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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
73
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.
Research Site
Berlin, Germany
Research Site
Grosshansdof, Germany
Research Site
Wiesbaden, Germany
Research Site
London, United Kingdom
Research Site
Manchester, United Kingdom
Change From Baseline in Trough FEV1 at Day 15
To evaluate the efficacy of inhaled AZD8871 600 μg in patients with moderate to severe chronic obstructive pulmonary disease (COPD).
Time frame: Day 15
Change From Baseline in Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) at Day 1 to Day 8, Day 9 to Day 14, Day 1 to Day 14
To evaluate the efficacy of inhaled AZD8871 600 μg in patients with moderate to severe COPD. At each visit, patients are asked to evaluate the impact of COPD on their wellbeing and daily life on a 6-point Likert scale ranging from 0 to 5, with higher scores indicating a higher impact of COPD. The CAT is expressed as a total score, which is a sum of the 8 questions, ranging from 0 to 40.
Time frame: Day 1 to Day 8, Day 9 to Day 14, Day 1 to Day 14
FEV1 AUC(0-4)/4h (Area Under the Curve for the Change in FEV1 From Baseline to 4h, Normalised by the Time Window)
To evaluate the efficacy of inhaled AZD8871 600 μg in patients with moderate to severe COPD
Time frame: At Day 1, Day 8, and Day 14
FEV1 AUC(0-8)/8h (Area Under the Curve for the Change in FEV1 From Baseline to 8h, Normalised by the Time Window)
To evaluate the efficacy of inhaled AZD8871 600 μg in patients with moderate to severe COPD
Time frame: Day 1 and Day 14
FEV1 AUC(0-12)/12h (Area Under the Curve for the Change in FEV1 From Baseline to 12h, Normalised by the Time Window)
To evaluate the efficacy of inhaled AZD8871 600 μg in patients with moderate to severe COPD
Time frame: Day 1 and Day 14
FEV1 AUC(0-24)/24h (Area Under the Curve for the Change in FEV1 From Baseline to 24h, Normalised by the Time Window)
To evaluate the efficacy of inhaled AZD8871 600 μg in patients with moderate to severe COPD
Time frame: Day 1 and Day 14
Change From Baseline in Trough FEV1 on Day 2 and Day 8.
To evaluate the efficacy of inhaled AZD8871 600 μg in patients with moderate to severe COPD
Time frame: Day 2 and Day 8.
Change From Baseline in Peak FEV1 on Day 1, Day 8 and Day 14.
To evaluate the efficacy of inhaled AZD8871 600 μg in patients with moderate to severe COPD
Time frame: At Day 1, Day 8, and Day 14.
Change From Baseline in Breathlessness, Cough and Sputum Scale (BCSS) Total Score at Day 1 to Day 8, Day 9 to Day 14, Day 1 to Day 14
To evaluate the efficacy of inhaled AZD8871 600 μg in patients with moderate to severe COPD. The BCSS questionnaire is a 3-item, patient-reported outcome (PRO) measure. On a daily basis, patients are asked to evaluate each of their 3 symptoms (breathlessness, cough, and sputum) on a 5-point Likert scale ranging from 0 to 4, with higher scores indicating a higher severity of the symptom. The BCSS questionnaire is expressed as a daily total score, which is the sum of the 3 symptom scores, ranging from 0 to 12.
Time frame: Day 1 to Day 8, Day 9 to Day 14, Day 1 to Day 14
Number of Participants With Adverse Events.
To evaluate the safety and tolerability of inhaled AZD8871 600 μg in patients with moderate to severe COPD
Time frame: From Screening to folow-up or discontinuation (42 days after last study drug)
Maximum Plasma Concentration (Cmax)
To investigate the Cmax of AZD8871 600 μg and its primary metabolite after multiple dose administration of inhaled AZD8871 in patients with moderate to severe COPD
Time frame: At Day 1 and Day 14 (at pre-dose and at 30 minutes (min), 1, 2, 4, 6, 8, 12, and 24 hours post-dose)
Time to Reach Maximum Plasma Concentration (Tmax)
To investigate the Tmax of AZD8871 600 μg and its primary metabolite after multiple dose administration of inhaled AZD8871 in patients with moderate to severe COPD
Time frame: At Day 1 and Day 14 (at pre-dose and at 30 minutes (min), 1, 2, 4, 6, 8, 12, and 24 hours post-dose)
Time to Reach Last Quantifiable Plasma Concentration (Tlast)
To investigate the Tlast of AZD8871 600 μg and its primary metabolite after multiple dose administration of inhaled AZD8871 in patients with moderate to severe COPD
Time frame: At Day 1 and Day 14 (at pre-dose and at 30 minutes (min), 1, 2, 4, 6, 8, 12, and 24 hours post-dose)
Area Under the Plasma Concentration-curve From Time 0 to the Time of Last Quantifiable Concentration (AUClast)
To investigate the AUClast of AZD8871 600 μg and its primary metabolite after multiple dose administration of inhaled AZD8871 in patients with moderate to severe COPD
Time frame: At Day 1 and Day 14 (at pre-dose and at 30 minutes (min), 1, 2, 4, 6, 8, 12, and 24 hours post-dose)
Area Under the Plasma Concentration-curve From Time 0 to 24 Hours Post-dose [AUC(0-24)]
To investigate the AUC(0-24) of AZD8871 600 μg and its primary metabolite after multiple dose administration of inhaled AZD8871 in patients with moderate to severe COPD
Time frame: At Day 1 and Day 14 (at pre-dose and at 30 minutes (min), 1, 2, 4, 6, 8, 12, and 24 hours post-dose)
Average Plasma Concentration During a Dosing Interval (Cavg)
To investigate the Cavg of AZD8871 600 μg and its primary metabolite after multiple dose administration of inhaled AZD8871 in patients with moderate to severe COPD
Time frame: At Day 14 (at pre-dose and at 30 minutes (min), 1, 2, 4, 6, 8, 12, and 24 hours post-dose)
Fluctuation Index During a Dosing Interval (%Fluctuation)
To investigate the %Fluctuation of AZD8871 600 μg and its primary metabolite after multiple dose administration of inhaled AZD8871 in patients with moderate to severe COPD. Fluctuation index during a dosing interval is estimated as 100\*(Cmax - Cmin)/Cavg (%), where Cmin is the minimum concentration at the end of the dosing interval.
Time frame: At Day 14 (at pre-dose and at 30 minutes (min), 1, 2, 4, 6, 8, 12, and 24 hours post-dose)
Accumulation Ratio for Cmax (Rac(Cmax))
To investigate the Rac (Cmax) of AZD8871 600 μg and its primary metabolite after multiple dose administration of inhaled AZD8871 in patients with moderate to severe COPD. Accumulation ratio for Cmax estimated as (Cmax on Day 14/Cmax on Day 1).
Time frame: At Day 14
Accumulation Ratio for AUC(0-24) Rac(AUC(0-24))
To investigate the Rac(AUC(0-24) of AZD8871 600 μg and its primary metabolite after multiple dose administration of inhaled AZD8871 in patients with moderate to severe COPD. Accumulation ratio for AUC0-24 estimated as (AUC0-24 on Day 14/AUC0-24 on Day 1).
Time frame: At Day 14
Change From Baseline in Use of Rescue Medication
To evaluate the efficacy of inhaled AZD8871 600 μg in patients with moderate to severe COPD
Time frame: Day 1 to Day 8 and Day 9 to Day 14
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