Study to Assess Efficacy and Safety of Aclidinium Bromide and Aclidinium Bromide/Formoterol Fumarate in Stabile COPD Patients

Phase 3

Completed

Conditions: COPD

Interventions: Drug: Formoterol Fumarate
Drug: Aclidinium bromide
Drug: Placebo
Drug: Aclidinium bromide/formoterol Fixed-Dose Combination

Registration Number: NCT03022097

Lead Sponsor: AstraZeneca

Brief Summary: This is a multiple dose, randomised, parallel, double blind, double dummy, multicentre and multinational Phase III study to determine the efficacy and safety of Aclidinium bromide/Formoterol fumarate compared with individual components and placebo and Aclidinium bromide compared with Placebo when administered to patients with stable Chronic Obstructive Pulmonary Disease (COPD).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 1625

Inclusion Criteria

1. Adult male or non-pregnant, non-lactating female patients aged ≥40
1. Patients with a diagnosis of COPD prior to Visit 1 (screening)
1. Patients with moderate to severe stable COPD (Stage II or Stage III) at Visit 1: post-bronchodilator FEV1 ≥30% and < 80% and post-bronchodilator FEV1/Forced vital capacity (FVC) < 70%
1. Current or former smokers with a smoking history of ≥ 10 pack-years
1. Patients able to perform repeatable pulmonary function testing for FEV1 according to the American Thoracic Society (ATS)/European Respiratory Society (ERS) 2005 criteria at Visit 1(screening)
1. Patients who understand the study procedures and are willing to participate in the study as indicated by signing the informed consent

Exclusion Criteria

1. Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff and/or site staff) or patients employed by or relatives of the employees of the site or sponsor.
1. Previous enrolment or randomisation in the present study
1. History or current diagnosis of asthma
1. Any respiratory tract infection (including the upper respiratory tract) or COPD exacerbation (including the mild COPD exacerbation) within 6 weeks prior to screening or during the run-in period
1. Patients hospitalized for COPD exacerbation (an emergency room visit for longer than 24 hours will be considered a hospitalization) within 3 months prior to screening and during the run-in period
1. Clinically significant respiratory conditions other than COPD
1. Patients who in the Investigator's opinion may need to start a pulmonary rehabilitation program during the study and/or patients who started/finished it within 3 months prior to screening
1. Use of long-term oxygen therapy (≥15 hours/day)
1. Patient who does not maintain regular day/night, waking/sleeping cycles including night shift workers
1. Clinically significant cardiovascular conditions
1. Patients with Type I or uncontrolled Type II diabetes, uncontrolled hypo-or hyperthyroidism, hypokalaemia, or hyperadrenergic state, uncontrolled or untreated hypertension
1. Patients with QT corrected interval (QTc) using Fridericia formula (QTcF) (QTc=QT/ Duration in milliseconds between two R peaks of two consecutive QRS complexes (RR1/3) >470 msec as indicated in the centralised reading report assessed at Screening (Visit 1)
1. Patients with clinically significant abnormalities in the clinical laboratory tests, ECG parameters (other than QTcF) or in the physical examination at Visit 1 (screening)
1. Patients with abnormal liver function tests defined as Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), or total bilirubin ≥ 2.5 times upper limit of normal ranges at screening
1. Patient with known non-controlled history of infection with human immunodeficiency virus and/or active hepatitis
1. Patient with a history of hypersensitivity reaction to inhaled anticholinergic drugs, sympathomimetic amines, inhaled medication or any component thereof
1. Patient with known narrow-angle glaucoma, symptomatic bladder neck obstruction, acute urinary retention, or patients with symptomatic non-stable prostatic hypertrophy
1. History of malignancy of any organ system (including lung cancer), treated or untreated, within the past 5 years other than basal or squamous cell skin cancer
1. Any other serious or uncontrolled physical or mental dysfunction
1. Patients with a history (within 2 years prior to Visit 1 (screening) of drug and/or alcohol abuse that may prevent study compliance based on the Investigator judgment
1. Patients unlikely to be cooperative or cannot comply with the study procedures
1. Patients treated with any investigational drug within 30 days (or 6 half-lives, whichever is longer) prior to screening
1. Patients who intended to use any concomitant medication not permitted by this protocol or who had not undergone the required washout period for a particular prohibited medication
1. Patients unable to give consent, or patients of consenting age but under guardianship, or vulnerable patients
1. Any other conditions that, in the Investigator's opinion, might have indicated the patient to be unsuitable for the study

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Comparator	Formoterol Fumarate	Formoterol fumarate 12 μg
Experimental 2	Aclidinium bromide	Aclidinium bromide 400 μg
Placebo	Placebo	Placebo
Experimental 1	Aclidinium bromide/formoterol Fixed-Dose Combination	Aclidinium bromide 400μg/Formoterol fumarate 12 μg

Primary Outcome Measures

Name	Time	Method
Change From Baseline in 1-hour Morning Post Forced Expiratory Volume in 1 Second (FEV1)	Week 24, 1-hour morning post-dose	Change from baseline in 1-hour morning post-dose FEV1 of Aclidinium bromide 400 μg/Formoterol fumarate 12 μg compared to Aclidinium bromide at Week 24. Baseline was defined as the average of the two FEV1 values measure prior to the administration of the first dose of the IP at randomisation visit. If one of the two values was missing, the available one was used as baseline. If both values were missing, the screening pre-bronchodilator value was used. Estimand is based on the while on-treatment approach, where treatment estimates are analysed while subjects are taking IP.
Change From Baseline in Morning Pre-dose (Trough) FEV1 for Aclidinium Bromide/Formoterol Fumarate	Week 24, morning pre-dose (trough)	Change from baseline in morning pre-dose (trough) FEV1 of Aclidinium bromide 400 μg/Formoterol fumarate 12 μg compared to Formoterol fumarate 12 μg at Week 24. Morning pre-dose (trough) FEV1 was defined as the average of the two FEV1 values at morning pre-dose of IP at Week 24. If one value was missing, the remaining was used as the trough value. Estimand is based on the while on-treatment approach, where treatment estimates are analysed while subjects are taking IP.
Change From Baseline in Morning Pre-dose (Trough) FEV1 for Aclidinium Bromide	Week 24, morning pre-dose (trough)	Change from baseline in morning pre-dose (trough) FEV1 of Aclidinium bromide 400 μg compared to placebo at Week 24. Morning pre-dose (trough) FEV1 was defined as the average of the two FEV1 values at morning pre-dose of IP at Week 24. If one value was missing, the remaining was used as the trough value. Estimand is based on the while on-treatment approach, where treatment estimates are analysed while subjects are taking IP.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Peak FEV1	Week 24, peak	Change from baseline in peak FEV1 of Aclidinium bromide 400 μg compared to placebo at week 24. Peak FEV1 was the highest value recorded at Week 24 after morning IP intake. Estimand is based on the while on-treatment approach, where treatment estimates are analysed while subjects are taking IP.
Improvements Transition Dyspnoea Index (TDI) Focal Score	Week 24	Improvements TDI focal score of Aclidinium bromide 400 μg/Formoterol fumarate 12 μg and Aclidinium bromide 400μg compared to placebo at week 24. Transition Dyspnoea Index (TDI) measures severity of breathlessness in symptomatic patients. An impairment severity score is assigned for three components: functional impairment; magnitude of task and magnitude of effort. Focal scores is derived as the sum of individual component scores. TDI focal score ranges from -9 to +9, with negative values indicating a worsening in dyspnoea, 0 showing no change from baseline and positive values associated with a post-baseline improvement. Estimand is based on the while on-treatment approach, where treatment estimates are analysed while subjects are taking IP.
Change From Baseline in St Georges Respiratory Questionnaire (SGRQ) Total Score	Week 24	Change from baseline in SGRQ total score of Aclidinium bromide 400 μg/Formoterol fumarate 12 μg and Aclidinium bromide 400μg compared to placebo at week 24. St. George's Respiratory Questionnaire (SGRQ) measures the impact of COPD on overall health, daily life and perceived well-being. It is composed of 50 items split into 17 parts, from which 3 dimension scores on Symptoms, Activity and Impact are derived. A total score utilising responses to all items can also be derived to assess the overall impact of COPD on quality of life. SGRQ dimension and total scores range from 0 to 100, with higher scores indicating a worse possible health status. Estimand is based on the while on-treatment approach, where treatment estimates are analysed while subjects are taking IP.