RISE: Comparing the Efficacy of Symbicort® pMDI and Formoterol Turbuhaler in Reducing Exacerbations in Patients With Cronic Obstructive Pulmonary Disease
Sponsor
AstraZeneca (Industry)
Overall Status
Completed
CT.gov ID
NCT02157935
Collaborator
(none)
2,026
373
2
19.4
5.4
0.3
Study Details
Study Description
Brief Summary
Comparing the efficacy of Symbicort® pMDI and Formoterol Turbuhaler in reducing exacerbations in patients with Chronic Obstructive Pulmonary Disease (COPD).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
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.
Study Design
Study Type:
Interventional
Actual Enrollment
:
2026 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official Title:
A Phase IIIB, 6-Month, Double-blind, Double-dummy, Randomized, Parallel-group, Multicenter Exacerbation Study of Symbicort® Pressurized Metered-Dose Inhaler (pMDI) 160/4.5 μg x 2 Actuations Twice-daily Compared to Formoterol Turbuhaler 4.5 μg x 2 Inhalations Twice-daily in Cronic Obstructive Pulmonary Disease (COPD) Patients.
Actual Study Start Date
:
Jun 27, 2014
Actual Primary Completion Date
:
Feb 8, 2016
Actual Study Completion Date
:
Feb 8, 2016
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: Symbicort pMDI Symbicort pMDI, budesonide/formoterol, 160/4.5 μg x 2 actuations BID, for oral inhalation |
Drug: Symbicort
Budesonide/formoterol pMDI, 160/4.5 μg x 2 actuations BID, for oral inhalation, 120 doses
Other: Placebo for Symbicort pMDI
pMDI, aerosol for oral inhalation, placebo, 120 doses
|
| Active Comparator: Formoterol Turbuhaler Formoterol Turbuhaler, 4.5 μg x 2 actuations BID, for oral inhalation |
Drug: Formoterol turbohaler
Formoterol Turbuhaler 4.5 μg x 2 actuations BID, for oral inhalation, 60 doses
Other: Placebo for Formoterol Turbohaler
PLacebo powder for oral inhalation, 60 doses
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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.
Eligibility Criteria
Criteria
Ages Eligible for Study:
40 Years
to 95 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
A current clinical diagnosis of COPD with COPD symptoms for more than 1 year, according to the GOLD guidelines.
-
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).
-
Post-bronchodilator FEV1/forced vital capacity (FVC) <0.7 (70%) and FEV1 ≤70% of predicted normal (PN) value.
-
Documented use of a short-acting inhaled bronchodilator (β2-agonists or anticholinergics) as rescue medication within 6 months prior to study start.
-
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:
-
A history of asthma at or after 18 years of age.
-
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.
-
Known homozygous alpha-1 antitrypsin deficiency.
-
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.
-
A history of malignancy (except basal cell carcinoma) within the past 5 years.
-
Active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis, primary pulmonary hypertension, interstitial lung disease, or other active pulmonary diseases.
-
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.
-
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.
-
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.).
-
Pneumonia not resolved within 14 days of Visit 1.
-
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.
-
Long-term oxygen therapy (LTOT) or nocturnal oxygen therapy required for greater than 12 hours a day.
-
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.
-
Treatment with oral, parenteral, or intra-articular corticosteroids within 4 weeks prior to Visit 1.
-
Omalizumab or any other monoclonal or polyclonal antibody therapy taken for any reason within 6 months prior to Visit 1.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
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| 1 | Research Site | Andalusia | Alabama | United States | 36420 |
| 2 | Research Site | Andalusia | Alabama | United States | |
| 3 | Research Site | Birmingham | Alabama | United States | 35209 |
| 4 | Research Site | Birmingham | Alabama | United States | |
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| 129 | Research Site | Biloxi | Mississippi | United States | |
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| 135 | Research Site | Bellevue | Nebraska | United States | |
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| 141 | Research Site | Marlton | New Jersey | United States | |
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| 143 | Research Site | Summit | New Jersey | United States | |
| 144 | Research Site | Jackson Heights | New York | United States | 11372 |
| 145 | Research Site | Jackson Heights | New York | United States | |
| 146 | Research Site | Rochester | New York | United States | 14618 |
| 147 | Research Site | Rochester | New York | United States | |
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| 149 | Research Site | Charlotte | North Carolina | United States | |
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| 151 | Research Site | Cornelius | North Carolina | United States | |
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| 153 | Research Site | Flat Rock | North Carolina | United States | |
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| 155 | Research Site | Greensboro | North Carolina | United States | |
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| 157 | Research Site | High Point | North Carolina | United States | |
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| 159 | Research Site | Cadiz | Ohio | United States | |
| 160 | Research Site | Cincinnati | Ohio | United States | 45231 |
| 161 | Research Site | Cincinnati | Ohio | United States | 45242 |
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| 167 | Research Site | Marion | Ohio | United States | 43302 |
| 168 | Research Site | Marion | Ohio | United States | |
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| 170 | Research Site | Maumee | Ohio | United States | |
| 171 | Research Site | Willoughby | Ohio | United States | 44094 |
| 172 | Research Site | Willoughby | Ohio | United States | |
| 173 | Research Site | Oklahoma City | Oklahoma | United States | 73103 |
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| 175 | Research Site | Medford | Oregon | United States | 97504 |
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| 189 | Research Site | Greenville | South Carolina | United States | 29615 |
| 190 | Research Site | Greenville | South Carolina | United States | |
| 191 | Research Site | Indian Land | South Carolina | United States | 29707 |
| 192 | Research Site | Indian Land | South Carolina | United States | |
| 193 | Research Site | Myrtle Beach | South Carolina | United States | 29588 |
| 194 | Research Site | Myrtle Beach | South Carolina | United States | |
| 195 | Research Site | Spartanburg | South Carolina | United States | 29303 |
| 196 | Research Site | Spartanburg | South Carolina | United States | |
| 197 | Research Site | Boerne | Texas | United States | 78006 |
| 198 | Research Site | Boerne | Texas | United States | |
| 199 | Research Site | Dallas | Texas | United States | 75225 |
| 200 | Research Site | Dallas | Texas | United States | |
| 201 | Research Site | El Paso | Texas | United States | 79903 |
| 202 | Research Site | El Paso | Texas | United States | |
| 203 | Research Site | Houston | Texas | United States | 77034 |
| 204 | Research Site | Houston | Texas | United States | |
| 205 | Research Site | McKinney | Texas | United States | 75069 |
| 206 | Research Site | McKinney | Texas | United States | |
| 207 | Research Site | Plano | Texas | United States | 75093 |
| 208 | Research Site | Plano | Texas | United States | |
| 209 | Research Site | Sealy | Texas | United States | 77474 |
| 210 | Research Site | Sealy | Texas | United States | |
| 211 | Research Site | Midvale | Utah | United States | 84047 |
| 212 | Research Site | Midvale | Utah | United States | |
| 213 | Research Site | Salt Lake City | Utah | United States | 84124 |
| 214 | Research Site | Salt Lake City | Utah | United States | |
| 215 | Research Site | Herndon | Virginia | United States | 20171 |
| 216 | Research Site | Herndon | Virginia | United States | |
| 217 | Research Site | Newport News | Virginia | United States | 23606 |
| 218 | Research Site | Newport News | Virginia | United States | |
| 219 | Research Site | Richmond | Virginia | United States | 23225 |
| 220 | Research Site | Richmond | Virginia | United States | |
| 221 | Research Site | Tacoma | Washington | United States | 98405 |
| 222 | Research Site | Tacoma | Washington | United States | |
| 223 | Research Site | Kingwood | West Virginia | United States | 26357 |
| 224 | Research Site | Kingwood | West Virginia | United States | |
| 225 | Research Site | Caba | Argentina | 1426 | |
| 226 | Research Site | Caba | Argentina | C1425BEN | |
| 227 | Research Site | Caba | Argentina | ||
| 228 | Research Site | Corrientes | Argentina | 3400 | |
| 229 | Research Site | Corrientes | Argentina | ||
| 230 | Research Site | Córdoba | Argentina | X5003DCE | |
| 231 | Research Site | Córdoba | Argentina | ||
| 232 | Research Site | Mendoza | Argentina | 5500 | |
| 233 | Research Site | Mendoza | Argentina | ||
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| 235 | Research Site | Nueve de julio | Argentina | ||
| 236 | Research Site | Ranelagh | Argentina | 1886 | |
| 237 | Research Site | Ranelagh | Argentina | ||
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| 239 | Research Site | San Miguel de Tucuman | Argentina | ||
| 240 | Research Site | Dupnitsa | Bulgaria | 2600 | |
| 241 | Research Site | Dupnitsa | Bulgaria | ||
| 242 | Research Site | Gotse Delchev | Bulgaria | 2900 | |
| 243 | Research Site | Gotse Delchev | Bulgaria | ||
| 244 | Research Site | Kozloduy | Bulgaria | 3320 | |
| 245 | Research Site | Kozloduy | Bulgaria | ||
| 246 | Research Site | Pazardzhik | Bulgaria | 4400 | |
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| 248 | Research Site | Sandanski | Bulgaria | 2800 | |
| 249 | Research Site | Sandanski | Bulgaria | ||
| 250 | Research Site | Sofia | Bulgaria | 1404 | |
| 251 | Research Site | Sofia | Bulgaria | 1407 | |
| 252 | Research Site | Sofia | Bulgaria | 1606 | |
| 253 | Research Site | Sofia | Bulgaria | 1618 | |
| 254 | Research Site | Sofia | Bulgaria | ||
| 255 | Research Site | Stara Zagora | Bulgaria | 6000 | |
| 256 | Research Site | Stara Zagora | Bulgaria | 6003 | |
| 257 | Research Site | Stara Zagora | Bulgaria | ||
| 258 | Research Site | Varna | Bulgaria | 9000 | |
| 259 | Research Site | Varna | Bulgaria | 9010 | |
| 260 | Research Site | Varna | Bulgaria | ||
| 261 | Research Site | Veliko Tarnovo | Bulgaria | 5000 | |
| 262 | Research Site | Veliko Tarnovo | Bulgaria | ||
| 263 | Research Site | Velingrad | Bulgaria | 4600 | |
| 264 | Research Site | Velingrad | Bulgaria | ||
| 265 | Research Site | Santiago | Chile | 7500698 | |
| 266 | Research Site | Santiago | Chile | 8380456 | |
| 267 | Research Site | Santiago | Chile | 8910131 | |
| 268 | Research Site | Santiago | Chile | ||
| 269 | Research Site | Beroun | Czechia | 266 00 | |
| 270 | Research Site | Beroun | Czechia | ||
| 271 | Research Site | Brandys nad Labem | Czechia | 250 01 | |
| 272 | Research Site | Brandys nad Labem | Czechia | ||
| 273 | Research Site | Krnov | Czechia | 794 01 | |
| 274 | Research Site | Krnov | Czechia | ||
| 275 | Research Site | Liberec | Czechia | 460 01 | |
| 276 | Research Site | Liberec | Czechia | ||
| 277 | Research Site | Ostrava-Poruba | Czechia | 708 68 | |
| 278 | Research Site | Ostrava-Poruba | Czechia | ||
| 279 | Research Site | Ostrava | Czechia | 728 80 | |
| 280 | Research Site | Ostrava | Czechia | ||
| 281 | Research Site | Praha 10 | Czechia | 108 00 | |
| 282 | Research Site | Praha 10 | Czechia | ||
| 283 | Research Site | Praha 5 | Czechia | 150 00 | |
| 284 | Research Site | Praha 5 | Czechia | 158 00 | |
| 285 | Research Site | Praha 5 | Czechia | ||
| 286 | Research Site | Praha 6 | Czechia | 163 00 | |
| 287 | Research Site | Praha 6 | Czechia | ||
| 288 | Research Site | Strakonice | Czechia | 38601 | |
| 289 | Research Site | Strakonice | Czechia | ||
| 290 | Research Site | Zatec | Czechia | 43801 | |
| 291 | Research Site | Zatec | Czechia | ||
| 292 | Research Site | Aschaffenburg | Germany | 63739 | |
| 293 | Research Site | Aschaffenburg | Germany | ||
| 294 | Research Site | Bad Lippspringe | Germany | 33175 | |
| 295 | Research Site | Bad Lippspringe | Germany | ||
| 296 | Research Site | Berlin | Germany | 10119 | |
| 297 | Research Site | Berlin | Germany | 10787 | |
| 298 | Research Site | Berlin | Germany | 13187 | |
| 299 | Research Site | Berlin | Germany | ||
| 300 | Research Site | Hannover | Germany | 30173 | |
| 301 | Research Site | Hannover | Germany | ||
| 302 | Research Site | Koblenz | Germany | 56068 | |
| 303 | Research Site | Koblenz | Germany | ||
| 304 | Research Site | Köln | Germany | 51069 | |
| 305 | Research Site | Köln | Germany | ||
| 306 | Research Site | Leipzig | Germany | 04207 | |
| 307 | Research Site | Leipzig | Germany | 04275 | |
| 308 | Research Site | Leipzig | Germany | ||
| 309 | Research Site | Magdeburg | Germany | 39120 | |
| 310 | Research Site | Magdeburg | Germany | ||
| 311 | Research Site | Guadalajara | Mexico | 44200 | |
| 312 | Research Site | Guadalajara | Mexico | 44670 | |
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| 314 | Research Site | Mexico | Mexico | 14050 | |
| 315 | Research Site | Mexico | Mexico | ||
| 316 | Research Site | Monterrey | Mexico | 64460 | |
| 317 | Research Site | Monterrey | Mexico | ||
| 318 | Research Site | San Juan del Rio | Mexico | 76800 | |
| 319 | Research Site | San Juan del Rio | Mexico | ||
| 320 | Research Site | Sonora | Mexico | 83000 | |
| 321 | Research Site | Sonora | Mexico | ||
| 322 | Research Site | Aleksandrów Łódzki | Poland | 95-070 | |
| 323 | Research Site | Aleksandrów Łódzki | Poland | ||
| 324 | Research Site | Białystok | Poland | 15-003 | |
| 325 | Research Site | Białystok | Poland | 15-430 | |
| 326 | Research Site | Białystok | Poland | ||
| 327 | Research Site | Bielsk Podlaski | Poland | 17-100 | |
| 328 | Research Site | Bielsk Podlaski | Poland | ||
| 329 | Research Site | Bydgoszcz | Poland | 85-231 | |
| 330 | Research Site | Bydgoszcz | Poland | ||
| 331 | Research Site | Kościan | Poland | 64-000 | |
| 332 | Research Site | Kościan | Poland | ||
| 333 | Research Site | Kraków | Poland | 31-209 | |
| 334 | Research Site | Kraków | Poland | ||
| 335 | Research Site | Lublin | Poland | 20-709 | |
| 336 | Research Site | Lublin | Poland | ||
| 337 | Research Site | Ostrowiec Świętokrzyski | Poland | 27-400 | |
| 338 | Research Site | Ostrowiec Świętokrzyski | Poland | ||
| 339 | Research Site | Pila | Poland | 64-920 | |
| 340 | Research Site | Pila | Poland | ||
| 341 | Research Site | Poznań | Poland | 60-685 | |
| 342 | Research Site | Poznań | Poland | ||
| 343 | Research Site | Rzeszów | Poland | 35-205 | |
| 344 | Research Site | Rzeszów | Poland | ||
| 345 | Research Site | Skarżysko-Kamienna | Poland | 26-110 | |
| 346 | Research Site | Skarżysko-Kamienna | Poland | ||
| 347 | Research Site | Turek | Poland | 62-700 | |
| 348 | Research Site | Turek | Poland | ||
| 349 | Research Site | Zabrze | Poland | 41-800 | |
| 350 | Research Site | Zabrze | Poland | ||
| 351 | Research Site | Żnin | Poland | 88-400 | |
| 352 | Research Site | Żnin | Poland | ||
| 353 | Research Site | San Juan | Puerto Rico | 00927 | |
| 354 | Research Site | San Juan | Puerto Rico | ||
| 355 | Research Site | Amanzimtoti | South Africa | 4126 | |
| 356 | Research Site | Amanzimtoti | South Africa | ||
| 357 | Research Site | Cape Town | South Africa | 1730 | |
| 358 | Research Site | Cape Town | South Africa | 7700 | |
| 359 | Research Site | Cape Town | South Africa | 7764 | |
| 360 | Research Site | Cape Town | South Africa | ||
| 361 | Research Site | Durban | South Africa | 4001 | |
| 362 | Research Site | Durban | South Africa | 4301 | |
| 363 | Research Site | Durban | South Africa | ||
| 364 | Research Site | Gauteng | South Africa | 2193 | |
| 365 | Research Site | Gauteng | South Africa | ||
| 366 | Research Site | Badalona(Barcelona) | Spain | 08916 | |
| 367 | Research Site | Badalona(Barcelona) | Spain | ||
| 368 | Research Site | Barcelona | Spain | 08003 | |
| 369 | Research Site | Barcelona | Spain | ||
| 370 | Research Site | Loja (Granada) | Spain | 18300 | |
| 371 | Research Site | Loja (Granada) | Spain | ||
| 372 | Research Site | Zaragoza | Spain | 50009 | |
| 373 | Research Site | Zaragoza | Spain |
Sponsors and Collaborators
- AstraZeneca
Investigators
- Principal Investigator: Gary T Ferguson, MD, Pulmonary Research Insititute of Southeast Michigan
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.Responsible Party:
AstraZeneca
ClinicalTrials.gov Identifier:
NCT02157935
Other Study ID Numbers:
- D589UC00001
First Posted:
Jun 6, 2014
Last Update Posted:
Nov 7, 2017
Last Verified:
Oct 1, 2017
Keywords provided by AstraZeneca
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail | 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. |
| Arm/Group Title | Symbicort pMDI | Formoterol Turbuhaler |
|---|---|---|
| Arm/Group Description | Symbicort pMDI, budesonide/formoterol, 160/4.5 μg x 2 actuations BID, for oral inhalation | Formoterol Turbuhaler, 4.5 μg x 2 actuations BID, for oral inhalation |
| Period Title: Overall Study | ||
| STARTED | 606 | 613 |
| COMPLETED | 567 | 548 |
| NOT COMPLETED | 39 | 65 |
Baseline Characteristics
| Arm/Group Title | Symbicort pMDI | Formoterol Turbuhaler | Total |
|---|---|---|---|
| Arm/Group Description | Symbicort pMDI, budesonide/formoterol, 160/4.5 μg x 2 actuations BID, for oral inhalation | Formoterol Turbuhaler, 4.5 μg x 2 actuations BID, for oral inhalation | Total of all reporting groups |
| Overall Participants | 606 | 613 | 1219 |
| Age (Years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [Years] |
63.1
(8.65)
|
63.9
(8.67)
|
63.5
(8.67)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
251
41.4%
|
270
44%
|
521
42.7%
|
| Male |
355
58.6%
|
343
56%
|
698
57.3%
|
| FEV1 post-bronchodilator categories (Number) [Number] | |||
| <30% |
59
9.7%
|
54
8.8%
|
113
9.3%
|
| >=30% to <50% |
234
38.6%
|
247
40.3%
|
481
39.5%
|
| >=50% to <=70% |
307
50.7%
|
308
50.2%
|
615
50.5%
|
| >70% |
4
0.7%
|
3
0.5%
|
7
0.6%
|
| Number of exacerbations during 2 - 52 weeks prior to enrollment (Number) [Number] | |||
| 1 |
430
71%
|
448
73.1%
|
878
72%
|
| 2 |
136
22.4%
|
117
19.1%
|
253
20.8%
|
| 3 |
29
4.8%
|
28
4.6%
|
57
4.7%
|
| 4 |
7
1.2%
|
13
2.1%
|
20
1.6%
|
| 5 |
2
0.3%
|
6
1%
|
8
0.7%
|
| 6 |
0
0%
|
1
0.2%
|
1
0.1%
|
| 7 |
2
0.3%
|
0
0%
|
2
0.2%
|
Outcome Measures
| Title | 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 |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Full analysis set including all randomized subjects |
| Arm/Group Title | Symbicort pMDI | Formoterol Turbuhaler |
|---|---|---|
| Arm/Group Description | Symbicort pMDI, budesonide/formoterol, 160/4.5 μg x 2 actuations BID, for oral inhalation | Formoterol Turbuhaler, 4.5 μg x 2 actuations BID, for oral inhalation |
| Measure Participants | 606 | 613 |
| Least Squares Mean (95% Confidence Interval) [COPD exacerbations per year] |
0.85
|
1.12
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Symbicort pMDI, Formoterol Turbuhaler |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0059 |
| Comments | ||
| Method | Negative binomial model | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Rate ratio |
| Estimated Value | 0.76 | |
| Confidence Interval |
(2-Sided) 95% 0.62 to 0.92 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Number of Patients With Moderate or Severe COPD Exacerbation. |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Symbicort pMDI | Formoterol Turbuhaler |
|---|---|---|
| Arm/Group Description | Symbicort pMDI, budesonide/formoterol, 160/4.5 μg x 2 actuations BID, for oral inhalation | Formoterol Turbuhaler, 4.5 μg x 2 actuations BID, for oral inhalation |
| Measure Participants | 606 | 613 |
| Number [Participants] |
171
28.2%
|
204
33.3%
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Symbicort pMDI, Formoterol Turbuhaler |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0164 |
| Comments | ||
| Method | Regression, Cox | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.78 | |
| Confidence Interval |
(2-Sided) 95% 0.64 to 0.96 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | St. George's Respiratory Questionnaire (SGRQ) |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Symbicort pMDI | Formoterol Turbuhaler |
|---|---|---|
| Arm/Group Description | Symbicort pMDI, budesonide/formoterol, 160/4.5 μg x 2 actuations BID, for oral inhalation | Formoterol Turbuhaler, 4.5 μg x 2 actuations BID, for oral inhalation |
| Measure Participants | 589 | 593 |
| Mean (Standard Deviation) [scores on a scale] |
-0.855
(8.941)
|
0.442
(9.457)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Symbicort pMDI, Formoterol Turbuhaler |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0070 |
| Comments | ||
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | -1.343 | |
| Confidence Interval |
(2-Sided) 95% -2.318 to -0.368 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Pre-dose/Pre-bronchodilator FEV1 at the Study Site |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Symbicort pMDI | Formoterol Turbuhaler |
|---|---|---|
| Arm/Group Description | Symbicort pMDI, budesonide/formoterol, 160/4.5 μg x 2 actuations BID, for oral inhalation | Formoterol Turbuhaler, 4.5 μg x 2 actuations BID, for oral inhalation |
| Measure Participants | 588 | 589 |
| Mean (Standard Deviation) [L] |
0.008
(0.210)
|
-0.025
(0.198)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Symbicort pMDI, Formoterol Turbuhaler |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0091 |
| Comments | ||
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | 0.030 | |
| Confidence Interval |
(2-Sided) 95% 0.008 to 0.053 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Total Rescue Medication Use (Average Puffs/Day) |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Symbicort pMDI | Formoterol Turbuhaler |
|---|---|---|
| Arm/Group Description | Symbicort pMDI, budesonide/formoterol, 160/4.5 μg x 2 actuations BID, for oral inhalation | Formoterol Turbuhaler, 4.5 μg x 2 actuations BID, for oral inhalation |
| Measure Participants | 602 | 607 |
| Mean (Standard Deviation) [puffs/day] |
0.135
(1.248)
|
0.343
(1.456)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Symbicort pMDI, Formoterol Turbuhaler |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0082 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | -0.203 | |
| Confidence Interval |
(2-Sided) 95% -0.353 to -0.053 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Nights With Awakening Due to COPD |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Symbicort pMDI | Formoterol Turbuhaler |
|---|---|---|
| Arm/Group Description | Symbicort pMDI, budesonide/formoterol, 160/4.5 μg x 2 actuations BID, for oral inhalation | Formoterol Turbuhaler, 4.5 μg x 2 actuations BID, for oral inhalation |
| Measure Participants | 603 | 610 |
| Mean (Standard Deviation) [awakening/night] |
-0.007
(0.173)
|
0.021
(0.195)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Symbicort pMDI, Formoterol Turbuhaler |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority or Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0048 |
| Comments | ||
| Method | ANCOVA | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | -0.028 | |
| Confidence Interval |
(2-Sided) 95% -0.048 to -0.009 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
Adverse Events
| Time Frame | During the randomized treatment period, ie from first treatment to one day after the last treatment. | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | ||||
| Arm/Group Title | Formoterol 4.5 ug x2 Bid | Symbicort 160/4.5 ug x2 Bid | ||
| Arm/Group Description | ||||
All Cause Mortality |
||||
| Formoterol 4.5 ug x2 Bid | Symbicort 160/4.5 ug x2 Bid | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | ||
Serious Adverse Events |
||||
| Formoterol 4.5 ug x2 Bid | Symbicort 160/4.5 ug x2 Bid | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 63/613 (10.3%) | 49/605 (8.1%) | ||
| Blood and lymphatic system disorders | ||||
| Anaemia | 1/613 (0.2%) | 1 | 0/605 (0%) | 0 |
| Retroperitoneal lymphadenopathy | 0/613 (0%) | 0 | 1/605 (0.2%) | 1 |
| Cardiac disorders | ||||
| Acute coronary syndrome | 1/613 (0.2%) | 1 | 0/605 (0%) | 0 |
| Angina pectoris | 2/613 (0.3%) | 2 | 2/605 (0.3%) | 2 |
| Atrial fibrillation | 1/613 (0.2%) | 1 | 1/605 (0.2%) | 1 |
| Cardiac arrest | 0/613 (0%) | 0 | 1/605 (0.2%) | 1 |
| Cardiac failure | 2/613 (0.3%) | 3 | 0/605 (0%) | 0 |
| Cardiac failure acute | 0/613 (0%) | 0 | 1/605 (0.2%) | 1 |
| Cardiac failure congestive | 0/613 (0%) | 0 | 1/605 (0.2%) | 1 |
| Cardio-respiratory arrest | 0/613 (0%) | 0 | 1/605 (0.2%) | 1 |
| Cardiogenic shock | 1/613 (0.2%) | 1 | 0/605 (0%) | 0 |
| Coronary artery disease | 1/613 (0.2%) | 1 | 0/605 (0%) | 0 |
| Myocardial infarction | 0/613 (0%) | 0 | 2/605 (0.3%) | 2 |
| Myocardial ischaemia | 1/613 (0.2%) | 1 | 1/605 (0.2%) | 2 |
| Sinoatrial block | 0/613 (0%) | 0 | 1/605 (0.2%) | 1 |
| Sinus tachycardia | 1/613 (0.2%) | 1 | 0/605 (0%) | 0 |
| Ventricular arrhythmia | 1/613 (0.2%) | 1 | 0/605 (0%) | 0 |
| Eye disorders | ||||
| Cataract | 0/613 (0%) | 0 | 1/605 (0.2%) | 1 |
| Retinal detachment | 0/613 (0%) | 0 | 1/605 (0.2%) | 1 |
| Visual impairment | 0/613 (0%) | 0 | 1/605 (0.2%) | 1 |
| Vitreous haemorrhage | 0/613 (0%) | 0 | 1/605 (0.2%) | 1 |
| Gastrointestinal disorders | ||||
| Abdominal hernia | 0/613 (0%) | 0 | 1/605 (0.2%) | 1 |
| Abdominal pain | 1/613 (0.2%) | 1 | 1/605 (0.2%) | 1 |
| Gastritis | 1/613 (0.2%) | 1 | 0/605 (0%) | 0 |
| Large intestine perforation | 1/613 (0.2%) | 1 | 0/605 (0%) | 0 |
| Hepatobiliary disorders | ||||
| Cholecystitis acute | 2/613 (0.3%) | 2 | 1/605 (0.2%) | 1 |
| Infections and infestations | ||||
| Appendicitis | 0/613 (0%) | 0 | 1/605 (0.2%) | 1 |
| Bronchitis | 2/613 (0.3%) | 2 | 0/605 (0%) | 0 |
| Cellulitis | 0/613 (0%) | 0 | 1/605 (0.2%) | 1 |
| Gastroenteritis salmonella | 1/613 (0.2%) | 1 | 0/605 (0%) | 0 |
| Lower respiratory tract infection bacterial | 2/613 (0.3%) | 2 | 1/605 (0.2%) | 1 |
| Orchitis | 1/613 (0.2%) | 1 | 0/605 (0%) | 0 |
| Otitis media | 1/613 (0.2%) | 1 | 0/605 (0%) | 0 |
| Pneumonia bacterial | 5/613 (0.8%) | 5 | 0/605 (0%) | 0 |
| Salmonella bacteraemia | 1/613 (0.2%) | 1 | 0/605 (0%) | 0 |
| Sepsis | 0/613 (0%) | 0 | 1/605 (0.2%) | 1 |
| Sepsis syndrome | 0/613 (0%) | 0 | 1/605 (0.2%) | 1 |
| Urinary tract infection | 2/613 (0.3%) | 2 | 1/605 (0.2%) | 1 |
| Injury, poisoning and procedural complications | ||||
| Accidental overdose | 0/613 (0%) | 0 | 1/605 (0.2%) | 1 |
| Extradural haematoma | 1/613 (0.2%) | 1 | 0/605 (0%) | 0 |
| Face injury | 1/613 (0.2%) | 1 | 0/605 (0%) | 0 |
| Foot fracture | 0/613 (0%) | 0 | 1/605 (0.2%) | 1 |
| Tibia fracture | 0/613 (0%) | 0 | 1/605 (0.2%) | 1 |
| Metabolism and nutrition disorders | ||||
| Dehydration | 1/613 (0.2%) | 1 | 0/605 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||
| Back pain | 0/613 (0%) | 0 | 1/605 (0.2%) | 1 |
| Intervertebral disc protrusion | 1/613 (0.2%) | 1 | 0/605 (0%) | 0 |
| Musculoskeletal chest pain | 1/613 (0.2%) | 1 | 0/605 (0%) | 0 |
| Osteoarthritis | 2/613 (0.3%) | 2 | 0/605 (0%) | 0 |
| Pain in extremity | 0/613 (0%) | 0 | 1/605 (0.2%) | 1 |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
| Breast cancer female | 1/613 (0.2%) | 1 | 0/605 (0%) | 0 |
| Chronic lymphocytic leukaemia | 1/613 (0.2%) | 1 | 0/605 (0%) | 0 |
| Lung neoplasm malignant | 1/613 (0.2%) | 1 | 0/605 (0%) | 0 |
| Plasma cell myeloma | 1/613 (0.2%) | 1 | 0/605 (0%) | 0 |
| Small cell lung cancer | 0/613 (0%) | 0 | 1/605 (0.2%) | 1 |
| Nervous system disorders | ||||
| Carotid artery stenosis | 0/613 (0%) | 0 | 1/605 (0.2%) | 1 |
| Cerebrovascular accident | 0/613 (0%) | 0 | 1/605 (0.2%) | 1 |
| Cerebrovascular insufficiency | 1/613 (0.2%) | 1 | 0/605 (0%) | 0 |
| Ischaemic stroke | 1/613 (0.2%) | 1 | 0/605 (0%) | 0 |
| Transient ischaemic attack | 0/613 (0%) | 0 | 1/605 (0.2%) | 1 |
| Product Issues | ||||
| Device malfunction | 0/613 (0%) | 0 | 1/605 (0.2%) | 1 |
| Renal and urinary disorders | ||||
| Acute kidney injury | 1/613 (0.2%) | 1 | 0/605 (0%) | 0 |
| Chronic kidney disease | 1/613 (0.2%) | 1 | 0/605 (0%) | 0 |
| Reproductive system and breast disorders | ||||
| Benign prostatic hyperplasia | 0/613 (0%) | 0 | 1/605 (0.2%) | 1 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Acute respiratory failure | 1/613 (0.2%) | 1 | 2/605 (0.3%) | 2 |
| Bronchitis chronic | 0/613 (0%) | 0 | 1/605 (0.2%) | 1 |
| Chronic obstructive pulmonary disease | 28/613 (4.6%) | 29 | 20/605 (3.3%) | 22 |
| Chronic respiratory failure | 0/613 (0%) | 0 | 2/605 (0.3%) | 2 |
| Dyspnoea | 0/613 (0%) | 0 | 2/605 (0.3%) | 2 |
| Epistaxis | 0/613 (0%) | 0 | 1/605 (0.2%) | 1 |
| Interstitial lung disease | 1/613 (0.2%) | 1 | 0/605 (0%) | 0 |
| Pneumothorax | 1/613 (0.2%) | 1 | 0/605 (0%) | 0 |
| Pulmonary embolism | 0/613 (0%) | 0 | 1/605 (0.2%) | 1 |
| Respiratory distress | 1/613 (0.2%) | 1 | 0/605 (0%) | 0 |
| Respiratory failure | 1/613 (0.2%) | 1 | 0/605 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
||||
| Formoterol 4.5 ug x2 Bid | Symbicort 160/4.5 ug x2 Bid | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 56/613 (9.1%) | 38/605 (6.3%) | ||
| Infections and infestations | ||||
| Nasopharyngitis | 32/613 (5.2%) | 35 | 30/605 (5%) | 34 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Chronic obstructive pulmonary disease | 27/613 (4.4%) | 31 | 8/605 (1.3%) | 8 |
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Tor Skärby |
|---|---|
| Organization | AstraZeneca |
| Phone | |
| tor.skarby@astrazeneca.com |
Responsible Party:
AstraZeneca
ClinicalTrials.gov Identifier:
NCT02157935
Other Study ID Numbers:
- D589UC00001
First Posted:
Jun 6, 2014
Last Update Posted:
Nov 7, 2017
Last Verified:
Oct 1, 2017