An 8-week Dose Ranging Study of CHF 718 pMDI in Asthmatic Subjects

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the dose-response of different doses of CHF 781 Pressurized Metered Dose Inhaler (pMDI) on lung function and other clinical outcomes, to identify the optimal dose(s) in terms of benefit/ risk ratio for further development in the target patient population.

Detailed Description
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This is a phase II, multicenter, randomized, double-blind, placebo and active controlled dose ranging 5-arm parallel group study to identify the optimal dose of CHF 781 pMDI with respect to lung function and other clinical efficacy and safety outcomes. After a 2 week run-in period under rescue albuterol as needed and background inhaled corticosteroid (ICS), patients will be randomized to one of the 5 study treatment groups. After randomization, patients will be assessed after 4 and 8 weeks of study treatment at the center. A follow-up phone call will be performed a week after the last visit. During the study, daily asthma symptoms, peak expiratory flow, rescue and background medication use, and compliance with the study medication will be recorded via subject diary. Treatment-Emergent Adverse Events (TEAEs) will be assessed and recorded throughout the study. At screening and subsequent visits, patients will undergo physical and vital signs examinations, spirometry measurements, and 12-lead ECG. Routine hematology, blood chemistry, and pregnancy testing will be performed before enrollment and at end of study. 24-hr urine cortisol and creatinine will be assessed before and after the first dose and just before the last dose of study treatment.

Official Title
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An 8-week, Multicenter, Randomized, Double-blind, Placebo and Active-controlled, Parallel Group, Dose-ranging Study to Evaluate the Efficacy and Safety of 3 Doses of CHF 718 pMDI (HFA Beclomethasone Dipropionate Via Pressured Metered Dose Inhaler) in Asthmatic Subjects.

Conditions
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Asthma

Intervention / Treatment
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* Drug: CHF 718 pMDI
* Drug: Placebo pMDI
* Drug: Beclomethasone Dipropionate (BDP)


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. Subjects with poorly controlled or uncontrolled asthma evidenced by a score at the Asthma Control Questionnaire 7 © (ACQ-7) ≥1.5 (this criterion must be met at screening and at randomization visits). Subjects with a pre-bronchodilator Forced Expiratory Volume in the 1st Second (FEV1) ≥50% 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 (pre - post BD), within 1 year prior to or at screening defined as ΔFEV1≥12% and ≥200 mL over baseline within 30 minutes after inhaling 4 puffs of albuterol HFA 90µg/actuation. Use of inhaled corticosteroids (low/medium dose according to GINA Report 2016) with or without a long-acting bronchodilator (LABD) for 3 months (stable dose in the last 4 weeks) before screening visit (V). A cooperative attitude and ability to demonstrate correct use of the diary, peak flow meter, and pMDI inhalers. A basal morning (7-10 am) serum cortisol level between 7-28 µg/dL at screening visit (V1). A Body Mass Index (BMI): 18.5 ≤ BMI <35 kg/m^2. Exclusion Criteria: Pregnant (as evident by a positive urine human chorionic gonadotropin (hCG) or serum β-hCG test) or lactating women and all women physiologically capable of becoming pregnant (i.e. women of childbearing potential) UNLESS they are willing to use a highly effective birth control method Subjects who suffer from chronic obstructive pulmonary disease (COPD) as defined by the GOLD Report 2017, or are suspected of having Asthma COPD Overlap Syndrome (ACOS) as defined in GINA Report, 2016. Inability to carry out pulmonary lung 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 corticosteroids within 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 or at randomization. Subjects with any clinically significant, uncontrolled condition 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 subject according to Investigator's judgement. Subjects whose 12-lead ECG shows Fridericia corrected QT interval (QTcF) >450 ms for males or QTcF >470 ms for females at screening and randomization visits. Subjects with known intolerance/hypersensitivity or contra-indication to treatment with ß2-adrenergic receptor agonists, inhaled 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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment A<br>CHF 718 pMDI 100 μg Total Daily Dose (TDD), Dose 1; CHF 718 pMDI 50 μg/actuation: 1 inhalation twice daily (BID); | Drug: CHF 718 pMDI<br>* Dose Response: Test one of three different doses of CHF 718 pMDI<br>|
| Experimental: Treatment B<br>CHF 718 pMDI 400 μg Total Daily Dose (TDD) 400 μg, Dose 2; CHF 718 pMDI 100 μg/actuation: 2 inhalations BID; | Drug: CHF 718 pMDI<br>* Dose Response: Test one of three different doses of CHF 718 pMDI<br>|
| Experimental: Treatment C<br>CHF 718 pMDI Total Daily Dose (TDD) 800 μg, Dose 3; CHF 718 pMDI 100 μg/actuation: 4 inhalations BID; | Drug: CHF 718 pMDI<br>* Dose Response: Test one of three different doses of CHF 718 pMDI<br>|
| Placebo Comparator: Treatment D<br>Placebo Control, Placebo; CHF 718 pMDI matched Placebo: 4 inhalations BID; | Drug: Placebo pMDI<br>* Placebo Control<br>|
| Active Comparator: Treatment E<br>Beclomethasone dipropionate (BDP) Hydrofluoroalkane (HFA), Total Daily Dose (TDD) 320 µg; QVAR® 80 μg/actuation: 2 inhalations BID; | Drug: Beclomethasone Dipropionate (BDP)<br>* Active Control<br>* Other names: QVAR® 80µg;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pre-dose Morning FEV1 at Week 8 - Change From Baseline | Change from baseline in pre-dose morning FEV1 (average of pre-dose FEV1 measurements) at Week 8. Spirometry, used to measure FEV1, was performed according to internationally accepted standards. Definitions: Baseline=Baseline values for pre-dose FEV1 were the average of measurements taken at V2 (Week 0) at 45 minutes and 15 minutes pre-dose; FEV1=Forced expiratory volume in the 1st second; | Baseline, Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pre-dose Morning FEV1 at Week 4 - Change From Baseline | Change from baseline in pre-dose morning FEV1 at Week 4. Spirometry, used to measure FEV1, was performed according to internationally accepted standards. Definitions: Baseline=Baseline values for pre-dose FEV1 were the average of measurements taken at V2 (Week 0) at 45 minutes and 15 minutes pre-dose; FEV1=Forced expiratory volume in the 1st second; | Baseline, Week 4 | 
| Pre-dose Morning FVC at Week 4 and 8 - Change From Baseline | Change from baseline in pre-dose morning FVC at Week 4 and 8. Spirometry, used to measure FVC, was performed according to internationally accepted standards. Definitions: Baseline=Baseline values for pre-dose FVC were the average of measurements taken at V2 (Week 0) at 45 minutes and 15 minutes pre-dose; FVC=Forced vital capacity; | Baseline, Week 4, Week 8 | 
| Asthma Control Questionnaire-7© (ACQ-7) Score at Week 4 and Week 8 - Change From Baseline | The ACQ consists of 7 items: 6 simple self-administered questions referring to asthma control and rescue treatment usage with 1 week recall, and a 7th item consisting of the percent (%) predicted FEV1 completed by clinic staff. Scoring uses a 7-point scale: 0 = totally controlled and 6 = severely uncontrolled. The ACQ score was calculated as the average of all 7 items. Definitions: ACQ-7 score=Asthma Control Questionnaire-7©; Information regarding the American Thoracic Society ACQ questionnaire is also available at: https://member.thoracic.org/members/assemblies/assemblies/srn/questionaires/acq.php; Baseline ACQ-7 score = ACQ score recorded at V2 (Week 0) Day 1, before randomization; FEV1=Forced expiratory volume in the 1st second; | Baseline, Week 4, Week 8 | 
| Average Use of Rescue Medication - Change From Baseline | Change from baseline in average use of rescue medication, during Inter-visit period 1, Inter-visit period 2, Entire treatment period. Definitions: Baseline=For the efficacy variable -- average use of rescue medication -- derived from the electronic diary (eDiary), baseline values were the averages recorded during the run-in period; Inter-visit period 1=Starts from the pm assessment of the Start of the Randomized Treatment Period to the am assessment at Visit 3 (Week 4); Inter-visit Period 2=Starts from the pm assessment of the day the subject returns to the clinic (Visit 3) to the am assessment of the date of Visit 4 (Week 8); Entire treatment period=Average of 8 weeks; am=morning pm=evening | Baseline (average of the 2-week run-in period); Inter-visit period 1 (average of the first 4 weeks); Inter-visit period 2 (average of the last 4 weeks); Entire treatment period (average of 8 weeks) | 
| Percentage (%) of Rescue Medication-free Days - Change From Baseline | Change from baseline in percentage (%) of rescue medication-free days. An increased value indicates improvement from baseline. Definitions: Baseline=For the efficacy variable -- percentage (%) of rescue medication-free days -- derived from the electronic diary (eDiary), baseline values were the averages/percentages recorded during the run-in period. Inter-visit period 1=Starts from the pm assessment of the Start of the Randomized Treatment Period to the am assessment at Visit 3 (Week 4); Inter-visit Period 2=Starts from the pm assessment of the day the subject returns to the clinic (Visit 3) to the am assessment of the date of Visit 4 (Week 8); Entire treatment period=Average of 8 weeks; am=morning pm=evening | Baseline (average of the 2-week run-in period); Inter-visit period 1 (average of the first 4 weeks); Inter-visit period 2 (average of the last 4 weeks); Entire treatment period (average of 8 weeks) | 
| Overall Daily Asthma Symptoms Scores - Change From Baseline | Overall daily asthma symptoms scores - Change From Baseline (am and pm). Subjects had to record asthma symptom score (overall symptoms, cough, wheeze, chest tightness and breathlessness) in the am (night-time asthma symptom score) and in the pm (daytime asthma symptom score). These data were collected in the subject's diary. Daily asthma symptoms score were performed separately for am score and pm score and also as a total, where the total equals the sum of the am and pm scores. Degree of asthma symptoms by score: 0=None, 1=Mild, 2=Moderate, and 3=Severe. Baseline=Averages values during the run-in period; Inter-visit period 1=Starts from the pm assessment of the Start of the Randomized Treatment Period to the am assessment at Visit 3 (Week 4); Inter-visit Period 2=Starts from the pm assessment of the day the subject returns to the clinic (Visit 3) to the am assessment of the date of Visit 4 (Week 8); Entire treatment period=Average of 8 weeks; am=morning pm=evening | Baseline (average of the 2-week run-in period); Inter-visit period 1 (average of the first 4 weeks); Inter-visit period 2 (average of the last 4 weeks); Entire treatment period (average of 8 weeks) | 
| Percentage (%) of Asthma Symptoms-free Days - Change From Baseline | Change from baseline in Percentage (%) of asthma symptoms-free days. Asthma symptoms-free days is the number of days with a total asthma score=0 (daily morning plus evening asthma score). Subjects recorded asthma symptom score as described in the Outcome measure #7. Definitions: Baseline=For the efficacy variables -- daytime and night-time asthma symptom scores -- derived from the eDiary, baseline values were the averages/percentages recorded during the run-in period; Inter-visit period 1=Starts from the pm assessment of the Start of the Randomized Treatment Period to the am assessment at Visit 3 (Week 4); Inter-visit Period 2=Starts from the pm assessment of the day the subject returns to the clinic (Visit 3) to the am assessment of the date of Visit 4 (Week 8); Entire treatment period=Average of 8 weeks; am=morning pm=evening | Baseline (average of the 2-week run-in period); Inter-visit period 1 (average of the first 4 weeks); Inter-visit period 2 (average of the last 4 weeks); Entire treatment period (average of 8 weeks) | 
| Percentage (%) of Asthma Control Days - Change From Baseline | Change from baseline in percentage (%) of asthma control days, during Inter-visit period 1, Inter-visit period 2, Entire treatment period. This outcome measure was calculated according to the following definition: Days with a total daily morning + evening asthma score = 0 AND No rescue medication use. Definitions: Baseline=For the efficacy variable -- asthma control days -- derived from the eDiary, baseline values were the averages/percentages recorded during the run-in period; Inter-visit period 1=Starts from the pm assessment of the Start of the Randomized Treatment Period to the am assessment at Visit 3 (Week 4); Inter-visit Period 2=Starts from the pm assessment of the day the subject returns to the clinic (Visit 3) to the am assessment of the date of Visit 4 (Week 8); Entire treatment period=Average of 8 weeks; am=morning pm=evening | Baseline (average of the 2-week run-in period); Inter-visit period 1 (average of the first 4 weeks); Inter-visit period 2 (average of the last 4 weeks); Entire treatment period (average of 8 weeks) | 
| Pre-dose Peak Expiratory Flow (PEF) (L/Min) (Morning and Evening) - Change From Baseline | Change from baseline in pre-dose Peak Expiratory Flow (PEF) (Liters/min), morning and evening measurements. Definitions: Baseline=For the efficacy variable -- morning and evening PEF -- derived from the eDiary, the baseline values were the averages/percentages recorded during the run-in period; PEF=evening peak expiratory flow; Inter-visit period 1=Starts from the pm assessment of the Start of the Randomized Treatment Period to the am assessment at Visit 3 (Week 4); Inter-visit Period 2=Starts from the pm assessment of the day the subject returns to the clinic (Visit 3) to the am assessment of the date of Visit 4 (Week 8); Entire treatment period=Average of 8 weeks; am=morning pm=evening | Baseline (average of the 2-week run-in period); Inter-visit period 1 (average of the first 4 weeks); Inter-visit period 2 (average of the last 4 weeks); Entire treatment period (average of 8 weeks) | 
| Vital Signs (Systolic and Diastolic Blood Pressure) - Change From Baseline | Vital signs (systolic and diastolic blood pressure) at baseline, week 4, and week 8. Change from baseline. Definitions: Baseline=Baseline values were defined at visit 2 (Week 0) pre-dose; DBP=Diastolic blood pressure; SBP=Systolic blood pressure; | Baseline, Week 4, Week 8 | 
| 12-lead ECG Parameters - Heart Rate - Change From Baseline | 12-lead electrocardiogram (12-lead ECG) parameter - heart rate (HR) was measured at baseline (Day 1) and Week 8. Change from baseline. Definitions: Baseline=Baseline values were defined at visit 2 (Week 0) pre-dose; bpm=Beats per minute; | Baseline, Week 8 | 
| 12-lead ECG Parameters - PR, QRS, QTcF - Change From Baseline. | 12-lead electrocardiogram (12-lead ECG) parameters - PR, QRS, QTcF intervals - were measured at baseline (Day 1) and Week 8. Changes from baseline. Definitions: Baseline=Baseline values were defined at visit 2 (Week 0); QTcF=Fridericia-corrected QT interval; msec=Millisecond; | Baseline, Week 8 | 
| 12-lead ECG Parameters - Prolonged QTcF - Change From Baseline | Number of participants with prolonged QTcF. Change from baseline. Baseline=Baseline values were defined at visit 2 (Week 0) pre-dose; QTcF=Fridericia-corrected QT interval; | Baseline, Week 8 | 
| 24-hr Urine Free Cortisol - Change From Baseline | 24-hr Urinary Free Cortisol - Change From Baseline. For the evaluation of the 24-hr Urine-Free cortisol excretion, 24-hour urine samples were collected. Urine-free cortisol was measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Definitions: Baseline=Baseline values were defined at visit 2 (Week 0) pre-dose; | Baseline, Week 8 | 
| 24-hr Creatinine - Change From Baseline. | 24-hr Creatinine - Change From Baseline. For the evaluation of the 24-hr creatinine excretion, 24-hour urine sample were collected. Creatinine was measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Definitions: Baseline=Baseline values were defined at visit 2 (Week 0) pre-dose; | Baseline, Week 8 |