Efficacy and Safety of CHF 6532 in Patients With Uncontrolled Severe Eosinophilic Asthma

Study Overview
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Brief Summary
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The purpose of this phase III Study is to demonstrate the efficacy of at least one dose of CHF 6532 on moderate and severe asthma exacerbations rate compared to placebo.

Detailed Description
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This is a phase III, randomised, double-blind, placebo controlled multinational, multicentre, 4-arm parallel-group, study evaluating 3 doses of CHF 6532. The effect of CHF 6532 compared to Placebo on severe asthma exacerbations over 52 weeks of treatment will be assessed. The effect of CHF 6532 compared to Placebo in terms of change from baseline in pre-dose morning Forced Expiratory Volume in the first second (FEV1) as well as on St. George's Respiratory Questionnaire (SGRQ), Asthma Control Questionnaire (ACQ-5) and Asthma Quality of Life Questionnaire (AQLQ+12), at Week 52 will be assessed . The inter-subject variability in the drug exposure and the effect of selected covariates on Pharmacokinetics (PK) will be investigated. The impact of study treatments on health economics outcomes will be also investigated. Standard safety assessments will be conducted during the Study, including electrocardiograms (ECGs), vital signs and laboratory tests. Approximately 1392 severe eosinophilic asthmatic adult subjects and additional 248 severe eosinophilic asthmatic adolescent subjects will be randomised in about 150 investigational sites.

Official Title
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A 52 Week, Randomised, Double Blind, Multinational, Multicentre, 4-arm Parallel Group Trial to Assess the Efficacy and Safety of 3 Doses of CHF 6532 Compared to Placebo on Top of Standard of Care in Patients With Uncontrolled Severe Eosinophilic Asthma

Conditions
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Asthma; Eosinophilic

Intervention / Treatment
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* Drug: Treatment A
* Drug: Treatment B
* Drug: Treatment C
* Drug: Treatment D


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects aged ≥12 years and ≤75 years with a diagnosis of asthma [according to Global Initiative for Asthma (GINA)] for a period of at least 24 months prior to screening. Subjects treated according to GINA step 4/5 with stable high-dose inhaled corticosteroids (ICS) plus a long-acting β2 agonist (LABA) 2 Asthma exacerbations history. A positive response to a reversibility test at screening. Subjects with evidenced eosinophilic airway inflammation at screening visit. Subjects with uncontrolled asthma as evidenced by ACQ-5 score ≥1.5 at screening and randomisation visits. Subjects with co-operative attitude and ability to perform all trial related procedures. Ability of patient to swallow tablets. Exclusion Criteria: Pregnant or lactating women and all women of childbearing potential unless are using a highly effective birth control method. Run-in compliance < 50% at randomisation Hospitalisation, emergency room admission or use of systemic corticosteroids for an asthma exacerbation or respiratory tract infection in the 4 weeks prior to screening visit or during the run-in period. Subjects with a history of near fatal asthma or of a past hospitalisation for asthma in intensive care unit which, in the judgement of the investigator, may place the subjects at undue risk. Subjects with a history of more than 2 episodes of confirmed bacterial lower respiratory tract infection within the year prior to screening or with a bacterial lower respiratory tract infection during the run-in. History of diagnosis of Chronic Obstructive Pulmonary Disease (COPD), cystic fibrosis, bronchiectasis or alpha-1 antitrypsin deficiency, or any other significant lung disease which may interfere with study evaluations. Subjects with a marked resting baseline prolongation of mean QTc interval. Subjects with a family history of long QT Syndrome. Subjects with hypokalemia at screening. Subjects who have known clinically significant cardiovascular conditions. Subjects with a history of symptoms or significant neurological disease. Subjects with clinically significant abnormal serum biochemistry, haematology (not associated with the study indication) at screening according to the investigators judgement. Current smokers or ex-smokers with total cumulative exposure ≥10 pack-years or having stopped smoking less than one year prior to screening visit. Subjects with historical or current evidence of uncontrolled concurrent disease. Subjects with a history of hypersensitivity and/or idiosyncrasy to any of the test compounds or excipients employed in this study. Subjects receiving treatment with any drug known to have a well-defined potential for hepatotoxicity within the previous 3 months before the screening visit. Subjects receiving treatment with one or more drugs listed in the prohibited medication section. Regular use of oral or systemic corticosteroids for diseases other than asthma within the past 12 months or any intra-articular or short-acting, intramuscular corticosteroid within 1 month or intramuscular, long-acting depot corticosteroids within 3 months prior to screening. Subjects with severe hepatitis chronic active hepatitis or evidence of uncontrolled chronic liver disease. Subjects with Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) at screening ≥2x Upper Limit of Normal. Subjects with other severe acute or chronic medical or malignancy or psychiatric conditions which are uncontrolled 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, would make the subjects inappropriate for entry into this study. Subjects with a history of lung volume resection. Subjects with a diagnosis of lung cancer or a history of lung cancer. Subjects with active cancer or a history of cancer (other than lung) with less than 5 years disease free survival time (whether or not there is evidence of local recurrence or metastases). Localised carcinoma (e.g. basal cell carcinoma, in situ carcinoma of the cervix adequately treated) is acceptable. Subjects who have received an investigational drug within 30 days (60 days for biologics) or five half-lives (whichever is greater) prior to screening visit. Subjects with a history of alcohol or drug abuse within two years prior to screening visit. Subjects with major surgery in the 3 months prior to screening visit or planned surgery during the trial. Subjects mentally or legally incapacitated or subjects accommodated in an establishment as a result of an official or judicial order.

Ages Eligible for Study
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Minimum Age: 12 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Placebo controlled
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment A<br>Administration of CHF 6532 Dose #1 | Drug: Treatment A<br>* Tablet of CHF 6532<br>* Other names: CHF 6532;|
| Experimental: Treatment B<br>Administration of CHF 6532 Dose #2 | Drug: Treatment B<br>* Tablet of CHF 6532<br>* Other names: CHF 6532;|
| Experimental: Treatment C<br>Administration of CHF 6532 Dose #3 | Drug: Treatment C<br>* Tablet of CHF 6532<br>* Other names: CHF 6532;|
| Placebo Comparator: Treatment D<br>Administration of CHF 6532 Placebo | Drug: Treatment D<br>* Tablet of CHF 6532 placebo<br>* Other names: CHF 6532;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of CHF 6532 on moderate and severe asthma exacerbations rate | Rate of moderate and severe asthma exacerbations during the treatment period with CH 6532 (3 doses tested) or Placebo | Over 52 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of CHF 6532 on severe asthma exacerbations compared to Placebo | Assessment of time to first moderate or severe exacerbation, and of time to first severe exacerbation | Over 52 weeks of treatment | 
| Effect of CHF 6532 compared to Placebo in terms of change from baseline in pre-dose morning FEV1 (Forced Expiratory Volume in 1 second) | Assessment of change from Baseline in pre-dose FEV1 | At Week 52 | 
| Effect of CHF 6532 compared to Placebo in terms of change from baseline on St. George's Respiratory Questionnaire (SGRQ) | Assessment of change from Baseline in SGRQ scores (Score range from 0 to 100, with lower scores corresponding to better health) | At Week 52 | 
| Effect of CHF 6532 compared to Placebo in terms of change from baseline on Asthma Control Questionnaire (ACQ-5) | Assessment of change from Baseline in ACQ-5 scores (Score range from 0=no impairment to 6= maximum impairment) | At Week 52 | 
| Effect of CHF 6532 compared to Placebo in terms of change from baseline on Asthma Quality of Life Questionnaire (AQLQ+12) | Assessment of change from Baseline in AQLQ+12 scores (Score range from 1=severe impairment to 7= no impairment) | At Week 52 | 
| Pharmacokinetic analysis of CHF 6532 | Assessment of the area Under of the plasma concentration-time curve from 0 to the last quantifiable concentration (AUC0-t) of CHF 6532 | At baseline and 3 months | 
| Pharmacokinetic analysis of CHF 6532 | Assessment of the area Under of the plasma concentration versus time curve observed from time 0 up to 8 hours post-dose (AUC0-8h) of CHF 6532 | At baseline and 3 months | 
| Pharmacokinetic analysis of CHF 6532 | Assessment of the value of the maximum plasma concentration (Cmax) of CHF 6532 | At baseline and 3 months | 
| Pharmacokinetic analysis of CHF 6532 | Assessment of the time of the maximum plasma concentration (tmax) of CHF 6532 | At baseline and 3 months |