Trial Outcomes & Findings for Comparing the Efficacy of Symbicort® pMDI and Formoterol Turbuhaler in Reducing Exacerbations in Patients With Cronic Obstructive Pulmonary Disease (NCT NCT02157935)

Last Updated: 2017-11-07

Results Overview

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).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

2026 participants

Primary outcome timeframe

Randomization at Week 0 to End of Treatment (EoT) W 26

Results posted on

2017-11-07

Participant Flow

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.

Participant milestones

Participant milestones
Measure	Symbicort pMDI Symbicort pMDI, budesonide/formoterol, 160/4.5 μg x 2 actuations BID, for oral inhalation	Formoterol Turbuhaler Formoterol Turbuhaler, 4.5 μg x 2 actuations BID, for oral inhalation
Overall Study STARTED	606	613
Overall Study COMPLETED	567	548
Overall Study NOT COMPLETED	39	65

Reasons for withdrawal

Reasons for withdrawal
Measure	Symbicort pMDI Symbicort pMDI, budesonide/formoterol, 160/4.5 μg x 2 actuations BID, for oral inhalation	Formoterol Turbuhaler Formoterol Turbuhaler, 4.5 μg x 2 actuations BID, for oral inhalation
Overall Study Withdrawal by Subject	25	39
Overall Study Screen failure	1	2
Overall Study Protocol Violation	1	0
Overall Study Progressive disease	0	2
Overall Study Other	5	12
Overall Study Lack of Efficacy	0	1
Overall Study Death	4	4
Overall Study Adverse Event	3	5

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Symbicort pMDI n=606 Participants Symbicort pMDI, budesonide/formoterol, 160/4.5 μg x 2 actuations BID, for oral inhalation	Formoterol Turbuhaler n=613 Participants Formoterol Turbuhaler, 4.5 μg x 2 actuations BID, for oral inhalation	Total n=1219 Participants Total of all reporting groups
Age, Continuous	63.1 Years STANDARD_DEVIATION 8.65 • n=5 Participants	63.9 Years STANDARD_DEVIATION 8.67 • n=7 Participants	63.5 Years STANDARD_DEVIATION 8.67 • n=5 Participants
Sex: Female, Male Female	251 Participants n=5 Participants	270 Participants n=7 Participants	521 Participants n=5 Participants
Sex: Female, Male Male	355 Participants n=5 Participants	343 Participants n=7 Participants	698 Participants n=5 Participants
FEV1 post-bronchodilator categories <30%	59 Participants n=5 Participants	54 Participants n=7 Participants	113 Participants n=5 Participants
FEV1 post-bronchodilator categories >=30% to <50%	234 Participants n=5 Participants	247 Participants n=7 Participants	481 Participants n=5 Participants
FEV1 post-bronchodilator categories >=50% to <=70%	307 Participants n=5 Participants	308 Participants n=7 Participants	615 Participants n=5 Participants
FEV1 post-bronchodilator categories >70%	4 Participants n=5 Participants	3 Participants n=7 Participants	7 Participants n=5 Participants
Number of exacerbations during 2 - 52 weeks prior to enrollment 1	430 Participants n=5 Participants	448 Participants n=7 Participants	878 Participants n=5 Participants
Number of exacerbations during 2 - 52 weeks prior to enrollment 2	136 Participants n=5 Participants	117 Participants n=7 Participants	253 Participants n=5 Participants
Number of exacerbations during 2 - 52 weeks prior to enrollment 3	29 Participants n=5 Participants	28 Participants n=7 Participants	57 Participants n=5 Participants
Number of exacerbations during 2 - 52 weeks prior to enrollment 4	7 Participants n=5 Participants	13 Participants n=7 Participants	20 Participants n=5 Participants
Number of exacerbations during 2 - 52 weeks prior to enrollment 5	2 Participants n=5 Participants	6 Participants n=7 Participants	8 Participants n=5 Participants
Number of exacerbations during 2 - 52 weeks prior to enrollment 6	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Number of exacerbations during 2 - 52 weeks prior to enrollment 7	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants

PRIMARY outcome

Timeframe: Randomization at Week 0 to End of Treatment (EoT) W 26

Population: Full analysis set including all randomized subjects

Outcome measures

Outcome measures
Measure	Symbicort pMDI n=606 Participants Symbicort pMDI, budesonide/formoterol, 160/4.5 μg x 2 actuations BID, for oral inhalation	Formoterol Turbuhaler n=613 Participants Formoterol Turbuhaler, 4.5 μg x 2 actuations BID, for oral inhalation
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 Interval 0.7 to 1.03	1.12 COPD exacerbations per year Interval 0.93 to 1.35

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Symbicort pMDI n=606 Participants Symbicort pMDI, budesonide/formoterol, 160/4.5 μg x 2 actuations BID, for oral inhalation	Formoterol Turbuhaler n=613 Participants Formoterol Turbuhaler, 4.5 μg x 2 actuations BID, for oral inhalation
Number of Patients With Moderate or Severe COPD Exacerbation.	171 Participants	204 Participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Symbicort pMDI n=589 Participants Symbicort pMDI, budesonide/formoterol, 160/4.5 μg x 2 actuations BID, for oral inhalation	Formoterol Turbuhaler n=593 Participants Formoterol Turbuhaler, 4.5 μg x 2 actuations BID, for oral inhalation
St. George's Respiratory Questionnaire (SGRQ)	-0.855 scores on a scale Standard Deviation 8.941	0.442 scores on a scale Standard Deviation 9.457

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Symbicort pMDI n=588 Participants Symbicort pMDI, budesonide/formoterol, 160/4.5 μg x 2 actuations BID, for oral inhalation	Formoterol Turbuhaler n=589 Participants Formoterol Turbuhaler, 4.5 μg x 2 actuations BID, for oral inhalation
Pre-dose/Pre-bronchodilator FEV1 at the Study Site	0.008 L Standard Deviation 0.210	-0.025 L Standard Deviation 0.198

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Symbicort pMDI n=602 Participants Symbicort pMDI, budesonide/formoterol, 160/4.5 μg x 2 actuations BID, for oral inhalation	Formoterol Turbuhaler n=607 Participants Formoterol Turbuhaler, 4.5 μg x 2 actuations BID, for oral inhalation
Total Rescue Medication Use (Average Puffs/Day)	0.135 puffs/day Standard Deviation 1.248	0.343 puffs/day Standard Deviation 1.456

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Symbicort pMDI n=603 Participants Symbicort pMDI, budesonide/formoterol, 160/4.5 μg x 2 actuations BID, for oral inhalation	Formoterol Turbuhaler n=610 Participants Formoterol Turbuhaler, 4.5 μg x 2 actuations BID, for oral inhalation
Nights With Awakening Due to COPD	-0.007 awakening/night Standard Deviation 0.173	0.021 awakening/night Standard Deviation 0.195

Adverse Events

Formoterol 4.5 ug x2 Bid

Serious events: 63 serious events

Other events: 56 other events

Deaths: 0 deaths

Symbicort 160/4.5 ug x2 Bid

Serious events: 49 serious events

Other events: 38 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Formoterol 4.5 ug x2 Bid n=613 participants at risk	Symbicort 160/4.5 ug x2 Bid n=605 participants at risk
Infections and infestations Nasopharyngitis	5.2% 32/613 • Number of events 35 • During the randomized treatment period, ie from first treatment to one day after the last treatment.	5.0% 30/605 • Number of events 34 • During the randomized treatment period, ie from first treatment to one day after the last treatment.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	4.4% 27/613 • Number of events 31 • During the randomized treatment period, ie from first treatment to one day after the last treatment.	1.3% 8/605 • Number of events 8 • During the randomized treatment period, ie from first treatment to one day after the last treatment.

Additional Information

Tor Skärby

AstraZeneca

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place