Chronic Obstructive Pulmonary Disease
Conditions
Keywords
Safety, Efficacy, Aclidinium bromide, Formoterol fumarate, Tiotropium, Bronchodilation, COPD
Brief summary
This is a multiple dose, randomized, parallel, double-blind, double-dummy, multicenter and multinational Phase III study to determine the efficacy and safety of Aclidinium bromide 400μg/Formoterol Fumarate (AB/FF) 12 μg compared to individual components and TIO (Tiotropium) 18 μg when administered to patients with stable chronic obstructive pulmonary disease (COPD).
Detailed description
This study was conducted to assess the bronchodilator efficacy and safety as well as effect on health related quality of life of AB/FF 400/12 μg compared to the individual components (AB 400 μg and FF 12 μg) in COPD patients. The trial duration of 24 weeks allows the assessment of the effect on symptoms improvement of the combined treatments versus individual components as well as the long term bronchodilation comparison between AB 400 μg and TIO 18 μg in minimizing the risk of COPD exacerbations in current or former smokers, aged ≥40 in symptomatic COPD patients.
Interventions
DRUGAclidinium bromide 400 μg/Formoterol Fumarate 12 μg (AB/FF 400/12 μg)
Inhalation powder
DRUGAclidinium bromide 400 μg (AB 400 μg)
Inhalation powder
DRUGFormoterol fumarate 12 μg (FF 12 μg)
Inhalation powder
OTHERPlacebo to AB/FF 400/12 μg, AB 400 μg and FF 12 μg
Inhalation powder
DRUGTiotropium 18 μg (TIO 18 μg)
Powder in capsules for oral inhalation
OTHERPlacebo to TIO 18 μg
Powder in capsules for oral inhalation
Sponsors
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
* Adult male or non-pregnant, non-lactating female patients aged ≥40. * Patients with diagnosis of moderate to very severe stable COPD: post-bronchodilator FEV1 \< 80% of the predicted normal and post-bronchodilator FEV1/FVC \< 70% at Screening Visit. * Symptomatic patients with a CAT score ≥10 at Screening and Randomization visit (Visits 1 and 2). * 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
* 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 D6571C00001. * Patients with predominant asthma. * 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. * Patients hospitalized for a COPD exacerbation (an emergency room visit for longer than 24 hours is considered a hospitalization) within 3 months prior to Screening Visit. * 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 Screening. * 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 centralised reading report assessed at Screening. * Patients with clinically significant abnormalities in the laboratory tests, ECG parameters (other than QTc) or in the physical examination at Screening Visit that might comprise patient safety. * Patient with known non-controlled history of infection with human immunodeficiency virus and/or active hepatitis. * Patient with a history of hypersensitivity reaction to inhaled medication or any component thereof, including paradoxical bronchospasm. * Patients with known narrow-angle glaucoma, symptomatic bladder neck obstruction, acute urinary retention or symptomatic non-stable 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 that cannot comply with the study procedures. * Patients treated with any investigational drug within 30 days (or 6 half-lives, whichever is longer) prior to Screening. * 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. Patients who demonstrate \< 80% compliance with the electronic diary during the run-in period.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 1-hour Morning Post-dose Dose Forced Expiratory Volume in 1 Second (FEV1) of AB/FF 400/12 μg Compared to AB 400 μg at Week 24 | At baseline 1-hour postdose and Week 24 | To assess the bronchodilatory effect by evaluating the mean changes from baseline in FEV1 at 1 hour post-dose of AB/FF 400/12 µg compared to AB 400 μg after administration of oral inhalation powder BID via DIP to participants with COPD. Baseline was defined as the average of the two FEV1 values measured just prior to the administration of the first dose of investigational product (IP) at randomization Visit. If one of the two was missing, then the available one would be used as baseline value. |
| Change From Baseline in Morning Predose (Trough) FEV1 of AB/FF 400/12 μg Compared to FF 12 μg at Week 24 | At baseline morning predose and Week 24 | To assess the bronchodilatory effect by evaluating the mean changes from baseline in FEV1 in morning pre-dose (trough) of AB/FF 400/12 µg compared to FF 12 μg after administration of oral inhalation powder BID via DPI to participants with COPD. Morning pre-dose (trough) FEV1 was defined as the average of the corresponding -30 minute and 0 minute before the morning study medication at Week 24. If one time-point was missing then the available one would be used as morning pre-dose. |
| Change From Baseline in Morning Predose (Trough) FEV1 at Week 24 Comparing AB 400 μg Versus TIO 18 μg to Demonstrate Non-inferiority | At baseline morning predose and Week 24 | To assess the non-inferior bronchodilatory effect by evaluating the mean changes from baseline in FEV1 in morning pre-dose (trough)of AB 400 µg compared to TIO 18 μg after administration of oral inhalation powder BID via DPI to participants with COPD. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Normalized Area Under Curve 3hours Post-dose (nAUC0-3/3h) FEV1 of AB/FF 400/12 μg Compared to AB 400 μg and and FF 12 μg at Week 24 | At Day 1 and Day 169 | To assess the bronchodilatory effect by evaluating the mean changes from baseline in nAUC0-3/3h FEV1 of AB/FF 400/12 µg compared to AB 400 μg and and FF 12 μg after administration of oral inhalation powder BID via DPI to participants with COPD. |
| Responder (Number of Participants) Analysis of St. George's Respiratory Questionnaire (SGRQ) Total Score With AB/FF 400/12 μg Versus AB 400 μg and FF 12 μg. | At baseline and Week 24 | SGRQ was a A standardized self-completed tool used to measure impaired health and perceived well-being (quality of life) in respiratory diseases. The questionnaire contained 50 items divided into 3 (symptoms, activity and impacts) dimensions. Each of the three dimensions of the questionnaire is scored separately in the range from 0 to 100%, zero score indicating no impairment of life quality. A summary score utilizing responses to all items is the total SGRQ score which also ranges from 0 to 100%. The SGRQ scores are calculated using weights attached to each item of the questionnaire which provides an estimate of the distress associated with the symptoms or state described in each item. Higher scores indicate poorer health. A decrease of at least 4 units in the SGRQ total score has been established as the criterion for minimal meaningful improvement. SGRQ responders will be those with a decrease in SGRQ total score of at least 4 units from baseline. |
Countries
Bulgaria, Czechia, Germany, Hungary, Israel, Poland, Spain, Ukraine, United Kingdom, United States
Participant flow
Recruitment details
Study was conducted on participants with stable chronic obstructive pulmonary disease (COPD), in 11 countries: United States (US), Germany, Poland, Hungary, Bulgaria, Ukraine, United Kingdom (UK), Czech Republic, Spain, Israel & Russia (was not finally started). First participant enrolled was 05 July 2016 & participant last visit was 08 June 2017
Pre-assignment details
Eligible Participants signed informed consent form (ICF) & entered screening (Run-in) period (14 ± 3 days), inclusion/exclusion criteria were checked by medical & COPD history, physical examination, laboratory analysis, electrocardiogram, & COPD severity (COPD Assessment Test \[CAT\] & post-bronchodilator forced expiratory volume in 1 second \[FEV1\])
Participants by arm
| Arm | Count |
|---|---|
| Aclidinium Bromide (AB)/Formoterol Fumarate (FF) 400/12 μg Randomized participants received AB 400 μg/FF 12 μg oral inhalation powder twice daily (BID) via dry powder inhaler (DPI). | 314 |
| AB 400 μg Randomized participants received AB 400 μg oral inhalation powder BID via DPI. | 475 |
| FF 12 μg Randomized participants received FF 12 μg oral inhalation powder BID via DPI. | 319 |
| Tiotropium (TIO) 18 μg Randomized participants received TIO 18 μg oral inhalation powder in capsule BID via DPI. | 475 |
| Total | 1,583 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 11 | 22 | 14 | 14 |
| Overall Study | Lack of Efficacy | 7 | 9 | 14 | 20 |
| Overall Study | Lost to Follow-up | 1 | 5 | 2 | 2 |
| Overall Study | Progressive disease | 6 | 15 | 13 | 18 |
| Overall Study | Protocol Violation | 7 | 5 | 4 | 8 |
| Overall Study | Reason not mentioned | 2 | 3 | 0 | 5 |
| Overall Study | Withdrawal by Subject | 4 | 14 | 6 | 7 |
Baseline characteristics
| Characteristic | Aclidinium Bromide (AB)/Formoterol Fumarate (FF) 400/12 μg | Total | Tiotropium (TIO) 18 μg | FF 12 μg | AB 400 μg |
|---|---|---|---|---|---|
| Age, Continuous | 64.4 Years STANDARD_DEVIATION 8.5 | 64.3 Years STANDARD_DEVIATION 8.4 | 64.0 Years STANDARD_DEVIATION 8.6 | 64.7 Years STANDARD_DEVIATION 8.3 | 64.4 Years STANDARD_DEVIATION 8.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 4 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 17 Participants | 77 Participants | 16 Participants | 16 Participants | 28 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 | 297 Participants | 1501 Participants | 457 Participants | 303 Participants | 444 Participants |
| Sex: Female, Male Female | 121 Participants | 620 Participants | 199 Participants | 129 Participants | 171 Participants |
| Sex: Female, Male Male | 193 Participants | 963 Participants | 276 Participants | 190 Participants | 304 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 | 1 / 314 | 1 / 475 | 4 / 319 | 2 / 475 |
| other Total, other adverse events | 173 / 314 | 222 / 475 | 178 / 319 | 241 / 475 |
| serious Total, serious adverse events | 23 / 314 | 41 / 475 | 22 / 319 | 37 / 475 |
Outcome results
Primary
Change From Baseline in 1-hour Morning Post-dose Dose Forced Expiratory Volume in 1 Second (FEV1) of AB/FF 400/12 μg Compared to AB 400 μg at Week 24
To assess the bronchodilatory effect by evaluating the mean changes from baseline in FEV1 at 1 hour post-dose of AB/FF 400/12 µg compared to AB 400 μg after administration of oral inhalation powder BID via DIP to participants with COPD. Baseline was defined as the average of the two FEV1 values measured just prior to the administration of the first dose of investigational product (IP) at randomization Visit. If one of the two was missing, then the available one would be used as baseline value.
Time frame: At baseline 1-hour postdose and Week 24
Population: Intention-to Treat (ITT) population: All randomized participants who took at least one dose of IP and had at least a baseline FEV1, under the ITT principle and regardless the adherence to the randomized treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AB/FF 400/12 μg | Change From Baseline in 1-hour Morning Post-dose Dose Forced Expiratory Volume in 1 Second (FEV1) of AB/FF 400/12 μg Compared to AB 400 μg at Week 24 | 0.253 Litres | Standard Error 0.013 |
| AB 400 μg | Change From Baseline in 1-hour Morning Post-dose Dose Forced Expiratory Volume in 1 Second (FEV1) of AB/FF 400/12 μg Compared to AB 400 μg at Week 24 | 0.169 Litres | Standard Error 0.011 |
| FF 12 μg | Change From Baseline in 1-hour Morning Post-dose Dose Forced Expiratory Volume in 1 Second (FEV1) of AB/FF 400/12 μg Compared to AB 400 μg at Week 24 | 0.168 Litres | Standard Error 0.013 |
| TIO 18 μg | Change From Baseline in 1-hour Morning Post-dose Dose Forced Expiratory Volume in 1 Second (FEV1) of AB/FF 400/12 μg Compared to AB 400 μg at Week 24 | 0.161 Litres | Standard Error 0.011 |
p-value: <0.000195% CI: [0.051, 0.117]Mixed model for repeated measures
Primary
Change From Baseline in Morning Predose (Trough) FEV1 at Week 24 Comparing AB 400 μg Versus TIO 18 μg to Demonstrate Non-inferiority
To assess the non-inferior bronchodilatory effect by evaluating the mean changes from baseline in FEV1 in morning pre-dose (trough)of AB 400 µg compared to TIO 18 μg after administration of oral inhalation powder BID via DPI to participants with COPD.
Time frame: At baseline morning predose and Week 24
Population: Per-Protocol (PP) population: A subset of the ITT population, consisted of participants who met all inclusion/exclusion criteria liable to affect the efficacy assessment, had sufficient treatment compliance, and did not present serious deviations of the protocol that might affect efficacy.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AB/FF 400/12 μg | Change From Baseline in Morning Predose (Trough) FEV1 at Week 24 Comparing AB 400 μg Versus TIO 18 μg to Demonstrate Non-inferiority | 0.064 Litres | Standard Error 0.013 |
| AB 400 μg | Change From Baseline in Morning Predose (Trough) FEV1 at Week 24 Comparing AB 400 μg Versus TIO 18 μg to Demonstrate Non-inferiority | 0.057 Litres | Standard Error 0.013 |
p-value: 0.637795% CI: [-0.021, 0.035]Mixed model for repeated measures
Primary
Change From Baseline in Morning Predose (Trough) FEV1 of AB/FF 400/12 μg Compared to FF 12 μg at Week 24
To assess the bronchodilatory effect by evaluating the mean changes from baseline in FEV1 in morning pre-dose (trough) of AB/FF 400/12 µg compared to FF 12 μg after administration of oral inhalation powder BID via DPI to participants with COPD. Morning pre-dose (trough) FEV1 was defined as the average of the corresponding -30 minute and 0 minute before the morning study medication at Week 24. If one time-point was missing then the available one would be used as morning pre-dose.
Time frame: At baseline morning predose and Week 24
Population: ITT population: All randomized participants who took at least one dose of IP and had at least a baseline FEV1, under the ITT principle and regardless the adherence to the randomized treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AB/FF 400/12 μg | Change From Baseline in Morning Predose (Trough) FEV1 of AB/FF 400/12 μg Compared to FF 12 μg at Week 24 | 0.080 Litres | Standard Error 0.014 |
| AB 400 μg | Change From Baseline in Morning Predose (Trough) FEV1 of AB/FF 400/12 μg Compared to FF 12 μg at Week 24 | 0.066 Litres | Standard Error 0.012 |
| FF 12 μg | Change From Baseline in Morning Predose (Trough) FEV1 of AB/FF 400/12 μg Compared to FF 12 μg at Week 24 | 0.025 Litres | Standard Error 0.014 |
| TIO 18 μg | Change From Baseline in Morning Predose (Trough) FEV1 of AB/FF 400/12 μg Compared to FF 12 μg at Week 24 | 0.060 Litres | Standard Error 0.012 |
p-value: 0.000995% CI: [0.023, 0.088]Mixed model for repeated measures
Secondary
Change From Baseline in Normalized Area Under Curve 3hours Post-dose (nAUC0-3/3h) FEV1 of AB/FF 400/12 μg Compared to AB 400 μg and and FF 12 μg at Week 24
To assess the bronchodilatory effect by evaluating the mean changes from baseline in nAUC0-3/3h FEV1 of AB/FF 400/12 µg compared to AB 400 μg and and FF 12 μg after administration of oral inhalation powder BID via DPI to participants with COPD.
Time frame: At Day 1 and Day 169
Population: ITT population: All randomized participants who took at least one dose of IP and had at least a baseline FEV1, under the ITT principle and regardless the adherence to the randomized treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AB/FF 400/12 μg | Change From Baseline in Normalized Area Under Curve 3hours Post-dose (nAUC0-3/3h) FEV1 of AB/FF 400/12 μg Compared to AB 400 μg and and FF 12 μg at Week 24 | 0.237 Litres | Standard Error 0.013 |
| AB 400 μg | Change From Baseline in Normalized Area Under Curve 3hours Post-dose (nAUC0-3/3h) FEV1 of AB/FF 400/12 μg Compared to AB 400 μg and and FF 12 μg at Week 24 | 0.162 Litres | Standard Error 0.01 |
| FF 12 μg | Change From Baseline in Normalized Area Under Curve 3hours Post-dose (nAUC0-3/3h) FEV1 of AB/FF 400/12 μg Compared to AB 400 μg and and FF 12 μg at Week 24 | 0.149 Litres | Standard Error 0.013 |
| TIO 18 μg | Change From Baseline in Normalized Area Under Curve 3hours Post-dose (nAUC0-3/3h) FEV1 of AB/FF 400/12 μg Compared to AB 400 μg and and FF 12 μg at Week 24 | 0.151 Litres | Standard Error 0.01 |
p-value: <0.000195% CI: [0.043, 0.107]Mixed model for repeated measures
p-value: <0.000195% CI: [0.052, 0.122]Mixed model for repeated measures
Secondary
Responder (Number of Participants) Analysis of St. George's Respiratory Questionnaire (SGRQ) Total Score With AB/FF 400/12 μg Versus AB 400 μg and FF 12 μg.
SGRQ was a A standardized self-completed tool used to measure impaired health and perceived well-being (quality of life) in respiratory diseases. The questionnaire contained 50 items divided into 3 (symptoms, activity and impacts) dimensions. Each of the three dimensions of the questionnaire is scored separately in the range from 0 to 100%, zero score indicating no impairment of life quality. A summary score utilizing responses to all items is the total SGRQ score which also ranges from 0 to 100%. The SGRQ scores are calculated using weights attached to each item of the questionnaire which provides an estimate of the distress associated with the symptoms or state described in each item. Higher scores indicate poorer health. A decrease of at least 4 units in the SGRQ total score has been established as the criterion for minimal meaningful improvement. SGRQ responders will be those with a decrease in SGRQ total score of at least 4 units from baseline.
Time frame: At baseline and Week 24
Population: ITT population: All randomized participants who took at least one dose of IP and had at least a baseline FEV1, under the ITT principle and regardless the adherence to the randomized treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AB/FF 400/12 μg | Responder (Number of Participants) Analysis of St. George's Respiratory Questionnaire (SGRQ) Total Score With AB/FF 400/12 μg Versus AB 400 μg and FF 12 μg. | Number of responders -Yes | 130 Participants |
| AB/FF 400/12 μg | Responder (Number of Participants) Analysis of St. George's Respiratory Questionnaire (SGRQ) Total Score With AB/FF 400/12 μg Versus AB 400 μg and FF 12 μg. | Number of responders- NO | 140 Participants |
| AB 400 μg | Responder (Number of Participants) Analysis of St. George's Respiratory Questionnaire (SGRQ) Total Score With AB/FF 400/12 μg Versus AB 400 μg and FF 12 μg. | Number of responders- NO | 195 Participants |
| AB 400 μg | Responder (Number of Participants) Analysis of St. George's Respiratory Questionnaire (SGRQ) Total Score With AB/FF 400/12 μg Versus AB 400 μg and FF 12 μg. | Number of responders -Yes | 188 Participants |
| FF 12 μg | Responder (Number of Participants) Analysis of St. George's Respiratory Questionnaire (SGRQ) Total Score With AB/FF 400/12 μg Versus AB 400 μg and FF 12 μg. | Number of responders -Yes | 128 Participants |
| FF 12 μg | Responder (Number of Participants) Analysis of St. George's Respiratory Questionnaire (SGRQ) Total Score With AB/FF 400/12 μg Versus AB 400 μg and FF 12 μg. | Number of responders- NO | 130 Participants |
| TIO 18 μg | Responder (Number of Participants) Analysis of St. George's Respiratory Questionnaire (SGRQ) Total Score With AB/FF 400/12 μg Versus AB 400 μg and FF 12 μg. | Number of responders -Yes | 197 Participants |
| TIO 18 μg | Responder (Number of Participants) Analysis of St. George's Respiratory Questionnaire (SGRQ) Total Score With AB/FF 400/12 μg Versus AB 400 μg and FF 12 μg. | Number of responders- NO | 192 Participants |
p-value: 0.871495% CI: [0.61, 1.51]Logistic random-effect model
p-value: 0.887395% CI: [0.59, 1.58]Logistic random-effect model