Relative Bioavailability Study With Abediterol Administered Via Three Different Inhalation Devices in Healthy Volunteers.

An Open-label, Single-center, Randomized, 4-period, Single Dose, Crossover Study to Assess the Relative Bioavailability of Abediterol Inhaled Via Two Different Nebulizers and Via Dry Powder Inhaler in Healthy Subjects.

The study is intended to assess the relative bioavailability of 2 different abediterol nebulised formulations (test) and the dry powder formulation (reference). The study results will provide information on the pharmacokinetic (PK) profile following use of the 3 devices to be used in further clinical development.

Study Overview

• Status: Terminated
• Conditions: Chronic Obstructive Pulmonary Disease
• Intervention / Treatment: Drug: Abediterol (2.4 μg); Drug: Abediterol (2.4 μg); Drug: Abediterol (4.8 μg); Drug: Abediterol (2.5 μg)

Detailed Description

This study will be an open-label, randomized, 4-period, single-dose, single-center, crossover study with a William's design in healthy subjects (males).

The study will comprise:

1. A screening period of maximum 28 days;
2. Four treatment periods during which subjects will be resident prior to the evening meal the night before dosing with abediterol (Day -1) until at least 48 hours following dosing for collection of PK samples; discharged on the morning of Day 3; and
3. A final safety post-treatment visit within 14 days after the last administration of abediterol.

There will be a minimum washout period of 14 days between each treatment period.

Each subject will be involved in the study for approximately 12 weeks.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 14050
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

1. Provision of signed and dated, written informed consent prior to any study-specific procedures.
2. Healthy male subjects aged 18 - 45 years, inclusive, with suitable veins for cannulation or repeated venipuncture.
3. Have a body mass index (BMI) between 18 and 29.9 kg/m2 inclusive and weigh at least 50 kg and no more than 100 kg inclusive.
4. Subject is able to understand and communicate in German.
5. Willing and able to comply with all required study procedures.

Exclusion Criteria:

1. History of any clinically significant disease or disorder which, in the opinion of the PI, may either put the volunteer at risk because of participation in the study, or influence the results or the volunteer's ability to participate in the study.
2. History or presence of gastrointestinal (GI), hepatic or renal disease, or any other conditions (e.g., including Gilbert's syndrome, gallstone and cholecystectomy) known to interfere with absorption, distribution, metabolism, or excretion of drugs.
3. History of tuberculosis, any other significant lung diseases like surgeries, asthma, COPD.
4. Upper respiratory tract infections within 14 days of the first study day, or lower respiratory tract infection within 3 months prior to screening.
5. Any clinically significant illness, medical/surgical procedure, or trauma within

4 weeks of the first administration of IMP. 6 Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results, at screening and first admission to the study unit (first treatment period) as judged by the PI. 7 Any clinically significant abnormal findings in vital signs at screening and first admission to the study unit (first treatment period), as judged by the PI, and defined as:

1. Systolic BP <90 mmHg or ≥140 mmHg and diastolic BP <50 mmHg or

   ≥90 mmHg

2. Heart rate <50 beats per minute [bpm] or >90 bpm Note: Assessments may be repeated once to confirm values. 8 Any clinically significant abnormalities on 12-lead ECG at screening and first admission to the study unit (first treatment period), as judged by the PI, and defined as:

(1) Sick sinus syndrome (2) Arrhythmia (3) Prolonged QT interval corrected using Fridericia's formula (QTcF) > 450 ms (4) Family history of long QT syndrome, persistent or intermittent bundle branch block (BBB), AV block grade II or III 9 Any positive result on screening for serum hepatitis B surface antigen (HBsAg) OR anti-hepatitis B core antigen (HBc) antibody, hepatitis C antibody, and human immunodeficiency virus (HIV) antibody. 10 Has received another new chemical and biologic entity (defined as a compound which has not been approved for marketing) within 3 months of the first administration of IMP in this study. The period of exclusion begins 3 months after the final dose or one month after the last visit whichever is the longest. Note: subjects consented and screened, but not randomized in this study or a previous phase I study, are not excluded. 11 Plasma donation within 1 month of screening or any blood donation/loss more than 500 mL during the 3 months prior to screening. 12 History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the PI or history of hypersensitivity to drugs with a similar chemical structure or class to abediterol. 13 Current smokers or those who have smoked or used nicotine products (including e- cigarettes; > 10 pack-year) within the 3 months prior to screening. 14 Use of drugs with enzyme-inducing properties such as St John's Wort within 3 weeks prior to the first administration of IMP. 15 Use of any prescribed or non-prescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, megadose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals during the 2 weeks prior to the first administration of IMP or longer if the medication has a long half-life.

16 Known or suspected history of alcohol or drug abuse or excessive intake of alcohol as judged by the PI or positive screen for drugs of abuse, cotinine, and/or alcohol at screening or on each admission to the Clinical Unit. 17 Subjects with a pregnant partner. 18 Involvement of any AstraZeneca, Parexel or study site employee or their close relatives. 19 Subjects who have previously received abediterol. 20 Judgement by the PI that the subject should not participate in the study if they have any ongoing or recent (i.e., during the screening period) minor medical complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions, and requirements. 21 Vulnerable subjects, e.g., kept in detention, protected adults under guardianship, trusteeship, or committed to an institution by governmental or juridical order.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: NONE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Treatment A (test product): Abediterol (2.4 μg); Randomized subjects will receive single dose treatment of Abediterol nebuliser solution for inhalation via PARI LC SPRINT nebulizer following an overnight fast of at least 8 hours	Drug: Abediterol (2.4 μg); 2.4 μg (delivered dose) abediterol via PARI LC SPRINT nebuliser; Drug: Abediterol (2.4 μg); 2.4 μg (delivered dose) abediterol via OMRON NE-C900-E nebuliser
EXPERIMENTAL: Treatment B (Test Product): Abediterol (4.8 μg); Randomized subjects will receive single dose treatment of Abediterol nebuliser solution for inhalation via PARI LC SPRINT nebulizer following an overnight fast of at least 8 hours	Drug: Abediterol (4.8 μg); 4.8 μg (delivered dose) abediterol via PARI LC SPRINT nebuliser
EXPERIMENTAL: Treatment C(Test Product):Abediterol(2.4 μg); Randomized subjects will receive single dose treatment of Abediterol nebuliser solution for inhalation via OMRON NE-C900-E nebulizer following an overnight fast of at least 8 hours	Drug: Abediterol (2.4 μg); 2.4 μg (delivered dose) abediterol via PARI LC SPRINT nebuliser; Drug: Abediterol (2.4 μg); 2.4 μg (delivered dose) abediterol via OMRON NE-C900-E nebuliser
EXPERIMENTAL: Treatment D (Reference Product): Abediterol (2.5 μg); Randomized subjects will receive single dose treatment of Abediterol (as napadisylate) inhalation powder via dry powder inhaler (DPI) following an overnight fast of at least 8 hours	Drug: Abediterol (2.5 μg); 2.5 μg (nominal dose) abediterol via DPI, reference

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Geometric mean ratios and 90% confidence intervals for area under plasma (AUC) for test versus abediterol reference treatments	To estimate the relative bioavailability of abediterol following inhalation via PARI LC SPRINT nebulizer (2 dose levels) or via OMRON NE-C900-E nebulizer (1 dose level) compared to inhalation via DPI SD2FL (1 dose level)	On Day 1: pre-dose, 5 min [only for DPI], 12, 30, and 45 min, and 1, 2, 4, 6, 8, 12 hours post-dose, on Day 2: 24 and 36 hours post-dose, on Day 3: 48 hours post-dose, on Day 4-7: 72, 96, 120 and 144 hours post-dose.
Geometric mean ratios and 90% confidence intervals for area under the plasma concentration-time curve from time zero to time of last quantifiable concentration (AUC[0-t]) for test versus reference abediterol treatments	To estimate the relative bioavailability of abediterol following inhalation via PARI LC SPRINT nebulizer (2 dose levels) or via OMRON NE-C900-E nebulizer (1 dose level) compared to inhalation via DPI SD2FL (1 dose level)	On Day 1: pre-dose, 5 min [only for DPI], 12, 30, and 45 min, and 1, 2, 4, 6, 8, 12 hours post-dose, on Day 2: 24 and 36 hours post-dose, on Day 3: 48 hours post-dose, on Day 4-7: 72, 96, 120 and 144 hours post-dose.
Geometric mean ratios and 90% confidence intervals for maximum observed plasma concentration (Cmax) the for test versus reference abediterol treatments	To estimate the relative bioavailability of abediterol following inhalation via PARI LC SPRINT nebulizer (2 dose levels) or via OMRON NE-C900-E nebulizer (1 dose level) compared to inhalation via DPI SD2FL (1 dose level)	On Day 1: pre-dose, 5 min [only for DPI], 12, 30, and 45 min, and 1, 2, 4, 6, 8, 12 hours post-dose, on Day 2: 24 and 36 hours post-dose, on Day 3: 48 hours post-dose, on Day 4-7: 72, 96, 120 and 144 hours post-dose.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC for each abediterol treatment	To evaluate the PK profile of abediterol when administered via the 3 devices (DPI and 2 nebulisers)	On Day 1: pre-dose, 5 min [only for DPI], 12, 30, and 45 min, and 1, 2, 4, 6, 8, 12 hours post-dose, on Day 2: 24 and 36 hours post-dose, on Day 3: 48 hours post-dose, on Day 4-7: 72, 96, 120 and 144 hours post-dose.
AUC (0-t) for each abediterol treatment	To evaluate the PK profile of abediterol when administered via the 3 devices (DPI and 2 nebulisers)	On Day 1: pre-dose, 5 min [only for DPI], 12, 30, and 45 min, and 1, 2, 4, 6, 8, 12 hours post-dose, on Day 2: 24 and 36 hours post-dose, on Day 3: 48 hours post-dose, on Day 4-7: 72, 96, 120 and 144 hours post-dose.
Cmax for each abediterol treatment	To evaluate the PK profile of abediterol when administered via the 3 devices (DPI and 2 nebulisers)	On Day 1: pre-dose, 5 min [only for DPI], 12, 30, and 45 min, and 1, 2, 4, 6, 8, 12 hours post-dose, on Day 2: 24 and 36 hours post-dose, on Day 3: 48 hours post-dose, on Day 4-7: 72, 96, 120 and 144 hours post-dose.
Area under the plasma concentration-time curve from time zero to 24 hours [AUC (0-24)] for each abediterol treatment	To evaluate the PK profile of abediterol when administered via the 3 devices (DPI and 2 nebulisers)	On Day 1: pre-dose, 5 min [only for DPI], 12, 30, and 45 min, and 1, 2, 4, 6, 8, 12 hours post-dose, on Day 2: 24 and 36 hours post-dose, on Day 3: 48 hours post-dose, on Day 4-7: 72, 96, 120 and 144 hours post-dose.
Maximum concentration (tmax) for each abediterol treatment	To evaluate the PK profile of abediterol when administered via the 3 devices (DPI and 2 nebulisers)	On Day 1: pre-dose, 5 min [only for DPI], 12, 30, and 45 min, and 1, 2, 4, 6, 8, 12 hours post-dose, on Day 2: 24 and 36 hours post-dose, on Day 3: 48 hours post-dose, on Day 4-7: 72, 96, 120 and 144 hours post-dose.
Terminal slope (λz) of a semi-logarithmic concentration-time curve (t1/2λz) for each abediterol treatment	To evaluate the PK profile of abediterol when administered via the 3 devices (DPI and 2 nebulisers)	On Day 1: pre-dose, 5 min [only for DPI], 12, 30, and 45 min, and 1, 2, 4, 6, 8, 12 hours post-dose, on Day 2: 24 and 36 hours post-dose, on Day 3: 48 hours post-dose, on Day 4-7: 72, 96, 120 and 144 hours post-dose.
Terminal elimination rate constant (λz) for each abediterol treatment	To evaluate the PK profile of abediterol when administered via the 3 devices (DPI and 2 nebulisers)	On Day 1: pre-dose, 5 min [only for DPI], 12, 30, and 45 min, and 1, 2, 4, 6, 8, 12 hours post-dose, on Day 2: 24 and 36 hours post-dose, on Day 3: 48 hours post-dose, on Day 4-7: 72, 96, 120 and 144 hours post-dose.
Time of last quantifiable plasma concentration (tlast) for each abediterol treatment	To evaluate the PK profile of abediterol when administered via the 3 devices (DPI and 2 nebulisers)	On Day 1: pre-dose, 5 min [only for DPI], 12, 30, and 45 min, and 1, 2, 4, 6, 8, 12 hours post-dose, on Day 2: 24 and 36 hours post-dose, on Day 3: 48 hours post-dose, on Day 4-7: 72, 96, 120 and 144 hours post-dose.
Apparent total body clearance of drug from plasma after extravascular administration (CL/F) for each abediterol treatment	To evaluate the PK profile of abediterol when administered via the 3 devices (DPI and 2 nebulisers)	On Day 1: pre-dose, 5 min [only for DPI], 12, 30, and 45 min, and 1, 2, 4, 6, 8, 12 hours post-dose, on Day 2: 24 and 36 hours post-dose, on Day 3: 48 hours post-dose, on Day 4-7: 72, 96, 120 and 144 hours post-dose.
Mean residence time of the unchanged drug in the systemic circulation from zero to infinity (MRT) for each abediterol treatment	To evaluate the PK profile of abediterol when administered via the 3 devices (DPI and 2 nebulisers)	On Day 1: pre-dose, 5 min [only for DPI], 12, 30, and 45 min, and 1, 2, 4, 6, 8, 12 hours post-dose, on Day 2: 24 and 36 hours post-dose, on Day 3: 48 hours post-dose, on Day 4-7: 72, 96, 120 and 144 hours post-dose.
Apparent volume of distribution during the terminal phase after extravascular administration (Vz/F) for each abediterol treatment	To evaluate the PK profile of abediterol when administered via the 3 devices (DPI and 2 nebulisers)	On Day 1: pre-dose, 5 min [only for DPI], 12, 30, and 45 min, and 1, 2, 4, 6, 8, 12 hours post-dose, on Day 2: 24 and 36 hours post-dose, on Day 3: 48 hours post-dose, on Day 4-7: 72, 96, 120 and 144 hours post-dose.
Number of subjects with adverse events	To further assess the safety of single doses administration of abediterol in healthy subjects	From Screening (Day -28) until follow-up (14 days after last dose)
Number of subjects with abnormal electrocardiogram (ECG)	To further assess the safety of single doses administration of abediterol in healthy subjects	From Screening (Day -28), Day -1 until Day 3
Number of subjects with abnormal telemetry	To further assess the safety of single doses administration of abediterol in healthy subjects	Day -1, 1 (pre-dose to 12 hours from the start of study drug administration)
Number of subjects with abnormal vital signs	To further assess the safety of single doses administration of abediterol in healthy subjects	From Screening (Day -28) until Day 3
Number of subjects with abnormal physical examination	To further assess the safety of single doses administration of abediterol in healthy subjects	From Screening (Day -28) until follow-up (14 days after last dose)
Number of subjects with abnormal spirometry	To further assess the safety of single doses administration of abediterol in healthy subjects	At Screening (Day -28) and Day 1
Number of subjects with abnormal taste questionnaire	To further assess the safety of single doses administration of abediterol in healthy subjects	Day 1
Number of subjects with abnormal White blood cell (WBC) count	To further assess the safety of single doses administration of abediterol in healthy subjects	From Screening (Day -28) until follow-up (14 days after last dose)
Number of subjects with abnormal Red blood cell (RBC) count	To further assess the safety of single doses administration of abediterol in healthy subjects	From Screening (Day -28) until follow-up (14 days after last dose)
Number of subjects with abnormal Hemoglobin (Hb)	To further assess the safety of single doses administration of abediterol in healthy subjects	From Screening (Day -28) until follow-up (14 days after last dose)
Number of subjects with abnormal Hematocrit (HCT)	To further assess the safety of single doses administration of abediterol in healthy subjects	From Screening (Day -28) until follow-up (14 days after last dose)
Number of subjects with abnormal Mean corpuscular volume (MCV)	To further assess the safety of single doses administration of abediterol in healthy subjects	From Screening (Day -28) until follow-up (14 days after last dose)
Number of subjects with abnormal Mean corpuscular hemoglobin (MCH)	To further assess the safety of single doses administration of abediterol in healthy subjects	From Screening (Day -28) until follow-up (14 days after last dose)
Number of subjects with abnormal Mean corpuscular hemoglobin concentration (MCHC)	To further assess the safety of single doses administration of abediterol in healthy subjects	From Screening (Day -28) until follow-up (14 days after last dose)
Number of subjects with abnormal Neutrophils absolute count	To further assess the safety of single doses administration of abediterol in healthy subjects	From Screening (Day -28) until follow-up (14 days after last dose)
Number of subjects with abnormal Lymphocytes absolute count	To further assess the safety of single doses administration of abediterol in healthy subjects	From Screening (Day -28) until follow-up (14 days after last dose)
Number of subjects with abnormal Monocytes absolute count	To further assess the safety of single doses administration of abediterol in healthy subjects	From Screening (Day -28) until follow-up (14 days after last dose)
Number of subjects with abnormal Eosinophils absolute count	To further assess the safety of single doses administration of abediterol in healthy subjects	From Screening (Day -28) until follow-up (14 days after last dose)
Number of subjects with abnormal Basophils absolute count	To further assess the safety of single doses administration of abediterol in healthy subjects	From Screening (Day -28) until follow-up (14 days after last dose)
Number of subjects with abnormal Reticulocytes absolute count	To further assess the safety of single doses administration of abediterol in healthy subjects	From Screening (Day -28) until follow-up (14 days after last dose)
Number of subjects with abnormal sodium	To further assess the safety of single doses administration of abediterol in healthy subjects	From Screening (Day -28) until follow-up (14 days after last dose)
Number of subjects with abnormal pottasium	To further assess the safety of single doses administration of abediterol in healthy subjects	From Screening (Day -28) until follow-up (14 days after last dose)
Number of subjects with abnormal urea	To further assess the safety of single doses administration of abediterol in healthy subjects	From Screening (Day -28) until follow-up (14 days after last dose)
Number of subjects with abnormal creatinine	To further assess the safety of single doses administration of abediterol in healthy subjects	From Screening (Day -28) until follow-up (14 days after last dose)
Number of subjects with abnormal albumin	To further assess the safety of single doses administration of abediterol in healthy subjects	From Screening (Day -28) until follow-up (14 days after last dose)
Number of subjects with abnormal calcium	To further assess the safety of single doses administration of abediterol in healthy subjects	From Screening (Day -28) until follow-up (14 days after last dose)
Number of subjects with abnormal phosphate	To further assess the safety of single doses administration of abediterol in healthy subjects	From Screening (Day -28) until follow-up (14 days after last dose)
Number of subjects with abnormal glucose (fasting)	To further assess the safety of single doses administration of abediterol in healthy subjects	From Screening (Day -28) until follow-up (14 days after last dose)
Number of subjects with abnormal C-reactive protein (CRP)	To further assess the safety of single doses administration of abediterol in healthy subjects	From Screening (Day -28) until follow-up (14 days after last dose)
Number of subjects with abnormal Alkaline phosphatase (ALP)	To further assess the safety of single doses administration of abediterol in healthy subjects	From Screening (Day -28) until follow-up (14 days after last dose)
Number of subjects with abnormal Alanine aminotransferase (ALT)	To further assess the safety of single doses administration of abediterol in healthy subjects	From Screening (Day -28) until follow-up (14 days after last dose)
Number of subjects with abnormal Aspartate aminotransferase (AST)	To further assess the safety of single doses administration of abediterol in healthy subjects	From Screening (Day -28) until follow-up (14 days after last dose)
Number of subjects with abnormal Total Bilirubin	To further assess the safety of single doses administration of abediterol in healthy subjects	From Screening (Day -28) until follow-up (14 days after last dose)
Number of subjects with abnormal Unconjugated bilirubin	To further assess the safety of single doses administration of abediterol in healthy subjects	Screening (Day -28), Day -1, 1 and 14 days after last dose
Number of subjects with abnormal Thyroid-stimulating hormone (TSH)	To further assess the safety of single doses administration of abediterol in healthy subjects	Screening (Day -28)
Number of subjects with abnormal urinalysis (glucose, blood and protein)	To further assess the safety of single doses administration of abediterol in healthy subjects	Screening (Day -28) and Day -1
Number of subjects with abnormal Gamma glutamyl transpeptidase (GGT)	To further assess the safety of single doses administration of abediterol in healthy subjects	From Screening (Day -28) until follow-up (14 days after last dose)
Number of subjects with abnormal platelet	To further assess the safety of single doses administration of abediterol in healthy subjects	From Screening (Day -28) until follow-up (14 days after last dose)

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Parexel
• Investigators: Principal Investigator: Dr. med. Rainard Fuhr, Parexel

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 28, 2020
• Primary Completion (ACTUAL): April 3, 2020
• Study Completion (ACTUAL): April 3, 2020

Study Registration Dates

• First Submitted: December 12, 2019
• First Submitted That Met QC Criteria: December 12, 2019
• First Posted (ACTUAL): December 16, 2019

Study Record Updates

• Last Update Posted (ACTUAL): April 21, 2020
• Last Update Submitted That Met QC Criteria: April 20, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: COPD; Crossover; Open-label; Healthy subjects; Phase 1; Bioavailability; Abediterol; Long-acting beta-2 agonist
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
• Other Study ID Numbers: D6541C00001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No