A Clinical Study to Evaluate Symbicort Turbuhaler Used 'as Needed' in Adults and Adolescents With Asthma. (SYGMA1)
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| ClinicalTrials.gov Identifier: NCT02149199 |
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Recruitment Status :
Completed
First Posted : May 29, 2014
Results First Posted : September 13, 2019
Last Update Posted : November 15, 2019
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Sponsor:
AstraZeneca
Information provided by (Responsible Party):
AstraZeneca
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Brief Summary:
The purpose of this study is to test if Symbicort® (budesonide/formoterol) Turbuhaler® is effective in treating asthma when used 'as needed' in patients with milder asthma. The efficacy of Symbicort® 'as needed' will be compared with: 1) terbutaline Turbuhaler® 'as needed' and with 2) Pulmicort (budesonide) Turbuhaler® twice daily plus terbutaline Turbuhaler® 'as needed'.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Asthma | Drug: budesonide/formoterol 'as needed' + budesonide placebo bid Drug: terbutaline 'as needed' + placebo budesonide bid Drug: budesonide bid + terbutaline 'as needed' | Phase 3 |
A 52-week, double-blind, randomised, multi-centre, parallel-group, Phase III study in patients 12 years and older with asthma, evaluating the efficacy and safety of Symbicort® (budesonide/formoterol) Turbuhaler® 160/4.5 μg 'as needed' compared with terbutaline Turbuhaler® 0.4 mg 'as needed' and with Pulmicort® (budesonide) Turbuhaler® 200 μg twice daily plus terbutaline Turbuhaler® 0.4 mg 'as needed'
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 3850 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Triple (Participant, Care Provider, Investigator) |
| Primary Purpose: | Treatment |
| Official Title: | A Clinical Study Comparing Symbicort® 'as Needed' With Terbutaline 'as Needed' and With Pulmicort® Twice Daily Plus Terbutaline 'as Needed' in Adult and Adolescent Patients With Asthma. |
| Actual Study Start Date : | July 7, 2014 |
| Actual Primary Completion Date : | August 2, 2017 |
| Actual Study Completion Date : | August 2, 2017 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Symbicort "as needed"+placebo Pulmicort bid
Symbicort (budesonide/formoterol) Turbuhaler 160/4.5 μg 'as needed' + Placebo Pulmicort Turbuhaler 200 μg bid
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Drug: budesonide/formoterol 'as needed' + budesonide placebo bid
Symbicort (budesonide/ formoterol) 160/4.5 μg powder for inhalation 'as needed' plus Pulmicort placebo 200 μg powder for inhalation, 1 inhalation twice daily (morning and evening), 52-week treatment |
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Active Comparator: terbutaline "as needed"+placebo Pulmicort bid
terbutaline Turbuhaler 0.4 mg 'as needed' + placebo Pulmicort 200 μg Turbuhaler bid
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Drug: terbutaline 'as needed' + placebo budesonide bid
Terbutaline 0.4 mg powder for inhalation 'as needed' plus placebo Pulmicort (budesonide) 200 μg powder for inhalation, 1 inhalation twice daily (morning and evening), 52-week treatment |
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Active Comparator: Pulmicort bid + terbutaline "as needed"
Pulmicort 200 μg Turbuhaler bid + terbutaline 0.4 mg Turbuhaler 'as needed'
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Drug: budesonide bid + terbutaline 'as needed'
Pulmicort (budesonide) 200 μg powder for inhalation, 1 inhalation twice daily (morning and evening) plus terbutaline 0.4 mg powder for inhalation 'as needed', 52-week treatment |
Primary Outcome Measures :
- 'Well-controlled Asthma Week' - a Derived Binary Variable (Yes/No) [ Time Frame: Weekly, up to 52 weeks ]A well-controlled asthma week is defined as the fulfilment of both conditions A) and B) below: A) Two or more of the following criteria are fulfilled: - No more than 2 days with a daily asthma symptom score >1 - No more than 2 days of 'as needed' medication use, up to a maximum of 4 occasions per week (multiple occasions per day should be regarded as separate occasions) - Morning PEF ≥80% of Predicted Normal every day B) Both of the following criteria are fulfilled: - No nighttime awakenings due to asthma - No additional inhaled and/or systemic glucocorticosteroid treatment due to asthma. The binary variable well-controlled asthma week was derived for each patient and study week. In addition, for each week, the percent of patients with well-controlled asthma week was derived. It is required that the eDiary had to be completed on at least 5 days in a week to be a well-controlled asthma week.
Secondary Outcome Measures :
- Number of Participants Experiencing at Least One Severe Asthma Exacerbation [ Time Frame: Day 1 up to 52 weeks ]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
- Number of Participants Experiencing at Least One Moderate or Severe Asthma Exacerbation [ Time Frame: Day 1 up to 52 weeks ]
A moderate exacerbation is defined as a deterioration of asthma requiring a change in treatment, i.e. initiation of prescribed additional ICS treatment to avoid progression of the worsening of asthma to a severe exacerbation.
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
- Average Change From Baseline in Pre-dose Forced Expiratory Volume in 1 Second (FEV1) [ Time Frame: Study weeks 0,4,16,28,40,52 ]Overall estimate of FEV1 (mL) pre-bronchodilator change from baseline. Baseline is the measurement at Visit 3 (prior to first dose of Investigational Product) from MMRM (mixed model repeated measures analysis).
- Average Change From Baseline in Morning Peak Expiratory Flow (PEF) [ Time Frame: up to 52 weeks ]Morning peak expiratory flow (eDiary) change from baseline over the randomised treatment period. Baseline is defined as the mean of all non-missing morning measurements during the last 10 days of the run-in period.
- Average Change From Baseline in Evening PEF [ Time Frame: up to 52 weeks ]Evening peak expiratory flow (eDiary) change from baseline during the randomised treatment period. Baseline is defined as the mean of all non-missing evening measurements during the last 10 days of the run-in period.
- Average Change From Baseline in Number of Inhalations of 'as Needed' Medication. [ Time Frame: up to 52 weeks ]'As needed' inhalations change from baseline over the randomised treatment period. Baseline is 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.
- Average Change From Baseline in Asthma Symptom Score [ Time Frame: up to 52 weeks ]Asthma symptom score (eDiary) change from baseline during the randomised treatment period. Symptom score is entered morning and evening by the patient on a 4-point scale from 0 to 3 with higher values indicating more severe symptoms. Asthma symptom score is then the sum of the day and night scores, which implies a range of scores from 0 - 6, with higher values indicating more severe symptoms. Baseline is defined as the mean of all non-missing measurements during the last 10 days of the run-in period.
- Change From Baseline in the Percentage of Nighttime Awakenings Due to Asthma [ Time Frame: up to 52 weeks ]Night-time awakenings (%) due to asthma change from baseline. Variable analysed is the proportion (%) of nights during the relevant period with night-time awakenings. Baseline refers to the last 10 nights of the run-in period.
- Change From Baseline in Percentage of Symptom-free Days [ Time Frame: up to 52 weeks ]Symptom-free days (%) change from baseline during the randomised treatment period.Variable analysed is the proportion (%) of symptom-free days during the relevant period. Baseline refers to the last 10 days of the run-in period.
- Change From Baseline in Percentage of 'As Needed' Free Days [ Time Frame: up to 52 weeks ]'As needed' free days (%) change from baseline during the randomised treatment period. An 'as needed' free day is defined as a day and night with no use of 'as needed' medication. Variable analysed is the proportion (%) of 'as needed' free days during the relevant period. Baseline refers to the last 10 days of the run-in period.
- Change From Baseline in Percentage of Asthma Control Days [ Time Frame: up to 52 weeks ]Asthma control days (%) change from baseline. An asthma control day is defined as the fulfilment of all of the following criteria; a day and night with no asthma symptoms, a night with no awakenings due to asthma symptoms and a day and night with no use of 'as needed' medication. Variable analysed is the proportion (%) of asthma control days during the randomised treatment period. Baseline refers to the last 10 days of the run-in period.
- Number of Patients With Study Specific Asthma Related Discontinuation [ Time Frame: up to 52 weeks ]Study specific asthma related discontinuation
- Poorly Controlled Asthma Weeks [ Time Frame: Weekly for up to 52 weeks ]A poorly-controlled asthma week is defined as a week meeting any one of the following conditions: Two or more consecutive days with awakenings due to asthma on both nights; A recorded use of 'as needed' medication for symptom relief of at least 3 occasions per day, for at least 2 consecutive days; Additional systemic GCS treatment required for severe exacerbation. If there were sufficient data within a week available to confirm the week was not poorly-controlled, the week is labelled as 'does not meet criteria for poorly-controlled'.
- Number of Participants Experiencing at Least One Occasion With Additional Steroids for Asthma [ Time Frame: Day 1 up to 52 weeks ]Additional steroids for asthma includes any additional inhaled and/or systemic glucocorticosteroids treatment due to asthma while in the randomised treatment period.
- Average Change From Baseline in Asthma Control Questionnaire (ACQ-5) [ Time Frame: Study weeks 0,4,16,28,40,52 ]Asthma Control Questionnaire 5-item version score change from baseline. 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.
- Average Change From Baseline in Asthma Quality of Life Questionnaire; Standard Version (AQLQ(S)) [ Time Frame: Study weeks 0,16,28,40,52 ]Asthma Quality of Life Questionnaire Standardised Version (AQLQ (S) overall score change from baseline. 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.
- Percentage of Controller Use Days [ Time Frame: up to 52 weeks ]ICS controller use days (%) during the randomised treatment period is calculated as the cumulative number of 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 exacerbations and/or long term poor asthma control (all treatment groups), divided by the number of days in the randomised treatment period.
- Annual Severe Asthma Exacerbation Rate [ Time Frame: up to 52 weeks ]Severe asthma exacerbations over the randomised treatment period.
- Annual Moderate or Severe Asthma Exacerbation Rate [ Time Frame: up to 52 weeks ]Moderate or severe asthma exacerbations during the randomised treatment period.
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| Ages Eligible for Study: | 12 Years to 130 Years (Child, Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
INCLUSION CRITERIA 1. Provision of informed consent prior to any study specific procedures. For patients under-age, signed informed consent from both the patient and the patient's parent/legal guardian is required 2. Male or Female, ≥12 years of age 3. Documented diagnosis of asthma for at least 6 months prior to Visit 1 4. Patients who are in need of Step 2 treatment according to Global Initiative for Asthma guidelines 5. Patients treated with 'as needed' inhaled short-acting bronchodilator(s) only should have pre-bronchodilator Forced Expiratory Volume in one second (FEV1) ≥ 60 % of Predicted Normal (PN) and post-bronchodilator FEV1 ≥ 80 % PN 6. Patients treated with low stable dose of inhaled corticosteroid or leukotriene antagonist in addition to 'as needed' use of inhaled short-acting bronchodilator(s) should have pre-bronchodilator FEV1 ≥80 % PN 7. Patients should have reversible airway obstruction 8. To be randomized patients must have used Bricanyl Turbuhaler 'as needed' on at least 3 separate days during the last week of the run in period. EXCLUSION CRITERIA 1. Patient has a history of life-threatening asthma including intubation and intensive care unit admission 2. Patient has had an asthma worsening requiring change in treatment other than inhaled short-acting bronchodilator(s) within 30 days prior to Visit 1 or between Visits 1 and 2; or a treatment other than Bricanyl Turbuhaler from Visit 2 until randomization 3. Patient has required treatment with oral, rectal or parenteral glucocorticosteroids (GCS) within 30 days and/or depot parenteral GCS within 12 weeks prior to Visit 1 4. Smoker (current or previous) with a smoking history of ≥ 10 pack years 5. Pregnancy, breast-feeding or planned pregnancy during the study.
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02149199
Locations
Show 257 study locations
Sponsors and Collaborators
AstraZeneca
Investigators
| Principal Investigator: | Paul M O'Byrne, MB, FRCP(C), FRSC | McMaster University, Hamilton, Canada |
Study Documents (Full-Text)
Documents provided by AstraZeneca:
Documents provided by AstraZeneca:
Statistical Analysis Plan [PDF] September 29, 2017
Study Protocol [PDF] December 22, 2016
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | AstraZeneca |
| ClinicalTrials.gov Identifier: | NCT02149199 |
| Other Study ID Numbers: |
D589SC00001 2013-004474-96 ( EudraCT Number ) |
| First Posted: | May 29, 2014 Key Record Dates |
| Results First Posted: | September 13, 2019 |
| Last Update Posted: | November 15, 2019 |
| Last Verified: | November 2019 |
Additional relevant MeSH terms:
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Asthma Bronchial Diseases Respiratory Tract Diseases Lung Diseases, Obstructive Lung Diseases Respiratory Hypersensitivity Hypersensitivity, Immediate Hypersensitivity Immune System Diseases Budesonide Terbutaline Formoterol Fumarate Anti-Inflammatory Agents Bronchodilator Agents Autonomic Agents |
Peripheral Nervous System Agents Physiological Effects of Drugs Anti-Asthmatic Agents Respiratory System Agents Glucocorticoids Hormones Hormones, Hormone Substitutes, and Hormone Antagonists Adrenergic beta-2 Receptor Agonists Adrenergic beta-Agonists Adrenergic Agonists Adrenergic Agents Neurotransmitter Agents Molecular Mechanisms of Pharmacological Action Sympathomimetics Tocolytic Agents |