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Comparing the Efficacy of Symbicort® pMDI and Formoterol Turbuhaler in Reducing Exacerbations in Patients With Cronic Obstructive Pulmonary Disease (RISE)

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ClinicalTrials.gov Identifier: NCT02157935
Recruitment Status : Completed
First Posted : June 6, 2014
Results First Posted : June 12, 2017
Last Update Posted : November 7, 2017
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition COPD Patients
Interventions Drug: Symbicort
Drug: Formoterol turbohaler
Other: Placebo for Symbicort pMDI
Other: Placebo for Formoterol Turbohaler
Enrollment 2026
Recruitment Details  
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.
Arm/Group Title Symbicort pMDI Formoterol Turbuhaler
Hide 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
Reason Not Completed
Withdrawal by Subject             25             39
Screen failure             1             2
Protocol Violation             1             0
Progressive disease             0             2
Other             5             12
Lack of Efficacy             0             1
Death             4             4
Adverse Event             3             5
Arm/Group Title Symbicort pMDI Formoterol Turbuhaler Total
Hide 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 Number of Baseline Participants 606 613 1219
Hide Baseline Analysis Population Description
Full analysis set including all randomized patients
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 606 participants 613 participants 1219 participants
63.1  (8.65) 63.9  (8.67) 63.5  (8.67)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 606 participants 613 participants 1219 participants
Female
251
  41.4%
270
  44.0%
521
  42.7%
Male
355
  58.6%
343
  56.0%
698
  57.3%
FEV1 post-bronchodilator categories  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 606 participants 613 participants 1219 participants
<30% 59 54 113
>=30% to <50% 234 247 481
>=50% to <=70% 307 308 615
>70% 4 3 7
Number of exacerbations during 2 - 52 weeks prior to enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 606 participants 613 participants 1219 participants
1 430 448 878
2 136 117 253
3 29 28 57
4 7 13 20
5 2 6 8
6 0 1 1
7 2 0 2
1.Primary Outcome
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
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set including all randomized subjects
Arm/Group Title Symbicort pMDI Formoterol Turbuhaler
Hide 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
Overall Number of Participants Analyzed 606 613
Least Squares Mean (95% Confidence Interval)
Unit of Measure: COPD exacerbations per year
0.85
(0.70 to 1.03)
1.12
(0.93 to 1.35)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Symbicort pMDI, Formoterol Turbuhaler
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0059
Comments [Not Specified]
Method Negative binomial model
Comments [Not Specified]
Method of Estimation Estimation Parameter Rate ratio
Estimated Value 0.76
Confidence Interval (2-Sided) 95%
0.62 to 0.92
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Number of Patients With Moderate or Severe COPD Exacerbation.
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Symbicort pMDI Formoterol Turbuhaler
Hide 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
Overall Number of Participants Analyzed 606 613
Measure Type: Number
Unit of Measure: Participants
171 204
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Symbicort pMDI, Formoterol Turbuhaler
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0164
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.78
Confidence Interval (2-Sided) 95%
0.64 to 0.96
Estimation Comments [Not Specified]
3.Secondary Outcome
Title St. George’s Respiratory Questionnaire (SGRQ)
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Overall Number of Participants Analyzed 589 593
Mean (Standard Deviation)
Unit of Measure: scores on a scale
-0.855  (8.941) 0.442  (9.457)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Symbicort pMDI, Formoterol Turbuhaler
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0070
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.343
Confidence Interval (2-Sided) 95%
-2.318 to -0.368
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Pre-dose/Pre-bronchodilator FEV1 at the Study Site
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Overall Number of Participants Analyzed 588 589
Mean (Standard Deviation)
Unit of Measure: L
0.008  (0.210) -0.025  (0.198)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Symbicort pMDI, Formoterol Turbuhaler
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0091
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.030
Confidence Interval (2-Sided) 95%
0.008 to 0.053
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Total Rescue Medication Use (Average Puffs/Day)
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Overall Number of Participants Analyzed 602 607
Mean (Standard Deviation)
Unit of Measure: puffs/day
0.135  (1.248) 0.343  (1.456)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Symbicort pMDI, Formoterol Turbuhaler
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0082
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.203
Confidence Interval (2-Sided) 95%
-0.353 to -0.053
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Nights With Awakening Due to COPD
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Overall Number of Participants Analyzed 603 610
Mean (Standard Deviation)
Unit of Measure: awakening/night
-0.007  (0.173) 0.021  (0.195)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Symbicort pMDI, Formoterol Turbuhaler
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0048
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.028
Confidence Interval (2-Sided) 95%
-0.048 to -0.009
Estimation Comments [Not Specified]
Time Frame During the randomized treatment period, ie from first treatment to one day after the last treatment.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Formoterol 4.5 ug x2 Bid Symbicort 160/4.5 ug x2 Bid
Hide Arm/Group Description [Not Specified] [Not Specified]
All-Cause Mortality
Formoterol 4.5 ug x2 Bid Symbicort 160/4.5 ug x2 Bid
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide 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 (10.28%)      49/605 (8.10%)    
Blood and lymphatic system disorders     
Anaemia  1  1/613 (0.16%)  1 0/605 (0.00%)  0
Retroperitoneal lymphadenopathy  1  0/613 (0.00%)  0 1/605 (0.17%)  1
Cardiac disorders     
Acute coronary syndrome  1  1/613 (0.16%)  1 0/605 (0.00%)  0
Angina pectoris  1  2/613 (0.33%)  2 2/605 (0.33%)  2
Atrial fibrillation  1  1/613 (0.16%)  1 1/605 (0.17%)  1
Cardiac arrest  1  0/613 (0.00%)  0 1/605 (0.17%)  1
Cardiac failure  1  2/613 (0.33%)  3 0/605 (0.00%)  0
Cardiac failure acute  1  0/613 (0.00%)  0 1/605 (0.17%)  1
Cardiac failure congestive  1  0/613 (0.00%)  0 1/605 (0.17%)  1
Cardio-respiratory arrest  1  0/613 (0.00%)  0 1/605 (0.17%)  1
Cardiogenic shock  1  1/613 (0.16%)  1 0/605 (0.00%)  0
Coronary artery disease  1  1/613 (0.16%)  1 0/605 (0.00%)  0
Myocardial infarction  1  0/613 (0.00%)  0 2/605 (0.33%)  2
Myocardial ischaemia  1  1/613 (0.16%)  1 1/605 (0.17%)  2
Sinoatrial block  1  0/613 (0.00%)  0 1/605 (0.17%)  1
Sinus tachycardia  1  1/613 (0.16%)  1 0/605 (0.00%)  0
Ventricular arrhythmia  1  1/613 (0.16%)  1 0/605 (0.00%)  0
Eye disorders     
Cataract  1  0/613 (0.00%)  0 1/605 (0.17%)  1
Retinal detachment  1  0/613 (0.00%)  0 1/605 (0.17%)  1
Visual impairment  1  0/613 (0.00%)  0 1/605 (0.17%)  1
Vitreous haemorrhage  1  0/613 (0.00%)  0 1/605 (0.17%)  1
Gastrointestinal disorders     
Abdominal hernia  1  0/613 (0.00%)  0 1/605 (0.17%)  1
Abdominal pain  1  1/613 (0.16%)  1 1/605 (0.17%)  1
Gastritis  1  1/613 (0.16%)  1 0/605 (0.00%)  0
Large intestine perforation  1  1/613 (0.16%)  1 0/605 (0.00%)  0
Hepatobiliary disorders     
Cholecystitis acute  1  2/613 (0.33%)  2 1/605 (0.17%)  1
Infections and infestations     
Appendicitis  1  0/613 (0.00%)  0 1/605 (0.17%)  1
Bronchitis  1  2/613 (0.33%)  2 0/605 (0.00%)  0
Cellulitis  1  0/613 (0.00%)  0 1/605 (0.17%)  1
Gastroenteritis salmonella  1  1/613 (0.16%)  1 0/605 (0.00%)  0
Lower respiratory tract infection bacterial  1  2/613 (0.33%)  2 1/605 (0.17%)  1
Orchitis  1  1/613 (0.16%)  1 0/605 (0.00%)  0
Otitis media  1  1/613 (0.16%)  1 0/605 (0.00%)  0
Pneumonia bacterial  1  5/613 (0.82%)  5 0/605 (0.00%)  0
Salmonella bacteraemia  1  1/613 (0.16%)  1 0/605 (0.00%)  0
Sepsis  1  0/613 (0.00%)  0 1/605 (0.17%)  1
Sepsis syndrome  1  0/613 (0.00%)  0 1/605 (0.17%)  1
Urinary tract infection  1  2/613 (0.33%)  2 1/605 (0.17%)  1
Injury, poisoning and procedural complications     
Accidental overdose  1  0/613 (0.00%)  0 1/605 (0.17%)  1
Extradural haematoma  1  1/613 (0.16%)  1 0/605 (0.00%)  0
Face injury  1  1/613 (0.16%)  1 0/605 (0.00%)  0
Foot fracture  1  0/613 (0.00%)  0 1/605 (0.17%)  1
Tibia fracture  1  0/613 (0.00%)  0 1/605 (0.17%)  1
Metabolism and nutrition disorders     
Dehydration  1  1/613 (0.16%)  1 0/605 (0.00%)  0
Musculoskeletal and connective tissue disorders     
Back pain  1  0/613 (0.00%)  0 1/605 (0.17%)  1
Intervertebral disc protrusion  1  1/613 (0.16%)  1 0/605 (0.00%)  0
Musculoskeletal chest pain  1  1/613 (0.16%)  1 0/605 (0.00%)  0
Osteoarthritis  1  2/613 (0.33%)  2 0/605 (0.00%)  0
Pain in extremity  1  0/613 (0.00%)  0 1/605 (0.17%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Breast cancer female  1  1/613 (0.16%)  1 0/605 (0.00%)  0
Chronic lymphocytic leukaemia  1  1/613 (0.16%)  1 0/605 (0.00%)  0
Lung neoplasm malignant  1  1/613 (0.16%)  1 0/605 (0.00%)  0
Plasma cell myeloma  1  1/613 (0.16%)  1 0/605 (0.00%)  0
Small cell lung cancer  1  0/613 (0.00%)  0 1/605 (0.17%)  1
Nervous system disorders     
Carotid artery stenosis  1  0/613 (0.00%)  0 1/605 (0.17%)  1
Cerebrovascular accident  1  0/613 (0.00%)  0 1/605 (0.17%)  1
Cerebrovascular insufficiency  1  1/613 (0.16%)  1 0/605 (0.00%)  0
Ischaemic stroke  1  1/613 (0.16%)  1 0/605 (0.00%)  0
Transient ischaemic attack  1  0/613 (0.00%)  0 1/605 (0.17%)  1
Product Issues     
Device malfunction  1  0/613 (0.00%)  0 1/605 (0.17%)  1
Renal and urinary disorders     
Acute kidney injury  1  1/613 (0.16%)  1 0/605 (0.00%)  0
Chronic kidney disease  1  1/613 (0.16%)  1 0/605 (0.00%)  0
Reproductive system and breast disorders     
Benign prostatic hyperplasia  1  0/613 (0.00%)  0 1/605 (0.17%)  1
Respiratory, thoracic and mediastinal disorders     
Acute respiratory failure  1  1/613 (0.16%)  1 2/605 (0.33%)  2
Bronchitis chronic  1  0/613 (0.00%)  0 1/605 (0.17%)  1
Chronic obstructive pulmonary disease  1  28/613 (4.57%)  29 20/605 (3.31%)  22
Chronic respiratory failure  1  0/613 (0.00%)  0 2/605 (0.33%)  2
Dyspnoea  1  0/613 (0.00%)  0 2/605 (0.33%)  2
Epistaxis  1  0/613 (0.00%)  0 1/605 (0.17%)  1
Interstitial lung disease  1  1/613 (0.16%)  1 0/605 (0.00%)  0
Pneumothorax  1  1/613 (0.16%)  1 0/605 (0.00%)  0
Pulmonary embolism  1  0/613 (0.00%)  0 1/605 (0.17%)  1
Respiratory distress  1  1/613 (0.16%)  1 0/605 (0.00%)  0
Respiratory failure  1  1/613 (0.16%)  1 0/605 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 19.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 3%
Formoterol 4.5 ug x2 Bid Symbicort 160/4.5 ug x2 Bid
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   56/613 (9.14%)      38/605 (6.28%)    
Infections and infestations     
Nasopharyngitis  1  32/613 (5.22%)  35 30/605 (4.96%)  34
Respiratory, thoracic and mediastinal disorders     
Chronic obstructive pulmonary disease  1  27/613 (4.40%)  31 8/605 (1.32%)  8
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 19.0
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
Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT02157935     History of Changes
Other Study ID Numbers: D589UC00001
First Submitted: June 5, 2014
First Posted: June 6, 2014
Results First Submitted: December 15, 2016
Results First Posted: June 12, 2017
Last Update Posted: November 7, 2017