A Study to Evaluate the Disposition of Drug in Body and Safety After Administration of Single Inhaled Doses of Drugs Abediterol and AZD7594 Administered Alone, in Fixed Dose Combination and in Free Combination Using the Dry Powder Inhaler in Healthy Male Participants

NCT02967159 | Completed Phase 1

• 1 other identifier: D7110C00001
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

Brief Summary

AZD7594 is a non steroidal, potent and selective modulator of the glucocorticoid receptor (GR) under development for once daily inhaled treatment of chronic obstructive pulmonary disease (COPD) and asthma. Abediterol is a novel and selective β2 adrenergic receptor agonist with the potential for once daily treatment of asthma and COPD in fixed dose combination (FDC) with an ICS or a novel anti inflammatory (AI) agent. This study will be the first clinical study for the combination exposure of AZD7594 with abediterol as 2 compounds in FDC or in free combination via 2 separate dry powder inhalers (DPIs). This study will be conducted in healthy male subjects to minimize the effects of concomitant disease states or medications on study measurements.

Conditions

Chronic Obstructive Pulmonary Disease (COPD); Asthma

Keywords

chronic obstructive pulmonary disease (COPD); asthma

Outcome Measures

Primary Outcomes (11)

• Area under the plasma concentration time curve (AUC) of abediterol and AZD7594 from time zero extrapolated to infinity. AUC is estimated by AUClast + Clast/λz where Clast is the last observed quantifiable concentration

  Pharmacokinetics of AZD7594 and abediterol following single inhaled doses of AZD7594 alone, abediterol alone and the 2 compounds in FDC or in free combination via 2 separate DPIs

  Day -1 to Day 3. Subjects will also return to the Unit at 72, 96, 144 and 240 hours post-dose (Days 4, 5, 7 and 11 respectively) for PK measurements

• Maximum observed plasma concentration (AUClast), taken directly from the individual concentration time curve of abediterol and AZD7594.

  Pharmacokinetics of AZD7594 and abediterol following single inhaled doses of AZD7594 alone, abediterol alone and the 2 compounds in FDC or in free combination via 2 separate DPIs

  Day -1 to Day 3. Subjects will also return to the Unit at 72, 96, 144 and 240 hours post-dose (Days 4, 5, 7 and 11 respectively) for PK measurements

• Observed maximum concentration (Cmax) of abediterol and AZD7594, taken directly from the individual concentration time curve.

  Pharmacokinetics of AZD7594 and abediterol following single inhaled doses of AZD7594 alone, abediterol alone and the 2 compounds in FDC or in free combination via 2 separate DPIs

  Day -1 to Day 3. Subjects will also return to the Unit at 72, 96, 144 and 240 hours post-dose (Days 4, 5, 7 and 11 respectively) for PK measurements

• Half life associated with terminal slope (λz) of a semi logarithmic concentration time curve (t½λz) of abediterol and AZD7594 using plasma concentrations, estimated as (ln2)/λz.

  Pharmacokinetics of AZD7594 and abediterol following single inhaled doses of AZD7594 alone, abediterol alone and the 2 compounds in FDC or in free combination via 2 separate DPIs

  Day -1 to Day 3. Subjects will also return to the Unit at 72, 96, 144 and 240 hours post-dose (Days 4, 5, 7 and 11 respectively) for PK measurements

• Time to reach maximum observed plasma concentration (tmax) of abediterol and AZD7594 using plasma concentrations, taken directly from the individual concentration time curve.

  Pharmacokinetics of AZD7594 and abediterol following single inhaled doses of AZD7594 alone, abediterol alone and the 2 compounds in FDC or in free combination via 2 separate DPIs

  Day -1 to Day 3. Subjects will also return to the Unit at 72, 96, 144 and 240 hours post-dose (Days 4, 5, 7 and 11 respectively) for PK measurements

• Mean residence time (MRT) of abediterol and AZD7594.

  Pharmacokinetics of AZD7594 and abediterol following single inhaled doses of AZD7594 alone, abediterol alone and the 2 compounds in FDC or in free combination via 2 separate DPIs

  Day -1 to Day 3. Subjects will also return to the Unit at 72, 96, 144 and 240 hours post-dose (Days 4, 5, 7 and 11 respectively) for PK measurements

• Apparent estimated as dose divided by AUC.total body clearance of drug from plasma after extravascular administration (CL/F) of abediterol and AZD7594,

  Pharmacokinetics of AZD7594 and abediterol following single inhaled doses of AZD7594 alone, abediterol alone and the 2 compounds in FDC or in free combination via 2 separate DPIs

  Day -1 to Day 3. Subjects will also return to the Unit at 72, 96, 144 and 240 hours post-dose (Days 4, 5, 7 and 11 respectively) for PK measurements

• The time interval (h) of the log linear regression to determine t1/2λz (λz upper and λz lower) of abediterol and AZD7594.

  Pharmacokinetics of AZD7594 and abediterol following single inhaled doses of AZD7594 alone, abediterol alone and the 2 compounds in FDC or in free combination via 2 separate DPIs

  Day -1 to Day 3. Subjects will also return to the Unit at 72, 96, 144 and 240 hours post-dose (Days 4, 5, 7 and 11 respectively) for PK measurements

• Terminal elimination rate constant, estimated by log linear least squares regression of the terminal part of the concentration time curve (λz, N) of abediterol and AZD7594.

  Pharmacokinetics of AZD7594 and abediterol following single inhaled doses of AZD7594 alone, abediterol alone and the 2 compounds in FDC or in free combination via 2 separate DPIs

  Day -1 to Day 3. Subjects will also return to the Unit at 72, 96, 144 and 240 hours post-dose (Days 4, 5, 7 and 11 respectively) for PK measurements

• Regression coefficient adjusted for λz, N observations, goodness of fit statistic for calculation of λz (Rsq_adj) of abediterol and AZD7594

  Pharmacokinetics of AZD7594 and abediterol following single inhaled doses of AZD7594 alone, abediterol alone and the 2 compounds in FDC or in free combination via 2 separate DPIs

  Day -1 to Day 3. Subjects will also return to the Unit at 72, 96, 144 and 240 hours post-dose (Days 4, 5, 7 and 11 respectively) for PK measurements

• Percentage of AUC obtained by extrapolating the area under the plasma concentration time curve from the time of the last quantifiable concentration to infinity (%AUCextr) of abediterol and AZD7594

  Pharmacokinetics of AZD7594 and abediterol following single inhaled doses of AZD7594 alone, abediterol alone and the 2 compounds in FDC or in free combination via 2 separate DPIs

  Day -1 to Day 3. Subjects will also return to the Unit at 72, 96, 144 and 240 hours post-dose (Days 4, 5, 7 and 11 respectively) for PK measurements

Secondary Outcomes (1)

• Safety and tolerability of single inhaled doses of AZD7594 and abediterol alone and in combination assessed by recording the AEs, physical examination, electrocardiogram readings, vital signs, spirometry and clinical laboratory assessments.

  From Screening (maximum of 28 days) till Follow up visit (10 to 14 days post final dose), an average of 24 weeks

Study Arms (4)

Treatment A (Abediterol )

EXPERIMENTAL

Treatment A: The subjects will receive Abediterol 2.5 μg via DPI

Drug: Abediterol

Treatment B (AZD7594)

EXPERIMENTAL

Treatment B: The subjects will receive AZD7594 440 μg via DPI

Drug: AZD7594

Treatment C (AZD7594/abediterol )

EXPERIMENTAL

Treatment C: The subjects will receive AZD7594/ abediterol 440 μg/2.5 μg FDC via DPI

Drug: AZD7594/abediterol

Treatment D (AZD7594 and abediterol)

EXPERIMENTAL

Treatment D: The subjects will receive AZD7594 440 μg and abediterol 2.5 μg free combination administered via 2 separate DPIs

Drug: AZD7594 and abediterol

Interventions

Abediterol DRUG

Treatment A: Abediterol 2.5 μg via DPI

Also known as: Treatment A

Treatment A (Abediterol )

AZD7594 DRUG

Treatment B: AZD7594 440 μg via DPI

Also known as: Treatment B

Treatment B (AZD7594)

AZD7594/abediterol DRUG

Treatment C: AZD7594/abediterol 440 μg/2.5 μg FDC via DPI

Also known as: Treatment C

Treatment C (AZD7594/abediterol )

AZD7594 and abediterol DRUG

Treatment D: AZD7594 440 μg and abediterol 2.5 μg free combination administered via 2 separate DPIs

Also known as: Treatment D

Treatment D (AZD7594 and abediterol)

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Provision of signed and dated, written informed consent prior to any study specific procedures
• Healthy male subjects aged 18 to 55 years (inclusive) with suitable veins for cannulation or repeated venipuncture
• 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.
• Subjects should be willing to follow reproductive restrictions #11 in Section 7.47.4.1 to prevent pregnancy and drug exposure of a female partner and refrain from donating sperm or fathering a child from the first day of dosing until 3 months after the last dose of IMP.
• Be able to inhale from the DPI devices according to given instructions.
• Able to understand, read and speak the German language.

You may not qualify if:

• History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study.
• History or presence of gastrointestinal, hepatic or renal disease or any other condition known to interfere with absorption, distribution, metabolism or excretion of drugs.
• Known Gilbert's syndrome, family history of Gilbert's syndrome or suspicion of Gilbert's syndrome based on liver function tests.
• Any contraindication against the use of vagolytic or sympaticomimetic drugs, as judged by the Investigator.
• Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of IMP.
• Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results, as judged by the Investigator.
• Any positive result on screening for serum hepatitis B surface antigen (HBsAg), hepatitis B core antibodies (anti HBc Ab), hepatitis C antibody and human immunodeficiency virus (HIV).
• Abnormal vital signs, after 10 minutes supine rest (confirmed by 1 controlled measurement), defined as any of the following:
• Systolic BP (SBP) \< 90 mmHg or ≥ 140 mmHg
• Diastolic BP (DBP) \< 50 mmHg or ≥ 90 mmHg
• Pulse \< 50 or \> 90 beats per minute (bpm)
• Subject with forced expiratory volume in 1 second (FEV1) \< 80% of the predicted value regarding age, height, gender and ethnicity (European Community for Coal and Steel \[ECCS/European Respiratory Society \[ERS\]) at screening.
• Subject with an acute infection of the upper and lower airway or other clinical relevant infections, which are not resolved at least 3 weeks before first drug administration.
• Subjects who are not able to perform correct spirometry tests at screening.
• Any clinically significant abnormalities in rhythm, conduction or morphology of the resting ECG and any clinically significant abnormalities in the 12 lead ECG, as considered by the Investigator that may interfere with the interpretation of QTc interval changes, including abnormal ST T wave morphology, particularly in the protocol defined primary lead or left ventricular hypertrophy.

Sponsors & Collaborators

• AstraZeneca: lead
• Parexel: collaborator

Study Sites (1)

Research Site

Berlin, 14050, Germany

Location

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive; Asthma

Interventions

5-(2-((6-(2,2-difluoro-2-phenylethoxy)hexyl)amino)-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one; velsecorat

Condition Hierarchy (Ancestors)

Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Bronchial Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 8, 2016
• First Posted: November 18, 2016
• Study Start: November 24, 2016
• Primary Completion: April 6, 2017
• Study Completion: April 6, 2017
• Last Updated: February 13, 2018

Record last verified: 2018-02

Locations

DE (1)