Chronic Obstructive Pulmonary Disease - COPD
Conditions
Keywords
Perforomist, Pressair, COPD, Cigarette smoking, Formoterol fumarate, long-acting β2-adrenergic agonists (LABA), long-acting muscarinic antagonists (LAMA)
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.
Interventions
DRUGFormoterol fumarate (6 μg)
Oral Inhalation (by Pressair® Dry Powder Inhaler, DPI)
Oral Inhalation (via a standard jet nebulizer connected to an air compressor.
DRUGPlacebo for formoterol fumarate
Oral Inhalation (by Pressair® Dry Powder Inhaler, DPI)
DRUGFormoterol fumarate (12 μg)
Oral Inhalation (by Pressair® Dry Powder Inhaler, DPI)
DRUGFormoterol fumarate (40 μg)
Oral Inhalation (via a standard jet nebulizer connected to an air compressor.
Sponsors
Parexel
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 130 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Day 7: 30 min, 1 to 4 hours, 6 hours, 9 hours and 12 hours post-dose | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in FEV1 AUC0-6/6h at Day 1 on Treatment | Day 1: zero time to 6 hours post-dose | 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. |
| Change From Baseline in FEV1 AUC0-6/6h at Day 7 on Treatment | Day 7: zero time to 6 hours post-dose | 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 |
| Change From Baseline in Morning Pre-dose (Trough) FEV1 at Day 7 on Treatment | At baseline and Day 7 | 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. |
Countries
United States
Participant flow
Recruitment details
This study was carried on 132 participants with moderate to severe chronic obstructive pulmonary disease (COPD) & reversible airway disease in the United States of America (USA; 21 sites) & were randomized to one of treatment sequences (each with 5 periods of different treatment, separated by wash-out period of 7 (+/1) days after treatment period).
Pre-assignment details
After signature of the informed consent, participants who were taking prohibited medication performed a wash-out period and were given Atrovent (2 puffs 4 times/day) before Screening and during the run-in period. All participants were provided with rescue drug (albuterol) and Atrovent to be taken during the wash-out between treatment periods.
Participants by arm
| Arm | Count |
|---|---|
| Overall Study Total All patients were randomized in a treatment sequence containing 5 treatment periods. All patients received FF12 and Perforomist 20 mcg, 90% received FF6, FF24 and Perforomist 40 mcg, and only 30% received placebo. Treatment was double blind for FF in Pressair, and open label for Perforomist. If treatment was FF6, FF12, FF24 or placebo, patients received two identical Pressair DPI and were instructed to take 1 puff from each of the inhalers in the morning and in the evening for 7 days. If treatment was Perforomist 20 mcg, patients were instructed to take 1 vial in the morning and 1 vial in the evening for 7 days. Treatment with Perforomist 40 mcg was a single dose administration.
Note: 132 participants were randomized. But, one participant was excluded from the ITT analysis set as the participant did not have a post-baseline forced expiratory volume in 1 second (FEV1) measurement. | 131 |
| Total | 131 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 6 |
| Overall Study | Lack of Efficacy | 1 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Other | 10 |
| Overall Study | Protocol Violation | 4 |
| Overall Study | Withdrawal by Subject | 4 |
Baseline characteristics
| Characteristic | Overall Study Total |
|---|---|
| Age, Continuous | 62.3 Years STANDARD_DEVIATION 7.5 |
| Age, Customized ≥50 to <65 years | 78 Participants |
| Age, Customized <50 years | 5 Participants |
| Age, Customized ≥65 years | 48 Participants |
| Sex: Female, Male Female | 66 Participants |
| Sex: Female, Male Male | 65 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 107 | 1 / 121 | 0 / 105 | 0 / 118 | 0 / 109 | 0 / 38 |
| other Total, other adverse events | 3 / 107 | 4 / 121 | 1 / 105 | 7 / 118 | 0 / 109 | 3 / 38 |
| serious Total, serious adverse events | 1 / 107 | 2 / 121 | 0 / 105 | 0 / 118 | 1 / 109 | 1 / 38 |
Outcome results
Primary
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.
Time frame: Day 7: 30 min, 1 to 4 hours, 6 hours, 9 hours and 12 hours post-dose
Population: The ITT analysis set consisted of all randomized participants who received at least 1 dose of investigational product (IP) and had a baseline FEV1 value and at least 1 post-baseline FEV1 measurement, regardless of a participant's adherence to the randomized treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Formoterol Fumarate 6 μg | 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 | 0.108 Litre/Hour |
| Formoterol Fumarate (FF) 12 μg | 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 | 0.117 Litre/Hour |
| Formoterol Fumarate (FF) 24 μg | 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 | 0.161 Litre/Hour |
| Perforomist 20 μg | 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 | 0.122 Litre/Hour |
| Placebo (Lactose Monohydrate) | 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 | 0.000 Litre/Hour |
p-value: <0.00195% CI: [0.055, 0.161]Mixed Models Analysis
p-value: <0.00195% CI: [0.064, 0.171]Mixed Models Analysis
p-value: <0.00195% CI: [0.107, 0.216]Mixed Models Analysis
p-value: <0.00195% CI: [0.069, 0.175]Mixed Models Analysis
p-value: 0.55695% CI: [-0.021, 0.039]Mixed Models Analysis
p-value: 0.00195% CI: [0.021, 0.085]Mixed Models Analysis
p-value: 0.36595% CI: [-0.016, 0.044]Mixed Models Analysis
p-value: 0.00695% CI: [0.013, 0.076]Mixed Models Analysis
p-value: 0.75695% CI: [-0.026, 0.036]Mixed Models Analysis
p-value: 0.01495% CI: [-0.071, -0.008]Mixed Models Analysis
Secondary
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.
Time frame: Day 1: zero time to 6 hours post-dose
Population: The ITT analysis set consisted of all randomized participants who received at least 1 dose of investigational product (IP) and had a baseline FEV1 value and at least 1 post-baseline FEV1 measurement, regardless of a participant's adherence to the randomized treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Formoterol Fumarate 6 μg | Change From Baseline in FEV1 AUC0-6/6h at Day 1 on Treatment | 0.111 Litre/Hour |
| Formoterol Fumarate (FF) 12 μg | Change From Baseline in FEV1 AUC0-6/6h at Day 1 on Treatment | 0.148 Litre/Hour |
| Formoterol Fumarate (FF) 24 μg | Change From Baseline in FEV1 AUC0-6/6h at Day 1 on Treatment | 0.205 Litre/Hour |
| Perforomist 20 μg | Change From Baseline in FEV1 AUC0-6/6h at Day 1 on Treatment | 0.195 Litre/Hour |
| Placebo (Lactose Monohydrate) | Change From Baseline in FEV1 AUC0-6/6h at Day 1 on Treatment | 0.246 Litre/Hour |
| Placebo (Lactose Monohydrate) | Change From Baseline in FEV1 AUC0-6/6h at Day 1 on Treatment | -0.019 Litre/Hour |
p-value: <0.00195% CI: [0.091, 0.169]Mixed Models Analysis
p-value: <0.00195% CI: [0.128, 0.206]Mixed Models Analysis
p-value: <0.00195% CI: [0.184, 0.263]Mixed Models Analysis
p-value: <0.00195% CI: [0.176, 0.253]Mixed Models Analysis
p-value: <0.00195% CI: [0.226, 0.304]Mixed Models Analysis
p-value: 0.00495% CI: [0.012, 0.062]Mixed Models Analysis
p-value: <0.00195% CI: [0.068, 0.119]Mixed Models Analysis
p-value: <0.00195% CI: [0.059, 0.11]Mixed Models Analysis
p-value: <0.00195% CI: [0.109, 0.161]Mixed Models Analysis
p-value: <0.00195% CI: [0.031, 0.082]Mixed Models Analysis
p-value: <0.00195% CI: [0.023, 0.071]Mixed Models Analysis
p-value: <0.00195% CI: [0.073, 0.123]Mixed Models Analysis
p-value: 0.46995% CI: [-0.035, 0.016]Mixed Models Analysis
p-value: 0.00295% CI: [0.015, 0.068]Mixed Models Analysis
p-value: <0.00195% CI: [0.025, 0.076]Mixed Models Analysis
Secondary
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
Time frame: Day 7: zero time to 6 hours post-dose
Population: The ITT analysis set consisted of all randomized participants who received at least 1 dose of investigational product (IP) and had a baseline FEV1 value and at least 1 post-baseline FEV1 measurement, regardless of a participant's adherence to the randomized treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Formoterol Fumarate 6 μg | Change From Baseline in FEV1 AUC0-6/6h at Day 7 on Treatment | 0.166 Litre/Hour |
| Formoterol Fumarate (FF) 12 μg | Change From Baseline in FEV1 AUC0-6/6h at Day 7 on Treatment | 0.177 Litre/Hour |
| Formoterol Fumarate (FF) 24 μg | Change From Baseline in FEV1 AUC0-6/6h at Day 7 on Treatment | 0.225 Litre/Hour |
| Perforomist 20 μg | Change From Baseline in FEV1 AUC0-6/6h at Day 7 on Treatment | 0.186 Litre/Hour |
| Placebo (Lactose Monohydrate) | Change From Baseline in FEV1 AUC0-6/6h at Day 7 on Treatment | 0.007 Litre/Hour |
p-value: <0.00195% CI: [0.105, 0.213]Mixed Models Analysis
p-value: <0.00195% CI: [0.116, 0.224]Mixed Models Analysis
p-value: <0.00195% CI: [0.163, 0.274]Mixed Models Analysis
p-value: <0.00195% CI: [0.125, 0.233]Mixed Models Analysis
p-value: 0.48895% CI: [-0.02, 0.042]Mixed Models Analysis
p-value: <0.00195% CI: [0.027, 0.092]Mixed Models Analysis
p-value: 0.20695% CI: [-0.011, 0.051]Mixed Models Analysis
p-value: 0.00495% CI: [0.016, 0.081]Mixed Models Analysis
p-value: 0.56795% CI: [-0.022, 0.041]Mixed Models Analysis
p-value: 0.01795% CI: [-0.072, -0.007]Mixed Models Analysis
Secondary
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.
Time frame: At baseline and Day 7
Population: The ITT analysis set consisted of all randomized participants who received at least 1 dose of investigational product (IP) and had a baseline FEV1 value and at least 1 post-baseline FEV1 measurement, regardless of a participant's adherence to the randomized treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Formoterol Fumarate 6 μg | Change From Baseline in Morning Pre-dose (Trough) FEV1 at Day 7 on Treatment | 0.077 Litre |
| Formoterol Fumarate (FF) 12 μg | Change From Baseline in Morning Pre-dose (Trough) FEV1 at Day 7 on Treatment | 0.067 Litre |
| Formoterol Fumarate (FF) 24 μg | Change From Baseline in Morning Pre-dose (Trough) FEV1 at Day 7 on Treatment | 0.102 Litre |
| Perforomist 20 μg | Change From Baseline in Morning Pre-dose (Trough) FEV1 at Day 7 on Treatment | 0.061 Litre |
| Placebo (Lactose Monohydrate) | Change From Baseline in Morning Pre-dose (Trough) FEV1 at Day 7 on Treatment | 0.002 Litre |
p-value: 0.02795% CI: [0.008, 0.141]Mixed Models Analysis
p-value: 0.05495% CI: [-0.001, 0.131]Mixed Models Analysis
p-value: 0.00495% CI: [0.032, 0.168]Mixed Models Analysis
p-value: 0.07595% CI: [-0.006, 0.123]Mixed Models Analysis
p-value: 0.61595% CI: [-0.048, 0.028]Mixed Models Analysis
p-value: 0.20995% CI: [-0.014, 0.065]Mixed Models Analysis
p-value: 0.40395% CI: [-0.053, 0.022]Mixed Models Analysis
p-value: 0.07495% CI: [-0.003, 0.074]Mixed Models Analysis
p-value: 0.7595% CI: [-0.045, 0.032]Mixed Models Analysis
p-value: 0.03595% CI: [-0.08, -0.003]Mixed Models Analysis