Crossover Trial to Assess Efficacy and Safety of Inhaled AQ001S Compared to a Budesonide Suspension in Mild Asthmatics

Study Overview
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Brief Summary
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This is a prospective, active-controlled, randomized, open label, single-center, multiple dose, two-period crossover clinical trial to assess the efficacy, safety and pharmacokinetics of AQ001S compared to a budesonide inhalation suspension (comparator) in adults with mild asthma. Both treatments will be administered by nebulization.

Detailed Description
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Adults patients with mild asthma (18 to 65 years old), who are 'inhaled corticosteroid (ICS)'-naïve for minimum 60 days at Screening Visit will be enrolled in the study. The patients will be treated for 28 days. The primary endpoint will be assessed by a provocative concentration of methacholine that results in a 20% drop (PC20) in the first second forced expiratory volume (FEV1) as determined by methacholine challenge test. The pharmacokinetics (PK) endpoint, i.e. PK profile of budesonide in plasma, and pharmacodynamics (PD) endpoints, i.e. recording of symptom scores, use of reliever drugs as needed, biomarkers of airway inflammation and pulmonary function tests will be assessed during the study.

Official Title
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A Prospective, Active-controlled, Randomized, Open Label, Single-center, Multiple Dose, Crossover Clinical Trial to Assess the Efficacy, Safety and PK of AQ001S Compared to a Budesonide Inhalation Suspension in Adults With Mild Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: AQ001S 0.125 mg/ml
* Drug: Budesonide 0.125 mg/ml inhalation suspension


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body mass index between 18.5 and 29 kg/m2. Documented clinical diagnosis of stable, persistent, asthma for at least 3 months Subjects who are ICS-naïve for minimum 60 days at Screening Visit. Positive methacholine (MCh) challenge test (concentration of MCh provoking an FEV1 fall of 20% [PC20] < 8 mg/ml or dose of MCh provoking an FEV1 fall of 20% [PD20] < 0.2 mg) in the last year. Post-bronchodilator FEV1 at least 80% of the predicted, documented in the last year. Clinical laboratory test results, 12-lead electrocardiogram (ECG), blood pressure and heart rate (supine) within normal reference range or judged to be not clinically significant by the Investigator. Female subjects of childbearing potential should have a negative pregnancy test at Screening Visit and use a highly effective method of contraception. Reliable subjects who are willing to be available for the duration of the clinical trial and willing to comply with clinical trial procedures. Subjects who have the ability to understand the requirements of the clinical trial. Subjects who have given written informed consent. Exclusion Criteria: Current smokers or recent (< 8 weeks) ex-smokers or ex-smokers if > 10 pack-years. Pregnant or breastfeeding female subjects. Inability to carry out pulmonary function testing. FEV1 < 70%. History of near-fatal asthma and/or intensive care unit admission for asthma symptoms. Exacerbations of asthma requiring oral steroids, hospitalization or change in asthma treatment in the previous three months. Evidence of symptomatic chronic or acute respiratory infection in the previous 8 weeks. Diagnosis of chronic obstructive pulmonary disease (COPD) or bronchiectasis. Pulmonary malformations, tuberculosis, cystic fibrosis. History of hypersensitivity or existing contraindication to budesonide or any other Investigational Medicinal Product (IMP) ingredients. Untreated oral candidiasis. Immunosuppressive treatment, including systemic corticosteroids (e.g., oral, parenteral, ocular, nasal), within 28 days before Screening Visit. Use of ICS within 60 days before Screening Visit. Use of anti-leukotrienes, immunoglobulins, beta-blockers, digitalis, amiodarone, antifungals, macrolides, antidepressants, monoamine oxidase inhibitors, antiretroviral drugs, cholinesterase inhibitors, histamine, theophylline, non-steroidal anti-inflammatory drugs, anticholinergic drugs, neuroleptics, curariform drugs, antihistaminic (anti-H1) drugs, calcium channel blockers, long acting beta2-antagonists, mast cell stabilizers (e.g. natrium cromoglycate). History of alcohol or drug abuse. Unstable or life-threatening cardiac disease History or presence of prolonged QT interval (> 470 ms), or any other clinically significant ECG abnormalities as judged by the Investigator based on 12-lead ECG recordings at Screening Visit. Diabetes mellitus. Neuropsychiatric diseases. Clinically relevant laboratory abnormalities at Screening Visit. Blood or plasma donation within 30 days prior to Screening Visit. History or presence of malignancy of any system organ class (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years prior to Screening Visit, regardless of whether there is evidence of local recurrence or metastases. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs, or which may jeopardize the subject in case of participation in the clinical trial. History or presence of any other clinically relevant disease of any major system organ class (e.g. cardiovascular, pulmonary, renal, hepatic, gastrointestinal, reproductive, endocrinological, neurological, psychiatric or orthopedic disease) as judged by the Investigator. Human immunodeficiency virus (HIV) and severe acute respiratory syndrome (SARS)-CoV-2 infections. Subjects who participated in an investigational trial within the 12 weeks prior to the start of the trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AQ001S 0.125 mg/ml<br>AQ001S 0.125 mg/ml is a budesonide inhalation solution administered by nebulization once daily. | Drug: AQ001S 0.125 mg/ml<br>* administered by nebulization once daily<br>* Other names: budesonide inhalation solution 0.125 mg/ml;Drug: Budesonide 0.125 mg/ml inhalation suspension<br>* administered by nebulization once daily<br>* Other names: Budesonide inhalation suspension 0.125 mg/ml;|
| Active Comparator: budesonide inhalation suspension 0.125 mg/ml<br>Budesonide 0.125 mg/ml is a budesonide inhalation suspension administered by nebulization once daily. | Drug: AQ001S 0.125 mg/ml<br>* administered by nebulization once daily<br>* Other names: budesonide inhalation solution 0.125 mg/ml;Drug: Budesonide 0.125 mg/ml inhalation suspension<br>* administered by nebulization once daily<br>* Other names: Budesonide inhalation suspension 0.125 mg/ml;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in PC20 assessed by methacholine (MCh) challenge test | At Visit 1 (baseline), Visit 2 (28-day treatment period 1) and Visit 4 (28-day treatment period 2), a MCh challenge test will be performed, i.e. up to the administration of a concentration of MCh provoking an FEV1 fall of 20% (PC20). FEV1 is measured by spirometry. The change in PC20 from baseline to the end of each period (two periods) will be assessed. | At the end of Period 1 and end of Period 2 (each period is 29 days) | 
| Incidence of Treatment-Emergent Adverse Events | Incidence of Treatment-Emergent Adverse Events as assessed by collection of (Serious) Adverse Events, general and local tolerability and hypothalamic-pituitary-adrenal (HPA) axis function | Over the treatment period, up to 29-day treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in FeNO measurements | Fractional exhaled nitric oxide (FeNO) measurements at Visit 1 (baseline), Visit 2 (treatment period 1) and Visit 4 (treatment period 2) | At the end of Period 1 and Period 2 (each period is 29 days) | 
| Change in blood eosinophil counts | Blood eosinophil counts at Visit 1 (baseline), Visit 2 (treatment period 1) and Visit 4 (treatment period 2) | At the end of Period 1 and Period 2 (each period is 29 days) | 
| Asthma symptoms | Day- and night-time of asthma symptoms over the treatment periods | 29-day treatment period | 
| Single dose budesonide levels in plasma | Budesonide PK level in plasma measured at Visit 1 (baseline) and following the first single dose treatment | 1-day treatment | 
| Budesonide levels in plasma | Budesonide PK level in plasma measured at Visit 2 (end of treatment period 1) and Visit 4 (end of treatment period 2). Blood samples will be performed at pre-dose and at 10, 20, 45, 120, 240 and 360 minutes after IMP administration (abridged PK). | At Day 28 of Period 1 and at Day 28 of Period 2 |