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

Phase 2

Completed

Conditions: Asthma

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

Registration Number: NCT03622112

Lead Sponsor: AstraZeneca

Brief Summary: 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: 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).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 808

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
AZD7594 Dose 3	AZD7594 DPI 198 µg/180 µg	The randomized subjects will receive treatment with AZD7594 198 µg/180 µg, oral inhalation via DPI once daily.
AZD7594 Dose 4	AZD7594 DPI 396 µg/360 µg once daily.	The randomized subjects will receive treatment with AZD7594 396 µg/360 µg, oral inhalation via DPI once daily.
AZD7594 Dose 5	AZD7594 DPI 792 µg/720 µg	The randomized subjects will receive treatment with AZD7594 792 µg/720 µg, oral inhalation via DPI once daily.
AZD7594 Dose 1	AZD7594 DPI 55μg/50μg.	The randomized subjects will receive AZD7594 55 μg/50 μg (nominal/delivered dose), oral inhalation via dry powder inhaler (DPI) once daily.
AZD7594 Dose 2	AZD7594 DPI 99 µg/90 µg	The randomized subjects will receive AZD7594 99 µg/90 µg, oral inhalation via DPI once daily.
Placebo	Placebo for AZD7594 once daily.	The randomized subjects will receive AZD7594 matching placebo oral inhalation via DPI once daily.
Fluticasone Furoate	FF 100 µg once daily (open-label)	The randomized subjects will receive treatment with fluticasone furoate (FF) oral inhalation via DPI, 100 µg per nominal dose, once daily (open-label).

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Trough FEV1 at Week 12	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).

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Asthma Control Questionnaire -5 (ACQ-5) at Week 12 and Average Over the Treatment Period	At week 12	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.
Change From Baseline in Average Evening PEF Over the Treatment Period	Week 0 (7 days prior to randomisation) to Week 12	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.
Area Under the Plasma Concentration-curve Within a Dosing Interval (AUCτ) of AZD7594 at Day 84	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)	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.
Average Plasma Concentration During a Dosing Interval at Steady State (Css,Avg) of AZD7594 at Day 84	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)	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.
Dose Normalised Css,Max (Css,Max/D) of AZD7594 at Day 84	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)	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.
Dose Normalised AUCτ (AUCτ/D) of AZD7594 at Day 84	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)	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.
Percentage Fluctuation of AZD7594 at Day 84	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)	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.
Change From Baseline in Area Under Plasma Cortisol Concentration-time Curve (AUEC0-24hrs Post Dose), of AZD7594 vs Placebo at Day 84	At Day -1 (-24 to -12 h prior to the dose on Day 0) and at Day 84 (0 to 12 hours post dose)	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.
Number of Participants With Adverse Events	From screening to follow-up period (7 to 10 days after visit 7)	To evaluate the safety and tolerability of AZD7594 in relation to Placebo in asthmatics symptomatic on low dose ICS
Change From Baseline in Trough FEV1 at Weeks 2, 4, 8 and Average Over the Treatment Period	At week 2, 4 and 8	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.
Change From Baseline in Fractional Exhaled Nitic Oxide (FENO) at Weeks 2, 4, 8, 12 and Average Over the Treatment Period	At week 2, 4, 8, and 12	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.
Change From Baseline in Trough Forced Vital Capacity (FVC) at Week 12 and Average Over the Treatment Period	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 MMRM with treatment, visit, treatment by visit interaction and region as fixed effects, and baseline value and baseline by visit interaction as covariates.
Change From Baseline in Average Morning Peak Expiratory Flow (PEF) Over the Treatment Period	Week 0 (7 days prior to randomisation) to Week 12	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.
Change From Baseline in Percent Night-time Awakening Days Over the Treatment Period	Week 0 (7 days prior to randomisation) to Week 12	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.
Change From Baseline in Average Daily Use of Rescue Medication Over the Treatment Period	Week 0 (7 days prior to randomisation) to Week 12	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.
Change From Baseline in Average Daily Asthma Symptom Score Over the Treatment Period	Week 0 (7 days prior to randomisation) to Week 12	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.
Change From Baseline in Percent Asthma Control Days Over the Treatment Period	Week 0 (7 days prior to randomisation) to Week 12	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.
Change From Baseline in Percent Rescue-free Days Over the Treatment Period	Week 0 (7 days prior to randomisation) to Week 12	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.
Change From Baseline in Percent Symptom-free Days Over the Treatment Period	Week 0 (7 days prior to randomisation) to Week 12	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.
Observed Maximum Concentration at Steady State (Css,Max) of AZD7594 at Day 84	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)	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.
Observed Minimum Concentration at the End of the Dosing Interval (Css,Min) of AZD7594 at Day 84	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)	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.
Time to Maximum Concentration at Steady State, Taken Directly From the Individual Concentration-time Curve (Tss, Max) of AZD7594 at Day 84	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)	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.
Time of Last Quantifiable Analyte Concentration (Tlast) of AZD7594 at Day 84	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)	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.
Area Under the Plasma Concentration-curve From Time Zero to the Time of Last Quantifiable Analyte Concentration (AUClast) of AZD7594 at Day 84	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)	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.