COPD Patients
Conditions
Keywords
COPD, turbuhaler, pMDI
Brief summary
Comparing the efficacy of Symbicort® pMDI and Formoterol Turbuhaler in reducing exacerbations in patients with Chronic Obstructive Pulmonary Disease (COPD).
Detailed description
A Phase IIIB, 6-Month, Double-blind, Double-dummy, Randomized, Parallel-group, Multicenter Exacerbation Study of Symbicort® pMDI 160/4.5 μg x 2 Actuations Twice-daily Compared to Formoterol Turbuhaler 4.5 μg x 2 Inhalations Twice-daily in COPD Patients.
Interventions
DRUGSymbicort
Budesonide/formoterol pMDI, 160/4.5 μg x 2 actuations BID, for oral inhalation, 120 doses
DRUGFormoterol turbohaler
Formoterol Turbuhaler 4.5 μg x 2 actuations BID, for oral inhalation, 60 doses
OTHERPlacebo for Symbicort pMDI
pMDI, aerosol for oral inhalation, placebo, 120 doses
OTHERPlacebo for Formoterol Turbohaler
PLacebo powder for oral inhalation, 60 doses
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 95 Years
Healthy volunteers
No
Inclusion criteria
3\. A current clinical diagnosis of COPD with COPD symptoms for more than 1 year, according to the GOLD guidelines. 4\. Current or previous smoker with a smoking history equivalent to 10 or more pack years (1 pack year = 20 cigarettes smoked per day for 1 year). 5\. Post-bronchodilator FEV1/forced vital capacity (FVC) \<0.7 (70%) and FEV1 ≤70% of predicted normal (PN) value. 6\. Documented use of a short-acting inhaled bronchodilator (β2-agonists or anticholinergics) as rescue medication within 6 months prior to study start. 7\. A score of ≥2 on the modified medical research council (MMRC) dyspnea scale. 8. Documented history of ≥1 moderate or severe COPD exacerbation(s) that required treatment with systemic (oral, IM, IV) corticosteroids (a minimum 3 day course of an oral corticosteroid treatment or single depot corticosteroid injection), or hospitalization (defined as an inpatient stay or \>24 hour stay in an observation area in the emergency department or other equivalent facility depending on the country and healthcare system) within 2-52 weeks before Visit 1 (i.e., not within the 14 days prior to Visit 1). A history of an exacerbation treated exclusively with antibiotics will not be considered adequate.
Exclusion criteria
1. A history of asthma at or after 18 years of age. 2. Subjects with significant or unstable ischemic heart disease, arrhythmia, cardiomyopathy, heart failure (including significant cor pulmonale), uncontrolled hypertension as defined by the Investigator, or any other relevant cardiovascular disorder as judged by the Investigator. 3. Known homozygous alpha-1 antitrypsin deficiency. 4. Any significant disease or disorder (e.g., gastrointestinal, liver, renal, neurological, musculoskeletal, endocrine, metabolic, malignant, psychiatric, major physical impairment) which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results of the study, or the subject's ability to participate in the study. 5. A history of malignancy (except basal cell carcinoma) within the past 5 years. 6. Active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, primary pulmonary hypertension, interstitial lung disease, or other active pulmonary diseases. 7. Subjects who have needed additions or alterations to their usual maintenance or change in formulation of rescue therapy for COPD due to worsening symptoms within the 14 days prior to Visit 1 and up to Visit 3. 8. CXR (frontal and lateral) with suspicion of pneumonia or other condition/abnormality that will require additional investigation/treatment, or put the subject at risk because of participation in the study. 9. Risk factors for pneumonia: immune suppression (HIV, lupus) or other risk for pneumonia (e.g. neurological disorders affecting control of the upper airway, such as Parkinson's disease, myasthenia gravis, etc.). 10. Pneumonia not resolved within 14 days of Visit 1. 11. Moderate or severe COPD exacerbation that has not resolved within 14 days prior to Visit 1 or a moderate or severe COPD exacerbation that occurs between Visit 1 and Visit 2. 12. Long-term oxygen therapy (LTOT) or nocturnal oxygen therapy required for greater than 12 hours a day. 13. Subjects who are currently in the intensive rehabilitation phase or scheduled to begin new participation (intensive rehabilitation phase) in a pulmonary rehabilitation program during the study or have started a new pulmonary rehabilitation program within 60 days of Visit 1. Subjects in the maintenance phase of pulmonary rehabilitation program are not excluded. 14. Treatment with oral, parenteral, or intra-articular corticosteroids within 4 weeks prior to Visit 1. 15. Omalizumab or any other monoclonal or polyclonal antibody therapy taken for any reason within 6 months prior to Visit 1.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Rate of Moderate and Severe COPD Exacerbations Defined as: Worsening of ≥2 Major Symptoms or Worsening of 1 Major Symptom Together With ≥1 Minor Symptom for ≥2 Consecutive Days | Randomization at Week 0 to End of Treatment (EoT) W 26 | The annual COPD exacerbation rate was analyzed and compared between two arms. Annual exacerbation rate for each subject is defined as number of exacerbations divided by duration of randomized treatment period in years. The annual COPD exacerbation rate of Symbicort group was compared with annual rate of Formoterol group. The rate ratio of Symbicort vs. Formoteroal was assessed by a negative binomial model. Exacerbations, that met the modified Anthonisen criteria and duration ≥2 days were classified as moderate and severe exacerbations. Moderate exacerbation: treatment of symptoms with systemic corticosteroids (≥3 days) and/or antibiotics. Severe exacerbation: symptoms that require hospitalization (including \>24 hours in ED/urgent care setting). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Moderate or Severe COPD Exacerbation. | From randomzation to EoT W 26 | The number of patients who developed moderate or severe COPD exacerbation during treatment period were reported. Cox proportional hazards regression model was fitted to data to compare the two treatment arms . The hazard ratio and 95% CI were estimated. |
| St. George's Respiratory Questionnaire (SGRQ) | From Run-in W -4 to EoT W 26 | SGRQ is a standardized, self-administered tool for measuring impaired health and perceived wellbeing in respiratory diseases; a validated electronic version of the questionnaire in the relevant validated languages was used in this study. The questionnaire contains 50 items divided into three dimensions (Symptoms, Activity and Impact). Each of the three dimensions of the questionnaire is scored separately in the range from 0 to 100: zero (0) score indicating no impairment of quality of life. The total SGRQ score ranging from 0 to 100 is a summary score utilizing responses to all items calculated using weights attached to each item of the questionnaire. Higher scores indicate poorer health and change of 4 units in the SGRQ has been determined to be the threshold for a clinically relevant change in health status. The change from baseline was statistically summarized and compared between two arms in a mixed model. |
| Pre-dose/Pre-bronchodilator FEV1 at the Study Site | From Run-in W -4 to EoT W 26 | FEV1 from pre-dose spirometry is a measurement of lung function. The change from baseline on pre-dose FEV1 was summarized and compared between Symbicort and Formoterol groups using a mixed model. |
| Total Rescue Medication Use (Average Puffs/Day) | From Run-in W -4 to EoT W 26 | Use of rescue medication is a measure of symptoms that need to be treated with a short-acting bronchodilator. The average daily use across the observation period was used for analysis. Change from baseline was summarized and compared between two arms using a mixed model. |
| Nights With Awakening Due to COPD | From Run-in W -4 to EoT W 26 | Nighttime awakening due to COPD symptoms correspond to the severity of nocturnal symptoms from COPD. The average number of awakening per night over the treatment period was analyzed. It was derived as the number of night with awakening divided by the total number of nights with data in the recording period. Change from baseline period on awakening was summarized and compared between two arms using a mixed model. |
Countries
Argentina, Bulgaria, Chile, Czechia, Germany, Mexico, Poland, Puerto Rico, South Africa, Spain, United States
Participant flow
Pre-assignment details
The enrollment number in the protocol section denotes the number of patients screened into the trial. Out of these 2026 patients screened, 1219 patients were randomized into the trial. This explains the discrepancy in patient number.
Participants by arm
| Arm | Count |
|---|---|
| Symbicort pMDI Symbicort pMDI, budesonide/formoterol, 160/4.5 μg x 2 actuations BID, for oral inhalation | 606 |
| Formoterol Turbuhaler Formoterol Turbuhaler, 4.5 μg x 2 actuations BID, for oral inhalation | 613 |
| Total | 1,219 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 5 |
| Overall Study | Death | 4 | 4 |
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Other | 5 | 12 |
| Overall Study | Progressive disease | 0 | 2 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Screen failure | 1 | 2 |
| Overall Study | Withdrawal by Subject | 25 | 39 |
Baseline characteristics
| Characteristic | Symbicort pMDI | Total | Formoterol Turbuhaler |
|---|---|---|---|
| Age, Continuous | 63.1 Years STANDARD_DEVIATION 8.65 | 63.5 Years STANDARD_DEVIATION 8.67 | 63.9 Years STANDARD_DEVIATION 8.67 |
| FEV1 post-bronchodilator categories <30% | 59 Participants | 113 Participants | 54 Participants |
| FEV1 post-bronchodilator categories >=30% to <50% | 234 Participants | 481 Participants | 247 Participants |
| FEV1 post-bronchodilator categories >=50% to <=70% | 307 Participants | 615 Participants | 308 Participants |
| FEV1 post-bronchodilator categories >70% | 4 Participants | 7 Participants | 3 Participants |
| Number of exacerbations during 2 - 52 weeks prior to enrollment 1 | 430 Participants | 878 Participants | 448 Participants |
| Number of exacerbations during 2 - 52 weeks prior to enrollment 2 | 136 Participants | 253 Participants | 117 Participants |
| Number of exacerbations during 2 - 52 weeks prior to enrollment 3 | 29 Participants | 57 Participants | 28 Participants |
| Number of exacerbations during 2 - 52 weeks prior to enrollment 4 | 7 Participants | 20 Participants | 13 Participants |
| Number of exacerbations during 2 - 52 weeks prior to enrollment 5 | 2 Participants | 8 Participants | 6 Participants |
| Number of exacerbations during 2 - 52 weeks prior to enrollment 6 | 0 Participants | 1 Participants | 1 Participants |
| Number of exacerbations during 2 - 52 weeks prior to enrollment 7 | 2 Participants | 2 Participants | 0 Participants |
| Sex: Female, Male Female | 251 Participants | 521 Participants | 270 Participants |
| Sex: Female, Male Male | 355 Participants | 698 Participants | 343 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 56 / 613 | 38 / 605 |
| serious Total, serious adverse events | 63 / 613 | 49 / 605 |
Outcome results
Primary
The Rate of Moderate and Severe COPD Exacerbations Defined as: Worsening of ≥2 Major Symptoms or Worsening of 1 Major Symptom Together With ≥1 Minor Symptom for ≥2 Consecutive Days
The annual COPD exacerbation rate was analyzed and compared between two arms. Annual exacerbation rate for each subject is defined as number of exacerbations divided by duration of randomized treatment period in years. The annual COPD exacerbation rate of Symbicort group was compared with annual rate of Formoterol group. The rate ratio of Symbicort vs. Formoteroal was assessed by a negative binomial model. Exacerbations, that met the modified Anthonisen criteria and duration ≥2 days were classified as moderate and severe exacerbations. Moderate exacerbation: treatment of symptoms with systemic corticosteroids (≥3 days) and/or antibiotics. Severe exacerbation: symptoms that require hospitalization (including \>24 hours in ED/urgent care setting).
Time frame: Randomization at Week 0 to End of Treatment (EoT) W 26
Population: Full analysis set including all randomized subjects
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Symbicort pMDI | The Rate of Moderate and Severe COPD Exacerbations Defined as: Worsening of ≥2 Major Symptoms or Worsening of 1 Major Symptom Together With ≥1 Minor Symptom for ≥2 Consecutive Days | 0.85 COPD exacerbations per year |
| Formoterol Turbuhaler | The Rate of Moderate and Severe COPD Exacerbations Defined as: Worsening of ≥2 Major Symptoms or Worsening of 1 Major Symptom Together With ≥1 Minor Symptom for ≥2 Consecutive Days | 1.12 COPD exacerbations per year |
p-value: 0.005995% CI: [0.62, 0.92]Negative binomial model
Secondary
Nights With Awakening Due to COPD
Nighttime awakening due to COPD symptoms correspond to the severity of nocturnal symptoms from COPD. The average number of awakening per night over the treatment period was analyzed. It was derived as the number of night with awakening divided by the total number of nights with data in the recording period. Change from baseline period on awakening was summarized and compared between two arms using a mixed model.
Time frame: From Run-in W -4 to EoT W 26
Population: The change from baseline on awakening were analyzed on randomized patients with a baseline and a post-baseline value. Among 1219 patients who were randomized, only 603 patients in Symbicort group and 610 patients in Formoterol group had valid data and included in analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Symbicort pMDI | Nights With Awakening Due to COPD | -0.007 awakening/night | Standard Deviation 0.173 |
| Formoterol Turbuhaler | Nights With Awakening Due to COPD | 0.021 awakening/night | Standard Deviation 0.195 |
p-value: 0.004895% CI: [-0.048, -0.009]ANCOVA
Secondary
Number of Patients With Moderate or Severe COPD Exacerbation.
The number of patients who developed moderate or severe COPD exacerbation during treatment period were reported. Cox proportional hazards regression model was fitted to data to compare the two treatment arms . The hazard ratio and 95% CI were estimated.
Time frame: From randomzation to EoT W 26
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Symbicort pMDI | Number of Patients With Moderate or Severe COPD Exacerbation. | 171 Participants |
| Formoterol Turbuhaler | Number of Patients With Moderate or Severe COPD Exacerbation. | 204 Participants |
p-value: 0.016495% CI: [0.64, 0.96]Regression, Cox
Secondary
Pre-dose/Pre-bronchodilator FEV1 at the Study Site
FEV1 from pre-dose spirometry is a measurement of lung function. The change from baseline on pre-dose FEV1 was summarized and compared between Symbicort and Formoterol groups using a mixed model.
Time frame: From Run-in W -4 to EoT W 26
Population: The change from baseline in pre-dose FEV1 were analyzed on randomized patients with a baseline pre-dose FEV1 and at least one post-baseline value. Among 1219 patients who were randomized, only 588 patients in Symbicort group and 589 patients in Formoterol group had valid data and included in analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Symbicort pMDI | Pre-dose/Pre-bronchodilator FEV1 at the Study Site | 0.008 L | Standard Deviation 0.21 |
| Formoterol Turbuhaler | Pre-dose/Pre-bronchodilator FEV1 at the Study Site | -0.025 L | Standard Deviation 0.198 |
p-value: 0.009195% CI: [0.008, 0.053]Mixed Models Analysis
Secondary
St. George's Respiratory Questionnaire (SGRQ)
SGRQ is a standardized, self-administered tool for measuring impaired health and perceived wellbeing in respiratory diseases; a validated electronic version of the questionnaire in the relevant validated languages was used in this study. The questionnaire contains 50 items divided into three dimensions (Symptoms, Activity and Impact). Each of the three dimensions of the questionnaire is scored separately in the range from 0 to 100: zero (0) score indicating no impairment of quality of life. The total SGRQ score ranging from 0 to 100 is a summary score utilizing responses to all items calculated using weights attached to each item of the questionnaire. Higher scores indicate poorer health and change of 4 units in the SGRQ has been determined to be the threshold for a clinically relevant change in health status. The change from baseline was statistically summarized and compared between two arms in a mixed model.
Time frame: From Run-in W -4 to EoT W 26
Population: The change from baseline in SGRQ were analyzed on randomized patients with a baseline SGRQ and at least one post-baseline value. Among 1219 patients who were randomized, only 589 patients in Symbicort group and 593 patients in Formoterol group had valid data and included in analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Symbicort pMDI | St. George's Respiratory Questionnaire (SGRQ) | -0.855 scores on a scale | Standard Deviation 8.941 |
| Formoterol Turbuhaler | St. George's Respiratory Questionnaire (SGRQ) | 0.442 scores on a scale | Standard Deviation 9.457 |
p-value: 0.00795% CI: [-2.318, -0.368]Mixed Models Analysis
Secondary
Total Rescue Medication Use (Average Puffs/Day)
Use of rescue medication is a measure of symptoms that need to be treated with a short-acting bronchodilator. The average daily use across the observation period was used for analysis. Change from baseline was summarized and compared between two arms using a mixed model.
Time frame: From Run-in W -4 to EoT W 26
Population: The change from baseline on rescue medication use were analyzed on randomized patients with a baseline and a post-baseline value. Among 1219 patients who were randomized, only 602 patients in Symbicort group and 607 patients in Formoterol group had valid data and included in analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Symbicort pMDI | Total Rescue Medication Use (Average Puffs/Day) | 0.135 puffs/day | Standard Deviation 1.248 |
| Formoterol Turbuhaler | Total Rescue Medication Use (Average Puffs/Day) | 0.343 puffs/day | Standard Deviation 1.456 |
p-value: 0.008295% CI: [-0.353, -0.053]ANCOVA