COPD
Conditions
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).
Interventions
DRUGAclidinium bromide/formoterol Fixed-Dose Combination
Inhaled Aclidinium bromide/formoterol Fixed-Dose Combination, twice per day via Genuair
Inhaled Aclidinium bromide 400 μg, twice per day via Genuair
DRUGFormoterol Fumarate
Inhaled Formoterol Fumarate 12 μg, twice per day via Turbuhaler
DRUGPlacebo
Inhaled dose-matched placebo, twice per day via Genuair or via Turbuhaler
Sponsors
Parexel
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
* 1\. Adult male or non-pregnant, non-lactating female patients aged ≥40 * 2\. Patients with a diagnosis of COPD prior to Visit 1 (screening) * 3\. 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% * 4\. Current or former smokers with a smoking history of ≥ 10 pack-years * 5\. 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) * 6\. 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. * 2\. Previous enrolment or randomisation in the present study * 3\. History or current diagnosis of asthma * 4\. 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 * 5\. 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 * 6\. Clinically significant respiratory conditions other than COPD * 7\. 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 * 8\. Use of long-term oxygen therapy (≥15 hours/day) * 9\. Patient who does not maintain regular day/night, waking/sleeping cycles including night shift workers * 10\. Clinically significant cardiovascular conditions * 11\. Patients with Type I or uncontrolled Type II diabetes, uncontrolled hypo-or hyperthyroidism, hypokalaemia, or hyperadrenergic state, uncontrolled or untreated hypertension * 12\. 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) * 13\. Patients with clinically significant abnormalities in the clinical laboratory tests, ECG parameters (other than QTcF) or in the physical examination at Visit 1 (screening) * 14\. 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 * 15\. Patient with known non-controlled history of infection with human immunodeficiency virus and/or active hepatitis * 16\. Patient with a history of hypersensitivity reaction to inhaled anticholinergic drugs, sympathomimetic amines, inhaled medication or any component thereof * 17\. Patient with known narrow-angle glaucoma, symptomatic bladder neck obstruction, acute urinary retention, or patients with symptomatic non-stable prostatic hypertrophy * 18\. 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 * 19\. Any other serious or uncontrolled physical or mental dysfunction * 20\. 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 * 21\. Patients unlikely to be cooperative or cannot comply with the study procedures * 22\. Patients treated with any investigational drug within 30 days (or 6 half-lives, whichever is longer) prior to screening * 23\. 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 * 24\. Patients unable to give consent, or patients of consenting age but under guardianship, or vulnerable patients * 25\. Any other conditions that, in the Investigator's opinion, might have indicated the patient to be unsuitable for the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
China, India, Philippines, Taiwan, Vietnam
Participant flow
Recruitment details
The study was conducted at 81 study centers in 5 countries China(50), India (15), Philippines (8), Taiwan (3) and Vietnam (5) between 02 February 2017 and 14 April 2022
Pre-assignment details
Subjects fulfilling inclusion/exclusion criteria at the time of the Screening entered into a run-in period of 14 ± 3 days to assess their disease stability before randomization. Participants who met the inclusion and none of the exclusion were considered for enrolment into the study. All study assessments were performed as per the schedule of assessments. A total of 1625 participants (consented) and undergone washout period and 1066 were randomised to treatment.
Participants by arm
| Arm | Count |
|---|---|
| AB/FF 400/12 μg Aclidinium bromide/formoterol fumarate fixed dose combination 400/12 μg | 263 |
| AB 400 μg Aclidinium bromide AB 400 μg | 266 |
| FF 12 μg Formoterol 12 μg | 264 |
| Placebo Placebo | 269 |
| Total | 1,062 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 4 | 1 | 3 |
| Overall Study | Due to COVID-19 pandemic | 0 | 1 | 0 | 0 |
| Overall Study | Lack of Efficacy | 0 | 0 | 3 | 3 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 1 |
| Overall Study | Other | 4 | 1 | 6 | 4 |
| Overall Study | Progressive Disease | 2 | 0 | 5 | 2 |
| Overall Study | Protocol Violation | 1 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 11 | 13 | 15 | 21 |
Baseline characteristics
| Characteristic | FF 12 μg | AB/FF 400/12 μg | Placebo | AB 400 μg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 65.4 Years STANDARD_DEVIATION 7.6 | 65.3 Years STANDARD_DEVIATION 7.1 | 64.9 Years STANDARD_DEVIATION 6.9 | 65.4 Years STANDARD_DEVIATION 6.8 | 65.2 Years STANDARD_DEVIATION 7.1 |
| Baseline FEV1 | 1.169 Litres STANDARD_DEVIATION 0.413 | 1.182 Litres STANDARD_DEVIATION 0.415 | 1.184 Litres STANDARD_DEVIATION 0.399 | 1.178 Litres STANDARD_DEVIATION 0.381 | 1.178 Litres STANDARD_DEVIATION 0.402 |
| Country China | 187 Participants | 186 Participants | 188 Participants | 186 Participants | 747 Participants |
| Country India | 35 Participants | 35 Participants | 37 Participants | 37 Participants | 144 Participants |
| Country Philippines | 29 Participants | 29 Participants | 30 Participants | 30 Participants | 118 Participants |
| Country Taiwan | 4 Participants | 3 Participants | 4 Participants | 3 Participants | 14 Participants |
| Country Vietnam | 9 Participants | 10 Participants | 10 Participants | 10 Participants | 39 Participants |
| Post-bronchodilator FEV1 at screening | 1.366 Litres STANDARD_DEVIATION 0.447 | 1.356 Litres STANDARD_DEVIATION 0.42 | 1.385 Litres STANDARD_DEVIATION 0.408 | 1.363 Litres STANDARD_DEVIATION 0.39 | 1.367 Litres STANDARD_DEVIATION 0.416 |
| Pre-bronchodilator FEV1 at screening | 1.199 Litres STANDARD_DEVIATION 0.415 | 1.187 Litres STANDARD_DEVIATION 0.404 | 1.212 Litres STANDARD_DEVIATION 0.383 | 1.192 Litres STANDARD_DEVIATION 0.385 | 1.197 Litres STANDARD_DEVIATION 0.396 |
| Race/Ethnicity, Customized Chinese | 187 Participants | 186 Participants | 188 Participants | 186 Participants | 747 Participants |
| Race/Ethnicity, Customized Filipino | 29 Participants | 29 Participants | 30 Participants | 30 Participants | 118 Participants |
| Race/Ethnicity, Customized Indian | 35 Participants | 35 Participants | 37 Participants | 37 Participants | 144 Participants |
| Race/Ethnicity, Customized Taiwanese | 4 Participants | 3 Participants | 4 Participants | 3 Participants | 14 Participants |
| Race/Ethnicity, Customized Vietnamese | 9 Participants | 10 Participants | 10 Participants | 10 Participants | 39 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 264 Participants | 263 Participants | 269 Participants | 266 Participants | 1062 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex/Gender, Customized Female | 13 Participants | 7 Participants | 13 Participants | 12 Participants | 45 Participants |
| Sex/Gender, Customized Male | 251 Participants | 256 Participants | 256 Participants | 254 Participants | 1017 Participants |
| Smoking status Current smoker | 86 Participants | 84 Participants | 85 Participants | 85 Participants | 340 Participants |
| Smoking status Former smoker | 178 Participants | 179 Participants | 184 Participants | 181 Participants | 722 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 263 | 0 / 266 | 1 / 264 | 2 / 269 |
| other Total, other adverse events | 53 / 263 | 44 / 266 | 54 / 264 | 55 / 269 |
| serious Total, serious adverse events | 19 / 263 | 21 / 266 | 26 / 264 | 21 / 269 |
Outcome results
Primary
Change From Baseline in 1-hour Morning Post Forced Expiratory Volume in 1 Second (FEV1)
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.
Time frame: Week 24, 1-hour morning post-dose
Population: Intention-to-Treat (ITT) population: All randomised participants who took at least one dose of IP and have a baseline FEV1 measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AB/FF 400/12 μg | Change From Baseline in 1-hour Morning Post Forced Expiratory Volume in 1 Second (FEV1) | 0.248 Litres | Standard Error 0.013 |
| AB 400 μg | Change From Baseline in 1-hour Morning Post Forced Expiratory Volume in 1 Second (FEV1) | 0.156 Litres | Standard Error 0.013 |
| FF 12 μg | Change From Baseline in 1-hour Morning Post Forced Expiratory Volume in 1 Second (FEV1) | 0.138 Litres | Standard Error 0.013 |
| Placebo | Change From Baseline in 1-hour Morning Post Forced Expiratory Volume in 1 Second (FEV1) | -0.050 Litres | Standard Error 0.013 |
p-value: <0.00195% CI: [0.06, 0.124]Mixed Models Analysis
Primary
Change From Baseline in Morning Pre-dose (Trough) FEV1 for Aclidinium Bromide
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.
Time frame: Week 24, morning pre-dose (trough)
Population: Intention-to-Treat (ITT) population: All randomised participants who took at least one dose of IP and have a baseline FEV1 measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AB/FF 400/12 μg | Change From Baseline in Morning Pre-dose (Trough) FEV1 for Aclidinium Bromide | 0.081 Litres | Standard Error 0.014 |
| AB 400 μg | Change From Baseline in Morning Pre-dose (Trough) FEV1 for Aclidinium Bromide | 0.050 Litres | Standard Error 0.014 |
| FF 12 μg | Change From Baseline in Morning Pre-dose (Trough) FEV1 for Aclidinium Bromide | -0.004 Litres | Standard Error 0.014 |
| Placebo | Change From Baseline in Morning Pre-dose (Trough) FEV1 for Aclidinium Bromide | -0.084 Litres | Standard Error 0.014 |
p-value: <0.00195% CI: [0.103, 0.166]Mixed Models Analysis
Primary
Change From Baseline in Morning Pre-dose (Trough) FEV1 for Aclidinium Bromide/Formoterol Fumarate
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.
Time frame: Week 24, morning pre-dose (trough)
Population: Intention-to-Treat (ITT) population: All randomised participants who took at least one dose of IP and have a baseline FEV1 measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AB/FF 400/12 μg | Change From Baseline in Morning Pre-dose (Trough) FEV1 for Aclidinium Bromide/Formoterol Fumarate | 0.081 Litres | Standard Error 0.014 |
| AB 400 μg | Change From Baseline in Morning Pre-dose (Trough) FEV1 for Aclidinium Bromide/Formoterol Fumarate | 0.050 Litres | Standard Error 0.014 |
| FF 12 μg | Change From Baseline in Morning Pre-dose (Trough) FEV1 for Aclidinium Bromide/Formoterol Fumarate | -0.004 Litres | Standard Error 0.014 |
| Placebo | Change From Baseline in Morning Pre-dose (Trough) FEV1 for Aclidinium Bromide/Formoterol Fumarate | -0.084 Litres | Standard Error 0.014 |
p-value: <0.00195% CI: [0.053, 0.117]Mixed Models Analysis
Secondary
Change From Baseline in Peak FEV1
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.
Time frame: Week 24, peak
Population: Intention-to-Treat (ITT) population: All randomised participants who took at least one dose of IP and have a baseline FEV1 measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AB/FF 400/12 μg | Change From Baseline in Peak FEV1 | 0.324 Litres | Standard Error 0.013 |
| AB 400 μg | Change From Baseline in Peak FEV1 | 0.225 Litres | Standard Error 0.013 |
| FF 12 μg | Change From Baseline in Peak FEV1 | 0.191 Litres | Standard Error 0.014 |
| Placebo | Change From Baseline in Peak FEV1 | 0.008 Litres | Standard Error 0.014 |
p-value: <0.00195% CI: [0.184, 0.25]Mixed Models Analysis
Secondary
Change From Baseline in St Georges Respiratory Questionnaire (SGRQ) Total Score
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.
Time frame: Week 24
Population: Intention-to-Treat (ITT) population: All randomised participants who took at least one dose of IP and have a baseline FEV1 measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AB/FF 400/12 μg | Change From Baseline in St Georges Respiratory Questionnaire (SGRQ) Total Score | -8.7 Units on a scale | Standard Error 1.2 |
| AB 400 μg | Change From Baseline in St Georges Respiratory Questionnaire (SGRQ) Total Score | -7.6 Units on a scale | Standard Error 1.2 |
| FF 12 μg | Change From Baseline in St Georges Respiratory Questionnaire (SGRQ) Total Score | -7.2 Units on a scale | Standard Error 1.2 |
| Placebo | Change From Baseline in St Georges Respiratory Questionnaire (SGRQ) Total Score | -4.7 Units on a scale | Standard Error 1.2 |
p-value: 0.03195% CI: [-5.5, -0.3]Mixed Models Analysis
p-value: 0.00395% CI: [-6.7, -1.4]Mixed Models Analysis
Secondary
Improvements Transition Dyspnoea Index (TDI) Focal Score
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.
Time frame: Week 24
Population: Intention-to-Treat (ITT) population: All randomised participants who took at least one dose of IP and have a baseline FEV1 measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AB/FF 400/12 μg | Improvements Transition Dyspnoea Index (TDI) Focal Score | 2.9 Units on a scale | Standard Error 0.2 |
| AB 400 μg | Improvements Transition Dyspnoea Index (TDI) Focal Score | 2.6 Units on a scale | Standard Error 0.2 |
| FF 12 μg | Improvements Transition Dyspnoea Index (TDI) Focal Score | 2.4 Units on a scale | Standard Error 0.2 |
| Placebo | Improvements Transition Dyspnoea Index (TDI) Focal Score | 2.1 Units on a scale | Standard Error 0.3 |
p-value: 0.00595% CI: [0.2, 1.3]Mixed Models Analysis
p-value: 0.13295% CI: [-0.1, 1]Mixed Models Analysis