Safety, Tolerability and Pharmacokinetics of Multiple Ascending Doses of AZD8871 in Healthy Male Japanese Subjects

NCT03159442 | Completed Phase 1

• 2 other identifiers: D6640C000052017-000890-35
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

Brief Summary

AZD8871 is a new chemical entity possessing long-acting dual-pharmacology (muscarinic receptor antagonist and β2 adrenoceptor agonist \[MABA\]) in a single molecule. This type of agent presents a novel approach to the treatment of chronic obstructive pulmonary disease (COPD) and potentially asthma (in combination with an inhaled corticosteroid). AZD8871 is being developed for inhalation, formulated with alpha lactose monohydrate and delivered by dry powder inhaler (DPI) that allows delivery of a single dose of the study drug. The primary objective is to investigate the safety and tolerability of AZD8871 at steady state in healthy male Japanese subjects.

Conditions

Chronic Obstructive Pulmonary Disease - COPD

Keywords

Chronic obstructive pulmonary disease (COPD); Asthma; AZD8871; muscarinic receptor antagonist and β2 adrenoceptor agonist (MABA); Phase I; Safety; Tolerability; Pharmacokinetics; long-acting muscarinic antagonist (LAMA); long-acting β2-agonist (LABA); Japanese

Outcome Measures

Primary Outcomes (9)

• Adverse events.

  Recording adverse events. 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 undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., laboratory findings, ECG). In clinical studies, an AE can include an undesirable medical condition occurring at any time, including run-in or washout periods, even if no study treatment has been administered.

  From time of ICF to Day 30 (end of follow-up period)

• Concomitant medication.

  Recording concomitant medications. Any concomitant medication or therapy given to the subject during the study conduct will be recorded.

  Change from screening up to follow-up period (Day 30 +/- 1)

• Physical examination.

  A full physical examination will include the examination of the following: general appearance, eyes, ears, nose, throat, chest/respiratory, heart/cardiovascular, gastrointestinal/liver, musculoskeletal/extremities, dermatological/skin, thyroid/neck, lymph nodes, neurological/psychiatric. A brief physical examination will include assessment of the following: skin, lungs, cardiovascular system and abdomen (liver and spleen). A complete physical examination will be performed at the Screening and Follow-up visit. Only relevant findings detected will be recorded in the physical examination findings.

  Change from screening up to follow-up period (Day 30 +/- 1)

• Vital signs.

  Recording vital signs. Systolic and diastolic blood pressure (in mmHg) will be measured after at least 10 minutes (can be reduced to 5 minutes at collection time points within the 1st hour after dosing) resting, and also, before taking any blood sample and conducting any spirometry. Measurements will be carried out with subject in the supine position and preferably always on the same arm. Subject's oral body temperature will be measured at each vital signs collection.

  Change from screening up to follow-up period (Day 30 +/- 1)

• Number of clinically relevant new findings or worsening of a pre-existing findings as assessed by Hematology.

  Haematocrit, hemoglobin, erythrocytes (red blood cells), mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), leucocytes (white blood cells), differential blood count (neutrophils, lymphocytes, monocytes, eosinophils and basophils) and thrombocytes (platelets)

  Change from screening up to follow-up period (Day 30 +/- 1)

• Number of clinically relevant new findings or worsening of a pre-existing findings as assessed by Clinical chemistry.

  Electrolytes: sodium, potassium, calcium, chloride and inorganic phosphorus. Enzymes: AST, ALT, ALP, GGT, LDH, creatine kinase. Substrates: glucose (fasting), total cholesterol, triglycerides, creatinine, TBL, total protein, albumin, uric acid, urea and BUN. Endocrinology: T4, TSH. Viral serology: HIV I and II antibodies, hepatitis C antibodies, HBsAg, HBc. Coagulation: INR, PT, aPTT.

  Change from screening up to follow-up period (Day 30 +/- 1)

• ECG.

  A 12-lead ECG will be obtained after the subject rested in the supine position for at least 10 minutes (can be reduced to 5 minutes at collection time points within the first hour after dosing; using the sites own ECG machines when not performing dECGs and using the same machine as the dECGs when time points coincide).

  Change from screening up to follow-up period (Day 30 +/- 1)

• 2-lead real-time telemetry ECG.

  Recording telemetry findings. A 2-lead real-time telemetry ECG will be performed for at least 4 hours on Day 1 and then on Days 1, 10 and 16 from 30 minutes predose until 24 hours postdose.

  Change from screening up to follow-up period (Day 30 +/- 1)

• Number of clinically relevant new findings or worsening of a pre-existing findings as assessed by urinalysis report.

  pH, blood, leucocytes, protein, glucose, bilirubin, urine bilirubin, ketones and nitrites. If clinically relevant abnormalities are detected (positive result in dipstick), microscopy (RBC, WBC and cast \[hyaline, granular and cellular\]).

  Change from screening up to follow-up period (Day 30 +/- 1)

Secondary Outcomes (9)

• Observed maximum concentration, taken directly from the individual concentration-time curve (Cmax) of AZD8871 and its metabolites.

  Day 1 and Day 16

• Time to reach maximum concentration, taken directly from the individual concentration-time curve (tmax) of AZD8871 and its metabolites.

  Day 1 and Day 16

• Terminal half-life (t½λz) of AZD8871 and its metabolites.

  Day 1 and Day 16

• Area under the plasma concentration-curve from time zero to 24 hours post-dose (AUCτ) of AZD8871 and its metabolites.

  Day 1 and Day 16

• Area under the concentration-time curve from time zero extrapolated to infinity (AUC) of AZD8871 and its metabolites.

  Day 1

Study Arms (3)

Cohort 1

EXPERIMENTAL

Multiple inhaled doses of AZD8871 will be administered via single dose DPI. Each subject will receive 300 μg AZD8871 or placebo. This dose will be given as 1 inhalation from the 300 μg AZD8871 or placebo inhaler. Single inhaled dose of AZD8871 or placebo will be administered on Day 1 and then single once daily inhalations of AZD8871 or placebo will be administered for 12 days from Day 5 until Day 16.

Drug: AZD8871; Drug: Placebo

Cohort 2

EXPERIMENTAL

Multiple inhaled doses of AZD8871 will be administered via single dose DPI. Each subject will receive 600 μg AZD8871 as 1 inhalation from the 600 μg AZD8871 or placebo inhaler. Single inhaled dose of AZD8871 or placebo will be administered on Day 1 and then single once daily inhalations of AZD8871 or placebo will be administered for 12 days from Day 5 until Day 16. Dose escalation to 600 μg dose will be done only after the SRC has determined the adequacy of the dose to be given.

Drug: AZD8871; Drug: Placebo

Cohort 3

EXPERIMENTAL

Multiple inhaled doses of AZD8871 will be administered via single dose DPI. Each subject will receive 900 μg AZD8871 as 1 inhalation from the 300 μg AZD8871 inhaler and 1 inhalation from the 600 μg AZD8871 inhaler, or placebo as 2 inhalations from 2 different placebo inhalers. Single inhaled dose of AZD8871 or placebo on Day 1 and then single once daily inhalations of AZD8871 or placebo will be administered for 12 days from Day 5 until Day 16. Dose escalation to the 900 μg dose will be done only after the SRC has determined the adequacy of the dose to be given.

Drug: AZD8871; Drug: Placebo

Interventions

AZD8871 DRUG

Powder for inhalation administered via single dose DPI 300 and 600 µg/inhalation.

Cohort 1; Cohort 2; Cohort 3

Placebo DRUG

Powder for inhalation administered via single dose DPI

Cohort 1; Cohort 2; Cohort 3

Eligibility Criteria

• Age: 20 Years - 55 Years
• Gender Eligibility Details: Male Japanese subjects aged 20 to 55 years, inclusive at Screening. A Japanese subject is defined as a subject who was born in Japan and has 2 Japanese biological parents and 4 Japanese grandparents, as confirmed by interview. The subject should not have been living outside of Japan for more than 5 years at the time of the Screening visit. The subjects should not have had a significant change in lifestyle or diet since leaving Japan.
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Provision of written informed consent prior to any study related procedures, including withdrawal of medications.
• Male Japanese subjects aged 20 to 55 years, inclusive at Screening.
• Body mass index (BMI) calculated as weight in kg/height in m2 from \>= 18 to \<= 30 kg/m2 and weight \>= 50 kg at Screening.
• Healthy, free from any clinically significant disease/conditions (including all cardiovascular conditions), as determined by medical history, physical examination, clinical laboratory testing, 12-lead ECG findings at Screening and admission to the unit.
• Spirometry readings (Forced Expiratory Volume in 1 second and Forced Vital Capacity) to be \>= 80% of predicted value calculated using equations at Screening (Quanjer et. al. 2012).
• Normal blood pressure (BP) (defined as systolic BP \>= 90 and \<= 140 mmHg and diastolic BP \>= 50 and \<= 90 mmHg) at Screening and admission to the unit, measured after resting in supine position for at least 10 minutes.
• Normal heart rate (HR) (defined as HR \>= 45 and \<= 90) measured after resting in supine position for at least 10 minutes at Screening and admission to the unit.
• Negative hepatitis B surface antigen (HBsAg), hepatitis B core (HBc) antibody (IgM), hepatitis C antibody and human immunodeficiency virus (HIV) I and II antibodies at Screening.
• Negative drugs of abuse and alcohol tests at Screening and at admission to the unit.
• Willing and able to comply with study specific procedures and restrictions.

You may not qualify if:

• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
• Surgical history clinically relevant for the purpose of the study or any clinically significant illness, medical/surgical procedure or trauma within 4 weeks of Screening.
• History of malignancy of any organ system, treated or untreated within the past 5 years, with the exception of localised basal cell carcinoma of the skin.
• Current smokers, or a smoking history during the last 6 months or total smoking history of more than 10 pack years. Use of electronic cigarettes or other forms of nicotine, current use or use within the last 6 months.
• Note: Pack years are calculated by dividing the number of cigarettes smoked per day by 20 (the number of cigarettes per pack) and multiplying tis figure by the number of years a person has been smoking. For example, a person who smoked 40 cigarettes a day and has been smoking for 10 years would have a 20 pack-year smoking history (40 cigarettes per day at 20 cigarettes per pack =2; 2 x 10 years of smoking =20 pack-year history).
• Prolonged QTcF corrected using Fredericia's formulae) interval, \> 450 ms at Screening, or family history of long QT syndrome.
• Any clinically significant abnormalities in rhythm, conduction or morphology noted on physical examination, ECG or telemetry recording, prior to randomisation.
• History of excessive use or abuse of alcohol within the past 2 years, defined as: subjects consuming more than 21 (male subjects) units of alcohol a week (1 unit = 1 glass of wine (125 mL) = 1 measure of spirits = half pint of beer).
• History of drug abuse within the past 2 years prior to Screening.
• Donation or loss of \> 400 ml blood and plasma within the previous 3 months prior to Screening.
• History or presence of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity to any drug, as judged by the Investigator or history of hypersensitivity to drugs pharmacologically related to study drug.
• PR (PQ) interval shortening \< 120 ms (PR \> 110 ms but \< 120 ms is acceptable if there is no evidence of ventricular pre-excitation) at Screening.
• PR (PQ) interval prolongation (\> 240 ms), intermittent second (Wenckebach block while asleep is not exclusive), or third degree AV block, or AV dissociation at Screening.
• Persistent or intermittent complete bundle branch block, incomplete bundle branch block.
• Intraventricular conduction delay with QRS (onset of ventricular depolarization) \> 110 ms at Screening.

Sponsors & Collaborators

• AstraZeneca: lead
• Parexel: collaborator
• Industrias Farmacéuticas Almirall S.A.: collaborator
• The Doctors Laboratory Ltd: collaborator
• Covance: collaborator

Study Sites (1)

Research Site

London, HA1 3UJ, United Kingdom

Location

Related Publications (1)

• Balaguer V, Albayaty M, Jimenez E, Wahlby-Hamren U, Astbury C, Seoane B, Malice MP, Lei A, Aggarwal A, Psallidas I. Navafenterol (AZD8871) in healthy volunteers: safety, tolerability and pharmacokinetics of multiple ascending doses of this novel inhaled, long-acting, dual-pharmacology bronchodilator, in two phase I, randomised, single-blind, placebo-controlled studies. Respir Res. 2020 Sep 9;21(Suppl 1):212. doi: 10.1186/s12931-020-01474-1.

  PMID: 32907575 DERIVED

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive; Asthma

Interventions

AZD-8871

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 Officials

• Muna Albayaty, MBChB, MSc, MFPM

  Parexel

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: This study is single-blind with regards to treatment (AZD8871 or placebo) at each dose level. However, the study centre staff are also blinded only during the clinical conduct of a given cohort prior to the respective safety review committee meeting (SRC).
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Single center, randomized, single blind, placebo-controlled study.

Study Record Dates

• First Submitted: May 17, 2017
• First Posted: May 18, 2017
• Study Start: June 19, 2017
• Primary Completion: October 13, 2017
• Study Completion: October 13, 2017
• Last Updated: October 25, 2017

Record last verified: 2017-10

Locations

GB (1)