Chronic Obstructive Pulmonary Disease (COPD)
Conditions
Brief summary
The purpose of this study is to assess the effect of aclidinium bromide compared with placebo in improving dilatation of the airways (bronchodilation), symptoms of chronic obstructive pulmonary disease (COPD), sleep quality and physical activity after 3 weeks of treatment with aclidinium bromide 400 μg administered twice daily in patients with stable moderate-and-severe COPD.
Interventions
DRUGPlacebo
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult male or non-pregnant, non-lactating female aged ≥40 years. Women of childbearing potential will follow specific study requirements (negative serum pregnancy test at the Screening Visit and are using, over the last two months before the Screening Visit, at least one medically approved and highly effective method of birth control * Current or ex-cigarette smoker (patients who quit smoking more than 6 months prior to the Screening Visit), with a smoking history of at least 10 pack-years. * Patients with a clinical diagnosis of chronic obstructive pulmonary disease (COPD) according to GOLD guidelines 2013, with a post bronchodilator FEV1 \<80%, and FEV1 ≥ 40% at Screening Visit * Patients must be able to perform repeatable pulmonary function testing for FEV1 according to American Thoracic Society \[ATS\]/European Respiratory Society \[ERS\] 2005 criteria at Screening Visit * Patients who are eligible and able to participate in the study and who consents to do so in writing after the purpose and nature of the investigation have been explained
Exclusion criteria
* History or current diagnosis of asthma * Patients with moderate to severe sleep apnoea assessed at screening * Patients who develop a respiratory tract infection or COPD exacerbation within 6 weeks (or 3 months if hospitalisation was required) before the Screening Visit (Visit 1) or during the run-in period * Clinically significant respiratory conditions * Patients with Type I or uncontrolled Type II diabetes, uncontrolled hypo-or hyperthyroidism, hypokalaemia, or hyperadrenergic state, uncontrolled or untreated hypertension * Patients who may need to start a pulmonary rehabilitation program during the study and/or patients who started/finished it within 3 months prior to the Screening Visit * Use of long-term oxygen therapy (15 hours/day) * Patients who does not maintain regular day/night, waking/sleeping cycles including night shift workers * Clinically significant cardiovascular conditions * QTc \>470 milliseconds in the manual ECG reading performed at Screening Visit * Patients with clinically relevant abnormalities in the opinion of the investigator at the Screening Visit (Visit 1) in the results of the clinical laboratory tests, ECG parameters or in the physical examination) * Patients with a history of hypersensitivity reaction to inhaled anticholinergics, long and short acting β2-agonists, sympathomimetic amines, or inhaled medication or any component there of (including report of paradoxical bronchospasm) * Patients with known narrow-angle glaucoma, symptomatic bladder neck obstruction, acute urinary retention, or patients with symptomatic non-stable prostatic hypertrophy * Patients with known non-controlled history of human immunodeficiency virus (HIV) infection and/or active hepatitis * 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, or moderate-to-severe depression, as confirmed by Beck Depression Inventory (BDI-II) total score \>28. * Patients with a history (within 2 years prior to the Screening Visit) of drug and/or alcohol abuse that may prevent study compliance based on investigator judgment * Patients unlikely to be cooperative or that can't comply with the study procedures. * Patients treated with any investigational drug within 30 days (or 6 half-lives, whichever is longer) prior to the Screening Visit * Patients who intends to use any concomitant medication not permitted by this protocol or who have not undergone the required stabilization periods for prohibited medication * Any other conditions that, in the investigator's opinion, might indicate the patient to be unsuitable for the study
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change From Baseline in Normalized Forced Expiratory Volume in One Second (FEV1) AUC0-24hr | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 11, 12, 12.5, 13, 14, 15, 16, 19, 22, 23, and 24 hours at Week 3 of treatment |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Peak FEV1 | Week 3 of treatment | — |
| Change From Baseline in Normalized FEV1 AUC0-12hr | 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 11 and 12 hours at Week 3 of treatment | — |
| Change From Baseline in Normalized FEV1 AUC12-24hr | 12, 12.5, 13, 14, 15, 16, 19, 22, 23, and 24 hours at Week 3 of treatment | — |
| Change From Baseline in the Average Rating of Overall Early Morning COPD Symptom Severity | Week 3 of treatment | Night-time and early-morning symptoms were recorded every morning using the Early-Morning Symptoms of COPD Instrument \[EMSCI\] and the Night-time Symptoms of COPD Instrument \[NiSCI\]. Scores ranged from 0 (no symptoms) to 4 (very severe symptoms). The questionnaires also evaluated nocturnal awakenings and limitation of early-morning activities (scores ranged from 0 \[no limitation\] to 4 \[a very great deal\]). Symptoms assessed over 24 weeks included change from baseline in the severity of night-time and early-morning cough, wheezing, shortness of breath and difficulty bringing up phlegm, overall night-time and early-morning symptom severity, number of nocturnal awakenings and limitation of early-morning activities due to COPD symptoms |
| Change From Baseline in the Average Rating of Overall Evening COPD Symptom Severity | Week 3 of treatment | The evening symptoms questionnaire was filled out after the second medication administration of the day and before bedtime. Scores ranged from 0 (no symptoms) to 4 (very severe symptoms). Symptoms assessed over 24 weeks included change from baseline in the severity of evening cough, wheezing, shortness of breath and tightness of the chest, chest congestion, difficulty bringing up phlegm, overall evening symptom severity, and limitation of evening activities due to COPD symptoms |
| Change From Baseline in the Average Rating of Overall Night-time COPD Symptom Severity | Week 3 of treatment | Night-time and early-morning symptoms were recorded every morning using the Early-Morning Symptoms of COPD Instrument \[EMSCI\] and the Night-time Symptoms of COPD Instrument \[NiSCI\]. Scores ranged from 0 (no symptoms) to 4 (very severe symptoms). The questionnaires also evaluated nocturnal awakenings and limitation of early-morning activities (scores ranged from 0 \[no limitation\] to 4 \[a very great deal\]). Symptoms assessed over 24 weeks included change from baseline in the severity of night-time and early-morning cough, wheezing, shortness of breath and difficulty bringing up phlegm, overall night-time and early-morning symptom severity, number of nocturnal awakenings and limitation of early-morning activities due to COPD symptoms |
| Change From Baseline in the Average Rating of COPD Symptoms Limiting Early Morning Activities | Week 3 of treatment | Night-time and early-morning symptoms were recorded every morning using the Early-Morning Symptoms of COPD Instrument \[EMSCI\] and the Night-time Symptoms of COPD Instrument \[NiSCI\]. Scores ranged from 0 (no symptoms) to 4 (very severe symptoms). The questionnaires also evaluated nocturnal awakenings and limitation of early-morning activities (scores ranged from 0 \[no limitation\] to 4 \[a very great deal\]). Symptoms assessed over 24 weeks included change from baseline in the severity of night-time and early-morning cough, wheezing, shortness of breath and difficulty bringing up phlegm, overall night-time and early-morning symptom severity, number of nocturnal awakenings and limitation of early-morning activities due to COPD symptoms |
| Change From Baseline in Morning Trough FEV1 | Week 3 of treatment | — |
| Change From Baseline in Apnea-hypopnea Index (AHI) Per Hour of Total Sleep Time | Week 3 of treatment | The Apnea Hypopnea Index (AHI) is used to indicate the severity of obstructive sleep apnea. The AHI is the number of apneas or hypopneas recorded during the study per hour of sleep |
| Change From Baseline in Oxygen Desaturation Index (ODI) Per Hour of Total Sleep Time | Week 3 of treatment | The oxygen desaturation index (ODI) is the number of times per hour of sleep that the blood's oxygen level drop by a certain degree from baseline. In this study, any event with a 4% decrease in blood oxygen levels counted towards the total |
| Change From Baseline in Proportion of Sleep Stage REM as a Percentage of Total Sleep Time | Week 3 of treatment | — |
| Change From Baseline in Sleep Efficiency | Week 3 of treatment | Sleep efficiency is calculated as the total sleep time as a proportion of total time in bed |
| Change From Baseline in Total Sleep Time | Week 3 of treatment | — |
| Change From Baseline in Duration of at Least Moderate Activity | Week 3 of treatment | Moderate activity was defined as any physical activity \>3 metabolic equivalents |
| Change From Baseline in Number of Steps Per Day | Week 3 of treatment | — |
| Change From Baseline in the Average Rating of COPD Symptoms Limiting Evening Activities | Week 3 of treatment | The evening symptoms questionnaire was filled out after the second medication administration of the day and before bedtime. Scores ranged from 0 (no symptoms) to 4 (very severe symptoms). Symptoms assessed over 24 weeks included change from baseline in the severity of evening cough, wheezing, shortness of breath and tightness of the chest, chest congestion, difficulty bringing up phlegm, overall evening symptom severity, and limitation of evening activities due to COPD symptoms |
Countries
Germany
Participant flow
Recruitment details
This study was conducted by 3 investigators at 3 sites in Germany. The first patient was screened in April 2014 and the last patient visit was in June 2015
Pre-assignment details
All patients who met the study entry criteria and completed the screening assessments and the 7-day run-in period were randomized. Nine (9/39) subjects were not randomized due to screening failure (primarily for non-fulfillment of inclusion/exclusion criteria)
Participants by arm
| Arm | Count |
|---|---|
| Overall Study All patients participating in the crossover study | 30 |
| Total | 30 |
Baseline characteristics
| Characteristic | Overall Study |
|---|---|
| Age, Continuous | 64.4 Years STANDARD_DEVIATION 7 |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 30 | 0 / 30 |
| serious Total, serious adverse events | 0 / 30 | 0 / 30 |
Outcome results
Primary
Change From Baseline in Normalized Forced Expiratory Volume in One Second (FEV1) AUC0-24hr
Time frame: 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 11, 12, 12.5, 13, 14, 15, 16, 19, 22, 23, and 24 hours at Week 3 of treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aclidinium | Change From Baseline in Normalized Forced Expiratory Volume in One Second (FEV1) AUC0-24hr | 0.0953 L/sec*hr | Standard Error 0.0381 |
| Placebo | Change From Baseline in Normalized Forced Expiratory Volume in One Second (FEV1) AUC0-24hr | -0.0429 L/sec*hr | Standard Error 0.0381 |
Other Pre-specified
Change From Baseline in Apnea-hypopnea Index (AHI) Per Hour of Total Sleep Time
The Apnea Hypopnea Index (AHI) is used to indicate the severity of obstructive sleep apnea. The AHI is the number of apneas or hypopneas recorded during the study per hour of sleep
Time frame: Week 3 of treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aclidinium | Change From Baseline in Apnea-hypopnea Index (AHI) Per Hour of Total Sleep Time | 0.4767 Events/hr | Standard Error 0.4478 |
| Placebo | Change From Baseline in Apnea-hypopnea Index (AHI) Per Hour of Total Sleep Time | 0.7700 Events/hr | Standard Error 0.4478 |
Other Pre-specified
Change From Baseline in Duration of at Least Moderate Activity
Moderate activity was defined as any physical activity \>3 metabolic equivalents
Time frame: Week 3 of treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aclidinium | Change From Baseline in Duration of at Least Moderate Activity | 9.4460 Minutes | Standard Error 6.7081 |
| Placebo | Change From Baseline in Duration of at Least Moderate Activity | -8.5943 Minutes | Standard Error 6.5879 |
Other Pre-specified
Change From Baseline in Morning Trough FEV1
Time frame: Week 3 of treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aclidinium | Change From Baseline in Morning Trough FEV1 | 0.1128 Liters/sec | Standard Error 0.0395 |
| Placebo | Change From Baseline in Morning Trough FEV1 | -0.0106 Liters/sec | Standard Error 0.0395 |
Other Pre-specified
Change From Baseline in Normalized FEV1 AUC0-12hr
Time frame: 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 11 and 12 hours at Week 3 of treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aclidinium | Change From Baseline in Normalized FEV1 AUC0-12hr | 0.1394 L/sec*hr | Standard Error 0.0406 |
| Placebo | Change From Baseline in Normalized FEV1 AUC0-12hr | -0.0100 L/sec*hr | Standard Error 0.0406 |
Other Pre-specified
Change From Baseline in Normalized FEV1 AUC12-24hr
Time frame: 12, 12.5, 13, 14, 15, 16, 19, 22, 23, and 24 hours at Week 3 of treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aclidinium | Change From Baseline in Normalized FEV1 AUC12-24hr | 0.0513 L/sec*hr | Standard Error 0.0369 |
| Placebo | Change From Baseline in Normalized FEV1 AUC12-24hr | -0.0758 L/sec*hr | Standard Error 0.0369 |
Other Pre-specified
Change From Baseline in Number of Steps Per Day
Time frame: Week 3 of treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aclidinium | Change From Baseline in Number of Steps Per Day | 268.5891 Number of steps per day | Standard Error 326.3649 |
| Placebo | Change From Baseline in Number of Steps Per Day | 22.2652 Number of steps per day | Standard Error 320.6754 |
Other Pre-specified
Change From Baseline in Oxygen Desaturation Index (ODI) Per Hour of Total Sleep Time
The oxygen desaturation index (ODI) is the number of times per hour of sleep that the blood's oxygen level drop by a certain degree from baseline. In this study, any event with a 4% decrease in blood oxygen levels counted towards the total
Time frame: Week 3 of treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aclidinium | Change From Baseline in Oxygen Desaturation Index (ODI) Per Hour of Total Sleep Time | -0.3033 Events/hr | Standard Error 0.9754 |
| Placebo | Change From Baseline in Oxygen Desaturation Index (ODI) Per Hour of Total Sleep Time | 2.2400 Events/hr | Standard Error 0.9754 |
Other Pre-specified
Change From Baseline in Peak FEV1
Time frame: Week 3 of treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aclidinium | Change From Baseline in Peak FEV1 | 0.1605 Liters/sec | Standard Error 0.0391 |
| Placebo | Change From Baseline in Peak FEV1 | -0.0149 Liters/sec | Standard Error 0.0391 |
Other Pre-specified
Change From Baseline in Proportion of Sleep Stage REM as a Percentage of Total Sleep Time
Time frame: Week 3 of treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aclidinium | Change From Baseline in Proportion of Sleep Stage REM as a Percentage of Total Sleep Time | 1.4100 Percentage of total sleep time | Standard Error 0.9851 |
| Placebo | Change From Baseline in Proportion of Sleep Stage REM as a Percentage of Total Sleep Time | -1.1167 Percentage of total sleep time | Standard Error 0.9851 |
Other Pre-specified
Change From Baseline in Sleep Efficiency
Sleep efficiency is calculated as the total sleep time as a proportion of total time in bed
Time frame: Week 3 of treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aclidinium | Change From Baseline in Sleep Efficiency | 1.0000 Percentage of total time in bed | Standard Error 2.4046 |
| Placebo | Change From Baseline in Sleep Efficiency | -2.5500 Percentage of total time in bed | Standard Error 2.4046 |
Other Pre-specified
Change From Baseline in the Average Rating of COPD Symptoms Limiting Early Morning Activities
Night-time and early-morning symptoms were recorded every morning using the Early-Morning Symptoms of COPD Instrument \[EMSCI\] and the Night-time Symptoms of COPD Instrument \[NiSCI\]. Scores ranged from 0 (no symptoms) to 4 (very severe symptoms). The questionnaires also evaluated nocturnal awakenings and limitation of early-morning activities (scores ranged from 0 \[no limitation\] to 4 \[a very great deal\]). Symptoms assessed over 24 weeks included change from baseline in the severity of night-time and early-morning cough, wheezing, shortness of breath and difficulty bringing up phlegm, overall night-time and early-morning symptom severity, number of nocturnal awakenings and limitation of early-morning activities due to COPD symptoms
Time frame: Week 3 of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aclidinium | Change From Baseline in the Average Rating of COPD Symptoms Limiting Early Morning Activities | -0.02 Score on a scale | Standard Deviation 0.457 |
| Placebo | Change From Baseline in the Average Rating of COPD Symptoms Limiting Early Morning Activities | 0.16 Score on a scale | Standard Deviation 0.43 |
Other Pre-specified
Change From Baseline in the Average Rating of COPD Symptoms Limiting Evening Activities
The evening symptoms questionnaire was filled out after the second medication administration of the day and before bedtime. Scores ranged from 0 (no symptoms) to 4 (very severe symptoms). Symptoms assessed over 24 weeks included change from baseline in the severity of evening cough, wheezing, shortness of breath and tightness of the chest, chest congestion, difficulty bringing up phlegm, overall evening symptom severity, and limitation of evening activities due to COPD symptoms
Time frame: Week 3 of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aclidinium | Change From Baseline in the Average Rating of COPD Symptoms Limiting Evening Activities | -0.18 Score on a scale | Standard Deviation 0.488 |
| Placebo | Change From Baseline in the Average Rating of COPD Symptoms Limiting Evening Activities | 0.03 Score on a scale | Standard Deviation 0.45 |
Other Pre-specified
Change From Baseline in the Average Rating of Overall Early Morning COPD Symptom Severity
Night-time and early-morning symptoms were recorded every morning using the Early-Morning Symptoms of COPD Instrument \[EMSCI\] and the Night-time Symptoms of COPD Instrument \[NiSCI\]. Scores ranged from 0 (no symptoms) to 4 (very severe symptoms). The questionnaires also evaluated nocturnal awakenings and limitation of early-morning activities (scores ranged from 0 \[no limitation\] to 4 \[a very great deal\]). Symptoms assessed over 24 weeks included change from baseline in the severity of night-time and early-morning cough, wheezing, shortness of breath and difficulty bringing up phlegm, overall night-time and early-morning symptom severity, number of nocturnal awakenings and limitation of early-morning activities due to COPD symptoms
Time frame: Week 3 of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aclidinium | Change From Baseline in the Average Rating of Overall Early Morning COPD Symptom Severity | -0.07 Score on a scale | Standard Deviation 0.575 |
| Placebo | Change From Baseline in the Average Rating of Overall Early Morning COPD Symptom Severity | 0.09 Score on a scale | Standard Deviation 0.476 |
Other Pre-specified
Change From Baseline in the Average Rating of Overall Evening COPD Symptom Severity
The evening symptoms questionnaire was filled out after the second medication administration of the day and before bedtime. Scores ranged from 0 (no symptoms) to 4 (very severe symptoms). Symptoms assessed over 24 weeks included change from baseline in the severity of evening cough, wheezing, shortness of breath and tightness of the chest, chest congestion, difficulty bringing up phlegm, overall evening symptom severity, and limitation of evening activities due to COPD symptoms
Time frame: Week 3 of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aclidinium | Change From Baseline in the Average Rating of Overall Evening COPD Symptom Severity | -0.15 Score on a scale | Standard Deviation 0.661 |
| Placebo | Change From Baseline in the Average Rating of Overall Evening COPD Symptom Severity | 0.11 Score on a scale | Standard Deviation 0.559 |
Other Pre-specified
Change From Baseline in the Average Rating of Overall Night-time COPD Symptom Severity
Night-time and early-morning symptoms were recorded every morning using the Early-Morning Symptoms of COPD Instrument \[EMSCI\] and the Night-time Symptoms of COPD Instrument \[NiSCI\]. Scores ranged from 0 (no symptoms) to 4 (very severe symptoms). The questionnaires also evaluated nocturnal awakenings and limitation of early-morning activities (scores ranged from 0 \[no limitation\] to 4 \[a very great deal\]). Symptoms assessed over 24 weeks included change from baseline in the severity of night-time and early-morning cough, wheezing, shortness of breath and difficulty bringing up phlegm, overall night-time and early-morning symptom severity, number of nocturnal awakenings and limitation of early-morning activities due to COPD symptoms
Time frame: Week 3 of treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aclidinium | Change From Baseline in the Average Rating of Overall Night-time COPD Symptom Severity | -0.14 Score on a scale | Standard Deviation 0.612 |
| Placebo | Change From Baseline in the Average Rating of Overall Night-time COPD Symptom Severity | -0.03 Score on a scale | Standard Deviation 0.526 |
Other Pre-specified
Change From Baseline in Total Sleep Time
Time frame: Week 3 of treatment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aclidinium | Change From Baseline in Total Sleep Time | 6.9200 Minutes | Standard Error 11.5802 |
| Placebo | Change From Baseline in Total Sleep Time | -11.8500 Minutes | Standard Error 11.5802 |