A Dose Ranging Study With CHF 1531 in Subjects With Asthma (FLASH)

Study Overview
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Brief Summary
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To evaluate the dose-response of different doses of CHF 1531 pressurized metered dose inhaler (pMDI) containing formoterol fumarate, on lung function and other clinical outcomes and to identify the optimal dose(s) with regard to benefit/ risk ratio for further development in the target subject population.

Detailed Description
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This is a phase II, randomized, double-blind, placebo and active controlled dose-ranging, 6 arm incomplete block cross-over study to identify the optimal dose of CHF 1531 pMDI (containing formoterol fumarate), with regard to lung function and other clinical efficacy and safety outcome measures. After a 2 week run-in period under rescue albuterol 'as needed' and background inhaled corticosteroid (ICS), subjects qualifying for the study were required to complete 4 treatment intervals of 2 weeks each, separated by 2 week wash-out intervals. During each treatment interval, the subject were randomly assigned to take one of 5 double-blind study treatments twice daily (BID) i.e. one of 4 doses of CHF 1531 pMDI or a matching placebo or the open-label active control treatment (Perforomist® Inhalation Solution [IS]) also BID. During the entire study, all subjects concomitantly received ICS treatment with QVAR® inhaler (beclomethasone dipropionate 40 or 80 µg /actuation) twice daily at a dose that matches their pre-enrollment ICS and an albuterol inhaler to use as asthma rescue medication on 'as needed' basis. The subjects visited the study center every 2 weeks to undergo study procedures, and received a safety follow-up phone call one week after their last visit. In total, the study lasted 18 weeks and required 10 visits to the study center. During the study, daily asthma symptoms, peak expiratory flow, rescue and background medication use, and compliance with the study medication were recorded in a subject diary. Treatment-Emergent Adverse Events (TEAEs) were assessed and recorded throughout the study. A full physical exam, routine hematology, blood chemistry, spirometry, vital signs measurement, 12-lead ECG, and pregnancy testing were performed before enrollment and at the end of the study. Furthermore, on Day 1 and 14 of each treatment interval, serial spirometry, 12-lead ECGs, blood pressure measurements (BP), serum potassium, and serum glucose were measured at the study center for up to 12 hours post-dose.

Official Title
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A Randomized, Double-blind, Placebo and Active-controlled, Incomplete Block Cross-over, Dose Ranging Study to Evaluate the Efficacy and Safety of 4 Doses of CHF 1531 pMDI (Formoterol Fumarate) in Asthmatic Subjects

Conditions
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Asthma

Intervention / Treatment
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* Drug: CHF 1531 pMDI
* Drug: Formoterol Inhalation Solution
* Drug: Placebo pMDI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects aged ≥18 and ≤75 years who have signed an Informed Consent Form prior to initiation of any study-related procedure. A diagnosis of asthma as defined in the Global Initiative for Asthma (GINA) Report, 2016, documented for at least 1 year prior to screening. Poorly controlled or uncontrolled asthma evidenced by a score ≥1.5 on the Asthma Control Questionnaire 7 © (ACQ-7) A pre-bronchodilator Forced Expiratory Volume in the 1st Second ( FEV1) ≥60% and <85% of their predicted normal value, after appropriate washout from bronchodilators, at the screening and randomization visits Subjects with a positive response to a reversibility test at screening, defined as change in FEV1 (ΔFEV1) ≥12% and ≥200 mL over baseline within 30 minutes after inhaling 4 puffs of albuterol hydrofluoroalkane(HFA) 90 µg/actuation. Use of ICS (low/medium dose according to GINA Report, 2016) with or without a long-acting bronchodilator for 3 months (at a stable dose in the last 4 weeks) before screening visit. A cooperative attitude and ability to demonstrate correct use of the diary, peak flow meter, and pMDI inhaler. Exclusion Criteria: Pregnant or lactating women and all women physiologically capable of becoming pregnant UNLESS they are willing to use a highly effective birth control methods Subjects who suffer from Chronic Obstructive Pulmonary Disease (COPD) as defined by the Global Strategy for Prevention, Diagnosis and Management of COPD (GOLD) Report, 2017, or are suspected of having Asthma COPD Overlap Syndrome (ACOS) as described in the GINA Report, 2016. Inability to carry out pulmonary function testing, to comply with study procedures or with study drug intake. Current smokers or ex-smokers (tobacco, vapor cigarettes, marijuana) with a smoking history of >10 pack-years or having stopped smoking one year or less prior to screening visit. History of life-threatening asthma, clinically significant uncontrolled disease or respiratory infection. An asthma exacerbation requiring oral/intravenous corticosteroids ≤ 30 days, intramuscular depot corticosteroid ≤3 months or hospitalization within 6 months prior to screening. Subjects with unresolved bacterial or viral respiratory tract, sinus, or middle ear infection affecting asthma status within 2 weeks prior to screening. Subjects who received a vaccination within 2 weeks prior to screening or during the run-in. Subjects with oral candidiasis at screening and at randomization. Subjects with any clinically significant, uncontrolled condition. Subjects with serum potassium levels <3.5 milliequivalents per litre (mEq/L) or (3.5 mmol/L) at screening. Subjects who have clinically significant cardiovascular condition. Subjects who have a clinically significant abnormal 12-lead ECG that results in active medical problem which may impact the safety of the patient according to Investigator's judgment. Subjects whose 12-lead ECG shows Fridericia's corrected QT interval (QTcF) >450 ms for males or QTcF >470 ms for females at screening or randomization visits. Subjects with known intolerance/hypersensitivity or contra-indication to treatment with inhaled β2-adrenergic receptor agonists, corticosteroids or propellant gases/excipients. Subjects with concomitant immunosuppressive therapy, use of oral or injected corticosteroids, anti- Immunoglobulin E (IgE), anti-Interleukin 5 (IL5) or other monoclonal or polyclonal antibodies within 12 weeks prior to screening. Use of potent cytochrome P450 3A4 inhibitors and inducers within 4 weeks prior to screening. History of alcohol abuse and/or substance/drug abuse within 12 months prior to screening. 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. Subjects who are mentally or legally incapacitated or subjects accommodated in an establishment as a result of an official or judicial order. Subjects who have undergone major surgery in the 3 months prior to screening visit or have a planned surgery during the trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment A<br>Treatment A, CHF 1531 pMDI: CHF 1531 pMDI 6 μg total daily dose (TDD): 1 inhalation of CHF 1531 pMDI 3 μg/actuation plus 1 inhalation of CHF 1531 matched Placebo BID. | Drug: CHF 1531 pMDI<br>* Dose Response: Test one of five different doses of CHF 1531<br>|
| Experimental: Treatment B<br>Treatment B, CHF 1531 pMDI: CHF 1531 pMDI 12 μg TDD: 1 inhalation of CHF 1531 pMDI 6 μg/actuation plus 1 inhalation of CHF 1531 matched Placebo BID. | Drug: CHF 1531 pMDI<br>* Dose Response: Test one of five different doses of CHF 1531<br>|
| Experimental: Treatment C<br>Treatment C, CHF 1531 pMDI: CHF 1531 pMDI 24 μg TDD: 2 inhalations of CHF 1531 pMDI 6 μg/actuation BID. | Drug: CHF 1531 pMDI<br>* Dose Response: Test one of five different doses of CHF 1531<br>|
| Experimental: Treatment D<br>Treatment D, CHF 1531 pMDI CHF 1531 pMDI 48 μg TDD: 2 inhalations of CHF 1531 pMDI 12 μg/actuation BID. | Drug: CHF 1531 pMDI<br>* Dose Response: Test one of five different doses of CHF 1531<br>|
| Experimental: Treatment E<br>Treatment E, Matched placebo Placebo: 2 inhalations of CHF 1531 pMDI matched Placebo BID. | Drug: Placebo pMDI<br>* Matched Placebo<br>|
| Active Comparator: Treatment F<br>Treatment F, Formoterol fumarate inhalation solution (IS) Perforomist® IS (active comparator, open-label) 40 μg TDD: 1 inhalation, 20 μg/ 2 mL vial, 1 vial BID. | Drug: Formoterol Inhalation Solution<br>* Active Control<br>* Other names: PERFOROMIST® 20 μg/ 2 mL vial, 1 vial BID;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FEV1 Area Under the Curve Between 0 and 12 h [AUC(0-12h)], Normalized by Time -- Change From Baseline to Post Dose Day 14 | Spirometry used to measure FEV1, was performed according to internationally accepted standards. Results show the change from baseline in FEV1 AUC(0-12h), normalized by time on Day 14; it was calculated by using the linear trapezoidal rule, based on the changes in FEV1 from the baseline values. Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended). Definitions: AUC=Area under the curve; AUC(0-12h)=AUC between 0 and 12 h; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period; FEV1=Forced expiratory volume in the 1st second; | Baseline, Day 14 post-dose | 
| Sensitivity Analysis 1: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14 | The primary analysis was repeated, considering patients as randomized and including only the first instance of each treatment. Patients receiving the same treatment in more than one period were included in the analysis with only data from the first instance of each treatment. | Baseline, Day 14 post-dose | 
| Sensitivity Analysis 2: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14 | The primary analysis was repeated, considering only patients and treatment periods for which treatment was assigned on or after the randomization error occurred. The number of patients shown represents those with at least one post-baseline assessment available. | Baseline, Day 14 post-dose | 
| Sensitivity Analysis 3: FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 14 | Patients receiving the same treatment during two treatment periods are considered twice in the ANCOVA model (once for each period attended). Patients considered in this analysis are those with at least one available post-baseline assessment. | Baseline, Day 14 post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FEV1 AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 1 | Spirometry used to measure FEV1, was performed according to internationally accepted standards. Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended). Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period; | Baseline, Day 1 post-dose | 
| FEV1 AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Spirometry used to measure FEV1, was performed according to internationally accepted standards. Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended). Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period; | Baseline, Day 1, Day 14 post-dose | 
| FEV1 Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Spirometry, used to measure FEV1, was performed according to internationally accepted standards. Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended). Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period; | Baseline, Day 1, Day 14 post-dose | 
| FVC AUC(0-12h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Spirometry, used to measure FVC, was performed according to internationally accepted standards. Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended). Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period; | Baseline, Day 1, Day 14 post-dose | 
| FVC AUC(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Spirometry, used to measure FVC, was performed according to internationally accepted standards. Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended). Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period; | Baseline, Day 1, Day 14 post-dose | 
| FVC Peak(0-4h), Normalized by Time -- Change From Baseline to Post Dose Day 1 and Day 14 | Spirometry, used to measure FVC, was performed according to internationally accepted standards. Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended). Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period; | Baseline, Day 1, Day 14 post-dose | 
| Pre-dose Morning FEV1 (L) -- Change From Baseline to Post Dose Day 14 | Spirometry, used to measure FEV1, was performed according to internationally accepted standards. Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended). Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period; | Baseline, Day 14 post-dose | 
| Pre-dose Morning FVC -- Change From Baseline to Post Dose Day 14 | Spirometry, used to measure FVC, was performed according to internationally accepted standards. Patients receiving the same treatment during two periods are considered twice in the ANCOVA model (once for each period attended). Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period; | Baseline, Day 14 post-dose | 
| Time to Onset of Action -- Change From Baseline in Post-dose FEV1 ≥12% and ≥200 mL to Post Dose Day 1 | Spirometry, used to measure FEV1, was performed according to internationally accepted standards. For patients receiving the same treatment twice, the analysis includes only data from the first instance of each treatment. Definitions: Time to onset of action=The time (in minutes) from receiving the study drug on Day 1, until the FEV1 change from baseline is ≥200 mL; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose) on Day 1 of the treatment period; | Baseline, Day 1 post-dose | 
| Patients Achieving Onset of Action -- Change From Baseline in Post-dose FEV1 ≥12% and ≥200 mL to Post Dose Day 1 | Patients achieving onset of action, defined as a change from baseline in post-dose FEV1 ≥12% and ≥200 mL, on Day 1. These are the subjects who contributed to the results, reported as median and 95% CI for 'Time to onset of action' presented in the Outcome Measure 13, above. For patients receiving the same treatment twice, the analysis includes only data from the first instance of each treatment. Definitions: Onset of action=Change from baseline in post-dose FEV1 ≥12% and ≥200 mL; Baseline=Baseline value was the average of the pre-dose measurements (at 45 mins and 15 mins pre-dose); | Baseline, Day 1 post-dose | 
| Vital Signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]) -- Change From Baseline for Post-dose on Day 1 and on Day 14 | Vital signs -- Systolic blood pressure (SBP) and Diastolic blood pressure (DBP) were measured at pre-specified times (at baseline - pre dose and on Day 14 of each treatment period or on the day of early study termination). Results are shown by treatment group, as change from baseline (in mmHg). For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation. Definitions: For safety variables, the baseline for each treatment period was defined as pre-dose measurements on Day 1 of each treatment period; Day 14=The day of the last dosing of a treatment period. Day 14 of the second, third, and fourth treatment periods (day of last dosing); treatments were separated by a 2-week wash-out interval; | Baseline, Day 1 and Day 14 post-dose | 
| 12-lead ECG Parameter -- Heart Rate (HR) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Results are shown by treatment group, as change from baseline (in bpm). For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation. For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period. | Baseline, Day 1, Day 14 post-dose | 
| Heart Rate (HR) AUC(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Heart rate HR AUC(0-4h) normalized by time. Results are shown by treatment group, as change from baseline (in bpm). The HR AUC(0-4h) normalized by time is calculated based on the actual times, using the linear trapezoidal rule. For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation. For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period. | Baseline, Day 1, Day 14 post-dose | 
| Heart Rate (HR) Peak(0-4h), Normalized by Time -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Heart rate (HR) peak(0-4h) normalized by time. Results are shown by treatment group, as change from baseline (in bpm). For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation. For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period. Definitions: HR=Heart rate; HR peak(0-4h)=The maximum observed value over 4 hours following dosing; | Baseline, Day 1, Day 14 post-dose | 
| Heart Rate (HR) AUC(0-4h) and Peak(0-4h), Normalized by Time -- Change From Pre-dose to Post Dose Day 14 | Heart rate (HR) AUC(0-4h) and HR peak(0-4h), normalized by time (in bpm). Results are shown as change from pre-dose on Day 14 (in bpm). For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation. Definitions: HR=Heart rate; HR AUC(0-4h)=Area under the curve between 0 and 4 h for heart rate; HR peak(0-4h)=The maximum observed value over 4 h after dosing; | Baseline, Day 14 post-dose | 
| 12-lead Electrocardiogram (ECG) Parameter (QTcF Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | 12-lead electrocardiogram (ECG) parameters were monitored during the study. Results are shown by treatment group, as change from baseline (in msec). For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation. For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period. | Baseline, Day 1, Day 14 post-dose | 
| 12-lead Electrocardiogram (ECG) Parameter (PR Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | 12-lead electrocardiogram (ECG) parameters were monitored during the study. Results are shown by treatment group, as change from baseline (in msec). For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation. For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period. | Baseline, Day 1, Day 14 post-dose | 
| 12-lead Electrocardiogram (ECG) Parameter (QRS Interval) -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | 12-lead electrocardiogram (ECG) parameters were monitored during the study. Results are shown by treatment group, as change from baseline (in msec). For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation. For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period. | Baseline, Day 1, Day 14 post-dose | 
| Serum Potassium -- Change From Baseline Post-dose to Post Dose Day 1 and Day 14 | Serum potassium level was monitored during the study. Results are shown by treatment group, as change from baseline (in mmol/L). For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation. For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period. | Baseline, Day 1, Day 14 post-dose | 
| Serum Glucose -- Change From Baseline to Post-dose Day 1 and Day 14 | Serum glucose level was monitored during the study. Results are shown by treatment group, as change from baseline (in mmol/L). For patients receiving the same treatment in 2 periods, the average of the 2 available data points was considered in the calculation. For safety variables, the baseline for each period was defined as pre-dose measurements on Day 1 of each treatment period. | Baseline, Day 1, Day 14 post-dose |