Trial Outcomes & Findings for A Clinical Study to Evaluate Symbicort Turbuhaler Used 'as Needed' in Adults and Adolescents With Asthma (NCT NCT02224157)

Last Updated: 2019-11-25

Results Overview

Severe asthma exacerbations over the randomised treatment period, negative binomial model for non-inferiority test evaluation

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

4215 participants

Primary outcome timeframe

up to 52 weeks

Results posted on

2019-11-25

Participant Flow

4215 patients were enrolled. 26 patients were randomised in error and hence never recieved treatment.

Screening Details Eligibility was assessed at Visits 1, 2 and 3. IC was obtained at V1. At V2, patients stopped pre-study asthma medications and entered a 2 to 4 week run-in period on SABA as needed only (Bricanyl Turbuhaler 0.5 mg). Lung function was assessed by spirometry to confirm eligibility. Eligible patients were randomised at V3.

Participant milestones

Participant milestones
Measure	Placebo Bid + Symbicort 'as Needed' (Experimental) Placebo for budesonide (Placebo Turbuhaler) + Symbicort Turbuhaler (budesonide/formoterol 160/4.5 μg)	Pulmicort Bid + Terbutaline 'as Needed' (Active Comparator) Pulmicort Turbuhaler (budesonide 200 μg) + Terbutaline Turbuhaler 0.4mg 'as needed'
Overall Study STARTED	2095	2094
Overall Study Patients Who Completed Treatment	1924	1903
Overall Study COMPLETED	1985	1983
Overall Study NOT COMPLETED	110	111

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Bid + Symbicort 'as Needed' (Experimental) Placebo for budesonide (Placebo Turbuhaler) + Symbicort Turbuhaler (budesonide/formoterol 160/4.5 μg)	Pulmicort Bid + Terbutaline 'as Needed' (Active Comparator) Pulmicort Turbuhaler (budesonide 200 μg) + Terbutaline Turbuhaler 0.4mg 'as needed'
Overall Study Severe non-compliance to protocol	2	2
Overall Study Other	13	10
Overall Study Subject decision	58	50
Overall Study Prematurely closed site	4	2
Overall Study Eligibility criteria not fulfilled	4	8
Overall Study Lost to Follow-up	27	35
Overall Study Death	1	1
Overall Study Adverse Event	1	3

Baseline Characteristics

Full Analysis Set

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo Bid + Symbicort 'as Needed' (Experimental) n=2089 Participants Placebo for budesonide (Placebo Turbuhaler) + Symbicort Turbuhaler (budesonide/formoterol 160/4.5 μg)	Pulmicort Bid + Terbutaline 'as Needed' (Active Comparator) n=2087 Participants Pulmicort Turbuhaler (budesonide 200 μg) + Terbutaline Turbuhaler 0.4mg 'as needed'	Total n=4176 Participants Total of all reporting groups
Age, Continuous	41.3 Years STANDARD_DEVIATION 16.8 • n=5 Participants	40.7 Years STANDARD_DEVIATION 17.1 • n=7 Participants	41.0 Years STANDARD_DEVIATION 17.0 • n=5 Participants
Sex/Gender, Customized Female	1308 Participants n=5 Participants	1289 Participants n=7 Participants	2597 Participants n=5 Participants
Sex/Gender, Customized Male	781 Participants n=5 Participants	798 Participants n=7 Participants	1579 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	36 Participants n=5 Participants • Full Analysis Set	32 Participants n=7 Participants • Full Analysis Set	68 Participants n=5 Participants • Full Analysis Set
Race/Ethnicity, Customized Asian	399 Participants n=5 Participants • Full Analysis Set	403 Participants n=7 Participants • Full Analysis Set	802 Participants n=5 Participants • Full Analysis Set
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	1 Participants n=5 Participants • Full Analysis Set	2 Participants n=7 Participants • Full Analysis Set	3 Participants n=5 Participants • Full Analysis Set
Race/Ethnicity, Customized Black or African American	34 Participants n=5 Participants • Full Analysis Set	33 Participants n=7 Participants • Full Analysis Set	67 Participants n=5 Participants • Full Analysis Set
Race/Ethnicity, Customized White	1408 Participants n=5 Participants • Full Analysis Set	1406 Participants n=7 Participants • Full Analysis Set	2814 Participants n=5 Participants • Full Analysis Set
Race/Ethnicity, Customized Other	211 Participants n=5 Participants • Full Analysis Set	211 Participants n=7 Participants • Full Analysis Set	422 Participants n=5 Participants • Full Analysis Set

PRIMARY outcome

Timeframe: up to 52 weeks

Population: Full analysis set

Severe asthma exacerbations over the randomised treatment period, negative binomial model for non-inferiority test evaluation

Outcome measures

Outcome measures
Measure	Placebo Bid + Symbicort 'as Needed' (Experimental) n=2089 Participants Placebo for budesonide (Placebo Turbuhaler) + Symbicort Turbuhaler (budesonide/formoterol 160/4.5 μg)	Pulmicort Bid + Terbutaline 'as Needed' (Active Comparator) n=2087 Participants Pulmicort Turbuhaler (budesonide 200 μg) + Terbutaline Turbuhaler 0.4mg 'as needed'
Annual Severe Asthma Exacerbation Rate - Non-inferiority Analysis	0.11 exacerbations per participant year Interval 0.1 to 0.13	0.12 exacerbations per participant year Interval 0.1 to 0.14

PRIMARY outcome

Timeframe: up to 52 weeks

Population: Full analysis set

Severe asthma exacerbations over the randomised treatment period, negative binomial model for superiority test evaluation

Outcome measures

Outcome measures
Measure	Placebo Bid + Symbicort 'as Needed' (Experimental) n=2089 Participants Placebo for budesonide (Placebo Turbuhaler) + Symbicort Turbuhaler (budesonide/formoterol 160/4.5 μg)	Pulmicort Bid + Terbutaline 'as Needed' (Active Comparator) n=2087 Participants Pulmicort Turbuhaler (budesonide 200 μg) + Terbutaline Turbuhaler 0.4mg 'as needed'
Annual Severe Asthma Exacerbation Rate - Superiority Analysis	0.11 exacerbations per participant year Interval 0.1 to 0.13	0.12 exacerbations per participant year Interval 0.1 to 0.14

SECONDARY outcome

Timeframe: Day 1 up to 52 weeks

Population: Full analysis set

A severe exacerbation is defined as a deterioration of asthma requiring any of the following: use of systemic glucocorticosteroids (GCS) for at least 3 days, inpatient hospitalization, or emergency room visit due to asthma that required systemic steroids.

Outcome measures

Outcome measures
Measure	Placebo Bid + Symbicort 'as Needed' (Experimental) n=2089 Participants Placebo for budesonide (Placebo Turbuhaler) + Symbicort Turbuhaler (budesonide/formoterol 160/4.5 μg)	Pulmicort Bid + Terbutaline 'as Needed' (Active Comparator) n=2087 Participants Pulmicort Turbuhaler (budesonide 200 μg) + Terbutaline Turbuhaler 0.4mg 'as needed'
Number of Participants Experiencing at Least One Severe Asthma Exacerbation	177 Participants	184 Participants

SECONDARY outcome

Timeframe: Study weeks 0,17, 34, 52

Population: Full analysis set

The average change from baseline (baseline defined by measurement at week 0, prior to first dose of IP) to the treatment period average assessed over the entire treatment period in pre-bronchodilator FEV1 was derived by computing a contrast for the mean across the post-randomisation visits (week 17, 34, 52) from the MMRM (mixed model repeated measures) analysis.

Outcome measures

Outcome measures
Measure	Placebo Bid + Symbicort 'as Needed' (Experimental) n=2089 Participants Placebo for budesonide (Placebo Turbuhaler) + Symbicort Turbuhaler (budesonide/formoterol 160/4.5 μg)	Pulmicort Bid + Terbutaline 'as Needed' (Active Comparator) n=2087 Participants Pulmicort Turbuhaler (budesonide 200 μg) + Terbutaline Turbuhaler 0.4mg 'as needed'
Average Change From Baseline in Pre-bronchodilator FEV1	104.0 mL Interval 88.5 to 119.6	136.6 mL Interval 121.1 to 152.2

SECONDARY outcome

Timeframe: Day 1 up to 52 weeks

Population: Full analysis set

The following two criteria lead to discontinuation from the IP due to asthma related events: A severe asthma exacerbation with duration for more than 3 weeks, and/or three severe asthma exacerbations during 6 months.

Outcome measures

Outcome measures
Measure	Placebo Bid + Symbicort 'as Needed' (Experimental) n=2089 Participants Placebo for budesonide (Placebo Turbuhaler) + Symbicort Turbuhaler (budesonide/formoterol 160/4.5 μg)	Pulmicort Bid + Terbutaline 'as Needed' (Active Comparator) n=2087 Participants Pulmicort Turbuhaler (budesonide 200 μg) + Terbutaline Turbuhaler 0.4mg 'as needed'
Number of Participants With Study Specific Asthma Related Discontinuation	0 Participants	4 Participants

SECONDARY outcome

Timeframe: Week 0 up to 52 weeks

Population: Full analysis set.

'As-needed' use change from baseline over the randomised treatment period. Baseline was defined as the last 10 days of the run-in period. 'As needed' use was calculated as the cumulative doses of 'as-needed' medication over the randomised treatment period divided by the follow-up time (number of days - 1). ie, average number of inhalations per day.

Outcome measures

Outcome measures
Measure	Placebo Bid + Symbicort 'as Needed' (Experimental) n=2089 Participants Placebo for budesonide (Placebo Turbuhaler) + Symbicort Turbuhaler (budesonide/formoterol 160/4.5 μg)	Pulmicort Bid + Terbutaline 'as Needed' (Active Comparator) n=2087 Participants Pulmicort Turbuhaler (budesonide 200 μg) + Terbutaline Turbuhaler 0.4mg 'as needed'
Average Change From Baseline in 'as Needed' Use	-0.84 Number of inhalations per day Interval -0.86 to -0.81	-0.87 Number of inhalations per day Interval -0.89 to -0.84

SECONDARY outcome

Timeframe: Week 0 up to 52 weeks

Population: Full analysis set

'As needed' free days (%) change from baseline during randomised treatment period. An 'as-needed' free day was defined as a day and night with no use of 'as needed' medication. Variable analysed is the percentage (%) of 'as-needed' free days during the randomised treatment period. Baseline is defined by the last 10 days of the run-in period.

Outcome measures

Outcome measures
Measure	Placebo Bid + Symbicort 'as Needed' (Experimental) n=2089 Participants Placebo for budesonide (Placebo Turbuhaler) + Symbicort Turbuhaler (budesonide/formoterol 160/4.5 μg)	Pulmicort Bid + Terbutaline 'as Needed' (Active Comparator) n=2087 Participants Pulmicort Turbuhaler (budesonide 200 μg) + Terbutaline Turbuhaler 0.4mg 'as needed'
Change From Baseline in Percent of 'as Needed' Free Days	41.01 Percentage of 'as needed' free days Interval 39.9 to 42.12	47.86 Percentage of 'as needed' free days Interval 46.75 to 48.98

SECONDARY outcome

Timeframe: Week 0 up to 52 weeks

Population: Full analysis set

ICS controller use days (%) during the randomised treatment period is calculated as the cumulative days when any controller medication (containing ICS) was taken including maintenance (Pulmicort bid group) and 'as needed' medication (Symbicort 'as needed' group) and additional prescribed ICS for asthma (all treatment groups), divided by the number of days in the randomised treatment period.

Outcome measures

Outcome measures
Measure	Placebo Bid + Symbicort 'as Needed' (Experimental) n=2089 Participants Placebo for budesonide (Placebo Turbuhaler) + Symbicort Turbuhaler (budesonide/formoterol 160/4.5 μg)	Pulmicort Bid + Terbutaline 'as Needed' (Active Comparator) n=2087 Participants Pulmicort Turbuhaler (budesonide 200 μg) + Terbutaline Turbuhaler 0.4mg 'as needed'
Percentage of Controller Use Days	30.45 Percentage of days Interval 29.2 to 31.7	67.92 Percentage of days Interval 66.67 to 69.17

SECONDARY outcome

Timeframe: Study weeks 0, 17, 34, 52

Population: Full analysis set.

ACQ questionnaire contains five questions on patients' symptoms, which are assessed on a 7-point scale from 0 (representing good control) to 6 (representing poor control). The score is the mean score of all questions for which responses are provided. The average change from baseline to treatment period average in ACQ-5 was derived by computing a contrast for the mean across all post-randomisation visits (week 17, 34, 52) from the MMRM (mixed model repeated measures) analysis.

Outcome measures

Outcome measures
Measure	Placebo Bid + Symbicort 'as Needed' (Experimental) n=2089 Participants Placebo for budesonide (Placebo Turbuhaler) + Symbicort Turbuhaler (budesonide/formoterol 160/4.5 μg)	Pulmicort Bid + Terbutaline 'as Needed' (Active Comparator) n=2087 Participants Pulmicort Turbuhaler (budesonide 200 μg) + Terbutaline Turbuhaler 0.4mg 'as needed'
Average Change From Baseline in Asthma Control Questionnaire (5-item Version) - ACQ-5 Score	-0.35 Score Interval -0.38 to -0.32	-0.46 Score Interval -0.49 to -0.43

SECONDARY outcome

Timeframe: Study weeks 0,17, 34, 52

Population: Full Analysis Set.

AQLQ(S) consists of 32 questions in 4 domains. Each question is assessed on a 7-point scale from 1 to 7, with higher values indicating better health-related quality of life. The overall score is calculated as the mean score of all 32 items. The average change from baseline to treatment period average in AQLQ(S) overall score was derived by computing a contrast for the mean across all post-randomisation visits (week 17, 34, 52) from the MMRM (mixed model repeated measures) analysis.

Outcome measures

Outcome measures
Measure	Placebo Bid + Symbicort 'as Needed' (Experimental) n=2089 Participants Placebo for budesonide (Placebo Turbuhaler) + Symbicort Turbuhaler (budesonide/formoterol 160/4.5 μg)	Pulmicort Bid + Terbutaline 'as Needed' (Active Comparator) n=2087 Participants Pulmicort Turbuhaler (budesonide 200 μg) + Terbutaline Turbuhaler 0.4mg 'as needed'
Average Change From Baseline in Asthma Quality of Life Questionnaire Standardised Version - AQLQ(S) Score	0.335 AQLQ(S) overall score Interval 0.305 to 0.366	0.431 AQLQ(S) overall score Interval 0.4 to 0.461

Adverse Events

Placebo Bid + Symbicort 'as Needed' (Experimental)

Serious events: 66 serious events

Other events: 491 other events

Deaths: 1 deaths

Pulmicort Bid + Terbutaline 'as Needed' (Active Comparator)

Serious events: 73 serious events

Other events: 519 other events

Deaths: 1 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Placebo Bid + Symbicort 'as Needed' (Experimental) n=2089 participants at risk Placebo for budesonide (Placebo Turbuhaler) + Symbicort Turbuhaler (budesonide/formoterol 160/4.5 μg)	Pulmicort Bid + Terbutaline 'as Needed' (Active Comparator) n=2087 participants at risk Pulmicort Turbuhaler (budesonide 200 μg) + Terbutaline Turbuhaler 0.4mg 'as needed'
Infections and infestations Viral upper respiratory tract infection	7.4% 155/2089 • Number of events 188 • Adverse events were summarised from Visit 2 throughout the randomised treatment period and including the follow-up period until the last telephone follow-up, or the last contact. Serious adverse events were recorded from the time of informed consent throughout the randomised treatment period and including the folow-up period until last telephone follow-up or last contact.	8.0% 168/2087 • Number of events 206 • Adverse events were summarised from Visit 2 throughout the randomised treatment period and including the follow-up period until the last telephone follow-up, or the last contact. Serious adverse events were recorded from the time of informed consent throughout the randomised treatment period and including the folow-up period until last telephone follow-up or last contact.
Respiratory, thoracic and mediastinal disorders Asthma	3.9% 81/2089 • Number of events 95 • Adverse events were summarised from Visit 2 throughout the randomised treatment period and including the follow-up period until the last telephone follow-up, or the last contact. Serious adverse events were recorded from the time of informed consent throughout the randomised treatment period and including the folow-up period until last telephone follow-up or last contact.	4.0% 84/2087 • Number of events 96 • Adverse events were summarised from Visit 2 throughout the randomised treatment period and including the follow-up period until the last telephone follow-up, or the last contact. Serious adverse events were recorded from the time of informed consent throughout the randomised treatment period and including the folow-up period until last telephone follow-up or last contact.
Nervous system disorders Headache	2.4% 51/2089 • Number of events 69 • Adverse events were summarised from Visit 2 throughout the randomised treatment period and including the follow-up period until the last telephone follow-up, or the last contact. Serious adverse events were recorded from the time of informed consent throughout the randomised treatment period and including the folow-up period until last telephone follow-up or last contact.	2.4% 50/2087 • Number of events 68 • Adverse events were summarised from Visit 2 throughout the randomised treatment period and including the follow-up period until the last telephone follow-up, or the last contact. Serious adverse events were recorded from the time of informed consent throughout the randomised treatment period and including the folow-up period until last telephone follow-up or last contact.
Infections and infestations Bronchitis	3.1% 64/2089 • Number of events 70 • Adverse events were summarised from Visit 2 throughout the randomised treatment period and including the follow-up period until the last telephone follow-up, or the last contact. Serious adverse events were recorded from the time of informed consent throughout the randomised treatment period and including the folow-up period until last telephone follow-up or last contact.	3.7% 78/2087 • Number of events 83 • Adverse events were summarised from Visit 2 throughout the randomised treatment period and including the follow-up period until the last telephone follow-up, or the last contact. Serious adverse events were recorded from the time of informed consent throughout the randomised treatment period and including the folow-up period until last telephone follow-up or last contact.
Infections and infestations Upper respiratory tract infection	3.9% 81/2089 • Number of events 90 • Adverse events were summarised from Visit 2 throughout the randomised treatment period and including the follow-up period until the last telephone follow-up, or the last contact. Serious adverse events were recorded from the time of informed consent throughout the randomised treatment period and including the folow-up period until last telephone follow-up or last contact.	4.3% 89/2087 • Number of events 112 • Adverse events were summarised from Visit 2 throughout the randomised treatment period and including the follow-up period until the last telephone follow-up, or the last contact. Serious adverse events were recorded from the time of informed consent throughout the randomised treatment period and including the folow-up period until last telephone follow-up or last contact.
Infections and infestations Pharyngitis	2.4% 51/2089 • Number of events 55 • Adverse events were summarised from Visit 2 throughout the randomised treatment period and including the follow-up period until the last telephone follow-up, or the last contact. Serious adverse events were recorded from the time of informed consent throughout the randomised treatment period and including the folow-up period until last telephone follow-up or last contact.	3.0% 62/2087 • Number of events 74 • Adverse events were summarised from Visit 2 throughout the randomised treatment period and including the follow-up period until the last telephone follow-up, or the last contact. Serious adverse events were recorded from the time of informed consent throughout the randomised treatment period and including the folow-up period until last telephone follow-up or last contact.
Respiratory, thoracic and mediastinal disorders Rhinitis allergic	2.4% 51/2089 • Number of events 56 • Adverse events were summarised from Visit 2 throughout the randomised treatment period and including the follow-up period until the last telephone follow-up, or the last contact. Serious adverse events were recorded from the time of informed consent throughout the randomised treatment period and including the folow-up period until last telephone follow-up or last contact.	2.1% 44/2087 • Number of events 46 • Adverse events were summarised from Visit 2 throughout the randomised treatment period and including the follow-up period until the last telephone follow-up, or the last contact. Serious adverse events were recorded from the time of informed consent throughout the randomised treatment period and including the folow-up period until last telephone follow-up or last contact.
Infections and infestations Influenza	1.6% 33/2089 • Number of events 34 • Adverse events were summarised from Visit 2 throughout the randomised treatment period and including the follow-up period until the last telephone follow-up, or the last contact. Serious adverse events were recorded from the time of informed consent throughout the randomised treatment period and including the folow-up period until last telephone follow-up or last contact.	2.0% 42/2087 • Number of events 46 • Adverse events were summarised from Visit 2 throughout the randomised treatment period and including the follow-up period until the last telephone follow-up, or the last contact. Serious adverse events were recorded from the time of informed consent throughout the randomised treatment period and including the folow-up period until last telephone follow-up or last contact.

Additional Information

Stefan Ivanov

AstraZeneca AB

Phone: 000000000

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place