Efficacy, Pharmacokinetics (PK), Safety and Tolerability Study of Inhaled AZD8871
Condition: Chronic Obstructive Pulmonary Disease COPD
MeSH terms: Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
Intervention: AZD8871 100 µg; AZD8871 600 µg; Placebo
Intervention description: The subjects will receive one dose of AZD8871 100 µg single dose DPI.; The subjects will receive AZD8871, 600 µg single dose DPI.; The subject will receive Placebo single dose DPI.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Enrollment: 42.0
Sex: All
Minimum age: 40 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: AZD8871; long-acting muscarinic antagonist (LAMA); long-acting β2-agonist (LABA); inhaled long-acting bronchodilator; pharmacokinetics; safety; tolerability; efficacy; Phase IIa; Muscarinic receptor antagonist β2 adrenoceptor agonist (MABA)

Summary:

      This is a study to evaluate the effects of AZD8871 in patients with COPD. Adult male or
      female patients with moderate to severe COPD, who agree to be in this study, will receive 3
      treatments, i.e. 2 different doses of AZD8871 and placebo (dummy medication containing no
      drug) at once a day for 2 weeks, in a random order. To make the comparison between AZD8871
      and placebo as fair as possible, this study is "double blinded." This means that neither
      patient nor the study doctor will know in which order the 3 treatments will be given. This
      study will include patients who are between 40 and 80 years of age. In total there will be 42
      patients participating in this study at two study centers in the United Kingdom and Germany.
      The study will have a total of 12 visits for each patient spanning for a period of 4 to 6
      months. The study is anticipated to run for approximately 8 months and should not exceed 10
      months.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patient who provided of informed consent prior to any study-specific procedures

          2. Male or female 40 to 80 years of age (both inclusive) at Screening (Visit 1). A female
             is eligible to enter and participate in the study if she is of non-childbearing
             potential.

             Note: A female is considered to be of non-childbearing potential if she meets one of
             the following criteria:

               -  Permanently or surgically sterilised, including hysterectomy and/or bilateral
                  oophorectomy and/or bilateral salpingectomy

               -  Post-menopausal; aged <50 years and amenorrhoeic for 12 months or more following
                  cessation of exogenous hormonal treatments and with luteinizing hormone (LH) and
                  follicle stimulating hormone (FSH) levels in the post-menopausal range of the
                  local laboratory.

               -  Post-menopausal; aged ≥50 years and amenorrhoeic for 12 months or more, following
                  cessation of all exogenous hormonal treatments.

          3. Male patient should use a condom and spermicide to prevent pregnancy and drug exposure
             of a partner, regardless of the gender or childbearing potential of the partner from
             the day of the first administration of the investigational product (IP) until 3 months
             after the last administration of the IP.

          4. COPD Diagnosis: Patient with an established clinical history of COPD for more than 1
             year at Screening, according to the Global Initiative for Chronic Obstructive Lung
             Disease 2016 COPD guidelines.

          5. Tobacco Use: Patient is a current or former smoker with a history of ≥10 pack-years of
             cigarette smoking. A former smoker is defined as one who has stopped smoking for at
             least 6 months prior to Screening.

          6. Patient with post-bronchodilator FEV1/FVC (Forced vital capacity) ratio <70% based on
             the value reached after inhalation of salbutamol (400 µg) at Visit 2. If criterion is
             not met, the test can be repeated at the latest, up to Day 14.

          7. Patient with post-bronchodilator FEV1 that must be ≥40% and <80% predicted normal
             value and must also be >750 mL at Visit 2. If criterion is not met, the test can be
             repeated at the latest, up to Day 14.

          8. Patient who fulfils reversibility criteria to salbutamol at Visit 2. Reversibility is
             defined as ≥12% and ≥200 mL increase in FEV1 after inhalation of 4 puffs of
             salbutamol. (400 µg). If criterion is not met, the test can be repeated at the latest,
             up to Day 14.

          9. Patient is willing and, in the opinion of the Investigator, able to change current
             COPD therapy as required by the protocol and willing to use ipratropium Four times a
             day (if needed, during run-in and wash-out periods) with or without Inhaled
             corticosteroid for maintenance therapy of COPD and as needed rescue salbutamol from
             Visit 1 up Visit 11.

         10. Patient is free from any clinically active disease other than COPD that may impact
             study outcome, as determined by medical history, physical examination, laboratory
             testing, and 12-lead ECG findings, at Screening.

         11. Patient is willing to remain at the study centre as required per protocol to complete
             all visit assessments.

         12. Patient with body mass index (BMI) <40 kg/m2 at the time of screening.

        Exclusion Criteria:

          1. Patient previously enrolled in the present study.

          2. Patient has significant diseases other than COPD, ie, disease or condition or an
             abnormality in laboratory, ECG, medical history or physical examination which, in the
             opinion of the Investigator, may put the patient at risk because of participation in
             the study or may influence either the results of the study or the patient'spatient's
             ability to participate in the study.

          3. Childbearing potential female, pregnant or lactating.

          4. Patient who, in the opinion of the Investigator, has a current diagnosis of asthma.

          5. Patient has alpha-1 antitrypsin deficiency as the cause of COPD.

          6. Patient has other active pulmonary disease such as active tuberculosis, lung cancer,
             bronchiectasis sarcoidosis, idiopathic interstitial pulmonary fibrosis, primary
             pulmonary hypertension, or uncontrolled sleep apnoea. Allergic rhinitis is not
             exclusionary.

          7. Lung surgery for volume reduction or lung transplantation: Patient has undergone lung
             volume reduction surgery, lobectomy, or bronchoscopic lung volume reduction
             (endobronchial blockers, airway bypass, endobronchial valves, thermal vapour ablation,
             biological sealants, massive pulmonary embolism and airway implants) within 1 year of
             Screening (Visit 1).

          8. Patient is using nocturnal positive pressure (eg, continuous positive airway pressure
             or bi level positive airway pressure). Patient is using any non-invasive positive
             pressure ventilation device.

             Note: A patient using continuous positive airway pressure or bi level positive airway
             pressure for Sleep Apnoea Syndrome is allowed in the study.

          9. Patient has been hospitalised due to poorly controlled COPD within 3 months of
             Screening.

         10. Patient has acute worsening of COPD that requires treatment with corticosteroids or
             antibiotics in the 6 week interval prior to Screening (Visit 1), or during the
             Screening Period (between Visits 1 and 3).

         11. Patient has had lower respiratory tract infections that required antibiotics within 6
             weeks prior to Screening.

         12. Patient cannot perform acceptable spirometry, ie, meet American Thoracic Society
             (ATS)/European Respiratory Society (ERS) acceptability criteria.

         13. Patient has changed their smoking status (ie, start or stop smoking) or initiation of
             a smoking cessation program within 6 weeks prior to Screening.

         14. Patient has participated in the acute phase of a pulmonary rehabilitation program
             within 4 weeks prior to Screening or who will enter the acute phase of a pulmonary
             rehabilitation program during the study. A patient in the maintenance phase of a
             pulmonary rehabilitation program is not to be excluded.

         15. Cardiac disease: Subject with significant cardiovascular disease cardiovascular
             instability. Patient with heart rate <50 beats per minute. Patient has clinically
             significant uncontrolled hypertension as assessed by the investigator.

         16. Neurological: Patient with seizures or history of seizures requiring anticonvulsants
             within 12 months prior to Screening. Patient is taking selective serotonin reuptake
             inhibitors or serotonin--norepinephrine reuptake inhibitors whose dose has not been
             stable for at least 4 weeks prior to Screening, or exceeds the maximum recommended
             dose.

         17. Renal: Patient with symptomatic bladder neck obstruction, acute urinary retention or
             symptomatic non-stable prostate hypertrophy. 35.23. Patient with a serum potassium
             value <3.5 mmol/L at Screening and on repeat testing. Note: however potassium
             replacement and rescreening is allowed if serum potassium concentration was <
             3.5mmol/l at screening.

         18. Others:

               -  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.

               -  History of malignancy of any organ system, treated or untreated within the past 5
                  years, with the exception of localized basal cell carcinoma of the skin

               -  Patient with known narrow-angle glaucoma.

               -  Patient has a history of hypersensitivity to β2-agonists, muscarinic
                  anticholinergics or lactose/milk protein. Lactose intolerance is not an exclusion
                  criterion.

               -  The patient has a known or suspected history of alcohol or drug of abuse within
                  the past 2-year period years or consuming more than 14 (female subjects) or 21
                  (male subjects) units of alcohol a week, or shows positive for drugs of abuse and
                  alcohol tests at screening and prior to randomization.

               -  Patient who, in the opinion of the Investigator, would be unable to abstain from
                  protocol-defined prohibited medications during the study.

               -  Patient who received a live attenuated vaccination within 30 days prior to
                  Screening.

               -  Patient involved in the planning and/or conduct of the study (applies to both
                  AstraZeneca staff and/or staff at the study site).

               -  Patient treated with investigational drug or device in another clinical trial
                  within the last 30 days or five half-lives (whichever is longer) prior to
                  Screening.

               -  Patient who donated or lost >500 mL of blood and plasma within the previous 3
                  months prior to screening.

               -  Patient is unlikely to co-operate with the requirements of the study,
                  instructions of the Principal Investigator., or have e-dairy completion rate of <
                  70% during the run in period.

               -  Patient with known human immunodeficiency virus (HIV) infection or chronic
                  hepatitis B or C infection.