change From Baseline in Peak FEV1 Within the First 3 Hours Post-dose at Week 0 | Baseline (pre-dose on Week 0) and 3 h post dose on Week 0. | The peak FEV1 at baseline (i.e. pre-dose on Week 0 \[V2\]) and the peak FEV1 within the first 3 hours post-dose at Week 0 (V2, post-dose) are presented by treatment group in the ITT population, as change from baseline. FEV1=Forced Expiratory Volume in the First Second |
| 5_Change From Baseline in Trough FEV1 at Week 12 | Baseline (pre-dose on Week 0) and Week 12. | The trough FEV1 at baseline (i.e. pre-dose on Week 0 \[V2\]), the trough FEV1 at Week 12 (V5) and the change from baseline in trough FEV1 at Week 12 (V5) are presented by treatment group in the ITT population, as change from baseline. FEV1=Forced Expiratory Volume in the First Second |
| 6_Change From Baseline in Pre-dose Morning FEV1 at Weeks 4, 8 and 12 | Baseline (pre-dose on Week 0) and Week 4, Week 8, Week 12. | The pre-dose MORNING FEV1 at baseline (i.e. pre-dose on Week 0 \[V2\]) and the pre-dose morning FEV1 at Week 4 (V3), Week 8 (V4) and Week 12 (V5) are presented by treatment group in the ITT population, as change from baseline. FEV1=Forced Expiratory Volume in the First Second |
| 7_Proportion of Pre-dose Morning FEV1 Responders at Weeks 4, 8 and 12 | Baseline (pre-dose on Week 0) and Week 4, Week 8, Week 12. | The proportion of pre-dose MORNING FEV1 responders at Week 4 (V3), Week 8 (V4) and Week 12 (V5) are presented by treatment group in the ITT population. The proportion of subjects classified as pre-dose morning FEV1 responders (i.e. those subjects who had change from baseline in pre-dose morning FEV1 ≥100 mL). FEV1=Forced Expiratory Volume in the First Second |
| 8_Proportion of Trough FEV1 Responders at Week 12 | Baseline (pre-dose on Week 0) and Week 4, Week 8, Week 12. | The proportion of trough FEV1 responders at Week 12 (V5) are presented by treatment group in the ITT population. The proportion of subjects classified as trough FEV1 responders (i.e. those subjects who had change from baseline in trough FEV1 ≥100 mL). FEV1=Forced Expiratory Volume in the First Second |
| 9_Change From Baseline in Average Morning Peak Expiratory Flow (PEF) Over the 12-Week Treatment Period | Baseline (Week 0) to Week 12. | The average MORNING PEF at baseline (i.e. average morning "Best PEF" values during the run-in period, over each inter-visit period and over the 12-week treatment period are presented by treatment group in the ITT population), as change from baseline. PEF=Peak Expiratory Flow |
| 10_Change From Baseline in Average Evening Peak Expiratory Flow (PEF) Over the 12-Week Treatment Period | Baseline (Week 0) to Week 12. | The average EVENING PEF at baseline (i.e. average evening "Best PEF" values during the run-in period, see Section 9.7.1.4), over each inter-visit period and over the 12-week treatment period are presented by treatment group in the ITT population, as change from baseline. PEF=Peak Expiratory Flow |
| 11_Change From Baseline in ACQ-7 Score and ACQ-5 Score at Week 12 | Baseline (pre-dose on Week 0) and Week 12. | The ACQ-7 and ACQ-5 scores at baseline (i.e. pre-dose on Week 0 \[V2\]) and at Week 12 (V5) are presented by treatment group in the ITT population, as change from baseline; only patients who provided required data at baseline and at specified times are included in the calculation. Asthma control was evaluated during the treatment period (Week 0 to Week 12 \[V2-V5\])/end of treatment (ET) if applicable, using ACQ-7; first 6 items refer to symptoms and rescue use in the previous 7 days. The 7th item, filled in by the clinical staff, was the FEV1 (% predicted) recorded at 15 min pre-dose, measured at each visit during the treatment period. ACQ-5 has 5 items on adequacy of asthma control. ACQ-7: Assess asthma symptoms over last 7 days (night-time awakenings due to symptoms, morning symptoms, activity limitation, shortness of breath, wheezing), average daily rescue medication use, and current FEV1 percent predicted. Score scale: 0=totally controlled; 6=severely uncontrolled. |
| 12_Change From Baseline in Percentage of Rescue Medication-free Days Over the 12-Week Treatment Period | Baseline (pre-dose on Week 0) and Week 12. | The percentage of rescue medication-free days at baseline (i.e. percentage of days during the run-in period with no rescue medication), over each inter-visit period and over the 12-week treatment period are presented by treatment group in the ITT population, as change from baseline. |
| 13_Change From Baseline in Percentage of Asthma Symptom-free Days Over the 12-Week Treatment Period | Baseline (pre-dose on Week 0) and Week 12. | The percentage of asthma symptom-free days at baseline (i.e. percentage of days during the run-in period with no asthma symptom, over each inter-visit period and over the 12-week treatment period are presented by treatment group in the ITT population, as change from baseline. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORSteven F. Weinstein, M.D.
Allergy and Asthma Specialists Medical Group and Research Center
Participant flow
Recruitment details
Overall, 1377 participants were enrolled into the study; of these, 576 met eligibility criteria and were randomized to treatment.
Participants by arm
| Arm | Count |
|---|---|
| CHF 1535 pMDI CHF 1535 pMDI 800/24µg TDD
Beclomethasone Dipropionate/Formoterol Fumarate: pressurized inhalation solution BDP/FF 200/6 µg | 283 |
| CHF 718 pMDI CHF 718 pMDI 800µg TDD
Beclomethasone Dipropionate: pressurized inhalation solution BDP 100 µg | 280 |
| Total | 563 |
Baseline characteristics
| Characteristic | CHF 1535 pMDI | CHF 718 pMDI | Total |
|---|---|---|---|
| ACQ score at baseline ACQ-5 | 0.92 score STANDARD_DEVIATION 0.95 | 0.88 score STANDARD_DEVIATION 0.98 | 0.90 score STANDARD_DEVIATION 0.96 |
| ACQ score at baseline ACQ-7 | 1.30 score STANDARD_DEVIATION 0.88 | 1.25 score STANDARD_DEVIATION 0.87 | 1.28 score STANDARD_DEVIATION 0.88 |
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 52 Participants | 43 Participants | 95 Participants |
| Age, Categorical Between 18 and 65 years | 231 Participants | 237 Participants | 468 Participants |
| Age, Continuous | 51.6 years STANDARD_DEVIATION 14.1 | 50.3 years STANDARD_DEVIATION 14.1 | 50.9 years STANDARD_DEVIATION 14.1 |
| Asthma medication at study entry High-dose ICS | 3 Participants | 5 Participants | 8 Participants |
| Asthma medication at study entry ICS/LABA fixed combination | 228 Participants | 221 Participants | 449 Participants |
| Asthma medication at study entry ICS+LABA free combination | 6 Participants | 9 Participants | 15 Participants |
| Asthma medication at study entry Inhaled Corticosteroid/Long-acting β2-adrenergic Receptor Agonists (ICS/LABA) combination | 234 Participants | 230 Participants | 464 Participants |
| Asthma medication at study entry Medium-dose ICS | 46 Participants | 45 Participants | 91 Participants |
| Body Mass Index (BMI) | 30.90 kg/m^2 STANDARD_DEVIATION 6.93 | 30.86 kg/m^2 STANDARD_DEVIATION 7.27 | 30.88 kg/m^2 STANDARD_DEVIATION 7.09 |
| Electronic cigarettes - Smoking status at screening Current smoker | 0 Participants | 0 Participants | 0 Participants |
| Electronic cigarettes - Smoking status at screening Ex-smoker | 0 Participants | 0 Participants | 0 Participants |
| Electronic cigarettes - Smoking status at screening Non-smoker | 283 Participants | 280 Participants | 563 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 154 Participants | 165 Participants | 319 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 129 Participants | 113 Participants | 242 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| FEV1 -- At baseline | 1.850 liters STANDARD_DEVIATION 0.535 | 1.860 liters STANDARD_DEVIATION 0.559 | 1.855 liters STANDARD_DEVIATION 0.546 |
| FEV1 (% of predicted normal value) at baseline | 64.104 percent of predicted STANDARD_DEVIATION 10.651 | 63.033 percent of predicted STANDARD_DEVIATION 10.739 | 63.572 percent of predicted STANDARD_DEVIATION 10.698 |
| FVC at baseline | 2.661 liters STANDARD_DEVIATION 0.899 | 2.614 liters STANDARD_DEVIATION 0.945 | 2.637 liters STANDARD_DEVIATION 0.922 |
| Number of asthma exacerbations in the 4 weeks prior to screening 0 | 283 Participants | 280 Participants | 563 Participants |
| Number of asthma exacerbations in the 4 weeks prior to screening 1+ | 0 Participants | 0 Participants | 0 Participants |
| Number of pack-years | 2.9 pack-years STANDARD_DEVIATION 2.7 | 3.7 pack-years STANDARD_DEVIATION 3.1 | 3.3 pack-years STANDARD_DEVIATION 2.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 6 Participants | 9 Participants |
| Race (NIH/OMB) Black or African American | 59 Participants | 49 Participants | 108 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) White | 216 Participants | 220 Participants | 436 Participants |
| Region of Enrollment United States | 283 Participants | 280 Participants | 563 Participants |
| Sex: Female, Male Female | 210 Participants | 202 Participants | 412 Participants |
| Sex: Female, Male Male | 73 Participants | 78 Participants | 151 Participants |
| Smoking duration | 13.58 years STANDARD_DEVIATION 10 | 12.67 years STANDARD_DEVIATION 9.29 | 13.11 years STANDARD_DEVIATION 9.57 |
| Smoking status at screening Current smoker | 0 Participants | 0 Participants | 0 Participants |
| Smoking status at screening Ex-smoker | 33 Participants | 36 Participants | 69 Participants |
| Smoking status at screening Non-smoker | 250 Participants | 244 Participants | 494 Participants |
| Time since first asthma diagnosis | 474.6 months STANDARD_DEVIATION 173.6 | 468.4 months STANDARD_DEVIATION 180.9 | 471.5 months STANDARD_DEVIATION 177.1 |
| Time since last documented exacerbation | 52.4 months STANDARD_DEVIATION 85.4 | 43.3 months STANDARD_DEVIATION 87.9 | 47.3 months STANDARD_DEVIATION 86.5 |
| Treatment of the most recent exacerbation Emergency room | 12 Participants | 7 Participants | 19 Participants |
| Treatment of the most recent exacerbation Hospitalisation | 1 Participants | 0 Participants | 1 Participants |
| Treatment of the most recent exacerbation Systemic corticosteroids | 35 Participants | 43 Participants | 78 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 283 | 0 / 280 |
| other Total, other adverse events | 44 / 283 | 53 / 280 |
| serious Total, serious adverse events | 3 / 283 | 0 / 280 |
Outcome results
Primary
1_Change From Baseline in FEV1 AUC0-12h Normalised by Time at Week 12
The pre-dose FEV1 at baseline (i.e. pre-dose on Week 0 \[Visit 2\]) and the FEV1 AUC0-12h normalised by time at Week 12 (Visit 5) are presented by treatment group in the ITT population, as change from baseline. AUC0=12h Area under the curve calculated between time 0 and 12 hours
Time frame: Baseline (pre-dose on Week 0) and Week 12.
Population: Intention-to-treat (ITT) population: all randomised subjects who received at least one administration of the study drug.~Statistical analysis used all available data and imputed missing data (i.e., whether due to missed visits, unperformed or unevaluable assessments at intermediate timepoints, or early study discontinuation) in ITT population (overall population N=283 in CHF 1535 pMDI 800/24 μg study group; N=280 in the CHF 718 pMDI 800 μg study group).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| CHF 1535 pMDI | 1_Change From Baseline in FEV1 AUC0-12h Normalised by Time at Week 12 | 0.279 liter |
| CHF 718 pMDI | 1_Change From Baseline in FEV1 AUC0-12h Normalised by Time at Week 12 | 0.174 liter |
Comparison: 1\_Change from baseline~Statistical analysis used all available data and imputed missing data (i.e., whether due to missed visits, unperformed or unevaluable assessments at intermediate timepoints, or early study discontinuation) in ITT population (overall population N=283 in CHF 1535 pMDI 800/24 μg study group; N=280 in the CHF 718 pMDI 800 μg study group).p-value: <0.00195% CI: [0.061, 0.148]ANCOVA
Secondary
10_Change From Baseline in Average Evening Peak Expiratory Flow (PEF) Over the 12-Week Treatment Period
The average EVENING PEF at baseline (i.e. average evening Best PEF values during the run-in period, see Section 9.7.1.4), over each inter-visit period and over the 12-week treatment period are presented by treatment group in the ITT population, as change from baseline. PEF=Peak Expiratory Flow
Time frame: Baseline (Week 0) to Week 12.
Population: Intention-to-treat (ITT) population: all randomised subjects who received at least one administration of the study drug.~Statistical analysis used all available data and imputed missing data (i.e., whether due to missed visits, unperformed or unevaluable assessments at intermediate timepoints, or early study discontinuation) in ITT population (overall population N=283 in CHF 1535 pMDI 800/24 μg study group; N=280 in the CHF 718 pMDI 800 μg study group).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| CHF 1535 pMDI | 10_Change From Baseline in Average Evening Peak Expiratory Flow (PEF) Over the 12-Week Treatment Period | 10.27 liter/min |
| CHF 718 pMDI | 10_Change From Baseline in Average Evening Peak Expiratory Flow (PEF) Over the 12-Week Treatment Period | 1.54 liter/min |
Comparison: 1\_Change From Baseline; Week 0 -- Week 12~Statistical analysis used all available data and imputed missing data (i.e., whether due to missed visits, unperformed or unevaluable assessments at intermediate timepoints, or early study discontinuation) in ITT population (overall population N=283 in CHF 1535 pMDI 800/24 μg study group; N=280 in the CHF 718 pMDI 800 μg study group).p-value: 0.00295% CI: [3.32, 14.14]ANCOVA
Secondary
11_Change From Baseline in ACQ-7 Score and ACQ-5 Score at Week 12
The ACQ-7 and ACQ-5 scores at baseline (i.e. pre-dose on Week 0 \[V2\]) and at Week 12 (V5) are presented by treatment group in the ITT population, as change from baseline; only patients who provided required data at baseline and at specified times are included in the calculation. Asthma control was evaluated during the treatment period (Week 0 to Week 12 \[V2-V5\])/end of treatment (ET) if applicable, using ACQ-7; first 6 items refer to symptoms and rescue use in the previous 7 days. The 7th item, filled in by the clinical staff, was the FEV1 (% predicted) recorded at 15 min pre-dose, measured at each visit during the treatment period. ACQ-5 has 5 items on adequacy of asthma control. ACQ-7: Assess asthma symptoms over last 7 days (night-time awakenings due to symptoms, morning symptoms, activity limitation, shortness of breath, wheezing), average daily rescue medication use, and current FEV1 percent predicted. Score scale: 0=totally controlled; 6=severely uncontrolled.
Time frame: Baseline (pre-dose on Week 0) and Week 12.
Population: Intention-to-treat (ITT) population: all randomised subjects who received at least one administration of the study drug.~Statistical analysis used all available data and imputed missing data (i.e., whether due to missed visits, unperformed or unevaluable assessments at intermediate timepoints, or early study discontinuation) in ITT population (overall population N=283 in CHF 1535 pMDI 800/24 μg study group; N=280 in the CHF 718 pMDI 800 μg study group).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| CHF 1535 pMDI | 11_Change From Baseline in ACQ-7 Score and ACQ-5 Score at Week 12 | ACQ-7 | -0.414 score |
| CHF 1535 pMDI | 11_Change From Baseline in ACQ-7 Score and ACQ-5 Score at Week 12 | ACQ-5 | -0.413 score |
| CHF 718 pMDI | 11_Change From Baseline in ACQ-7 Score and ACQ-5 Score at Week 12 | ACQ-7 | -0.302 score |
| CHF 718 pMDI | 11_Change From Baseline in ACQ-7 Score and ACQ-5 Score at Week 12 | ACQ-5 | -0.433 score |
Comparison: 1\_Change From Baseline in ACQ-7 at Week 12~Statistical analysis used all available data and imputed missing data (i.e., whether due to missed visits, unperformed or unevaluable assessments at intermediate timepoints, or early study discontinuation) in ITT population (overall population N=283 in CHF 1535 pMDI 800/24 μg study group; N=280 in the CHF 718 pMDI 800 μg study group).p-value: 0.02695% CI: [-0.211, -0.013]ANCOVA
Comparison: 2\_Change from baseline in ACQ-5 at Week 12~Statistical analysis used all available data and imputed missing data (i.e., whether due to missed visits, unperformed or unevaluable assessments at intermediate timepoints, or early study discontinuation) in ITT population (overall population N=283 in CHF 1535 pMDI 800/24 μg study group; N=280 in the CHF 718 pMDI 800 μg study group).p-value: 0.68695% CI: [-0.077, 0.118]ANCOVA
Secondary
12_Change From Baseline in Percentage of Rescue Medication-free Days Over the 12-Week Treatment Period
The percentage of rescue medication-free days at baseline (i.e. percentage of days during the run-in period with no rescue medication), over each inter-visit period and over the 12-week treatment period are presented by treatment group in the ITT population, as change from baseline.
Time frame: Baseline (pre-dose on Week 0) and Week 12.
Population: Intention-to-treat (ITT) population: all randomised subjects who received at least one administration of the study drug.~Statistical analysis used all available data and imputed missing data (i.e., whether due to missed visits, unperformed or unevaluable assessments at intermediate timepoints, or early study discontinuation) in ITT population (overall population N=283 in CHF 1535 pMDI 800/24 μg study group; N=280 in the CHF 718 pMDI 800 μg study group).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| CHF 1535 pMDI | 12_Change From Baseline in Percentage of Rescue Medication-free Days Over the 12-Week Treatment Period | 17.923 percentage of days |
| CHF 718 pMDI | 12_Change From Baseline in Percentage of Rescue Medication-free Days Over the 12-Week Treatment Period | 14.103 percentage of days |
Comparison: 1\_Change From Baseline~Statistical analysis used all available data and imputed missing data (i.e., whether due to missed visits, unperformed or unevaluable assessments at intermediate timepoints, or early study discontinuation) in ITT population (overall population N=283 in CHF 1535 pMDI 800/24 μg study group; N=280 in the CHF 718 pMDI 800 μg study group).p-value: 0.03395% CI: [0.31, 7.33]ANCOVA
Secondary
13_Change From Baseline in Percentage of Asthma Symptom-free Days Over the 12-Week Treatment Period
The percentage of asthma symptom-free days at baseline (i.e. percentage of days during the run-in period with no asthma symptom, over each inter-visit period and over the 12-week treatment period are presented by treatment group in the ITT population, as change from baseline.
Time frame: Baseline (pre-dose on Week 0) and Week 12.
Population: Intention-to-treat (ITT) population: all randomised subjects who received at least one administration of the study drug.~Statistical analysis used all available data and imputed missing data (i.e., whether due to missed visits, unperformed or unevaluable assessments at intermediate timepoints, or early study discontinuation) in ITT population (overall population N=283 in CHF 1535 pMDI 800/24 μg study group; N=280 in the CHF 718 pMDI 800 μg study group).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| CHF 1535 pMDI | 13_Change From Baseline in Percentage of Asthma Symptom-free Days Over the 12-Week Treatment Period | 20.872 percentage of days |
| CHF 718 pMDI | 13_Change From Baseline in Percentage of Asthma Symptom-free Days Over the 12-Week Treatment Period | 17.092 percentage of days |
Comparison: 1\_Change From Baseline~Statistical analysis used all available data and imputed missing data (i.e., whether due to missed visits, unperformed or unevaluable assessments at intermediate timepoints, or early study discontinuation) in ITT population (overall population N=283 in CHF 1535 pMDI 800/24 μg study group; N=280 in the CHF 718 pMDI 800 μg study group).p-value: 0.07895% CI: [-0.425, 7.985]ANCOVA
Secondary
2_Change From Baseline in Peak FEV1 Within the First 3 Hours Post-dose at Week 12
The peak FEV1 at baseline (i.e. pre-dose on Week 0 \[V2\]) and the peak FEV1 within the first 3 hours post-dose at Week 12 (V5) are presented by treatment group in the ITT population, as change from baseline. FEV1=Forced Expiratory Volume in the First Second
Time frame: Baseline (pre-dose on Week 0) and Week 12.
Population: Intention-to-treat (ITT) population: all randomised subjects who received at least one administration of the study drug.~Statistical analysis used all available data and imputed missing data (i.e., whether due to missed visits, unperformed or unevaluable assessments at intermediate timepoints, or early study discontinuation) in ITT population (overall population N=283 in CHF 1535 pMDI 800/24 μg study group; N=280 in the CHF 718 pMDI 800 μg study group).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| CHF 1535 pMDI | 2_Change From Baseline in Peak FEV1 Within the First 3 Hours Post-dose at Week 12 | 0.419 liter |
| CHF 718 pMDI | 2_Change From Baseline in Peak FEV1 Within the First 3 Hours Post-dose at Week 12 | 0.295 liter |
Comparison: 1\_Change from baseline~Statistical analysis used all available data and imputed missing data (i.e., whether due to missed visits, unperformed or unevaluable assessments at intermediate timepoints, or early study discontinuation) in ITT population (overall population N=283 in CHF 1535 pMDI 800/24 μg study group; N=280 in the CHF 718 pMDI 800 μg study group).p-value: <0.00195% CI: [0.076, 0.173]ANCOVA
Secondary
3_Change From Baseline in FEV1 AUC0-12h Normalised by Time at Week 0
The pre-dose FEV1 at baseline (i.e. pre-dose on Week 0 \[V2\]) and the FEV1 AUC0-12h normalised by time at Week 0 (V2, post-dose) are presented by treatment group in the ITT population, as change from baseline.
Time frame: Baseline (pre-dose on Week 0) and Week 12.
Population: Intention-to-treat (ITT) population: all randomised subjects who received at least one administration of the study drug.~Statistical analysis used all available data and imputed missing data (i.e., whether due to missed visits, unperformed or unevaluable assessments at intermediate timepoints, or early study discontinuation) in ITT population (overall population N=283 in CHF 1535 pMDI 800/24 μg study group; N=280 in the CHF 718 pMDI 800 μg study group).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| CHF 1535 pMDI | 3_Change From Baseline in FEV1 AUC0-12h Normalised by Time at Week 0 | 0.250 liter |
| CHF 718 pMDI | 3_Change From Baseline in FEV1 AUC0-12h Normalised by Time at Week 0 | 0.149 liter |
Comparison: 1\_Change from baseline~Statistical analysis used all available data and imputed missing data (i.e., whether due to missed visits, unperformed or unevaluable assessments at intermediate timepoints, or early study discontinuation) in ITT population (overall population N=283 in CHF 1535 pMDI 800/24 μg study group; N=280 in the CHF 718 pMDI 800 μg study group).p-value: <0.00195% CI: [0.063, 0.139]ANCOVA
Secondary
4_Change From Baseline in Peak FEV1 Within the First 3 Hours Post-dose at Week 0
The peak FEV1 at baseline (i.e. pre-dose on Week 0 \[V2\]) and the peak FEV1 within the first 3 hours post-dose at Week 0 (V2, post-dose) are presented by treatment group in the ITT population, as change from baseline. FEV1=Forced Expiratory Volume in the First Second
Time frame: Baseline (pre-dose on Week 0) and 3 h post dose on Week 0.
Population: Intention-to-treat (ITT) population: all randomised subjects who received at least one administration of the study drug.~Statistical analysis used all available data and imputed missing data (i.e., whether due to missed visits, unperformed or unevaluable assessments at intermediate timepoints, or early study discontinuation) in ITT population (overall population N=283 in CHF 1535 pMDI 800/24 μg study group; N=280 in the CHF 718 pMDI 800 μg study group).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| CHF 1535 pMDI | 4_Change From Baseline in Peak FEV1 Within the First 3 Hours Post-dose at Week 0 | 0.374 liter |
| CHF 718 pMDI | 4_Change From Baseline in Peak FEV1 Within the First 3 Hours Post-dose at Week 0 | 0.262 liter |
Comparison: 1\_Change from baseline~Statistical analysis used all available data and imputed missing data (i.e., whether due to missed visits, unperformed or unevaluable assessments at intermediate timepoints, or early study discontinuation) in ITT population (overall population N=283 in CHF 1535 pMDI 800/24 μg study group; N=280 in the CHF 718 pMDI 800 μg study group).p-value: <0.00195% CI: [0.071, 0.154]ANCOVA
Secondary
5_Change From Baseline in Trough FEV1 at Week 12
The trough FEV1 at baseline (i.e. pre-dose on Week 0 \[V2\]), the trough FEV1 at Week 12 (V5) and the change from baseline in trough FEV1 at Week 12 (V5) are presented by treatment group in the ITT population, as change from baseline. FEV1=Forced Expiratory Volume in the First Second
Time frame: Baseline (pre-dose on Week 0) and Week 12.
Population: Intention-to-treat (ITT) population: all randomised subjects who received at least one administration of the study drug.~Statistical analysis used all available data and imputed missing data (i.e., whether due to missed visits, unperformed or unevaluable assessments at intermediate timepoints, or early study discontinuation) in ITT population (overall population N=283 in CHF 1535 pMDI 800/24 μg study group; N=280 in the CHF 718 pMDI 800 μg study group).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| CHF 1535 pMDI | 5_Change From Baseline in Trough FEV1 at Week 12 | 0.212 liter |
| CHF 718 pMDI | 5_Change From Baseline in Trough FEV1 at Week 12 | 0.143 liter |
Comparison: 1\_Change from baseline~Statistical analysis used all available data and imputed missing data (i.e., whether due to missed visits, unperformed or unevaluable assessments at intermediate timepoints, or early study discontinuation) in ITT population (overall population N=283 in CHF 1535 pMDI 800/24 μg study group; N=280 in the CHF 718 pMDI 800 μg study group).p-value: 0.00395% CI: [0.023, 0.115]ANCOVA
Secondary
6_Change From Baseline in Pre-dose Morning FEV1 at Weeks 4, 8 and 12
The pre-dose MORNING FEV1 at baseline (i.e. pre-dose on Week 0 \[V2\]) and the pre-dose morning FEV1 at Week 4 (V3), Week 8 (V4) and Week 12 (V5) are presented by treatment group in the ITT population, as change from baseline. FEV1=Forced Expiratory Volume in the First Second
Time frame: Baseline (pre-dose on Week 0) and Week 4, Week 8, Week 12.
Population: Intention-to-treat (ITT) population: all randomised subjects who received at least one administration of the study drug.~Statistical analysis used all available data and imputed missing data (i.e., whether due to missed visits, unperformed or unevaluable assessments at intermediate timepoints, or early study discontinuation) in ITT population (overall population N=283 in CHF 1535 pMDI 800/24 μg study group; N=280 in the CHF 718 pMDI 800 μg study group).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| CHF 1535 pMDI | 6_Change From Baseline in Pre-dose Morning FEV1 at Weeks 4, 8 and 12 | Week 4 (V3) | 0.152 liter |
| CHF 1535 pMDI | 6_Change From Baseline in Pre-dose Morning FEV1 at Weeks 4, 8 and 12 | Week 8 (V4) | 0.188 liter |
| CHF 1535 pMDI | 6_Change From Baseline in Pre-dose Morning FEV1 at Weeks 4, 8 and 12 | Week 12 (V5) | 0.162 liter |
| CHF 718 pMDI | 6_Change From Baseline in Pre-dose Morning FEV1 at Weeks 4, 8 and 12 | Week 12 (V5) | 0.120 liter |
| CHF 718 pMDI | 6_Change From Baseline in Pre-dose Morning FEV1 at Weeks 4, 8 and 12 | Week 4 (V3) | 0.107 liter |
| CHF 718 pMDI | 6_Change From Baseline in Pre-dose Morning FEV1 at Weeks 4, 8 and 12 | Week 8 (V4) | 0.147 liter |
Comparison: 1\_Change from baseline -- Week 4~Statistical analysis used all available data and imputed missing data (i.e., whether due to missed visits, unperformed or unevaluable assessments at intermediate timepoints, or early study discontinuation) in ITT population (overall population N=283 in CHF 1535 pMDI 800/24 μg study group; N=280 in the CHF 718 pMDI 800 μg study group).p-value: 0.0595% CI: [0, 0.088]ANCOVA
Comparison: 2\_Change from baseline -- Week 8~Statistical analysis used all available data and imputed missing data (i.e., whether due to missed visits, unperformed or unevaluable assessments at intermediate timepoints, or early study discontinuation) in ITT population (overall population N=283 in CHF 1535 pMDI 800/24 μg study group; N=280 in the CHF 718 pMDI 800 μg study group).p-value: 0.09895% CI: [-0.007, 0.089]ANCOVA
Comparison: 3\_Change from baseline -- Week 12~Statistical analysis used all available data and imputed missing data (i.e., whether due to missed visits, unperformed or unevaluable assessments at intermediate timepoints, or early study discontinuation) in ITT population (overall population N=283 in CHF 1535 pMDI 800/24 μg study group; N=280 in the CHF 718 pMDI 800 μg study group).p-value: 0.05695% CI: [-0.001, 0.086]ANCOVA
Secondary
7_Proportion of Pre-dose Morning FEV1 Responders at Weeks 4, 8 and 12
The proportion of pre-dose MORNING FEV1 responders at Week 4 (V3), Week 8 (V4) and Week 12 (V5) are presented by treatment group in the ITT population. The proportion of subjects classified as pre-dose morning FEV1 responders (i.e. those subjects who had change from baseline in pre-dose morning FEV1 ≥100 mL). FEV1=Forced Expiratory Volume in the First Second
Time frame: Baseline (pre-dose on Week 0) and Week 4, Week 8, Week 12.
Population: Intention-to-treat (ITT) population: all randomised subjects who received at least one administration of the study drug.~Statistical analysis used all available data and imputed missing data (i.e., whether due to missed visits, unperformed or unevaluable assessments at intermediate timepoints, or early study discontinuation) in ITT population (overall population N=283 in CHF 1535 pMDI 800/24 μg study group; N=280 in the CHF 718 pMDI 800 μg study group).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| CHF 1535 pMDI | 7_Proportion of Pre-dose Morning FEV1 Responders at Weeks 4, 8 and 12 | Week 4 (V3) | 154 Participants |
| CHF 1535 pMDI | 7_Proportion of Pre-dose Morning FEV1 Responders at Weeks 4, 8 and 12 | Week 8 (V4) | 162 Participants |
| CHF 1535 pMDI | 7_Proportion of Pre-dose Morning FEV1 Responders at Weeks 4, 8 and 12 | Week 12 (V5) | 162 Participants |
| CHF 718 pMDI | 7_Proportion of Pre-dose Morning FEV1 Responders at Weeks 4, 8 and 12 | Week 4 (V3) | 130 Participants |
| CHF 718 pMDI | 7_Proportion of Pre-dose Morning FEV1 Responders at Weeks 4, 8 and 12 | Week 8 (V4) | 141 Participants |
| CHF 718 pMDI | 7_Proportion of Pre-dose Morning FEV1 Responders at Weeks 4, 8 and 12 | Week 12 (V5) | 125 Participants |
Comparison: 1\_Responders at Week 4p-value: 0.09895% CI: [0.949, 1.855]Logistic regression model
Comparison: 2\_Responders at Week 8p-value: 0.1895% CI: [0.898, 1.772]Logistic regression model
Comparison: 3\_Responders at Week 12p-value: 0.00995% CI: [1.117, 2.203]Logistic regression model
Secondary
8_Proportion of Trough FEV1 Responders at Week 12
The proportion of trough FEV1 responders at Week 12 (V5) are presented by treatment group in the ITT population. The proportion of subjects classified as trough FEV1 responders (i.e. those subjects who had change from baseline in trough FEV1 ≥100 mL). FEV1=Forced Expiratory Volume in the First Second
Time frame: Baseline (pre-dose on Week 0) and Week 4, Week 8, Week 12.
Population: Intention-to-treat (ITT) population: all randomised subjects who received at least one administration of the study drug.~Statistical analysis used all available data and imputed missing data (i.e., whether due to missed visits, unperformed or unevaluable assessments at intermediate timepoints, or early study discontinuation) in ITT population (overall population N=283 in CHF 1535 pMDI 800/24 μg study group; N=280 in the CHF 718 pMDI 800 μg study group).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CHF 1535 pMDI | 8_Proportion of Trough FEV1 Responders at Week 12 | 181 Participants |
| CHF 718 pMDI | 8_Proportion of Trough FEV1 Responders at Week 12 | 136 Participants |
Comparison: 1\_Responders at Week 12p-value: <0.00195% CI: [1.284, 2.587]Logistic regression model
Secondary
9_Change From Baseline in Average Morning Peak Expiratory Flow (PEF) Over the 12-Week Treatment Period
The average MORNING PEF at baseline (i.e. average morning Best PEF values during the run-in period, over each inter-visit period and over the 12-week treatment period are presented by treatment group in the ITT population), as change from baseline. PEF=Peak Expiratory Flow
Time frame: Baseline (Week 0) to Week 12.
Population: Intention-to-treat (ITT) population: all randomised subjects who received at least one administration of the study drug.~Statistical analysis used all available data and imputed missing data (i.e., whether due to missed visits, unperformed or unevaluable assessments at intermediate timepoints, or early study discontinuation) in ITT population (overall population N=283 in CHF 1535 pMDI 800/24 μg study group; N=280 in the CHF 718 pMDI 800 μg study group).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| CHF 1535 pMDI | 9_Change From Baseline in Average Morning Peak Expiratory Flow (PEF) Over the 12-Week Treatment Period | 13.45 liter/min |
| CHF 718 pMDI | 9_Change From Baseline in Average Morning Peak Expiratory Flow (PEF) Over the 12-Week Treatment Period | 4.67 liter/min |
Comparison: 1\_Change From Baseline; Week 0 -- Week 12~Statistical analysis used all available data and imputed missing data (i.e., whether due to missed visits, unperformed or unevaluable assessments at intermediate timepoints, or early study discontinuation) in ITT population (overall population N=283 in CHF 1535 pMDI 800/24 μg study group; N=280 in the CHF 718 pMDI 800 μg study group).p-value: 0.00295% CI: [3.3, 14.27]ANCOVA