Chronic Obstructive Pulmonary Disease
Conditions
Keywords
Chronic obstructive pulmonary disease (COPD), respiratory, long-acting beta agonist (LABA)
Brief summary
This is a multi-center study to evaluate the long-term safety of arformoterol 15 mcg twice daily (BID) in the treatment of subjects with moderate-to-severe COPD. Study participation will consist of a total of 6 visits over approximately 1 year.
Detailed description
This is a multi-center, double-blind, randomized, placebo-controlled, parallel-group, outpatient, safety study to evaluate the long-term safety of arformoterol 15 mcg twice daily (BID) in the treatment of subjects with moderate-to-severe COPD. The administration of arformoterol in subjects with moderate to severe COPD will not result in a meaningfully greater incidence of respiratory death and COPD exacerbation -related hospitalizations compared to placebo (nebulized saline and non-long-acting beta2-agonist \[LABA\] COPD standard of care treatments). This study was previously posted by Sepracor Inc. In October 2009, Sepracor Inc. was acquired by Dainippon Sumitomo Pharma., and in October 2010, Sepracor Inc's name was changed to Sunovion Pharmaceuticals Inc.
Interventions
DRUGArformoterol
Arformoterol Tartrate Inhalation Solution 15 mcg twice daily (BID) for a duration of one year
DRUGPlacebo
Placebo inhalation solution, twice daily (BID) for a duration of one year.
Sponsors
Sumitomo Pharma America, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
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
* Subject must give written informed consent, including privacy authorization as well as adherence to concomitant medication withholding periods, prior to participation. * Females considered not of childbearing potential must be surgically sterile (total hysterectomy, bilateral salpingo oophorectomy, or tubal ligation) or post-menopausal, which is defined as a complete cessation of menstruation for at least 1 year. * Male and female subjects must be at least 40 years old at the time of consent. * Subjects must have a pre-established, documented primary clinical diagnosis of non-asthmatic COPD or are referred for diagnosis of non-asthmatic COPD. * Subjects must have a baseline FEV1 of ≤50% predicted volume at Visits 1 and 2 (pre-dose). * Subjects must have a FEV1 \>0.50 L at either Visit 1 or 2 (pre-dose). * Subject's respiratory status must be clinically stable. * Subjects must have a FEV1/forced vital capacity (FVC) ratio of ≤70% at either Visit 1 or 2 (pre-dose). * Subjects must have had at least 1 COPD exacerbation within the last year (defined as initiation or an increase in the dose of oral steroids or antibiotics for the treatment of COPD). * Subjects must have a ≥15 pack-year smoking history and a baseline breathlessness severity grade of ≥2 (Modified Medical Research Council \[MMRC\] Dyspnea Scale Score) at Visit 2. * Female subjects ≤65 years of age must have a negative serum pregnancy test conducted at Visit 1 prior to randomization. Females of childbearing potential must be using an acceptable method of birth control. * Subjects' overall health must be sufficiently stable to complete the study requirements based on the screening physical examination (defined as the absence of any clinically relevant abnormalities), medical history, 12-lead ECG, and clinical laboratory values (hematology, serum chemistry and urinalysis), and vital signs (heart rate, respiratory rate, and blood pressure) that have been conducted within 30 days of Visit 2 (randomization). If any of the hematology, chemistry, or urinalysis results are not within the laboratory's reference range, then the subject can be included only if the investigator judges the deviations to be not clinically significant. * Subjects must have a minimum blood pressure of 105/60 mmHg and a minimum resting pulse of 50 bpm at Screening Visit 1. Subjects who do not meet these criteria at Screening Visit 1 must meet the criteria on the first day of dosing (Day 1) in order to be eligible for the study. Subjects with a medical condition which causes low blood pressure or low heart rate, but, in the opinion of the Principal Investigator or designee the medical condition could resolve, may be rescreened when the condition is resolved. * Subjects must be willing and able to complete all study questionnaires and logs reliably. * Subjects must be willing and able to comply with study procedures and visit schedule. * Subjects must have sufficient understanding of English to complete all questionnaires and logs.
Exclusion criteria
* Female subjects who are pregnant or lactating. * Subjects with a history of asthma, with the exception of asthma diagnosed in childhood. * Subjects with a blood eosinophil count \>5% of total white blood cell count. * Subjects with a febrile illness within 3 days before Screening. * Subjects with a malignant neoplasm other than non melanomatous basal cell skin cancer. Subjects with a history of malignancy who have been cancer free for 5 years or more may be enrolled. * Subjects who are currently using disallowed medications or will be unable to complete the medication washout periods. Subjects taking a prohibited concurrent medication which requires a washout of \>30 days may be rescreened when the washout of the prohibited concurrent medication has been met. * Subjects with life threatening/unstable respiratory status, including upper or lower respiratory tract infection, within the previous 30 days prior to screening. * Subjects who have had a change in dose or type of any medications for COPD within 2 weeks prior to the screening visit. Subjects not on a stable dose of COPD medications may be rescreened after being on a stable dose for at least 14 days * Subjects with a chest x ray taken ≤3 months prior to screening that suggests a diagnosis other than COPD (eg, diagnostic of pneumonia, other infection, atelectasis, or pneumothorax or other active/ongoing pulmonary conditions). If there is no chest x ray taken ≤3 months prior to screening, or if recent results are unavailable for review, a chest x ray must be performed prior to visit 2. Subjects with a medical condition that caused the abnormal finding, but, in the opinion of the Principal Investigator or designee the medical condition could resolve, may be rescreened when the condition is resolved * Subjects with a positive urine drug test during screening. * Subjects with a known history of alcohol abuse may be enrolled in the study if the subject's current alcohol use does not exceed more than 3 alcoholic beverages per day. * Subjects whose schedule or travel prevents the completion of all required visits. * Subjects who are scheduled for inpatient hospitalization or elective surgery (inpatient or outpatient) during the trial. Subjects may be rescreened when the condition is resolved. * Subjects have participated in an investigational drug study and/or any COPD interventional trial within 30 days prior to screening or who are currently participating in another investigational drug study or COPD interventional trial. * Subjects with a history of allergic reaction to the study medication or any components of the study medications. * Subjects who are study site staff members or relatives of study site staff members directly involved in this study. * Subjects with clinically significant cardiac, (Functional Class III and IV; Objective Class C and D by New York Heart Association \[NYHA\] Functional Classification),hepatic, renal, gastrointestinal, endocrine, metabolic, neurologic, or psychiatric disorder that may interfere with successful completion of this protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time From Randomization to Respiratory Death or First COPD Exacerbation Related Hospitalization (Whichever Occurs First). | 0-12 months | COPD exacerbation: an increase in COPD symptoms that necessitated any change in baseline medication (bronchodilators,anti-inflammatory agents, antibiotics, supplemental oxygen therapy, etc.).Hospitalization: any inpatient admission or any emergency department visit \> 24 hours in duration. Hospice was considered hospitalization.COPD exacerbation related hospitalization: hospitalization that was due to 1) COPD exacerbation or 2) a COPD exacerbation preceded, or occurred concomitantly with the onset of, the event for which the subject was hospitalized.Respiratory-related death: For each death the Primary Investigator designated a 'probable cause', which was the primary condition that precipitated the terminal events that were the immediate cause of death. If a probable cause could not be ascertained, the cause of death was considered 'UNKNOWN'. Cause other than 'UNKNOWN' was categorized as either respiratory or non-respiratory. Deaths of 'UNKNOWN' cause were counted as primary events. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Incidence of All Cause Mortality | 0-12 months | Survival status at the end of the study will be determined for each subject. The proportion of subjects dead and the annual event rate will be summarized by treatment. |
| The Incidence of Treatment Emergent AEs | 0-12 months | TEAEs were defined as: 1) adverse events that occurred on or after the date of first dose of study medication, 2) adverse events with a missing start date and a stop date on or after the date of first does of study medication, or 3) adverse events with both a missing start and stop date. The frequency and percentage of subjects with TEAEs were summarized. At each level of summarization, a subject was counted only once for each AE he/she experienced within that level. The percentage of subjects having had at least 1 AE at each level was calculated. |
| SGRQ: Mean Change From Baseline in Total Score | Baseline and on treatment at months 3, 6 and 12 (or early termination) | The SGRQ assessed health status and consisted of 3 component scores (Symptoms, Activity, and Impacts) as well as a total score. Items were scored in accordance with the developer's guidelines. Scores were expressed as a percentage of overall impairment, where 100 represented worst possible health status and 0 indicated best possible health status. The SGRQ was assessed pre-dose at baseline, months 3, 6 and 12 or the end of study (EOS). Visit 2 was defined as baseline. A change from baseline in the Total Score of ≥ 4 units is considered the minimal clinically important difference (MCID) for SGRQ. |
| The Incidence of Protocol Defined COPD Exacerbations. | 0-12 months | A protocol-defined exacerbation of COPD was defined as an increase in respiratory symptoms (classically, increased shortness of breath, increased sputum production, and/or increased sputum purulence) that necessitates any change in baseline medication other than bronchodilators (e.g., anti-inflammatory agents, antibiotics, supplemental oxygen therapy, etc) or causes the subject to require additional medical attention (i.e., emergency room visit or hospitalization). |
| Percent Predicted FEV1: Mean Change From Baseline | Baseline and on treatments at months 3, 6, 9 and 12 (or early termination) | Percent predicted FEV1: measured FEV1 as a percent of the predicted values for the patients of similar characteristics (height, age, sex, and sometimes race and weight). Best FEV1 percent predicted was measured at Visit 1 (screening), pre-dose at baseline, months 3, 6, 9 and 12/EOS, as described for FEV1. |
| Forced Vital Capacity (FVC): Mean Change From Baseline | Baseline and on treatment at months 3, 6, 9 and 12 (or early termination) | Forced Vital capacity: the volume of air that can forcibly be blown out after full inspiration. Best FVC was measured at Visit 1 (screening), pre-dose at baseline, months 3, 6, 9 and 12/EOS. The best FVC from at least 3 acceptable maneuvers was recorded. |
| Inspiratory Capacity (IC): Mean Change From Baseline | Baseline and on treatment at months 3, 6, 9 and 12 (or early termination) | IC: the total amount of air that can be drawn into the lungs after normal expiration. IC was measured pre- and post-albuterol administration at Visit 1 (screening), pre-dose at baseline, months 3, 6, 9 and 12/EOS. IC maneuvers were done in triplicate. The mean of all recorded IC values was used for each subject at each time point. Study baseline was defined as the Visit 2 pre-dose value. If the Visit 2 pre-dose value was missing, the last IC value obtained prior to first treatment dose was used for baseline. |
| FEV1: Mean Change From Baseline | Baseline and on treatments at months 3, 6, 9 and 12 (or early termination) | FEV1 was measured at Visit 1 (screening), pre- and post-albuterol administration for reversibility testing, pre-dose at baseline, months 3, 6, 9 and 12/EOS. The best FEV1 from at least 3 acceptable maneuvers was recorded. Study baseline was defined as the Visit 2 pre-dose value. If the Visit 2 pre-dose value was missing, the last FEV1 value obtained prior to first treatment was used for baseline. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Comparator: Placebo Twice Daily Placebo twice daily by nebulization. All subjects will be dispensed albuterol HFA metered-dose inhaler (MDI) to be used as needed as rescue medication for bronchospasm and acute treatment of COPD symptoms. | 421 |
| Experimental: Arformoterol 15 Mcg Twice Daily Arformoterol 15 mcg twice daily by nebulization. All subjects will be dispensed albuterol HFA metered-dose inhaler (MDI) to be used as needed as rescue medication for bronchospasm and acute treatment of COPD symptoms. | 420 |
| Total | 841 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 53 | 55 |
| Overall Study | Lack of Efficacy | 7 | 4 |
| Overall Study | Lost to Follow-up | 19 | 15 |
| Overall Study | Medical Monitor Decision | 1 | 0 |
| Overall Study | Noncompliance | 1 | 1 |
| Overall Study | Physician Decision | 8 | 2 |
| Overall Study | Protocol Violation | 2 | 5 |
| Overall Study | Randomized in error | 1 | 1 |
| Overall Study | Site Ceasing Operation | 2 | 2 |
| Overall Study | Withdrawal by Subject | 116 | 80 |
Baseline characteristics
| Characteristic | Total | Experimental: Arformoterol 15 Mcg Twice Daily | Placebo Comparator: Placebo Twice Daily |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 415 Participants | 216 Participants | 199 Participants |
| Age, Categorical Between 18 and 65 years | 426 Participants | 204 Participants | 222 Participants |
| Age Continuous | 63.8 years STANDARD_DEVIATION 9.4 | 64.2 years STANDARD_DEVIATION 9.3 | 63.3 years STANDARD_DEVIATION 9.5 |
| Baseline Oral/Inhaled Corticosteroid Use No | 404 participants 48 | 202 participants 48.1 | 202 participants 48 |
| Baseline Oral/Inhaled Corticosteroid Use Yes | 437 participants 52 | 218 participants 51.9 | 219 participants 52 |
| Baseline Oxygen Therapy Use No | 664 participants 79 | 334 participants 79.5 | 330 participants 78.4 |
| Baseline Oxygen Therapy Use Yes | 177 participants 21 | 86 participants 20.5 | 91 participants 21.6 |
| Baseline smoking status Current | 432 Current | 214 Current | 218 Current |
| Baseline smoking status Former | 409 Current | 206 Current | 203 Current |
| Ethnicity (NIH/OMB) Hispanic or Latino | 24 Participants | 9 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 813 Participants | 411 Participants | 402 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 0 Participants | 4 Participants |
| FEV1 | 1.177 Liter STANDARD_DEVIATION 0.485 | 1.176 Liter STANDARD_DEVIATION 0.482 | 1.178 Liter STANDARD_DEVIATION 0.487 |
| Number of COPD exacerbations in last year | 0.9 Number of occurrences STANDARD_DEVIATION 1.3 | 1.0 Number of occurrences STANDARD_DEVIATION 1.4 | 0.8 Number of occurrences STANDARD_DEVIATION 1.1 |
| Number of pack-years smoked ≥ 15 - < 25 | 81 Pack-years 9.6 | 40 Pack-years 9.5 | 41 Pack-years 9.7 |
| Number of pack-years smoked ≥ 25 - < 30 | 65 Pack-years 7.7 | 29 Pack-years 6.9 | 36 Pack-years 8.6 |
| Number of pack-years smoked ≥ 30 | 695 Pack-years 82.6 | 351 Pack-years 83.6 | 344 Pack-years 81.7 |
| Percent predicted FEV1 (%) | 39.5 Percentage (%) STANDARD_DEVIATION 13.5 | 39.7 Percentage (%) STANDARD_DEVIATION 13.2 | 39.4 Percentage (%) STANDARD_DEVIATION 13.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 88 Participants | 45 Participants | 43 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 746 Participants | 372 Participants | 374 Participants |
| Region of Enrollment United States | 841 participants | 420 participants | 421 participants |
| Sex/Gender, Customized Female | 361 participants | 183 participants | 178 participants |
| Sex/Gender, Customized Male | 479 participants | 236 participants | 243 participants |
| Sex/Gender, Customized Undifferentiated | 1 participants | 1 participants | 0 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 180 / 421 | 174 / 420 |
| serious Total, serious adverse events | 95 / 421 | 86 / 420 |
Outcome results
Primary
Time From Randomization to Respiratory Death or First COPD Exacerbation Related Hospitalization (Whichever Occurs First).
COPD exacerbation: an increase in COPD symptoms that necessitated any change in baseline medication (bronchodilators,anti-inflammatory agents, antibiotics, supplemental oxygen therapy, etc.).Hospitalization: any inpatient admission or any emergency department visit \> 24 hours in duration. Hospice was considered hospitalization.COPD exacerbation related hospitalization: hospitalization that was due to 1) COPD exacerbation or 2) a COPD exacerbation preceded, or occurred concomitantly with the onset of, the event for which the subject was hospitalized.Respiratory-related death: For each death the Primary Investigator designated a 'probable cause', which was the primary condition that precipitated the terminal events that were the immediate cause of death. If a probable cause could not be ascertained, the cause of death was considered 'UNKNOWN'. Cause other than 'UNKNOWN' was categorized as either respiratory or non-respiratory. Deaths of 'UNKNOWN' cause were counted as primary events.
Time frame: 0-12 months
Population: Intent-to-treat population: subjects who were randomized to treatment and received at least 1 dose of study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Experimental: Arformoterol 15 Mcg Twice Daily | Time From Randomization to Respiratory Death or First COPD Exacerbation Related Hospitalization (Whichever Occurs First). | 155.0 Days | Standard Deviation 91.2 |
| Placebo | Time From Randomization to Respiratory Death or First COPD Exacerbation Related Hospitalization (Whichever Occurs First). | 171.7 Days | Standard Deviation 98.7 |
Comparison: The null hypothesis is: There is 40% or higher excess risk of the primary events in the arformoterol group relative to placebo (a constant hazard ratio of 1.4).~The primary analysis was a Cox proportional hazards regression model, with treatment group, baseline smoking status, sex, age, BMI, and baseline FEV1 as covariates. The hazard ratio and 90% two-sided confidence interval for the hazard ratio (adjusted for the interim analysis) comparing arformoterol to placebo were estimated.95% CI: [0.425, 0.864]Regression, Cox
Secondary
FEV1: Mean Change From Baseline
FEV1 was measured at Visit 1 (screening), pre- and post-albuterol administration for reversibility testing, pre-dose at baseline, months 3, 6, 9 and 12/EOS. The best FEV1 from at least 3 acceptable maneuvers was recorded. Study baseline was defined as the Visit 2 pre-dose value. If the Visit 2 pre-dose value was missing, the last FEV1 value obtained prior to first treatment was used for baseline.
Time frame: Baseline and on treatments at months 3, 6, 9 and 12 (or early termination)
Population: Intent-to-treat population: subjects who were randomized to treatment and received at least 1 dose of study medication.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Experimental: Arformoterol 15 Mcg Twice Daily | FEV1: Mean Change From Baseline | Month 3 (n=289,331) | 0.027 Liter | Standard Error 0.018 |
| Experimental: Arformoterol 15 Mcg Twice Daily | FEV1: Mean Change From Baseline | Month 12 (n=206,253) | 0.020 Liter | Standard Error 0.02 |
| Experimental: Arformoterol 15 Mcg Twice Daily | FEV1: Mean Change From Baseline | Month 9 (n=223,268) | 0.048 Liter | Standard Error 0.019 |
| Experimental: Arformoterol 15 Mcg Twice Daily | FEV1: Mean Change From Baseline | EOS (n=380,391) | 0.047 Liter | Standard Error 0.016 |
| Experimental: Arformoterol 15 Mcg Twice Daily | FEV1: Mean Change From Baseline | Month 6 (n=248,300) | 0.036 Liter | Standard Error 0.023 |
| Placebo | FEV1: Mean Change From Baseline | EOS (n=380,391) | 0.072 Liter | Standard Error 0.016 |
| Placebo | FEV1: Mean Change From Baseline | Month 3 (n=289,331) | 0.093 Liter | Standard Error 0.016 |
| Placebo | FEV1: Mean Change From Baseline | Month 6 (n=248,300) | 0.090 Liter | Standard Error 0.021 |
| Placebo | FEV1: Mean Change From Baseline | Month 9 (n=223,268) | 0.092 Liter | Standard Error 0.018 |
| Placebo | FEV1: Mean Change From Baseline | Month 12 (n=206,253) | 0.059 Liter | Standard Error 0.018 |
Secondary
Forced Vital Capacity (FVC): Mean Change From Baseline
Forced Vital capacity: the volume of air that can forcibly be blown out after full inspiration. Best FVC was measured at Visit 1 (screening), pre-dose at baseline, months 3, 6, 9 and 12/EOS. The best FVC from at least 3 acceptable maneuvers was recorded.
Time frame: Baseline and on treatment at months 3, 6, 9 and 12 (or early termination)
Population: Intent-to-treat population: subjects who were randomized to treatment and received at least 1 dose of study medication.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Experimental: Arformoterol 15 Mcg Twice Daily | Forced Vital Capacity (FVC): Mean Change From Baseline | Month 6 (n=248,300) | 0.056 Liter | Standard Error 0.031 |
| Experimental: Arformoterol 15 Mcg Twice Daily | Forced Vital Capacity (FVC): Mean Change From Baseline | Month 12 (n=206,253) | 0.040 Liter | Standard Error 0.029 |
| Experimental: Arformoterol 15 Mcg Twice Daily | Forced Vital Capacity (FVC): Mean Change From Baseline | Month 3 (n=289,331) | 0.039 Liter | Standard Error 0.024 |
| Experimental: Arformoterol 15 Mcg Twice Daily | Forced Vital Capacity (FVC): Mean Change From Baseline | EOS (n=380,391) | 0.056 Liter | Standard Error 0.022 |
| Experimental: Arformoterol 15 Mcg Twice Daily | Forced Vital Capacity (FVC): Mean Change From Baseline | Month 9 (n=223,268) | 0.049 Liter | Standard Error 0.029 |
| Placebo | Forced Vital Capacity (FVC): Mean Change From Baseline | EOS (n=380,391) | 0.102 Liter | Standard Error 0.022 |
| Placebo | Forced Vital Capacity (FVC): Mean Change From Baseline | Month 3 (n=289,331) | 0.139 Liter | Standard Error 0.022 |
| Placebo | Forced Vital Capacity (FVC): Mean Change From Baseline | Month 6 (n=248,300) | 0.120 Liter | Standard Error 0.028 |
| Placebo | Forced Vital Capacity (FVC): Mean Change From Baseline | Month 9 (n=223,268) | 0.139 Liter | Standard Error 0.027 |
| Placebo | Forced Vital Capacity (FVC): Mean Change From Baseline | Month 12 (n=206,253) | 0.088 Liter | Standard Error 0.027 |
Secondary
Inspiratory Capacity (IC): Mean Change From Baseline
IC: the total amount of air that can be drawn into the lungs after normal expiration. IC was measured pre- and post-albuterol administration at Visit 1 (screening), pre-dose at baseline, months 3, 6, 9 and 12/EOS. IC maneuvers were done in triplicate. The mean of all recorded IC values was used for each subject at each time point. Study baseline was defined as the Visit 2 pre-dose value. If the Visit 2 pre-dose value was missing, the last IC value obtained prior to first treatment dose was used for baseline.
Time frame: Baseline and on treatment at months 3, 6, 9 and 12 (or early termination)
Population: Intent-to-treat population: subjects who were randomized to treatment and received at least 1 dose of study medication.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Experimental: Arformoterol 15 Mcg Twice Daily | Inspiratory Capacity (IC): Mean Change From Baseline | Month 6 (n=243,298) | -0.011 Liter | Standard Error 0.026 |
| Experimental: Arformoterol 15 Mcg Twice Daily | Inspiratory Capacity (IC): Mean Change From Baseline | Month 12 (n=199,246) | 0.004 Liter | Standard Error 0.029 |
| Experimental: Arformoterol 15 Mcg Twice Daily | Inspiratory Capacity (IC): Mean Change From Baseline | Month 9 (n=218,258) | 0.046 Liter | Standard Error 0.029 |
| Experimental: Arformoterol 15 Mcg Twice Daily | Inspiratory Capacity (IC): Mean Change From Baseline | EOS (n=374,384) | 0.031 Liter | Standard Error 0.022 |
| Experimental: Arformoterol 15 Mcg Twice Daily | Inspiratory Capacity (IC): Mean Change From Baseline | Month 3 (n=284,320) | 0.030 Liter | Standard Error 0.023 |
| Placebo | Inspiratory Capacity (IC): Mean Change From Baseline | EOS (n=374,384) | 0.058 Liter | Standard Error 0.021 |
| Placebo | Inspiratory Capacity (IC): Mean Change From Baseline | Month 3 (n=284,320) | 0.054 Liter | Standard Error 0.021 |
| Placebo | Inspiratory Capacity (IC): Mean Change From Baseline | Month 6 (n=243,298) | 0.067 Liter | Standard Error 0.024 |
| Placebo | Inspiratory Capacity (IC): Mean Change From Baseline | Month 9 (n=218,258) | 0.096 Liter | Standard Error 0.027 |
| Placebo | Inspiratory Capacity (IC): Mean Change From Baseline | Month 12 (n=199,246) | 0.035 Liter | Standard Error 0.027 |
Secondary
Percent Predicted FEV1: Mean Change From Baseline
Percent predicted FEV1: measured FEV1 as a percent of the predicted values for the patients of similar characteristics (height, age, sex, and sometimes race and weight). Best FEV1 percent predicted was measured at Visit 1 (screening), pre-dose at baseline, months 3, 6, 9 and 12/EOS, as described for FEV1.
Time frame: Baseline and on treatments at months 3, 6, 9 and 12 (or early termination)
Population: Intent-to-treat population: subjects who were randomized to treatment and received at least 1 dose of study medication.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Experimental: Arformoterol 15 Mcg Twice Daily | Percent Predicted FEV1: Mean Change From Baseline | Month 6 (n=248,300) | 1.768 Liter | Standard Error 0.648 |
| Experimental: Arformoterol 15 Mcg Twice Daily | Percent Predicted FEV1: Mean Change From Baseline | Month 12 (n=206,252) | 1.678 Liter | Standard Error 0.642 |
| Experimental: Arformoterol 15 Mcg Twice Daily | Percent Predicted FEV1: Mean Change From Baseline | Month 9 (n=223,268) | 2.606 Liter | Standard Error 0.626 |
| Experimental: Arformoterol 15 Mcg Twice Daily | Percent Predicted FEV1: Mean Change From Baseline | EOS (n=380,391) | 2.156 Liter | Standard Error 0.493 |
| Experimental: Arformoterol 15 Mcg Twice Daily | Percent Predicted FEV1: Mean Change From Baseline | Month 3 (n=289,331) | 1.410 Liter | Standard Error 0.533 |
| Placebo | Percent Predicted FEV1: Mean Change From Baseline | EOS (n=380,391) | 2.936 Liter | Standard Error 0.486 |
| Placebo | Percent Predicted FEV1: Mean Change From Baseline | Month 3 (n=289,331) | 3.480 Liter | Standard Error 0.498 |
| Placebo | Percent Predicted FEV1: Mean Change From Baseline | Month 6 (n=248,300) | 3.460 Liter | Standard Error 0.594 |
| Placebo | Percent Predicted FEV1: Mean Change From Baseline | Month 9 (n=223,268) | 3.651 Liter | Standard Error 0.576 |
| Placebo | Percent Predicted FEV1: Mean Change From Baseline | Month 12 (n=206,252) | 2.662 Liter | Standard Error 0.586 |
Secondary
SGRQ: Mean Change From Baseline in Total Score
The SGRQ assessed health status and consisted of 3 component scores (Symptoms, Activity, and Impacts) as well as a total score. Items were scored in accordance with the developer's guidelines. Scores were expressed as a percentage of overall impairment, where 100 represented worst possible health status and 0 indicated best possible health status. The SGRQ was assessed pre-dose at baseline, months 3, 6 and 12 or the end of study (EOS). Visit 2 was defined as baseline. A change from baseline in the Total Score of ≥ 4 units is considered the minimal clinically important difference (MCID) for SGRQ.
Time frame: Baseline and on treatment at months 3, 6 and 12 (or early termination)
Population: Intent-to-treat population: subjects who were randomized to treatment and received at least 1 dose of study medication.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Experimental: Arformoterol 15 Mcg Twice Daily | SGRQ: Mean Change From Baseline in Total Score | Month 3 (n=276,308) | -1.544 Score | Standard Error 0.609 |
| Experimental: Arformoterol 15 Mcg Twice Daily | SGRQ: Mean Change From Baseline in Total Score | Month 6 (n=233,287) | -1.855 Score | Standard Error 0.746 |
| Experimental: Arformoterol 15 Mcg Twice Daily | SGRQ: Mean Change From Baseline in Total Score | Month 12 (n=199,236) | -2.673 Score | Standard Error 0.8 |
| Experimental: Arformoterol 15 Mcg Twice Daily | SGRQ: Mean Change From Baseline in Total Score | EOS (n=375,379) | -0.587 Score | Standard Error 0.616 |
| Placebo | SGRQ: Mean Change From Baseline in Total Score | EOS (n=375,379) | -3.231 Score | Standard Error 0.613 |
| Placebo | SGRQ: Mean Change From Baseline in Total Score | Month 3 (n=276,308) | -3.876 Score | Standard Error 0.575 |
| Placebo | SGRQ: Mean Change From Baseline in Total Score | Month 12 (n=199,236) | -4.796 Score | Standard Error 0.735 |
| Placebo | SGRQ: Mean Change From Baseline in Total Score | Month 6 (n=233,287) | -4.054 Score | Standard Error 0.679 |
Secondary
The Incidence of All Cause Mortality
Survival status at the end of the study will be determined for each subject. The proportion of subjects dead and the annual event rate will be summarized by treatment.
Time frame: 0-12 months
Population: Intent-to-treat population: subjects who were randomized to treatment and received at least 1 dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Experimental: Arformoterol 15 Mcg Twice Daily | The Incidence of All Cause Mortality | 10 participants |
| Placebo | The Incidence of All Cause Mortality | 12 participants |
Secondary
The Incidence of Protocol Defined COPD Exacerbations.
A protocol-defined exacerbation of COPD was defined as an increase in respiratory symptoms (classically, increased shortness of breath, increased sputum production, and/or increased sputum purulence) that necessitates any change in baseline medication other than bronchodilators (e.g., anti-inflammatory agents, antibiotics, supplemental oxygen therapy, etc) or causes the subject to require additional medical attention (i.e., emergency room visit or hospitalization).
Time frame: 0-12 months
Population: Intent-to-treat population: subjects who were randomized to treatment and received at least 1 dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Experimental: Arformoterol 15 Mcg Twice Daily | The Incidence of Protocol Defined COPD Exacerbations. | Overall | 132 participants |
| Experimental: Arformoterol 15 Mcg Twice Daily | The Incidence of Protocol Defined COPD Exacerbations. | 1 COPD event | 72 participants |
| Experimental: Arformoterol 15 Mcg Twice Daily | The Incidence of Protocol Defined COPD Exacerbations. | 2 COPD events | 34 participants |
| Experimental: Arformoterol 15 Mcg Twice Daily | The Incidence of Protocol Defined COPD Exacerbations. | 3 or more COPD events | 26 participants |
| Placebo | The Incidence of Protocol Defined COPD Exacerbations. | 3 or more COPD events | 22 participants |
| Placebo | The Incidence of Protocol Defined COPD Exacerbations. | Overall | 122 participants |
| Placebo | The Incidence of Protocol Defined COPD Exacerbations. | 2 COPD events | 29 participants |
| Placebo | The Incidence of Protocol Defined COPD Exacerbations. | 1 COPD event | 71 participants |
Secondary
The Incidence of Treatment Emergent AEs
TEAEs were defined as: 1) adverse events that occurred on or after the date of first dose of study medication, 2) adverse events with a missing start date and a stop date on or after the date of first does of study medication, or 3) adverse events with both a missing start and stop date. The frequency and percentage of subjects with TEAEs were summarized. At each level of summarization, a subject was counted only once for each AE he/she experienced within that level. The percentage of subjects having had at least 1 AE at each level was calculated.
Time frame: 0-12 months
Population: Intent-to-treat population: subjects who were randomized to treatment and received at least 1 dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Experimental: Arformoterol 15 Mcg Twice Daily | The Incidence of Treatment Emergent AEs | 287 participants |
| Placebo | The Incidence of Treatment Emergent AEs | 306 participants |