A Study to Assess the Efficacy and Safety of Multiple Dose Levels of AZD7594 Administered Once Daily by Inhalation in Asthmatic Subjects

Study Overview
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Brief Summary
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This study will assess the efficacy and safety of multiple dose levels of AZD7594 administered once daily (QD) by inhalation in a 12-week treatment period on asthma subjects. The activity will be assessed by comparing AZD7594 to placebo. The comparison between active comparator (FF) and placebo will be used for bench marking. The efficacy is assessed by the evaluation of change in trough forced expiratory volume in 1 second (FEV1). The aim is to develop AZD7594 as a once daily inhaled non-steroidal selective GR modulator (SGRM), which may ultimately lead to better disease control of both chronic obstructive pulmonary disease (COPD) and asthma through improved efficacy and compliance. The overall rationale for developing a once daily AZD7594 in a dry powder inhaler (DPI) is to provide a safe and effective future treatment option for both asthma and COPD subjects.

Detailed Description
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This is a randomised, placebo-controlled, double-blind multi center (8 countries: Europe, United States [US], South Africa, and Japan) study conducted on 714 subjects (102 subject per arm) with asthma symptomatic on low dose inhaled corticosteroids (ICS). The study consists of 3 periods: Run-in period (21-28 days; visits 1 to 3) Treatment period (12-week; Visits 4 to 7) Follow-up (1-week; visit 8). The Run-in period consist of 3 visits: Screening visit (1), reversibility visit (2) and randomization visit (3). All subjects will sign an informed consent form (ICF) prior to participating in any study-specific procedures. Subjects found to be eligible at Visit 1 (Screening Visit) will discontinue all asthma medications and switch to low dose budesonide (200 μg twice a day [BID] in Europe and 180 μg BID in US) and rescue medication will be taken as needed. Subjects on long-acting beta agonist (LABA), fixed dose combination ICS/LABA treatment or a long-acting muscarinic antagonist (LAMA) will return for Visit 2 between 2 to 7 days after Visit 1 to have a sufficient wash-out time of their asthma medications. If reversibility criteria are met at Visit 2, subjects will proceed to Visit 3 (Randomization will occur within 21 to 28 days of Visit 1). At Visit 3, subjects who remain symptomatic while on low dose budesonide will be randomized in an overall ratio of 1:1:1:1:1:1:1 to one of 7 possible treatments and will receive inhalation powder via oral route: AZD7594 DPI 55μg [nominal strength]/50 μg [delivered dose] (QD) AZD7594 DPI 99 μg/90 μg QD AZD7594 DPI 198 μg/180 μg QD AZD7594 DPI 396 μg/360 μg QD AZD7594 DPI 792 μg/720 μg QD Placebo for AZD7594 QD FF 100 μg QD (open-label) The follow-up will be done by telephone contact within 7 to 10 days after Visit 7 or last investigational product (IP) intake. The total duration of the study will be between 113 to 135 days for each individual subject and is planned to run approximately 12 months (it should not exceed 18 months).

Official Title
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A Phase 2b Randomised, Double Blind, Placebo-Controlled, Parallel Arm, Multi-Centre Study to Assess Efficacy and Safety of Multiple Dose Levels of AZD7594 DPI Given Once Daily for Twelve Weeks, Compared to Placebo, in Asthmatics Symptomatic on Low Dose ICS

Conditions
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Asthma

Intervention / Treatment
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* Drug: AZD7594 DPI 55μg/50μg.
* Drug: AZD7594 DPI 99 µg/90 µg
* Drug: AZD7594 DPI 198 µg/180 µg
* Drug: AZD7594 DPI 396 µg/360 µg once daily.
* Drug: AZD7594 DPI 792 µg/720 µg
* Drug: Placebo for AZD7594 once daily.
* Drug: FF 100 µg once daily (open-label)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria 1. Provision of informed consent prior to any study-specific procedures 2. Men and women 18 to 85 years of age, inclusive, with body mass index (BMI)≤35 3. Subjects need to be non-smokers or ex-smokers (have quit e cigarettes or other inhaled tobacco products ≥6 months before Visit 1) with a total smoking history of less than 10 pack-years (not applicable for e cigarettes) 4. Documented clinical diagnosis of asthma for ≥6 months before Visit 1 5. Subjects on stable medium to high dose ICS (equivalent of budesonide >400 μg/day) or low to medium dose ICS/LABA for at least 4 weeks prior to screening (Visit 1) (Appendix A, GINA, 2018) 6. Subjects must demonstrate reversibility to inhaled bronchodilators at Visit 2 (a ≥12% and ≥200 mL improvement in FEV1 after administration of a 4 puffs of salbutamol/albuterol) 7. Pre-bronchodilator FEV1 at Visit 3 between 40% and 90% predicted at either -45 or -15 minutes pre-dose 8. At Visit 3, subjects need to be symptomatic on low dose ICS as evidenced by combined daily asthma mean symptom score of >1 over the previous 7 days or SABA use on ≥3 of the last 7 days during the Run-in Period 9. Demonstrate the ability to use the study inhalation device properly 10. Subject able to perform acceptable pulmonary function testing for FEV1 according to American Thoracic Society/European Respiratory Society (ATS/ERS) acceptability criteria 11. Subject is willing and able to follow study procedures and restrictions. Women of child bearing potential (WOCBP) should be stable on their chosen method of highly effective birth control for a minimum of 3 months prior to Visit 1, and willing to use that for the entire duration of the study (from the time they sign the informed consent), and for 1 month after the last dose of IP 12. For optional inclusion in the Gx component of the study, subjects must provide separate informed consent for the genomic sampling and analysis Exclusion criteria Known or suspected hypersensitivity to any of the IPs, including budesonide, or excipients, including lactose Systemic steroid use within the 6 weeks before Visit 1 Concomitant chronic respiratory disease (including current sleep apnea) History or clinical suspicion of any clinically relevant or active disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study, or any other safety concerns in the opinion of the Investigator Use of prohibited medications that cannot be stopped during the entire period of the study (starting Visit 1). Subjects with <80% eDiary compliance during Run in Period at Visit 3 ACQ-5 of ≥3 at Visit 1, Visit 2, or Visit 3 Daily rescue use of SABA ≥12 puffs for ≥3 consecutive days at any time during Run-in Period, before randomisation Any clinically important abnormalities in rhythm, conduction or morphology of the digital ECG at rest and any abnormalities in the digital ECG (at Visit 1 or Visit 3) that, as considered by the Investigator, may interfere with the interpretation of QT interval corrected (QTc) interval changes Prolonged QT interval corrected using Fridericia's formula (QTcF) ≥450 msec based on ECG at Visit 1 or Visit 3; or family history of long QT syndrome PR (PQ) interval prolongation (>240 msec), intermittent second or third degree atrial-ventricular (AV) block or AV dissociation at Visit 1 or Visit 3 Subjects with implantable cardiac defibrillator and subjects with sustained symptomatic ventricular and/or atrial tachyarrhythmia Subjects with unstable angina pectoris or stable angina pectoris classified higher than Canadian Cardiovascular Society Class II, or a myocardial infarction or stroke within 6 months before Visit 1 History of hospitalisation within 12 months before Visit 1 caused by heart failure or a diagnosis of heart failure higher than New York Heart Association Class II Subjects who are positive for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody or human immunodeficiency virus (HIV) at Visit 1 Donation of blood (≥ 450 mL) within 3 months or donation of plasma within 14 days before Visit 1 Suspected poor capability to follow instructions of the study, as judged by the Investigator Previous participation or prior screen failure in the current study, or participation in any other research study within 1 month prior to Visit 1 Subject under treatment with biologicals such as monoclonal antibodies or chimeric biomolecules including omalizumab, mepolizumab, and reslizumab within 6 months or 5 half-lives before Visit 1, whichever is longer Subject treated with any investigational drug within 30 days (or 5 half-lives, whichever is longer) prior to Visit 1 Positive drug screening result that cannot be justified by subject's medical history and its relevant treatment (over-the-counter product or a valid prescription), or history of or current alcohol or drug abuse (including marijuana and marijuana-containing valid prescriptions), as judged by the Investigator Planned in-patient surgery, major dental procedure or hospitalisation during the study Pregnant woman or lactating woman Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff, contract research organisation staff and/or staff at the study centre) Suspicion of Gilbert's syndrome Vulnerable persons (eg, persons kept in detention)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AZD7594 Dose 1<br>The randomized subjects will receive AZD7594 55 μg/50 μg (nominal/delivered dose), oral inhalation via dry powder inhaler (DPI) once daily. | Drug: AZD7594 DPI 55μg/50μg.<br>* A non-steroidal and selective modulator of the GR.<br>|
| Experimental: AZD7594 Dose 2<br>The randomized subjects will receive AZD7594 99 µg/90 µg, oral inhalation via DPI once daily. | Drug: AZD7594 DPI 99 µg/90 µg<br>* A non-steroidal and selective modulator of the GR.<br>|
| Experimental: AZD7594 Dose 3<br>The randomized subjects will receive treatment with AZD7594 198 µg/180 µg, oral inhalation via DPI once daily. | Drug: AZD7594 DPI 198 µg/180 µg<br>* A non-steroidal and selective modulator of the GR.<br>|
| Experimental: AZD7594 Dose 4<br>The randomized subjects will receive treatment with AZD7594 396 µg/360 µg, oral inhalation via DPI once daily. | Drug: AZD7594 DPI 396 µg/360 µg once daily.<br>* A non-steroidal and selective modulator of the GR.<br>|
| Experimental: AZD7594 Dose 5<br>The randomized subjects will receive treatment with AZD7594 792 µg/720 µg, oral inhalation via DPI once daily. | Drug: AZD7594 DPI 792 µg/720 µg<br>* A non-steroidal and selective modulator of the GR.<br>|
| Placebo Comparator: Placebo<br>The randomized subjects will receive AZD7594 matching placebo oral inhalation via DPI once daily. | Drug: Placebo for AZD7594 once daily.<br>* Placebo for AZD7594<br>|
| Active Comparator: Fluticasone Furoate<br>The randomized subjects will receive treatment with fluticasone furoate (FF) oral inhalation via DPI, 100 µg per nominal dose, once daily (open-label). | Drug: FF 100 µg once daily (open-label)<br>* Fluticasone furoate<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Trough FEV1 at Week 12 | Trough value was defined as the mean of the 2 measurements 30 minutes apart (23 hours after last dose) pre-dose for every visit throughout the Treatment Period (Visit 4/Week 2 to Visit 7/Week 12). Baseline was defined as the mean of the 2 measured values before first IP administration (30 minutes apart, at -45 minutes and -15 minutes, before IP administration) on Day 1 (Visit 3). Analyses were based on a Mixed-effects model for repeated measures (MMRM) with treatment, visit, treatment by visit interaction and region as fixed effects, and baseline value and baseline by visit interaction as covariates. To investigate the clinical efficacy of AZD7594 at different dose levels in asthmatics symptomatic on low dose Inhaled corticosteroid (ICS). | At week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Trough FEV1 at Weeks 2, 4, 8 and Average Over the Treatment Period | Trough value was defined as the mean of the 2 measurements 30 minutes apart (23 hours after last dose) pre-dose for every visit throughout the Treatment Period (Visit 4/Week 2 to Visit 7/Week 12). Baseline was defined as the mean of the 2 measured values before first IP administration (30 minutes apart, at -45 minutes and -15 minutes, before IP administration) on Day 1 (Visit 3). Analysis of covariance (ANCOVA) with treatment and region (ie, US, Japan, and RoW) as fixed effects, and baseline as covariate was used for the analysis of average over the Treatment Period. To investigate the clinical efficacy of AZD7594 at different dose levels in asthmatics symptomatic on low dose ICS. | At week 2, 4 and 8 | 
| Change From Baseline in Fractional Exhaled Nitic Oxide (FENO) at Weeks 2, 4, 8, 12 and Average Over the Treatment Period | Baseline was defined as the last value obtained prior to the first dose of investigational product. Analyses were based on a MMRM with change from baseline on the log-scale as the response, treatment, visit, treatment by visit interaction and region as fixed effects, and log-transformed baseline value and baseline by visit interaction as covariates. | At week 2, 4, 8, and 12 | 
| Change From Baseline in Trough Forced Vital Capacity (FVC) at Week 12 and Average Over the Treatment Period | Trough value was defined as the mean of the 2 measurements 30 minutes apart (23 hours after last dose) pre-dose for every visit throughout the Treatment Period (Visit 4/Week 2 to Visit 7/Week 12). Baseline was defined as the mean of the 2 measured values before first IP administration (30 minutes apart, at -45 minutes and -15 minutes, before IP administration) on Day 1 (Visit 3). Analyses were based on a MMRM with treatment, visit, treatment by visit interaction and region as fixed effects, and baseline value and baseline by visit interaction as covariates. | At week 12 | 
| Change From Baseline in Asthma Control Questionnaire -5 (ACQ-5) at Week 12 and Average Over the Treatment Period | Baseline was defined as the ACQ-5 score at Visit 3. Analyses were based on a MMRM with treatment, visit, treatment by visit interaction and region as fixed effects, and baseline value and baseline by visit interaction as covariates. To investigate the clinical efficacy of AZD7594 at different dose levels in asthmatics symptomatic on low dose ICS. Patients are asked to recall how their asthma was during the previous week and to evaluate their symptoms. The questionnaire has 5 items each item is scored on a scale of 0 to 6, where higher scores represent more severe impairment/symptoms. ACQ is the sum of the scores from all 5 items. | At week 12 | 
| Change From Baseline in Average Morning Peak Expiratory Flow (PEF) Over the Treatment Period | Baseline was defined as the average over the 7 days prior to randomisation. Analyses were based on an ANCOVA model with treatment and region as fixed effects, and baseline value as a covariate. To investigate the clinical efficacy of AZD7594 at different dose levels in asthmatics symptomatic on low dose ICS. | Week 0 (7 days prior to randomisation) to Week 12 | 
| Change From Baseline in Average Evening PEF Over the Treatment Period | Baseline was defined as the average over the 7 days prior to randomisation. Analyses were based on an ANCOVA model with treatment and region as fixed effects, and baseline value as a covariate. To investigate the clinical efficacy of AZD7594 at different dose levels in asthmatics symptomatic on low dose ICS. | Week 0 (7 days prior to randomisation) to Week 12 | 
| Change From Baseline in Average Daily Use of Rescue Medication Over the Treatment Period | To investigate the clinical efficacy of AZD7594 at different dose levels in asthmatics symptomatic on low dose ICS. Baseline was defined as the average over the 7 days prior to randomisation. Analyses were based on an ANCOVA model with treatment and region as fixed effects, and baseline value as a covariate. | Week 0 (7 days prior to randomisation) to Week 12 | 
| Change From Baseline in Percent Night-time Awakening Days Over the Treatment Period | To investigate the clinical efficacy of AZD7594 at different dose levels in asthmatics symptomatic on low dose ICS. Baseline was defined as the average over the 7 days prior to randomisation. Analyses were based on an ANCOVA model with treatment and region as fixed effects, and baseline value as a covariate. | Week 0 (7 days prior to randomisation) to Week 12 | 
| Change From Baseline in Average Daily Asthma Symptom Score Over the Treatment Period | To investigate the clinical efficacy of AZD7594 at different dose levels in asthmatics symptomatic on low dose ICS (Full Analysis Set). Baseline was defined as the average over the 7 days prior to randomisation. Analyses were based on an ANCOVA model with treatment and region as fixed effects, and baseline value as a covariate. During the Run-in and Treatment Periods, subjects recorded the severity of their asthma symptoms during night-time and day-time each morning and evening, using the eDiary. Asthma symptom scores during night-time/day-time were assessed by the subject each morning/evening according to the following scoring system and recorded on the eDiary: 0: No asthma symptoms, 1: The subjects were aware of their asthma symptoms but they can easily tolerate the symptoms, 2: asthma was causing enough discomfort to cause problems with sleep, 3: Subjects were unable to sleep/do normal activities because of their asthma. | Week 0 (7 days prior to randomisation) to Week 12 | 
| Change From Baseline in Percent Asthma Control Days Over the Treatment Period | To investigate the clinical efficacy of AZD7594 at different dose levels in asthmatics symptomatic on low dose ICS. Asthma-control days is defined as days with no symptoms, nonight-waking, no reliever use, and no exacerbation. Baseline was defined as the average over the 7 days prior to randomisation. Analyses were based on an ANCOVA model with treatment and region as fixed effects, and baseline value as a covariate. | Week 0 (7 days prior to randomisation) to Week 12 | 
| Change From Baseline in Percent Rescue-free Days Over the Treatment Period | To investigate the clinical efficacy of AZD7594 at different dose levels in asthmatics symptomatic on low dose ICS. A rescue-free day (RFD) was defined as a day where the number of puffs of medication for the relief of asthma symptoms was reported as zero. Baseline was defined as the average over the 7 days prior to randomisation. Analyses were based on an ANCOVA model with treatment and region as fixed effects, and baseline value as a covariate. | Week 0 (7 days prior to randomisation) to Week 12 | 
| Change From Baseline in Percent Symptom-free Days Over the Treatment Period | To investigate the clinical efficacy of AZD7594 at different dose levels in asthmatics symptomatic on low dose ICS. Days without asthma symptoms, or symptom-free days, are defined as a day without asthma symptoms, short-acting β-agonist (SABA) use, systemic corticosteroid use, or need for urgent asthma care. | Week 0 (7 days prior to randomisation) to Week 12 | 
| Observed Maximum Concentration at Steady State (Css,Max) of AZD7594 at Day 84 | Summary of PK parameter Css,mx, observed maximum concentration, of AZD7594 at day 84 in PK analysis set. The presented results are summary statistics of the PK parameter. | Day 84 (pre-dose and 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, 16.0 and 24 h post-dose) | 
| Observed Minimum Concentration at the End of the Dosing Interval (Css,Min) of AZD7594 at Day 84 | Summary of PK parameter Css,min, observed minimum concentration, of AZD7594 at day 84 in PK analysis set. The presented results are summary statistics of the PK parameter. | Day 84 (pre-dose and 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, 16.0 and 24 h post-dose) | 
| Time to Maximum Concentration at Steady State, Taken Directly From the Individual Concentration-time Curve (Tss, Max) of AZD7594 at Day 84 | Summary of PK parameter tss, max, Time to maximum concentration at steady state, taken directly from the individual concentration-time curve, of AZD7594 at day 84 in PK analysis set. The presented results are summary statistics of the PK parameter. | Day 84 (pre-dose and 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, 16.0 and 24 h post-dose) | 
| Time of Last Quantifiable Analyte Concentration (Tlast) of AZD7594 at Day 84 | Summary of PK parameter Tlast, Time of last quantifiable analyte concentration, of AZD7594 at day 84 in PK analysis set. The presented results are summary statistics of the PK parameter. | Day 84 (pre-dose and 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, 16.0 and 24 h post-dose) | 
| Area Under the Plasma Concentration-curve From Time Zero to the Time of Last Quantifiable Analyte Concentration (AUClast) of AZD7594 at Day 84 | Summary of PK parameter AUClast, Area under the plasma concentration-curve from time zero to the time of last quantifiable analyte concentration, of AZD7594 at day 84 in PK analysis set. The presented results are summary statistics of the PK parameter. | Day 84 (pre-dose and 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, 16.0 and 24 h post-dose) | 
| Area Under the Plasma Concentration-curve Within a Dosing Interval (AUCτ) of AZD7594 at Day 84 | Summary of PK parameter AUCτ, Area under the plasma concentration-curve within a dosing interval, of AZD7594 at day 84 in PK analysis set. The presented results are summary statistics of the PK parameter. | Day 84 (pre-dose and 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, 16.0 and 24 h post-dose) | 
| Average Plasma Concentration During a Dosing Interval at Steady State (Css,Avg) of AZD7594 at Day 84 | Summary of PK parameter Css,avg, Average plasma concentration during a dosing interval at steady state, of AZD7594 at day 84 in PK analysis set. The presented results are summary statistics of the PK parameter. | Day 84 (pre-dose and 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, 16.0 and 24 h post-dose) | 
| Dose Normalised Css,Max (Css,Max/D) of AZD7594 at Day 84 | Summary of PK parameter Css,max/D Dose normalised Css,max, of AZD7594 at day 84 in PK analysis set. The presented results are summary statistics of the PK parameter. | Day 84 (pre-dose and 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, 16.0 and 24 h post-dose) | 
| Dose Normalised AUCτ (AUCτ/D) of AZD7594 at Day 84 | Summary of PK parameter AUCτ/D, Dose normalised AUCτ, of AZD7594 at day 84 in PK analysis set. The presented results are summary statistics of the PK parameter. | Day 84 (pre-dose and 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, 16.0 and 24 h post-dose) | 
| Percentage Fluctuation of AZD7594 at Day 84 | To describe the (steady state) PK of AZD7594 in a subset of asthmatics symptomatic on low dose ICS (subset of subjects at EU sites) (PK Analysis Set). The presented results are summary statistics of the PK parameter. No statistical analysis is done for this endpoint. Fluctuation index during a dosing interval estimated as 100*(Css,max - Css,min)/Css,avg (%), where Css,min is the minimum concentration at the end of the dosing interval. | Day 84 (pre-dose and 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, 16.0 and 24 h post-dose) | 
| Change From Baseline in Area Under Plasma Cortisol Concentration-time Curve (AUEC0-24hrs Post Dose), of AZD7594 vs Placebo at Day 84 | Area under the plasma cortisol concentration-time curve from zero to 24 hours after dosing compared to Placebo, of AZD7594 at day 84 in PK analysis set. The presented results are summary statistics of the PK parameter. | At Day -1 (-24 to -12 h prior to the dose on Day 0) and at Day 84 (0 to 12 hours post dose) | 
| Number of Participants With Adverse Events | To evaluate the safety and tolerability of AZD7594 in relation to Placebo in asthmatics symptomatic on low dose ICS | From screening to follow-up period (7 to 10 days after visit 7) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Inhaled non-steroidal glucocorticoid receptor modulator, Asthma, Inhaled corticosteroids., Glucocorticoid receptor (GA) agonists., Chronic obstructive pulmonary disease., Short-acting B2 agonist., Fluticasone furoate.