Formoterol Dose Ranging Study (ACHIEVE Duaklir USA Phase IIb)

Study Overview
=================
Brief Summary
-----------------
To assess the bronchodilation of three doses of formoterol fumarate (6 μg, 12 μg and 24 μg) twice daily (BID) administered via Pressair® compared to placebo and to open-label nebulized formoterol fumarate (20 μg and 40 μg).

Detailed Description
-----------------
This is a prospective, randomized, double-blind, 5-period incomplete unbalanced crossover, placebo and active comparator (open-label) controlled, multicenter clinical trial to assess the efficacy and safety of three doses of formoterol fumarate (6 μg, 12 μg and 24 μg) BID administered via Pressair® compared to placebo and to open-label formoterol fumarate (20 μg BID and 40 μg single dose) administered as an inhalation solution via a standard jet nebulizer (with a mouthpiece) connected to an air compressor (Perforomist® Inhalation Solution). The drug product is an inhalation powder comprising of micronized aclidinium bromide and micronized formoterol fumarate with α-lactose monohydrate as the carrier, presented in a breathactuated device-metered dry-powder inhaler (DPI). It has been approved under the trademarks of Genuair® and/or Pressair® in some territories.

Official Title
-----------------
A Randomized, Double-blind, Placebo-controlled, Incomplete Unbalanced, Crossover Study to Assess the Efficacy and Safety of Three Doses of Formoterol Fumarate in Pressair® Compared With Perforomist® Inhalation Solution (20 and 40 μg Open-label) in Moderate to Severe COPD Patients With Reversible Airway Disease.

Conditions
-----------------
Chronic Obstructive Pulmonary Disease - COPD

Intervention / Treatment
-----------------
* Drug: Formoterol fumarate (6 μg)
* Drug: Formoterol furmarate (20 μg)
* Drug: Placebo for formoterol fumarate
* Drug: Formoterol fumarate (12 μg)
* Drug: Formoterol fumarate (40 μg)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adult male or non-pregnant, non-lactating female patients aged ≥40. Patients with a diagnosis of COPD (GOLD guidelines, 2016) for a period of at least 6 months prior to Visit 1. Patients with moderate to severe stable COPD: post-bronchodilator FEV1 ≥ 30% and <80% of the predicted normal and post-bronchodilator FEV1/FVC < 70% at Visit 1. Patients with reversible airway obstruction defined as an increase in FEV1 of at least 12% and 200 mL over the baseline value after four inhalations of albuterol sulfate 108 µg via a pMDI at Visit 1. Current or former-smokers, with a smoking history of ≥ 10 pack-years. Patients able to perform acceptable and repeatable pulmonary function testing for FEV1 according to the American Thoracic Society (ATS)/European Respiratory Society (ERS) 2005 criteria at Visit 1. Patients eligible and able to participate in the study and who had signed an Informed Consent Form prior to initiation of any study-related procedures. Exclusion Criteria: Patients with asthma. Any respiratory tract infection (including the upper respiratory tract) or COPD exacerbation (including the mild COPD exacerbation) within 6 weeks prior to Visit 1 or during the run-in period. Patients hospitalized for a COPD exacerbation (an emergency room visit for longer than 24 hours is considered a hospitalization) within 3 months prior to Visit 1. Clinically significant respiratory conditions other than COPD. 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 Visit 1. Use of long-term oxygen therapy (≥ 15 hours/day). Patients who do not maintain regular day/night, waking/sleeping cycles including night shift workers. Clinically significant cardiovascular conditions. Patients with uncontrolled Type I or Type II diabetes, uncontrolled hypo-or hyperthyroidism, hypokalaemia, or hyperadrenergic state, uncontrolled hypertension. Patients with history of long QT syndrome or whose QTc (calculated according to Fridericia's Formula QTc=QT/RR1/3) > 470 ms as indicated in the centralized reading report assessed at Visit 1. Patients with clinically significant abnormalities in the laboratory tests, ECG parameters (other than QTc) or in the physical examination at Visit 1 that might compromise patient safety. Patients with a history of hypersensitivity reaction to an inhaled medication or any component thereof, including paradoxical bronchospasm. Patients with known narrow-angle glaucoma, symptomatic bladder neck obstruction, acute urinary retention or symptomatic unstable prostate hypertrophy. 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. Patients with any other serious or uncontrolled physical or mental dysfunction. Patients with a history (within 2 years prior to screening) of drug and/or alcohol abuse that may prevent study compliance based on the Investigator judgment. Patients unlikely to be cooperative or who cannot comply with the study procedures. Patients treated with any investigational drug within 30 days (or 6 half-lives, whichever is longer) prior to Visit 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. Patients unable to give consent, or patients of consenting age but under guardianship, or vulnerable patients. Any other conditions that, in the investigator's opinion, might render the patient to be unsuitable for the study. 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. Previous randomization in the present study D6571C00002.

Ages Eligible for Study
-----------------
Minimum Age: 40 Years
Maximum Age: 130 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Formoterol 6 μg<br>Participants received formoterol fumarate 6 μg administered via Pressair twice daily (BID). | Drug: Formoterol fumarate (6 μg)<br>* Oral Inhalation (by Pressair® Dry Powder Inhaler, DPI)<br>* Other names: Formoterol (Pressair®);|
| Experimental: Formoterol 12 μg<br>Participants received formoterol fumarate 12 μg administered via Pressair BID. | Drug: Formoterol fumarate (12 μg)<br>* Oral Inhalation (by Pressair® Dry Powder Inhaler, DPI)<br>* Other names: Formoterol (Pressair®);|
| Experimental: Formoterol 24 μg<br>Participants received formoterol fumarate 24 μg administered via Pressair BID. | Drug: Formoterol fumarate (12 μg)<br>* Oral Inhalation (by Pressair® Dry Powder Inhaler, DPI)<br>* Other names: Formoterol (Pressair®);|
| Placebo Comparator: Placebo<br>Participants received placebo to formoterol fumarate administered via Pressair BID. | Drug: Placebo for formoterol fumarate<br>* Oral Inhalation (by Pressair® Dry Powder Inhaler, DPI)<br>* Other names: Placebo (Pressair®);|
| Experimental: Formoterol 20 μg<br>Participants received Perforomist inhalation solution and were instructed to take one puff from each of the two Pressair inhalers or to inhale one vial from the Perforomist 20 μg inhalation solution BID for 7 ± 1 consecutive days. | Drug: Formoterol furmarate (20 μg)<br>* Oral Inhalation (via a standard jet nebulizer connected to an air compressor.<br>* Other names: Perforomist® Inhalation Solution;|
| Experimental: Formoterol 40 μg<br>Participants received Perforomist 40 μg (2 vials of Performist 20 μg) as a single dose of administration. | Drug: Formoterol fumarate (40 μg)<br>* Oral Inhalation (via a standard jet nebulizer connected to an air compressor.<br>* Other names: Perforomist® Inhalation Solution;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Normalized Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve (AUC) Over the 12 h Period Immediately After Morning Study Drug Administration, AUC0-12/12h at Day 7 on Treatment | To assess the bronchodilation of 3 doses of formoterol fumarate (6 μg, 12 μg and 24 μg) twice daily (BID administered via Pressair® compared to placebo and to open-label nebulised formoterol fumarate(20 μg). Pre-dose spirometry was performed before the morning daily dose at Day 1 and Day 7 of each treatment period. Two sets of measurements were performed during the hour preceding the scheduled morning study drug administration, allowing approximately 30 minutes between them. Note: Perforomist® 40 μg treatment periods lasted for 1 day only. Hence, was not included in the calculation. | Day 7: 30 min, 1 to 4 hours, 6 hours, 9 hours and 12 hours post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in FEV1 AUC0-6/6h at Day 1 on Treatment | To assess the bronchodilation of 3 doses of formoterol fumarate (6 μg, 12 μg and 24 μg) BID administered via Pressair® compared to placebo and to open-label nebulised formoterol fumarate (20 μg and 40 μg). 6-hour serial spirometry was performed at Day 1 of each treatment period: spirometry was performed post-dose at 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours and 6 hours post-dose. | Day 1: zero time to 6 hours post-dose | 
| Change From Baseline in FEV1 AUC0-6/6h at Day 7 on Treatment | To assess the bronchodilation of 3 doses of formoterol fumarate (6 μg, 12 μg and 24 μg) BID administered via Pressair® compared to placebo and to open-label nebulised formoterol fumarate (20 μg). 6-hour serial spirometry was performed at Day 7 of each treatment period: spirometry was performed post-dose at 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours and 6 hours post-dose Note: Perforomist® 40 μg treatment periods lasted for 1 day only. Hence, was not included in the calculation | Day 7: zero time to 6 hours post-dose | 
| Change From Baseline in Morning Pre-dose (Trough) FEV1 at Day 7 on Treatment | To assess the bronchodilation of 3 doses of formoterol fumarate (6 μg, 12 μg and 24 μg) BID administered via Pressair® compared to placebo and to open-label nebulised formoterol fumarate (20 μg). Trough value was defined as the mean of the 2 pre-dose measurements on Day 7. If 1 of the 2 measurements was missing, the non-missing measurement was used as the trough value. Note: Perforomist® 40 μg treatment periods lasted for 1 day only. Hence, was not included in the calculation. | At baseline and Day 7 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Perforomist, Pressair, COPD, Cigarette smoking, Formoterol fumarate, long-acting β2-adrenergic agonists (LABA), long-acting muscarinic antagonists (LAMA)