A Single Dose PD & PK Study With Two Formulations of Abediterol in Patients With Asthma

Study Overview
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Brief Summary
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The purpose of this study is to investigate the pharmacodynamics of single doses of abediterol given by 2 different devices in participants with asthma. Abediterol (AZD0548) is a potential for once daily treatment of asthma and chronic obstructive pulmonary disease (COPD) in fixed dose combination (FDC) with an inhaled corticosteroid (ICS) or a novel anti-inflammatory agent. The aim of the clinical studies is to enable further investigations in participants with asthma and COPD to evaluate and develop abediterol as an effective long acting bronchodilator with an acceptable safety profile compared to other inhaled bronchodilators on the market, for the treatment of asthma and COPD.

Detailed Description
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This is a randomised, double-blinded, double-dummy, placebo-controlled, multi-centre, six-way William's design, crossover study to assess the pharmacodynamics, pharmacokinetics, and safety of abediterol single dose, given by dry powder inhaler or pressurised metered-dose inhaler, in patients with asthma, on inhaled corticosteroids. During the screening period, all patients will take their own baseline inhaled corticosteroid for 2 weeks. Patients on long-acting β2-agonist/ inhaled corticosteroids will be switched over to the respective inhaled corticosteroid monocomponent. Patients will be provided salbutamol as rescue medication for use throughout the study. Abediterol is an investigational product in early stages of clinical development, therefore individual participants in the clinical studies may not have a clinical benefit, especially in view of alternative therapies (bronchodilators) being available for the treatment of asthma and COPD.

Official Title
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A Randomised, Double-Blinded, Double-Dummy, Placebo-Controlled, MultiCentre-, Six-Way, Crossover Study to Assess the Pharmacodynamics, Pharmacokinetics, and Safety of Abediterol Single Dose, Given by Dry Powder Inhaler (DPI) or Pressurised Metered-Dose Inhaler (pMDI), in Patients With Asthma on Inhaled Corticosteroids.

Conditions
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Asthma

Intervention / Treatment
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* Drug: Abediterol 0.156 μg
* Drug: Abediterol 2.5 μg
* Drug: Abediterol 0.05 μg
* Drug: Abediterol 0.156 μg
* Drug: Abediterol 2.5 μg
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of informed consent before any study specific procedures. Men or non-pregnant, non-lactating women 18 to 75 years of age, inclusive. Non-smoker or ex-smoker (quit ≥6months prior to Visit 1) with a total smoking history of ≤10 pack years. Documented clinical diagnosis of asthma for ≥6 months before Visit 1 according to GINA guidelines. On stable dose of ICS or ICS/LABA FDC, for at least 1 month prior to Visit 1, at the doses approved in the country of enrolment. Prebronchodilator FEV1 at Visit 2 ≥40% and ≤85% of predicted (1 repetition of the test is allowed before screen failure). Reversibility to salbutamol (per American Thoracic Society (ATS)/European Respiratory Society (ERS) criteria, 2005 ie, ≥12% and ≥200 mL) at Visit 2 (1 repetition of the test is allowed before screen failure). Demonstrate the ability to use the study inhalation device properly. Able to perform repeated pulmonary function testing for FEV1. Able to read, speak and understand German. Patient must agree to all restrictions during the study. Exclusion Criteria: Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). Participation in another clinical study with an IP during the last 3 months. Known or suspected hypersensitivity to the IP or excipients, including lactose (Note: lactose intolerance is not an exclusion). Systemic steroid use in the 6 weeks before Visit 1. Hospitalization due to asthma in the 6 months prior to Visit 1. Any active pulmonary disease other than asthma. Non-compliance with study procedures in the run in period - as judged by the Investigator. 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). Treatment with any investigational drug within 30 days or 5 half-lives (whichever is longer) prior to Visit 1. Plasma donation within 1 month of screening or any blood donation/loss more than 500 mL during the 3 months prior to Visit 1. Any laboratory abnormality or suspicion of any clinically relevant disease or disorder (on history or examination), including uncontrolled hypertension or uncontrolled diabetes, 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. Known chronic hepatitis or HIV infections at the time of enrolment. Any active malignancy or treatment thereof within the 3 years prior to enrolment. Any clinically important abnormalities in rhythm, conduction, or morphology of the screening 12-lead ECG as judged by the Investigator on the screening ECG. Prolonged QT interval using Fridericia's correction 450 msec for males and 470 msec for females on the screening ECG or family history of long QT syndrome. PR (PQ) interval prolongation (> 240 msec), intermittent second or third degree atrialventricular (AV) block or AV dissociation on the screening ECG. Implantable cardiac defibrillator and patients with sustained symptomatic ventricular and/or atrial tachyarrhythmia. Any contraindication against the use of sympathomimetic drugs as judged by the Investigator. 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 caused by heart failure or a diagnosis of heart failure higher than New York Heart Association Class II. Suspected poor capability to follow instructions of the study, as judged by the Investigator. History of or current alcohol or drug abuse (including marijuana), as judged by the Investigator. Planned in-patient surgery, major dental procedure or hospitalisation during the study. Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff, contract research organisation staff and/or staff at the study site). Vulnerable persons (eg, persons kept in detention). 26 Daily rescue medication (salbutamol) use of ≥ 12 puffs for ≥ 3 consecutive days during the run-in period. 27. Patient who intends to use any concomitant medication not permitted by this protocol or not to meet the restrictions. 28. Patient on treatment with strong CYP3A4 inhibitors such as ketoconazole or itraconazole or CYP3A4 inducers such as rifampin at Visit 1. 29. Procedures for withdrawal of incorrectly enrolled patients.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Abediterol dry powder inhaler 0.156 μg<br>Dry powder for inhalation administered via dry powder inhaler 0.156 μg/inhalation; (1 inhalation) | Drug: Abediterol 0.156 μg<br>* Dry powder for inhalation<br>|
| Experimental: Abediterol dry powder inhaler 2.5 μg<br>Dry powder for inhalation, administered via dry powder, inhaler 2.5 μg/inhalation; (1 inhalation). | Drug: Abediterol 2.5 μg<br>* Dry powder for inhalation<br>|
| Experimental: Abediterol pressurised metered-dose inhaler 0.05μg<br>Pressurised metered-dose, inhaler 0.025 μg/puff; (2 puffs). | Drug: Abediterol 0.05 μg<br>* Pressurised metered-dose inhaler<br>|
| Experimental: Abediterol pressurised metered-dose inhaler 0.156 μg<br>Pressurised metered-dose, inhaler 0.078 μg/puff; (2 puffs). | Drug: Abediterol 0.156 μg<br>* Pressurised metered-dose inhaler<br>|
| Experimental: Abediterol pressurised metered-dose inhaler 2.5μg<br>Pressurised metered-dose inhaler 1.25 μg/puff; (2 puffs). | Drug: Abediterol 2.5 μg<br>* Pressurised metered-dose inhaler<br>|
| Placebo Comparator: Placebo<br>Pressurised metered-dose inhaler (2 puffs) and Dry powder for inhalation administered via dry powder inhaler (1 inhalation). | Other: Placebo<br>* Pressurised metered-dose inhaler and dry powder for inhalation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1). | Baseline for FEV1 was defined as the mean of the two measured values for the corresponding variable (2 measurements 30 min apart, at -45 min and -15 min), prior to the morning investigational product (IP) administration on Day 1 of each treatment period. If both were missing the screening value was used instead. Trough is defined as the mean of the FEV1 values obtained at 23 h and 24 h after the morning IP administration. If one of the values was missing, the other one was used as trough. | 45 mins and 15 mins pre-dose, and 23.00-24.00 h post-dose on Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving a ≥ 200 mL and ≥12% Increase From Baseline in Peak FEV1 on Day 1. | The percentage of patients achieving at least 200 mL and 12% increase from baseline in peak FEV1 on Day 1 of each treatment. The peak was the highest value observed during the 6 hour-period immediately after the IP dose in the morning on Day 1. | Predose and 5 mins, 15 mins, 30 mins, 1 h, 2 h, 4 h and 6 h post-dose on Day 1 | 
| Time to Peak FEV1 at Day 1 | The peak is the highest forced expiratory volume in one second (FEV1) value observed during the 6 hour-period immediately after the IP dose in the morning on Day 1. | 5 mins, 15 mins, 30 mins, 1 h, 2 h, 4 h and 6 h post-dose on Day 1 | 
| Observed Maximum Concentration of Abediterol (Cmax) | Observed maximum concentration (Cmax) of Abediterol, taken directly from the individual concentration-time curve. | Pre-dose, 5, 15, 30, and 45 minutes, at 1, 2.5, 4, 6, 8, 12, 24 and 36 hours after IP administration on Day 1. | 
| Time (h) to Maximum Concentration of Abediterol (Tmax). | Time to maximum concentration (Tmax) of Abediterol (h), taken directly from the individual concentration-time curve. | Pre-dose, 5, 15, 30, and 45 minutes, at 1, 2.5, 4, 6, 8, 12, 24 and 36 hours after IP administration on Day 1. | 
| Terminal Rate Constant of Abediterol (λz) | Terminal rate constant (λz) of Abediterol, estimated by log-linear least square regression of the terminal part of the concentration-time curve. | Pre-dose, 5, 15, 30, and 45 minutes, at 1, 2.5, 4, 6, 8, 12, 24 and 36 hours after IP administration on Day 1. | 
| Terminal Half-life (h) of Abediterol (t½λz) | Terminal half-life (h), estimated as (ln2)/λz (t1/2λz). | Pre-dose, 5, 15, 30, and 45 minutes, at 1, 2.5, 4, 6, 8, 12, 24 and 36 hours after IP administration on Day 1. | 
| AUClast of Abediterol | Area under the plasma concentration-curve of Abediterol from time zero to the time of last quantifiable analyte concentration. | Pre-dose, 5, 15, 30, and 45 minutes, at 1, 2.5, 4, 6, 8, 12, 24 and 36 hours after IP administration on Day 1. | 
| AUC of Abediterol. | Area under the Abediterol concentration-time curve from time zero extrapolated to infinity (AUC). AUC is estimated by AUClast + Clast/λz where Clast is the last observed quantifiable concentration (AUC). PK blood samples were collected 5, 15, 30, and 45 minutes, at 1, 2.5, 4, 6, 8, 12, 24 and 36 hours after IP administration on Day 1 (Note that 24 h and 36 h time-points post-dose correspond to Day 2). | Pre-dose, 5, 15, 30, and 45 minutes, at 1, 2.5, 4, 6, 8, 12, 24 and 36 hours after IP administration on Day 1. | 
| Apparent Plasma Clearance for Abediterol (CL/F). | Apparent plasma clearance for parent drug estimated as dose divided by AUC (CL/F). | Pre-dose, 5, 15, 30, and 45 minutes, at 1, 2.5, 4, 6, 8, 12, 24 and 36 hours after IP administration on Day 1. | 
| Apparent Volume of Distribution for Abediterol at Terminal Phase (Vz/F). | Apparent volume of distribution for parent drug at terminal phase, estimated by dividing the apparent clearance (CL/F) by λz (Vz/F). | Pre-dose, 5, 15, 30, and 45 minutes, at 1, 2.5, 4, 6, 8, 12, 24 and 36 hours after IP administration on Day 1. | 
| Mean Residence Time (MRT) of Abediterol. | Mean residence time (h), calculated by AUMC/AUC, where AUMC is the area under the first moment-time curve (MRT). | Pre-dose, 5, 15, 30, and 45 minutes, at 1, 2.5, 4, 6, 8, 12, 24 and 36 hours after IP administration on Day 1. | 
| Number of Participants With Any Treatment-emergent Adverse Event | All treatment emergent adverse events (TEAEs), including serious AEs. An AE is the development of an undesirable medical condition or the deterioration of a preexisting medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product. An AE was considered a TEAE if it was not present prior to the date of the first dose of IP or was present prior to the date of the first dose of IP, but increased in severity after IP administration. | From screening (Day -14) up to follow-up phone call (14 days after last IP administration). | 
| Number of Participants With Post-baseline Potentially Clinically Significant Abnormalities in Electrocardiogram (ECG) Parameters | Standard 12-lead ECG evaluations were performed prior to IP administration and 1, 4 and 24 h post IP administration at randomisation and after each IP administration. ECGs were recorded after approximately 5 minutes resting in supine position before any blood sampling and spirometry test, preferably always by the same technician for each patient. Clinically significant abnormalities were defined as listed in the table below for QT interval, QTcB, QTcF, QRS interval, PR interval and heart rate (HR). BL incr. = increase from baseline. | Up to last treatment visit (Day 112) | 
| Time to Peak FVC at Day 1 | The peak is the highest forced vital capacity (FVC) value observed during the 6 hour-period immediately after the IP dose in the morning on Day 1. | 5 mins, 15 mins, 30 mins, 1 h, 2 h, 4 h and 6 h post-dose on Day 1 | 
| Percentage of Participants Achieving a ≥ 200 mL and ≥12% Increase From Baseline in Trough FEV1. | The percentage of patients achieving at least 200 mL and 12% increase from baseline in trough forced expiratory volume in one second (FEV1). Trough was defined as the mean of the FEV1 values obtained at 23 hours and 24 hours after the morning IP administration. | Predose and 5 mins, 15 mins, 30 mins, 1 h, 2 h, 4 h and 6 h post-dose on Day 1 | 
| Change From Baseline in Peak FEV1. | The peak is the highest forced expiratory volume in one second (FEV1) value observed during the 6 hour-period immediately after the IP dose in the morning on Day 1. | Predose and 5 mins, 15 mins, 30 mins, 1 h, 2 h, 4 h and 6 h post-dose on Day 1 | 
| Change From Baseline in Normalised FEV1 AUC0-24. | Change from baseline in normalised FEV1 area under the concentration-curve of Abediterol from time zero to 24 hours post-dose. Baseline for FEV1 was defined as the mean of the 2 measured values for the corresponding variable (2 measurements 30 min apart, at -45 min and -15 min before the morning IP administration). If both values were missing, the screening value (pre-bronchodilator FEV1 from Visit 2) was used instead. | 45 mins and 15 mins predose, and 5 mins, 15 mins, 30 mins, 1 h, 2 h, 4 h, 6 h, 12 h, 16 h, 22 h, and 23.00-24.00 h post-dose on Day 1 | 
| Change From Baseline in Normalised FEV1 AUC0-12. | Change from baseline in normalised FEV1 area under the concentration time curve for Abediterol from time zero to 12 hours post-dose. Baseline for FEV1 was defined as the mean of the 2 measured values for the corresponding variable (2 measurements 30 min apart, at -45 min and -15 min before the morning IP administration). If both values were missing, the screening value (pre-bronchodilator FEV1 from Visit 2) was used instead. | 45 mins and 15 mins predose, and 5 mins, 15 mins, 30 mins, 1 h, 2 h, 4 h, 6 h, and 12 h post-dose on Day 1 | 
| Change From Baseline in Normalised FEV1 AUC0-6. | Change from baseline in normalised FEV1 area under the concentration-curve for Abediterol from time zero to 6 hours post-dose. Baseline for FEV1 was defined as the mean of the 2 measured values for the corresponding variable (2 measurements 30 min apart, at -45 min and -15 min before the morning IP administration). If both values were missing, the screening value (pre-bronchodilator FEV1 from Visit 2) was used instead. | 45 mins and 15 mins predose, and 5 mins, 15 mins, 30 mins, 1 h, 2 h, 4 h, and 6 h post dose on Day 1 | 
| Change From Baseline in Normalised FEV1 AUC12-24. | Change from baseline in normalised FEV1 area under the concentration-curve for Abediterol from time 12 hours post-dose to 24 hours post-dose. Baseline for FEV1 was defined as the mean of the 2 measured values for the corresponding variable (2 measurements 30 min apart, at -45 min and -15 min before the morning IP administration). If both values were missing, the screening value (pre-bronchodilator FEV1 from Visit 2) was used instead. | 45 mins and 15 mins predose, and 12 h, 16 h, 22 h, and 23.00-24.00 h post-dose on Day 1 | 
| Change From Baseline in Peak FVC. | Baseline for FVC was defined as the mean of the 2 measured values for the corresponding variable (2 measurements 30 min apart, at -45 min and -15 min before the morning IP administration). If both values were missing, the screening value (pre-bronchodilator FEV1 from Visit 2) was used instead. The peak is the highest forced vital capacity (FVC) value observed during the 6 hour-period immediately after the IP dose in the morning on Day 1. | Predose and 5 mins, 15 mins, 30 mins, 1 h, 2 h, 4 h and 6 h post-dose on Day 1 | 
| Change From Baseline in Trough FVC. | Baseline for FVC was defined as the mean of the two measured values for the corresponding variable (2 measurements 30 min apart, at -45 min and -15 min), prior to the morning investigational product (IP)administration on Day 1 of each treatment period. If both were missing the screening value was used instead. Trough was defined as the mean of the FEV1 values obtained at 23 h and 24 h after the morning IP administration. If one of the values was missing, the other one was used as trough. | 45 mins and 15 mins pre-dose, and 23.00-24.00 h post-dose on Day 1 | 
| Change From Baseline in Normalised FVC AUC0-24. | Change from baseline in normalised FVC area under the concentration curve for Abediterol from time zero to 24 hours post-dose. Baseline for FVC was defined as the mean of the 2 measured values for the corresponding variable (2 measurements 30 min apart, at -45 min and -15 min before the morning IP administration). If both values were missing, the screening value (pre-bronchodilator FVC from Visit 2) was used instead. | 45 mins and 15 mins predose, and 5 mins, 15 mins, 30 mins, 1 h, 2 h, 4 h, 6 h, 12 h, 16 h, 22 h, and 23.00-24.00 h post-dose on Day 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Abediterol, Dry powder inhaler, Pressured metered-dose inhaler, Pharmacokinetic, Pharmacodynamic, Safety