Safety, Tolerability and Pharmacokinetics of Multiple Ascending Doses of AZD8871 in Healthy Subjects
Condition: Chronic Obstructive Pulmonary Disease
MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
Study type: Interventional
Phase: Phase 1

Summary: 
      AZD8871 is a new chemical entity possessing long-acting effect in a single molecule which
      presents a novel treatment approach to chronic obstructive pulmonary disease [COPD] and
      potentially also asthma (in combination with an inhaled corticosteroid [ICS]). The
      therapeutic goal for AZD8871 is a treatment with greater efficacy than single mechanism
      bronchodilators, with an equivalent or superior safety and tolerability profile. The primary
      purpose of this study is to check the safety and tolerability of AZD8871 at steady state. A
      multiple ascending dose (MAD) design has been selected for this study following the first
      time in man (FTIM), single ascending dose (SAD) study. Three dose levels will be tested in an
      ascending manner. The first dose to be administered will be 300 μg and the 2 subsequent doses
      will be decided based on safety, tolerability and pharmacokinetic (PK) data generated in the
      previous dose. The aim of this study is to also enable further investigations in healthy
      subjects to evaluate and develop AZD8871 as a dual action bronchodilator with an acceptable
      side-effect profile compared to other inhaled bronchodilators on the market as a treatment
      for COPD and asthma.
    

Detailed description: 
      AZD8871 is a new chemical entity possessing long-acting dualpharmacology (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 also asthma (in combination with an inhaled corticosteroid [ICS]). 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. By
      combining this bi-functional activity, the therapeutic goal for AZD8871 is a treatment with
      greater efficacy than single mechanism bronchodilators, equivalent to long-acting β2-agonist
      (LABA) and long-acting muscarinic antagonist (LAMA) administered as free- or fixed-dose
      combination (FDC) therapies, with an equivalent or superior safety and tolerability profile.
      The current study will start with a single dose of 300 μg AZD8871 or placebo administered to
      8 healthy subjects following a 3-day washout period, dosing will then continue for a further
      12 days. Following the 1st cohort, 2 further cohorts of 8 subjects each will be administered
      multiple ascending doses (MAD) of AZD8871 in the same manner as Cohort 1. A MAD design has
      been selected for this study following the first time in man (FTIM), single ascending dose
      (SAD) study. Each subject will only be dosed in 1 cohort. The study design allows a gradual
      escalation of dose (Cohorts 2 and 3) with intensive safety monitoring to ensure the safety of
      the subjects. In Cohort 1, subjects will receive a single dose of AZD8871 300 μg or placebo
      on Day 1, followed by once daily dosing on Days 5 to 16. The dosing schedule of all cohorts
      will be single dose of IMP (active or placebo) on Day 1, followed by once daily dosing on
      Days 5 to 16. Within 5 to 7 days of discharge from the unit, there will be a Follow-up Visit.
      Dosing of Cohorts 2 and 3 will be preceded by a safety review committee (SRC) meeting, which
      will decide the exact dose to be given in the subsequent cohort. The dose escalation between
      cohorts will not exceed a multiple of 3 and the AZD8871 dose level in the study, for any
      cohort, will not exceed 2100 μg per day. The planned dose for Cohort 2 is either 600 or 900
      μg, however the SRC may decide a different dose level. A minimum of 5 subjects on active
      treatment need to complete dosing per cohort in order to proceed to the next dose level. The
      aim of this study is to also enable further investigations in healthy subjects to evaluate
      and develop AZD8871 as a dual action bronchodilator with an acceptable side-effect profile
      compared to other inhaled bronchodilators on the market as a treatment for COPD and asthma.
    

Intervention name(s): AZD8871; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Multiple inhaled doses of AZD8871 will be administered via single dose dry powder inhaler (DPI). Each subject will receive a single inhaled dose of AZD8871 on Day 1 and then single once daily inhalations of AZD8871 will be administered for 12 days from Day 5 until Day 16.; Multiple inhaled doses of placebo powder will be administered via single dose DPI. Each subject will receive a single inhaled dose of placebo on Day 1 and then single once daily inhalations of placebo will be administered for 12 days from Day 5 until Day 16.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Treatment
Keywords: muscarinic receptor antagonist and β2 adrenoceptor agonist [MABA]; chronic obstructive pulmonary disease; Asthma (in combination with an inhaled corticosteroid [ICS]; alpha-lactose monohydrate; dry powder inhaler; long-acting β2-agonist (LABA); long-acting muscarinic antagonist (LAMA); fixed-dose combination (FDC)