A Single Inhalation Dose Study to Assess Efficacy, Pharmacokinetics (PK), Safety and Tolerability of AZD8871 in Patients With Long-term Lung Diseases.
A Single Inhalation Dose Study to Assess Efficacy, Pharmacokinetics (PK), Safety and Tolerability of AZD8871 in Patients With Long-term Lung Diseases.
This study will evaluate the efficacy and safety data of AZD8871 in patients with moderate to
 severe chronic obstructive pulmonary disease (COPD). This study will determine the 24-hour
 efficacy (lung function) profile of AZD8871 600 μg relative to placebo dry powder inhaler
 (DPI) based on trough forced expiratory volume in 1 second (FEV1) following repeated dosing
 (2 weeks). Anoro® Ellipta® (umeclidinium/vilanterol) once daily is included as an active
 control. This study aims at providing a novel approach to the treatment of COPD with greater
 efficacy than single-mechanism bronchodilators, equivalent to long-acting muscarinic
 antagonist (LAMA) and long-acting β2-agonist (LABA) administered as free- or fixed-dose
 combination therapies, with an equivalent or superior safety and tolerability profile.
This randomized, double-blind, placebo and active-controlled crossover study will be
 conducted at 5 sites in Germany and the United Kingdom (UK). Approximately 180 patients will
 be screened in order to randomize 72 patients into the study. Based on previous studies
 estimate, it is anticipated that 54 patients will be evaluable (study completers) assuming an
 approximate 25% dropout rate. A subset of 36 patients, who will have specifically consented
 for pharmacokinetics (PK), will undergo PK assessments. The study will consist of -

 -  A Screening period: Will last up to 28 days and consists of 2 Screening visits (Visit 1
 and Visit 2) and a run-in period (between a minimum of 14 and a maximum of 28 days; from
 Visit 2 to Visit 3).

 -  Three treatment periods (Visit 3; 14 days each; each separated by a wash-out period of
 42 to 49 days) and

 -  A Follow-up Visit: 42 days (up to 49 days) after last investigational product (IP)
 administration.

 Patients will be requested to stop their usual COPD therapy after signing the informed
 consent form (ICF) at Visit 1 and will be maintained on a mono-component inhaled
 corticosteroid (ICS) therapy, if required. Patients that were taking any LAMA will be
 maintained with ipratropium (34 µg × 2 puffs 4 times per day) between Visit 1 and Visit 2. In
 addition, salbutamol 100 µg will be provided as rescue medication during the study as needed
 (rescue medication has to be discontinued 6 hours before any pulmonary function test). Visit
 1 and Visit 2 could be performed on the same day if no wash-out of prior medication is
 required and the patient visits the site in fasting condition. In case any wash-out of prior
 medication is required, then Visit 2 will be performed after the wash-out is complete. If
 reversibility criteria and forced expiratory volume in 1 second (FEV1) predicted values are
 fulfilled according to inclusion criteria, the patient will be started on run-in period to
 assess clinical stability. If reversibility criteria or FEV1 predicted values are not met,
 pulmonary function tests could be rescheduled at the latest, up to Day 14. During the run in
 period, all patients will receive ipratropium 34 µg × 2 puffs 4 times per day (must be
 discontinued 8 hours prior to previous any pulmonary function test). A paper diary will be
 used to collect adverse events (AEs) and concomitant medication during run-in and wash-out
 periods.

 Eligible patients will be randomized in 1:1:1:1:1:1 ratio to 1 of 6 treatment sequences and
 will receive orally 1 of the following 3 treatments sequence in the form of inhalation powder
 using DPI :

 -  AZD8871 600 µg once daily (double-blind).

 -  Anoro® Ellipta® (55 µg umeclidinium [UMEC]/ 22 µg vilanterol [VI]) once daily
 (double-blind).

 -  Placebo (double-blind). Study treatment administration during all the visits at the
 sites (Day 1, Day 2, Day 8, and Day 14 of each treatment period) will be supervised by
 study personnel.

 During the treatment period Visits, safety and tolerability assessments and pulmonary
 function measurements will be taken pre-dose and up to 24 hours (Day 1) and up to 4 hours
 (Day 8) post-dose, respectively.

 At Visits 3 to 11, a subset of 36 patients will undergo PK assessments. Blood samples will be
 collected pre-dose and up to 24 hours post dose.

 In follow-up visit, AEs, safety laboratory, electrocardiogram (ECG), vital signs and physical
 examination will be assessed.

 The study includes 12 visits and the entire study period is scheduled to take from a minimum
 of 6.5 months (182 days) to a maximum of 7.5 months (217 days) for each individual patient.
 The estimated study duration is 12 months.
Inclusion Criteria:

 1. Provision of signed and dated, written ICF prior to any study-specific procedures,
 sampling, and analyses.

 2. Patient must be 40 to 85 years male and/or females of non-childbearing potential who
 are not pregnant/lactating at the time of signing the ICF (Screening; Visit 1).

 3. Patient with an established clinical history of moderate to severe COPD for more than
 1 year at Screening, according to the GOLD COPD guidelines.

 4. Patient who is a current or former smoker (defined as one who has stopped smoking for
 at least 6 months prior to Screening) with a history of ≥10 pack-years of cigarette
 smoking [Number of pack-years=(number of cigarettes per day/20)* number of years
 smoked (eg, 1 pack-year=20 cigarettes smoked per day for 1 year)].

 5. Patient with post-bronchodilator FEV1/forced vital capacity (FVC) 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.

 6. Patient with post-bronchodilator FEV1 that must be ≥40% and <80% predicted normal
 value at Visit 2. If criterion is not met, the test can be repeated at the latest, up
 to Day -14.

 7. 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 following the
 approved dosage and regimen (during run-in and wash-out periods) with or without ICS
 for maintenance therapy of COPD and rescue medication salbutamol (as needed) from
 Visit 1 to Visit 11.

 8. Patient must be able to read, speak and understand local language, and be willing to
 remain at the study centre as required per-protocol to complete all visit assessments.

 9. Body mass index (BMI) <40 kg/m2 at the time of Screening.

 10. Female patients must be of non-childbearing potential defined as:

 -  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.

 11. Male patients 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 IP until 3 months after the
 last administration of the IP. In addition to a condom with spermicide, a second
 highly effective method of contraception (oral, intravaginal or transdermal hormonal
 contraceptives, intrauterine device, intrauterine hormone-releasing system, or sexual
 abstinence until 3 months after the last administration of the IP) should be used with
 female partners of childbearing potential. Double barrier methods (a combination of
 male condom with either a cap, diaphragm or sponge with spermicide) are not considered
 to be highly effective methods of contraception. Male patients with a pregnant partner
 should use a condom and spermicide.

 Exclusion Criteria:

 1. Patient has significant diseases other than COPD, (ie, clinically relevant disease or
 condition or an abnormality in prior ECGs, medical history or physical examinations)
 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's ability to participate in the study.

 2. Patient has alpha-1 antitrypsin deficiency as the cause of COPD.

 3. Patient has other active pulmonary disease such as predominant asthma, active
 tuberculosis, lung cancer, bronchiectasis, sarcoidosis, idiopathic interstitial
 pulmonary fibrosis, primary pulmonary hypertension, or uncontrolled sleep apnoea.
 Allergic rhinitis is not exclusionary.

 4. 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).

 5. 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.

 6. Patient who had 2 or more exacerbations of COPD (moderate or severe in intensity)
 within the last year prior to Screening (see Section 7.1 for definition of
 exacerbation of COPD).

 7. Patient has been hospitalised due to poorly controlled COPD within 3 months of the
 Screening period.

 8. Patient has acute worsening of COPD that requires treatment with corticosteroids or
 antibiotics in the 6 week interval prior to or during the Screening period.

 9. Patient has had lower respiratory tract infection(s) that required antibiotics within
 6 weeks prior to the Screening period.

 10. Patient has significant cardiovascular disease that may be vulnerable to
 cardiovascular instability. Note: Some examples of clinically significant
 cardiovascular conditions are:

 -  Myocardial infarction within the 6 months prior to Screening Visit (Visit 1).

 -  Unstable angina or unstable arrhythmia which has required changes in the
 pharmacological therapy or other intervention within 12 months prior to Screening
 (Visit 1), or newly diagnosed arrhythmia within the previous 3 months prior to
 Screening (Visit 1).

 -  Second degree atrio-ventricular block.

 -  Use of pacemaker.

 -  Hospitalisation within 12 months prior to Screening (Visit 1) for heart failure
 functional classes III (marked limitation of activity and only comfortable at
 rest) and IV per the "New York Heart Association".

 11. Patient with a QT interval corrected using Fridericia's formula (QTcF) value >450 ms
 for male and >470 ms for female or an ECG that is not suitable for QT measurements
 (eg, poorly defined termination of the T wave).

 12. Patient with a heart rate <50 or >120 beats per minute (bpm).

 13. Patient has clinically significant uncontrolled hypertension (>180 mmHg) as assessed
 by the Investigator.

 14. Patient has seizures or a history of seizures requiring anticonvulsants within 12
 months prior to Screening.

 15. 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.

 16. Patient has a symptomatic bladder neck obstruction, acute urinary retention or
 symptomatic non-stable prostate hypertrophy.

 17. Any laboratory abnormality or suspicion of any clinically relevant disease or disorder
 (on history or examination), including uncontrolled diabetes or hypokalaemia (serum
 potassium <3.5 mmol/L), 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. Note: Potassium replacement and re-test is allowed once
 if serum potassium concentration was <3.5 mmol/L at Screening or prior to
 randomisation.

 18. Patient has known human immunodeficiency virus (HIV) infection or chronic hepatitis B
 or C infection.

 19. 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.

 20. Patient has known narrow-angle glaucoma.

 21. Patient has a history of drug of abuse within the past 2 years or consuming more than
 14 (female patients) or 21 (male patients) units of alcohol a week, or shows positive
 for drugs of abuse and alcohol tests at Screening and prior to randomisation.

 Note: If a patient tests positive to any drugs of abuse tests, which cannot be
 explained by use of prescription medication, he/she will be excluded from the study.
 Unit=1 glass of wine (125 mL)=1 measure of spirits=½ pint of beer.

 22. Patient has a history of hypersensitivity (including paradoxical bronchospasm) to
 β2-agonists, muscarinic anticholinergics or lactose/milk protein. Lactose intolerance
 is not an exclusion criterion.

 23. Patient has received a live attenuated vaccination within 30 days prior to Screening.

 Note: Inactivated influenza vaccination, pneumococcal vaccination, or any other
 inactivated vaccine is acceptable provided it is not administered within 7 days prior
 to Screening or randomisation (Visit 3).

 24. Patient who, in the opinion of the Investigator, is unable to abstain from
 protocol-defined prohibited medications during the study.

 25. Patient was treated with an investigational drug or device in another clinical trial
 within the last 30 days or 5 half-lives (whichever is longer) prior to Screening.

 Note: Patient participation in observational studies (ie, studies that do not require
 change to medication or an additional intervention) is not exclusionary.

 26. Previous participation or prior screen failure in the present study.

 27. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
 staff and/or staff at the study site).

 28. Patient has changed their smoking status (ie, restarted or stopped smoking) or
 initiation of a smoking cessation program within 6 weeks of Screening.

 29. 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.

 30. Judgment by the Investigator that the patient should not participate in the study if
 the patient is unlikely to comply with study procedures, restrictions and
 requirements. Inability to comply with requirements includes having an e-Diary
 completion rate of <70% during the run-in period.

 31. Patient who have donated or lost >500 mL of blood and/or plasma within the previous 3
 months prior to Screening.

 32. Vulnerable patients (who has been placed in an institution due to a regulatory or
 court order).