A Single Inhalation Dose Study to Assess Efficacy, Pharmacokinetics (PK), Safety and Tolerability of AZD8871 in Patients With Long-term Lung Diseases.
Condition: Chronic Obstructive Pulmonary Disease
MeSH terms: Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
Intervention: AZD8871; Anoro® Ellipta®
Intervention description: Randomized patients will receive 14 repeated daily doses of AZD8871 600 µg inhalation powder via DPI.; Randomized patients will receive 14 repeated daily doses of Anoro® Ellipta® (55 µg/22 µg) inhalation powder via DPI.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Masking description: This study will be performed in a double-blind manner. Each investigational product (IP) and its placebo will be supplied in identical packaging to enable double-blind conditions.
Enrollment: 73.0
Sex: All
Minimum age: 40 Years
Maximum age: 85 Years
Healthy volunteers: No
Keywords: Moderate to severe COPD; Muscarinic receptor antagonist; β2 adrenoceptor agonist (MABA); Long-acting muscarinic antagonist (LAMA); Long-acting β2-agonist (LABA); Inhaled long-acting bronchodilator; Small airways disease (obstructive bronchiolitis); Parenchymal destruction (emphysema),

Summary:

      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.
    

Eligibility criteria:

        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).