Efficacy, Safety and Tolerability of Aclidinium Bromide/Formoterol Fumarate Compared With Aclidinium Bromide and Formoterol Fumarate in Patients With Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD)

Study Overview
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Brief Summary
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The purpose of this Phase III study is to assess the maintenance bronchodilator effects of the fixed dose combination versus monotherapies. This study will also assess the effects of the fixed dose combination in terms of COPD symptoms, disease related health status and the long-term safety and tolerability of the fixed dose combination. This study will include a 24 week treatment period, preceding by a run-in period, followed by a two week follow up visit. All patients will be randomized to one of four treatment arms or placebo.

Official Title
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A Phase III, Randomized, Double-blind, Placebo-Controlled Study Evaluating the Efficacy, Safety, and Tolerability of Two Fixed Dose Combinations of Aclidinium Bromide/Formoterol Fumarate Compared With Aclidinium Bromide, Formoterol Fumarate and Placebo for 24- Weeks Treatment in Patients With Moderate to Severe, Stable Chronic Obstructive Pulmonary Disease (COPD).

Conditions
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Chronic Obstructive Pulmonary Disease

Intervention / Treatment
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* Drug: Aclidinium Bromide/Formoterol Fumarate
* Drug: Aclidinium Bromide/Formoterol Fumarate
* Drug: Aclidinium Bromide
* Drug: Formoterol Fumarate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients at least 40 years of age Current or former cigarette smoker with a cigarette smoking history of at least 10 pack-years A diagnosis of stable moderate to severe COPD and stable airway obstruction as defined by the GOLD guidelines and stable airway obstruction. Patients had to have a postbronchodilator FEV1/FVC ratio < 70% at Visit 1 (GOLD, 2010) Post-albuterol/salbutamol FEV1 values ≥ 30% and < 80% of predicted value. FEV1 was measured at the Screening Visit (Visit 1) 10 to 15 minutes after inhalation of albuterol/salbutamol. Predicted normal used for calculation purposes were based on National Health and Nutrition Examination Survey III predicted values (Hankinson et al, 1999) Able to perform acceptable and repeatable pulmonary function testing for FEV1 according to ATS/ERS criteria (Miller et al, 2005) at Screening Visit (Visit 1) and throughout their participation in the trial Negative serum β-human chorionic gonadotropin pregnancy test at Visit 1 and must have been using hormonal contraceptives or a barrier method plus a spermicidal agent; otherwise at least 1-year postmenopausal or surgically sterile, defined as having a hysterectomy or tubal ligation (applied to female patients only) Judged by the Principal Investigator to be in otherwise good stable health based on medical history, physical examination, ECGs, and routine laboratory data evaluations Patients previously randomized in an aclidinium monotherapy trial were permitted as long as it had been at least 6 months since the completion of their previous trial participation Able to understand the study procedures and be willing to participate in the study as indicated by signing the informed consent Exclusion Criteria: Hospitalization for an acute COPD exacerbation within 3 months before Visit 1 Any respiratory tract infection (including the upper respiratory tract) or COPD exacerbation in the 6 weeks before Visit 1. Patients who developed a respiratory tract infection or COPD exacerbation during the washout or run-in period were discontinued from the study before randomization Any clinically significant respiratory conditions other than COPD, including active tuberculosis, history of interstitial lung disease, pulmonary thromboembolic disease, history of α1-antitrypsin deficiency, pulmonary resection, lung volume surgery, or any other thoracic surgery during the past 12 months, history of bronchiectasis secondary to respiratory diseases other than COPD (eg, cystic fibrosis, Kartagener syndrome), post organ transplantation, or expected to require thoracotomy or other lung surgery during the study Clinical history suggesting that the patient had asthma as opposed to COPD (Study Physician was to be contacted to discuss eligibility, if necessary) Chronic use of oxygen therapy ≥ 15 hours/day Body mass index(BMI) ≥ 40 kg/m2 Patients who intended to start a pulmonary rehabilitation program during the trial were excluded, as well as those who finished or started it within 3 months prior to Screening Visit Clinically significant cardiovascular conditions including: myocardial infarction within the previous 6 months; newly diagnosed arrhythmia within the previous 3 months; unstable angina; unstable arrhythmia that had required changes in pharmacological therapy or other intervention within the previous 6 months; the presence of an automated implantable cardioverter-defibrillator; history of thoracic surgery within the past year before screening; hospitalization within the previous 12 months for heart failure of New York Heart Association functional class III (marked limitation of physical activity and only comfortable at rest, less than ordinary activity causes fatigue, palpitation or dyspnea), or class IV (unable to carry out any physical activity without discomfort) (Criteria Committee of the New York Heart Association criteria, 1994) Any uncontrolled infection that may have placed the patient at risk resulting from human immunodeficiency virus, active hepatitis and/or patients with diagnosed active tuberculosis QTcB > 470 msec in the resting ECGs performed at Screening (Visit 1), as indicated in the centralized ECG vendor generated report. Patients who were on a stable dose of medication that may prolong the QTc, but had a documented, stable, and normal QTc, could have been considered QTcB > 470 msec in the resting ECGs performed before randomization at Visit 2, as indicated in the paper tracing generated by the Sponsor-provided ECG equipment Clinically relevant abnormalities in the results of the clinical laboratory tests, in ECG parameters other than QTc, or in the physical examination or vital signs at Visit 1 except for those related to COPD History of drug or alcohol abuse within the previous 5 years Any other serious or uncontrolled physical or mental condition/disease that, as judged by the Investigator, could have placed the patient at higher risk derived from his/her participation in the study, could have confounded the results of the study, or would be likely to have prevented the patient from complying with the requirements of the study or completing the study. If there was a history of such disease, but the condition had been stable for more than 1 year and was judged by the Investigator not to interfere with the patient's participation in the study, the patient may have been included, with the documented approval of the Study Physician History of hypersensitivity reaction to inhaled anticholinergics, beta-2 agonists, sympathomimetic amines, or inhaled medication or any component thereof (including report of paradoxical bronchospasm) or a history of acute urinary retention, symptomatic benign prostatic hyperplasia, bladder neck obstruction, or narrow-angle glaucoma. (Note: Patients who had well controlled, stable, asymptomatic benign prostatic hyperplasia were not to be excluded) Sitting, resting systolic BP ≥ 160 mm Hg and/or diastolic BP ≥ 100 mm Hg at Visit 1 and Visit 2 Unable to use a multidose dry-powder inhaler or a pressurized metered-dose inhaler Treatment with any other investigational product within 30 days (or 6 half-lives, whichever was longer) before Visit 1 Previous participation in a clinical trial with aclidinium bromide in an FDC therapy Pregnant or breastfeeding Current diagnosis of cancer (present in the patient) other than basal or squamous cell skin cancer. Patients who had a history of cancer must have been cleared before Visit 1 (Screening) on a case-by-case basis Patients who did not maintain regular day/night, waking/sleeping cycles (eg, night shift workers) 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 (Appendix III of the protocol, which can be found in Appendix 16.1.1 of this report) Patients who were unlikely to be compliant with study requirements (eg, take their medication, complete their electronic diaries, attend clinic at the required times) Patients who were employees or relatives of employees of the investigative study center, FRI, Almirall, SA, or Pharmaceutical Product Development (PPD, Inc.) Patients who had any other conditions that, in the Investigator's opinion, might have indicated the patient to be unsuitable for the study or supported excluding the patient from the study

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Aclidinium/formoterol Fixed Dose Combination (FDC) 400/12μg | Drug: Aclidinium Bromide/Formoterol Fumarate<br>* Inhaled Aclidinium/formoterol FDC 400/12μg, twice per day<br>|
| Experimental: 2<br>Aclidinium/formoterol Fixed Dose Combination (FDC) 400/6μg | Drug: Aclidinium Bromide/Formoterol Fumarate<br>* Inhaled Aclidinium/formoterol FDC 400/6μg, twice per day<br>|
| Active Comparator: 3<br>Aclidinium monotherapy 400 μg | Drug: Aclidinium Bromide<br>* Inhaled Aclidinium 400 μg, twice per day<br>|
| Active Comparator: 4<br>Formoterol monotherapy 12 μg | Drug: Formoterol Fumarate<br>* Inhaled Formoterol 12 μg, twice per day<br>|
| Placebo Comparator: 5<br>Placebo | Drug: Placebo<br>* Inhaled dose-matched placebo, twice per day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in 1-hour Morning Post-dose Forced Expiratory Volume in One Second (FEV1) |  | Week 24 of treatment | 
| Change From Baseline in Morning Trough Forced Expiratory Volume in One Second (FEV1) |  | Week 24 of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Transition Dyspnea Index (TDI) Focal Score | The TDI measures the change from baseline in severity of breathlessness in symptomatic patients. The TDI contains a rating for 3 categories (functional impairment, magnitude of task, magnitude of effort).TDI scale ranges from -3 (major deterioration) to +3 (major improvement) including a 0 score to indicate no change. The 3 categories are added to obtain a focal score ranging from -9 (including 0) to +9. | Week 24 of treatment | 
| Change From Baseline in St George's Respiratory Questionnaire (SGRQ) Total Score | St George's Respiratory Questionnaire (SGRQ) measures COPD-specific health outcomes and consists of 2 parts with 3 dimension scores (a symptom score and an activity and impacts score). SGRQ total score is the sum of these scores and ranges from 0 (best health status) to 100 (worst health status). | Week 24 of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COPD, Chronic Obstructive Pulmonary Disease, Chronic Bronchitis, Emphysema, Airflow Obstruction, Chronic, Chronic Airflow Obstruction, Chronic Obstructive Airway Disease, Chronic Obstructive Lung Disease