Trial Outcomes & Findings for A Study to Assess the Efficacy and Safety of Multiple Dose Levels of AZD7594 Administered Once Daily by Inhalation in Asthmatic Subjects (NCT NCT03622112)

The study was conducted in 92 sites in 8 countries; Bulgaria, Germany, Hungary, Poland, and Ukraine, United States (US), South Africa, and Japan. In this study, 806 patients (including 82 Japanese patients) were randomised. For sites in the US, no patients were randomised to the AZD7594 792 μg/720 μg once daily (QD) treatment arm.

Subjects attended a Screening Visit within 28 days before receiving their first dose. All subjects underwent inclusion exclusion criteria assessment and all eligible subjects signed the informed consent before undergoing any study related procedures. One patient in the AZD7594 50 μg treatment arm did not receive any treatment and was randomised in error (protocol deviation).

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

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

To evaluate the safety and tolerability of AZD7594 in relation to Placebo in asthmatics symptomatic on low dose ICS