A Multiple Dosing (14 Days) Study to Assess Efficacy and Safety of Three Dose Levels of AZD7594, Given Once Daily by Inhalation, in Patients With Mild to Moderate Asthma

AstraZeneca54 enrolled

Overview

This study will be a randomised, double-blind, multiple dose (14 days), placebo-controlled, multi-center study to assess efficacy and safety of three dose levels of AZD7594, given once daily by inhalation, in patients with mild to moderate asthma.

This is a randomized, double-blind, multiple dosing (14 ± 1 days), placebo-controlled, incomplete block crossover, multi-center study to assess efficacy and safety of 3 dose levels of AZD7594, given once daily by inhalation, in patients with mild to moderate asthma. This multi-center study will be conducted at multiple sites in Europe. It is planned that approximately 48 patients with mild to moderate asthma will be randomized into the study

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Conditions

Asthma Efficacy Safety

Interventions

800 μg AZD7594 once dailyDRUG

Once daily dosing of 800 µg AZD7594 for 14 days; each dose of AZD7594 inhalation powder will be administered via a dry powder monodose inhaler as 2 hard capsules with 2 inhalations per capsule

250 µg AZD7594 once dailyDRUG

Once daily dosing of 800 µg AZD7594 for 14 days; each dose of AZD7594 inhalation powder will be administered via a dry powder monodose inhaler as 2 hard capsules with 2 inhalations per capsule

58 µg AZD7594 once dailyDRUG

Once daily dosing of 800 µg AZD7594 for 14 days; each dose of AZD7594 inhalation powder will be administered via a dry powder monodose inhaler as 2 hard capsules with 2 inhalations per capsule

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Body mass index of 18 to 35 kg/m2 * Men and women 18 to 75 years of age, inclusive * Patients need to be non-smokers or ex-smokers (quit ≥ 6 months before the Visit 1) with total smoking history of \< 10 pack years * Documented clinical diagnosis of asthma for ≥ 6 months before the Visit 1 * Patients on low-dose inhaled corticosteroids (ICS) (equivalent of budesonide ≤ 400 μg per day) or low-dose ICS/long-acting β-2 agonist (LABA), or not on any inhaled steroids, or patients on montelukast * Patients should be controlled on low dose budesonide during the first 14 ±2 days of Run-in Part 1, i.e., they need to have ACQ-5 of ≤ 1.5 at Visit 2. * Prebronchodilator FEV1 at Visit 3 should be between 40% and 90% of predicted (mean of 2 predose measurements taken 30 minutes apart). * All patients need to have FeNO concentrations of ≥ 25 parts per billion at Visit 3 * Demonstrate the ability to use the study inhalation device properly * Women must be of nonchildbearing potential defined as meeting 1 of the following criteria: * Permanently or surgically sterilized, including hysterectomy and/or bilateral oophorectomy and/or bilateral salpingectomy * Postmenopausal; aged ≤ 50 years and have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone and follicle stimulating hormone levels in the postmenopausal range * Postmenopausal; aged \> 50 years and have been amenorrheic for 12 months or more, following cessation of all exogenous hormonal treatments * Male patients should be willing to use a condom to prevent pregnancy and exposure of a female partner to AZD7594 and should refrain from donating sperm or fathering a child from the first day of dosing until 3 months after the last dose of IMP. Exclusion Criteria: * Known or suspected hypersensitivity to the IMPs or excipients, including lactose * Systemic steroid use in the 6 weeks before Visit 1 * Any active disease other than asthma * Patients on medium to high-dose ICS (equivalent of budesonide \> 400 μg per day) or on inhaled anticholinergic combination within the 6 weeks prior to Visit 1 * Compliance with the eDiary of at least 80% of the days is expected in both Run-in and Treatment Periods. Patients with \< 80% eDiary compliance during Run-in Periods would not be randomized * Treatment with biologicals such as monoclonal antibodies or chimeric biomolecules including omalizumab within 6 months or 5 half-lives before Visit 1, whichever is longer * History or clinical suspicion of any clinically relevant disease or disorder which, in the opinion of the Investigator, may either put the patient at risk because of participation in the study, or influence the results or the patient's ability to participate in the study, or any other safety concerns in the opinion of the Investigator * ACQ-5 ≥ 3 at any time between Visits 1 and 3 * Any contraindication against the use of vagolytic or sympathomimetic drugs as judged by the Investigator. * Patients with hepatitis B surface antigen, hepatitis C virus antibody or human immunodeficiency virus (HIV) * Donation of blood (≥ 450 mL) within 3 months or donation of plasma within 14 days before Visit 1 * Pregnant woman or a nursing mother * Suspicion of Gilbert's syndrome * Vulnerable persons (e.g., persons kept in detention) * ACQ-5 of ≥ 3 or daily rescue use of ≥ 12 puffs for ≥ 3 consecutive days during the enrollment period * Hypersensitivity to the active substance or to any of the excipients of the Run-in medication (i.e., budesonide)

Locations (10)

Research Site

Sofia, Bulgaria

Research Site

Berlin, Germany

Research Site

Berlin, Germany

Research Site

Berlin, Germany

Outcomes

Primary Outcomes

Efficacy of AZD7594 by Assessment of the Change From Baseline in Morning Trough Forced Expiratory Volume in 1 Second (FEV1) on Day 15

Comparison of the efficacy of AZD7594 in terms of change from baseline in morning trough forced expiratory volume in 1 second (FEV1) on Day 15 (defined as the average of the values at 23:00 and 23:30 hours after last dose of investigational medicinal product \[IMP\] on Day 14) with placebo

Time frame: On Day 1 (pre-dose) and on Day 15 in each period

Secondary Outcomes

Efficacy of AZD7594 by Assessment of the Change From Baseline in Fractional Exhaled Nitric Oxide (FeNO) on Day 8

The efficacy of AZD7594 was assessed in terms of change from baseline in fractional exhaled nitric oxide (FeNO) on Day 8

Time frame: On Day 1 (pre-dose) and on Day 8 in each period

Efficacy of AZD7594 by Assessment of the Change From Baseline in Fractional Exhaled Nitric Oxide (FeNO) on Day 15

The efficacy of AZD7594 was assessed in terms of change from baseline in fractional exhaled nitric oxide (FeNO) on Day 15

Time frame: On Day 1 (pre-dose) and on Day 15 in each period

Efficacy of AZD7594 by Assessment of the Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) on Day 8

The efficacy of AZD7594 was assessed in terms of change from baseline in morning trough forced expiratory volume in 1 second (FEV1) on Day 8 (defined as the average of the values at 23:00 and 23:30 hours after last dose of investigational medicinal product \[IMP\] on Day 7)

Time frame: On Day 1 (pre-dose) and on Day 8 (pre-dose) in each period

Efficacy of AZD7594 by Assessment of the Change From Baseline in Trough Forced Vital Capacity (FVC) on Day 15

The efficacy of AZD7594 was assessed in terms of change from baseline in morning trough forced vital capacity (FVC) on Day 15 (defined as the average of the values at 23:00 and 23:30 hours after last dose of investigational medicinal product \[IMP\] on Day 14)

Data from ClinicalTrials.gov

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Placebo once dailyDRUG

Once daily dosing of Placebo to AZD7594 for 14 days; each dose of Placebo inhalation powder will be administered via a dry powder monodose inhaler as 2 hard capsules with 2 inhalations per capsule

SalbutamolDRUG

Inhalation as needed

Research Site

Frankfurt, Germany

Research Site

Großhansdorf, Germany

Research Site

Hamburg, Germany

Research Site

Hamburg, Germany

Research Site

Lübeck, Germany

Research Site

Wiesbaden, Germany

Time frame: On Day 1 (pre-dose) and on Day 15 (pre-dose) in each period

Efficacy of AZD7594 by Assessment of the Change From Baseline in Trough Forced Vital Capacity (FVC) on Day 8

The efficacy of AZD7594 was assessed in terms of change from baseline in morning trough forced vital capacity (FVC) on Day 8 (defined as the average of the values at 23:00 and 23:30 hours after last dose of investigational medicinal product \[IMP\] on Day 7)

Time frame: On Day 1 (pre-dose) and on Day 8 (pre-dose) in each period

Efficacy of AZD7594 by Assessment of the Change From Baseline in Morning Peak Expiratory Flow (mPEF) Before Administration Over the Treatment Period

The efficacy of AZD7594 was assessed in terms of change from baseline in morning peak expiratory flow (mPEF) before administration of the investigational medicinal product (IMP) in each treatment period. The first PEF measurement was on the evening of Visit 1. Every morning and every evening after Visit 1, patients were required to perform 3 maneuvers for PEF assessment. The highest value from among the 3 assessments was marked as mPEF with the date and time of the measurement. The final PEF assessment was done on the morning of Visit 11 (Day 15 of Treatment Period 3).

Time frame: Every morning at pre-dose from Day 1 to Day 15

Efficacy of AZD7594 by Assessment of the Change From Baseline in Evening Peak Expiratory Flow (ePEF) Before Administration Over the Treatment Period

The efficacy of AZD7594 was assessed in terms of change from baseline in evening peak expiratory flow (ePEF) in each treatment period. The first PEF measurement was on the evening of Visit 1. Every morning and every evening after Visit 1, patients were required to perform 3 maneuvers for PEF assessment. The highest value from among the 3 assessments was marked as ePEF together with the date and time of the measurement. The final PEF assessment was done on the morning of Visit 11 (Day 15 of Treatment Period 3).

Time frame: Every evening from Day 1 to Day 14 in each period

Efficacy of AZD7594 by Assessment of the Change From Baseline in Average Daily Use of Rescue Salbutamol Over the Treatment Period

The efficacy of AZD7594 was assessed in terms of change from baseline in average daily use of salbutamol (each morning and evening) in each treatment period.

Time frame: Every day from Day 1 to Day 15 (from evening of Day 1 to morning of Day 15)

Efficacy of AZD7594 by Assessment of the Change From Baseline to Day 15 in Asthma Control Questionnaire-5

The efficacy of AZD7594 was assessed in terms of change from baseline to Day 15 in Asthma Control Questionnaire-5 in each treatment period. Five questions were asked and each question was scored on a scale of 0 to 6, where a higher score represents a more severe impairment/symptom. The ACQ-5 score at a given visit was defined as the average of the scores given for each of the questions, calculated as ACQ-5 score = Sum of 5 scores/5.

Time frame: At baseline and on Day 15 in each period

Efficacy of AZD7594 by Assessment of the Change From Baseline to Day 8 in Asthma Control Questionnaire-5

The efficacy of AZD7594 was assessed in terms of change from baseline to Day 15 in Asthma Control Questionnaire-5 in each treatment period. Five questions were asked and each question was scored on a scale of 0 to 6, where a lower score represents a more severe impairment/symptom. The ACQ-5 score at a given visit was defined as the average of the scores given for each of the questions, calculated as ACQ-5 score = Sum of 5 scores/5.

Time frame: At baseline and on Day 8 in each period

Efficacy of AZD7594 by Assessment of Night-time Awakenings

The efficacy of AZD7594 was assessed in terms of change in nighttime awakenings in each treatment period. The patients were asked to answer 'Yes' or 'No' to the question of "Did your asthma cause you to wake up last night?". If yes, the number and percentage of days that had a night-time awakening were determined for each of the study periods.

Time frame: At baseline and from Day 2 to Day 15 in each period

Efficacy of AZD7594 by Assessment of Daily Symptom Score

The efficacy of AZD7594 was assessed in terms of change in daily symptom score from baseline to average of treatment period post dose (Day 1-14) in each treatment period. Severity scores for asthma symptoms were recorded twice daily, once in the morning and once in the evening with the scoring system of 0-no asthma symptoms, 1-toleratable asthma symptoms, 2-discomfort asthma symptoms with normal activities (or with sleep) and 3-asthma symptoms with impaired normal activities (or to sleep).

Time frame: At baseline and from Day 1 to Day 14 in each period

Efficacy of AZD7594 by Assessment of Asthma Control Days

The efficacy of AZD7594 was assessed in terms of amount of asthma control days in each treatment period. An asthma control day was defined as a day with asthma symptom score = 0, a night with no awakenings due to asthma symptoms and a day with no use of rescue medication. A given calendar day was defined as an asthma control day if it fulfills the criteria for a symptom-free day and for a rescue medication-free day

Time frame: At baseline and from Day 1 to Day 14 post-dose in each period

Number of Participants With Adverse Events

Assessment of safety and tolerability of three dose levels of AZD7594 in participants with mild to moderate asthma. IP referred to investigational product.

Time frame: From Screening to Follow-up (these two examinations are up to 165 days apart)

Rate and Extent of Absorption of Three Dose Levels of AZD7594 by Assessment of Cmax of AZD7594

Comparison of Cmax (maximum observed plasma concentration) of AZD7594 on Day 1 of each treatment period; up to 6 samples were collected in each period (i.e. in participants with intensive pharmacokinetic assessments, at pre-dose and 15 and 30 minutes, and 1, 2, and 4 h post-dose)

Time frame: On Day 1 in each period (in participants with intensive pharmacokinetic assessments, at pre-dose and 15 and 30 minutes, and 1, 2, and 4 h post-dose)

Rate and Extent of Absorption of Three Dose Levels of AZD7594 by Assessment of AUC(0-4) of AZD7594

Comparison of AUC(0-4) (Area under the plasma concentration-time curve from time zero to 4 hours after administration) of AZD7594 on Day 1 of each treatment period; up to 6 samples were collected in each period (i.e. in participants with intensive pharmacokinetic assessments, at pre-dose and 15 and 30 minutes, and 1, 2, and 4 h post-dose).

Time frame: On Day 1 in each period (in participants with intensive pharmacokinetic assessments, at pre-dose and 15 and 30 minutes, and 1, 2, and 4 h post-dose)

Rate and Extent of Absorption of Three Dose Levels of AZD7594 Following Multiple Dose Administration by Assessment of Cmax,ss of AZD7594

Comparison of Cmax,ss (observed maximum plasma concentration at steady state) of AZD7594 on Day 14 of each treatment period; up to 10 samples were collected in each period (i.e. in participants with intensive pharmacokinetic assessments, at pre-dose and 15 and 30 minutes, and 1, 2, 4, 8, 12, 16 and 24 h post-dose)

Time frame: On Day 14 in each period (in participants with intensive pharmacokinetic assessments, at pre-dose and 15 and 30 minutes, and 1, 2, 4, 8, 12, 16 and 24 h post-dose)

Rate and Extent of Absorption of Three Dose Levels of AZD7594 Following Multiple Dose Administration by Assessment of AUC(0-24) of AZD7594

Comparison of AUC(0-24) (Area under the plasma concentration-time curve from time zero to 24 hours after administration) of AZD7594 on Day 14 of each treatment period; up to 10 samples were collected in each period (i.e. in participants with intensive pharmacokinetic assessments, at pre-dose and 15 and 30 minutes, and 1, 2, 4, 8, 12, 16 and 24 h post-dose)

Time frame: On Day 14 in each period (in participants with intensive pharmacokinetic assessments, at pre-dose and 15 and 30 minutes, and 1, 2, 4, 8, 12, 16 and 24 h post-dose)

Rate and Extent of Absorption of Three Dose Levels of AZD7594 Following Multiple Dose Administration by Assessment of AUC(0-last) of AZD7594

Comparison of AUC(0-last) (Area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration (Day 1 and Day 14)) of AZD7594 (i.e. in participants with intensive pharmacokinetic assessments)

Time frame: On Day 1 and Day 14 in each period (in participants with intensive pharmacokinetic assessments, on Day 1 at pre-dose and 15 and 30 minutes, and 1, 2 and 4 h post-dose, on Day 14 at pre-dose and 15 and 30 minutes, and 1, 2, 4, 8, 12, 16 and 24 h post-dose)

Rate and Extent of Absorption of Three Dose Levels of AZD7594 by Assessment of Tmax of AZD7594

Comparison of tmax (time to reach maximum plasma concentration) of AZD7594 on Day 1 of each treatment period; up to 6 samples were collected in each period (i.e. in participants with intensive pharmacokinetic assessments, at pre-dose and 15 and 30 minutes, and 1, 2, and 4 h post-dose)

Time frame: On Day 1 in each period (in participants with intensive pharmacokinetic assessments, at pre-dose and 15 and 30 minutes, and 1, 2, and 4 h post-dose)

Rate and Extent of Absorption of Three Dose Levels of AZD7594 Following Multiple Dose Administration by Assessment of Tmax,ss of AZD7594

Comparison of tmax,ss (time to reach maximum plasma concentration at steady state) of AZD7594 on Day 14 of each treatment period; up to 10 samples were collected in each period (i.e. in participants with intensive pharmacokinetic assessments, at pre-dose and 15 and 30 minutes, and 1, 2, 4, 8, 12, 16 and 24 h post-dose)

Time frame: On Day 14 in each period (in participants with intensive pharmacokinetic assessments, at pre-dose and 15 and 30 minutes, and 1, 2, 4, 8, 12, 16 and 24 h post-dose)

Rate and Extent of Absorption of Three Dose Levels of AZD7594 Following Multiple Dose Administration by Assessment of Cavg,ss of AZD7594

Comparison of Cavg,ss (average plasma concentration during a dosing interval at steady state) of AZD7594 on Day 14 of each treatment period; up to 10 samples were collected in each period (i.e. in participants with intensive pharmacokinetic assessments, at pre-dose and 15 and 30 minutes, and 1, 2, 4, 8, 12, 16 and 24 h post-dose)

Time frame: On Day 14 in each period (in participants with intensive pharmacokinetic assessments, at pre-dose and 15 and 30 minutes, and 1, 2, 4, 8, 12, 16 and 24 h post-dose)

Rate and Extent of Absorption of Three Dose Levels of AZD7594 Following Multiple Dose Administration by Assessment of Cmax/D of AZD7594

Comparison of Cmax/D (dose-normalized Cmax) of AZD7594

Time frame: On Day 1 in each period

Rate and Extent of Absorption of Three Dose Levels of AZD7594 Following Multiple Dose Administration by Assessment of AUC(0-24)/D of AZD7594

Comparison of AUC(0-24)/D (dose-normalized AUC(0-24)) of AZD7594

Time frame: On Day 14 in each period

Rate and Extent of Absorption of Three Dose Levels of AZD7594 Following Multiple Dose Administration by Assessment of Cmin of AZD7594

Comparison of steady-state minimum (pre-dose) concentration (Cmin) of AZD7594 in each treatment period

Time frame: On Day 14 at pre-dose in each period