AsthmaPhase 3SYGMA1NCT02149199
A Clinical Study to Evaluate Symbicort Turbuhaler Used 'as Needed' in Adults and Adolescents With Asthma.
A Phase 3 study testing budesonide bid + terbutaline 'as needed' in people with Asthma, run by AstraZeneca at 255 sites in 18 countries.
Trial 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)… Read more about this study
- Who is it for?
- Ages 12 to 130 years
- Conditions the study is for
- Asthma
- What is being tested?
- budesonide bid + terbutaline 'as needed'
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 3,850 participants
- Where
- 255 sitesin 18 countries
- Study dates
- 7 Jul 2014to 2 Aug 2017
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 12 to 130 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
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.
Trial locations and contacts
255 sites in 18 countries.
255 sites in 18 countries
Russia41 sites
Research Site
Chelyabinsk, 454021
Research Site
Gatchina, 188300
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Ivanovo, 153005
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Kazan', 420012
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Kemerovo, 650002
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Kemerovo, 650099
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Krasnoyarsk, 660022
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Moscow, 105077
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Moscow, 109240
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Moscow, 117630
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Moscow, 119992
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Moscow, 123995
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Moscow, 127018
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Moscow, 142160
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Nizhny Novgorod, 603126
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Novosibirsk, 630008
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Novosibirsk, 630084
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Penza, 440067
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Perm, 614056
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Perm, 6144090
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Petrozavodsk, 185019
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Pyatigorsk, 357538
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Ryazan, 390026
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Saint Petersburg, 193312
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Saint Petersburg, 194100
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Saint Petersburg, 194354
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Saint Petersburg, 196084
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Saint Petersburg, 196211
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Saint Petersburg, 196657
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Saint Petersburg, 197022
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Saratov, 410012
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Ulyanovsk, 432009
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Vladikavkaz, 362007
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Volgograd, 400001
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Volgograd, 400131
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Voronezh, 394066
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Yaroslavl, 150002
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Yaroslavl, 150003
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Yekaterinburg, 620039
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Yekaterinburg, 620109
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Yekaterinburg, 620219
Canada34 sites
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Ajax, Ontario, L1S 2J5
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Burlington, Ontario, L7N 3V2
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Cornwall, Ontario, K6H 4M4
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Edmonton, Alberta, T5A 4L8
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Etobicoke, Ontario, M9W 4L6
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Hamilton, Ontario, L8N 4A6
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Kanata, Ontario, K2L 3C8
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Lévis, Quebec, G6W 0M5
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London, Ontario, N6H 0G6
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Maple Ridge, British Columbia, V2X 2L5
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Mississauga, Ontario, L5A 3V4
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Montreal, Quebec, H1M 1B1
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Montreal, Quebec, H3G 1L5
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Montreal, Quebec, H4J 1C5
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Mount Pearl, Newfoundland and Labrador, A1N 1W7
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Newmarket, Ontario, L3Y 5G8
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North Vancouver, British Columbia, V7M 2H9
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North York, Ontario, M3M 3E5
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Ottawa, Ontario, K2H 8T5
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Pointe-Claire, Quebec, H9R 4S3
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Québec, Quebec, G1G 3Y8
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Québec, Quebec, G1V 4W2
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Québec, Quebec, G1W 4R4
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Québec, Quebec, G2J 0C4
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Saint-Charles-Borromée, Quebec, J6E 2B4
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Sarnia, Ontario, N7T 4X3
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Sherwood Park, Alberta, T8L 0N2
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St. John's, Newfoundland and Labrador, A1A 3R5
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Toronto, Ontario, M9C 4Z5
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Toronto, Ontario, M9V 4B4
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Trois-Rivières, Quebec, G8T 7A1
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Vancouver, British Columbia, V5Z 1M9
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Victoriaville, Quebec, G6P 6P6
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Windsor, Ontario, N8X 2G1
Poland26 sites
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Bialystok, 15-003
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Bialystok, 15-430
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Elblag, 82-300
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Grodzisk Mazowiecki, 05-825
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Grudziądz, 86-300
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Kielce, 25-734
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Krakow, 30-901
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Krakow, 31-011
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Krakow, 31-209
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Krakow, 31-455
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Lodz, 90-141
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Lodz, 90-203
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Lodz, 91-103
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Poznan, 60-685
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Poznan, 60-823
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Rzeszów, 35-051
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Rzeszów, 35-612
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Skierniewice, 96-100
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Słupca, 62-400
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Strzelce Opolskie, 47-100
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Szczecin, 70-111
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Szczecin, 71-124
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Tarnów, 33-100
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Trzebnica, 55-100
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Turek, 62-700
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Zabrze, 41-800
China23 sites
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Beijing, 100043
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Beijing, 100050
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Changsha, 430033
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Chengdu, 610041
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Chengdu, 610083
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Guangzhou, 510120
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Guangzhou, 510515
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Haikou, 570311
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Hohhot, 010017
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Nanchang, 330006
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Shanghai, 200000
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Shanghai, 200032
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Shanghai, 200040
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Shanghai, 200120
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Shanghai, 200240
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Shanghai, 200433
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Shenyang, 110015
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Wenzhou, 325027
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Wuhan, CN-430030
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Xi'an, 710004
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Xi'an, 710038
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Xiamen, 361004
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Xuzhou, 221006
Ukraine18 sites
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Cherkasy, 18009
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Dnipropetrovsk, 49074
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Ivano-Frankivsk, 76012
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Kharkiv, 61002
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Kharkiv, 61035
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Kharkiv, 61039
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Kharkiv, 61058
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Kharkiv, 61075
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Kharkiv, 61093
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Kyiv, 03049
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Kyiv, 03680
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Kyiv
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Lutsk, 43000
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Lutsk, 43024
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Lviv, 79066
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Odesa, 65025
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Vinnytsia, 21018
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Zaporizhzhya, 69068
Bulgaria17 sites
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Dupnitsa, 2600
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Gotse Delchev, 2900
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Kozloduy, 3320
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Pazardzhik, 4400
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Plovdiv, 4002
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Razgrad, 7200
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Roman, 3130
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Rousse, 7002
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Sandanski, 2800
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Sofia, 1000
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Sofia, 1152
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Sofia, 1431
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Sofia, 1606
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Sofia, 1618
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Varna, 9000
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Velingrad, 4600
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Vratsa, 3000
Hungary14 sites
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Balassagyarmat, 2660
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Berettyóújfalu, 4100
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Budapest, 1195
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Budapest, 1204
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Edelény, 3780
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Hajdúnánás, 4080
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Mátészalka, 4700
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Miskolc, 3529
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Monor, 2200
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Nyírbátor, 4300
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Nyíregyháza, 4420
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Pécs, 7626
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Pécs, 7635
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Szeged, H-6722
South Korea11 sites
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Bucheon-si, 14584
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Cheongju-si, 28644
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Cheongju-si, 362-804
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Incheon, 21431
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Seoul, 03181
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Seoul, 03312
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Seoul, 03722
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Seoul, 05505
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Seoul, 06591
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Seoul, 07985
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Seoul, 110-744
Brazil10 sites
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Alphaville, 06454-010
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Botucatu, 18618-970
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Porto Alegre, 90020-060
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Porto Alegre, 90470-340
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Porto Alegre, 90610-000
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Salvador, 41940-455
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Santo André, 09080-110
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São Paulo, 04020-060
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São Paulo, 04101-000
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Sorocaba, 18040-425
South Africa10 sites
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Boksburg North, 1460
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Durban, 4001
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Durban, 4037
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Durban, 4170
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Johannesburg, 1818
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Johannesburg, 2001
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KwaDukuza, 4450
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Middelburg, 1055
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Queenswood
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Verulam, 4345
Peru9 sites
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Cusco, CUSCO 01
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Lima, 41
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Lima, L18
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Lima, L27
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Lima, LIMA 1
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Lima, LIMA 31
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Lima, LIMA 41
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Piura
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Surco, LIMA 33
Mexico8 sites
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D.F., 03020
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Durango, 43080
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México, 04530
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México, 06700
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México, 06720
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Monterrey, 64461
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Morelia, 58070
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Villahermosa, 86035
Romania7 sites
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Bragadiru, 077025
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Brasov, 500051
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Brasov, 500283
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Cluj-Napoca, 400371
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Constanța, 900002
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Piteşti, 110084
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Timișoara, 300310
Chile6 sites
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Quillota, 2260000
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Santiago, 404366
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Santiago, 7750495
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Santiago, 7980378
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Santiago, 8380453
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Talcahuano, 4270918
Vietnam6 sites
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Đông Nãi, 810000
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Haiphong, 180000
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Hanoi, 100000
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Ho Chi Minh City, 700000
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Ho Chi Minh City
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Hochiminh
Australia5 sites
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Bedford Park, 5042
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Concord, 2139
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Maroubra, 2035
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Murdoch, 6150
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Wollongong, 2522
Philippines5 sites
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Lipa City, 4217
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Manila, 1000
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Manila, 1003
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Pasig, 1000
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Quezon City, 1101
United Kingdom5 sites
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Bath, BA3 2UH
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Coventry, CV6 4DD
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Mortimer Reading, RG7 3SQ
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Royal Leamington Spa, CV32 4RA
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Trowbridge, BA14 8QA
About this study
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.
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'.
Read the detailed description
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'
- Conditions
- Asthma
- Being tested
- budesonide/formoterol 'as needed' + budesonide placebo bid, terbutaline 'as needed' + placebo budesonide bid, budesonide bid + terbutaline 'as needed'
- Medical subject headings
- Asthma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
budesonide/formoterol 'as needed' + budesonide placebo bidDrug
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
terbutaline 'as needed' + placebo budesonide bidDrug
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
budesonide bid + terbutaline 'as needed'Drug
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
| Study group | Role | What they receive |
|---|---|---|
| Symbicort "as needed"+placebo Pulmicort bid | Experimental | Symbicort (budesonide/formoterol) Turbuhaler 160/4.5 μg 'as needed' + Placebo Pulmicort Turbuhaler 200 μg bid Receives: Drug: budesonide/formoterol 'as needed' + budesonide placebo bid |
| terbutaline "as needed"+placebo Pulmicort bid | Active comparator | terbutaline Turbuhaler 0.4 mg 'as needed' + placebo Pulmicort 200 μg Turbuhaler bid Receives: Drug: terbutaline 'as needed' + placebo budesonide bid |
| Pulmicort bid + terbutaline "as needed" | Active comparator | Pulmicort 200 μg Turbuhaler bid + terbutaline 0.4 mg Turbuhaler 'as needed' Receives: Drug: budesonide bid + terbutaline 'as needed' |
What is being measured
The primary outcome is the main question the study is designed to answer.
'Well-controlled Asthma Week' - a Derived Binary Variable (Yes/No)
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.
Measured: Weekly, up to 52 weeks
Secondary outcomes (19)
Number of Participants Experiencing at Least One Severe Asthma 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
Measured: Day 1 up to 52 weeks
Number of Participants Experiencing at Least One Moderate or Severe Asthma Exacerbation
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
Measured: Day 1 up to 52 weeks
Average Change From Baseline in Pre-dose Forced Expiratory Volume in 1 Second (FEV1)
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).
Measured: Study weeks 0,4,16,28,40,52
Average Change From Baseline in Morning Peak Expiratory Flow (PEF)
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.
Measured: up to 52 weeks
Average Change From Baseline in Evening PEF
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.
Measured: up to 52 weeks
Average Change From Baseline in Number of Inhalations of 'as Needed' Medication.
'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.
Measured: up to 52 weeks
Average Change From Baseline in Asthma Symptom Score
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.
Measured: up to 52 weeks
Change From Baseline in the Percentage of Nighttime Awakenings Due to Asthma
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.
Measured: up to 52 weeks
Change From Baseline in Percentage of Symptom-free Days
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.
Measured: up to 52 weeks
Change From Baseline in Percentage of 'As Needed' Free Days
'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.
Measured: up to 52 weeks
Change From Baseline in Percentage of Asthma Control Days
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.
Measured: up to 52 weeks
Number of Patients With Study Specific Asthma Related Discontinuation
Study specific asthma related discontinuation
Measured: up to 52 weeks
Poorly Controlled Asthma 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'.
Measured: Weekly for up to 52 weeks
Number of Participants Experiencing at Least One Occasion With Additional Steroids for Asthma
Additional steroids for asthma includes any additional inhaled and/or systemic glucocorticosteroids treatment due to asthma while in the randomised treatment period.
Measured: Day 1 up to 52 weeks
Average Change From Baseline in Asthma Control Questionnaire (ACQ-5)
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.
Measured: Study weeks 0,4,16,28,40,52
Average Change From Baseline in Asthma Quality of Life Questionnaire; Standard Version (AQLQ(S))
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.
Measured: Study weeks 0,16,28,40,52
Percentage of Controller Use Days
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.
Measured: up to 52 weeks
Annual Severe Asthma Exacerbation Rate
Severe asthma exacerbations over the randomised treatment period.
Measured: up to 52 weeks
Annual Moderate or Severe Asthma Exacerbation Rate
Moderate or severe asthma exacerbations during the randomised treatment period.
Measured: up to 52 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 May 2014 (estimated)
- Study start7 Jul 2014
- Primary completion2 Aug 2017
- Study completion2 Aug 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for AsthmaStudies of the same condition, open and under way.
- More trials run by AstraZenecaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 3,850 participants (actual)
Sponsor and investigators
- Lead sponsor
- AstraZeneca
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Paul M O'Byrne, MB, FRCP(C), FRSC, Principal investigator, McMaster University, Hamilton, Canada
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02149199
- Sponsor's protocol ID
- D589SC00001
- Other IDs
- 2013-004474-96
- Acronym
- SYGMA1
- Status last verified
- Nov 2019
- First submitted
- 16 May 2014
- Last updated
- 15 Nov 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
FitzGerald JM, O'Byrne PM, Bateman ED, Barnes PJ, Zheng J, Ivanov S, Lamarca R, Larsdotter U, Emerath U, Jansen G, Puu M, Alagappan VKT, Surmont F, Reddel HK. Safety of As-Needed Budesonide-Formoterol in Mild Asthma: Data from the Two Phase III SYGMA Studies. Drug Saf. 2021 Apr;44(4):467-478. doi: 10.1007/s40264-020-01041-z. Epub 2021 Feb 6.
PubMed 33548020O'Byrne PM, FitzGerald JM, Bateman ED, Barnes PJ, Zheng J, Gustafson P, Lamarca R, Puu M, Keen C, Alagappan VKT, Reddel HK. Effect of a single day of increased as-needed budesonide-formoterol use on short-term risk of severe exacerbations in patients with mild asthma: a post-hoc analysis of the SYGMA 1 study. Lancet Respir Med. 2021 Feb;9(2):149-158. doi: 10.1016/S2213-2600(20)30416-1. Epub 2020 Oct 1.
PubMed 33010810O'Byrne PM, FitzGerald JM, Bateman ED, Barnes PJ, Zhong N, Keen C, Jorup C, Lamarca R, Ivanov S, Reddel HK. Inhaled Combined Budesonide-Formoterol as Needed in Mild Asthma. N Engl J Med. 2018 May 17;378(20):1865-1876. doi: 10.1056/NEJMoa1715274.
PubMed 29768149O'Byrne PM, FitzGerald JM, Zhong N, Bateman E, Barnes PJ, Keen C, Almqvist G, Pemberton K, Jorup C, Ivanov S, Reddel HK. The SYGMA programme of phase 3 trials to evaluate the efficacy and safety of budesonide/formoterol given 'as needed' in mild asthma: study protocols for two randomised controlled trials. Trials. 2017 Jan 10;18(1):12. doi: 10.1186/s13063-016-1731-4.
PubMed 28069068Reddel HK, Busse WW, Pedersen S, Tan WC, Chen YZ, Jorup C, Lythgoe D, O'Byrne PM. Should recommendations about starting inhaled corticosteroid treatment for mild asthma be based on symptom frequency: a post-hoc efficacy analysis of the START study. Lancet. 2017 Jan 14;389(10065):157-166. doi: 10.1016/S0140-6736(16)31399-X. Epub 2016 Nov 30.
PubMed 27912982
Study at a glance
From the registry record, last updated by the sponsor on 15 Nov 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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.
- ClinicalTrials.gov ID
- NCT02149199
- Acronym / sponsor ID
- SYGMA1 / D589SC00001
- Conditions
- Asthma
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 3,850 participants (actual)
- Lead sponsor
- AstraZenecaIndustry (pharma, biotech, devices)
- Study start
- 7 Jul 2014 (actual)
- Primary completion
- 2 Aug 2017 (actual)
- Study completion
- 2 Aug 2017 (actual)
- First posted
- 29 May 2014 (estimated)
- Results
- Posted 13 Sep 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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'.
Detailed description
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Symbicort "as needed"+placebo Pulmicort bid | Experimental | Drug: budesonide/formoterol 'as needed' + budesonide placebo bidSymbicort (budesonide/formoterol) Turbuhaler 160/4.5 μg 'as needed' + Placebo Pulmicort Turbuhaler 200 μg bid |
| terbutaline "as needed"+placebo Pulmicort bid | Active comparator | Drug: terbutaline 'as needed' + placebo budesonide bidterbutaline Turbuhaler 0.4 mg 'as needed' + placebo Pulmicort 200 μg Turbuhaler bid |
| Pulmicort bid + terbutaline "as needed" | Active comparator | Drug: budesonide bid + terbutaline 'as needed'Pulmicort 200 μg Turbuhaler bid + terbutaline 0.4 mg Turbuhaler 'as needed' |
Who may qualify
- Ages
- 12 to 130 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| budesonide/formoterol 'as needed' + budesonide placebo bidSymbicort (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 | Drug | Symbicort "as needed"+placebo Pulmicort bid |
| terbutaline 'as needed' + placebo budesonide bidTerbutaline 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 | Drug | terbutaline "as needed"+placebo Pulmicort bid |
| 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 | Drug | Pulmicort bid + terbutaline "as needed" |
Primary outcome
'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.
19 secondary outcomes
Number of Participants Experiencing at Least One Severe Asthma Exacerbation
Time frame: Day 1 up to 52 weeks
Number of Participants Experiencing at Least One Moderate or Severe Asthma Exacerbation
Time frame: Day 1 up to 52 weeks
Average Change From Baseline in Pre-dose Forced Expiratory Volume in 1 Second (FEV1)
Time frame: Study weeks 0,4,16,28,40,52
Average Change From Baseline in Morning Peak Expiratory Flow (PEF)
Time frame: up to 52 weeks
Average Change From Baseline in Evening PEF
Time frame: up to 52 weeks
Average Change From Baseline in Number of Inhalations of 'as Needed' Medication.
Time frame: up to 52 weeks
Average Change From Baseline in Asthma Symptom Score
Time frame: up to 52 weeks
Change From Baseline in the Percentage of Nighttime Awakenings Due to Asthma
Time frame: up to 52 weeks
Change From Baseline in Percentage of Symptom-free Days
Time frame: up to 52 weeks
Change From Baseline in Percentage of 'As Needed' Free Days
Time frame: up to 52 weeks
Change From Baseline in Percentage of Asthma Control Days
Time frame: up to 52 weeks
Number of Patients With Study Specific Asthma Related Discontinuation
Time frame: up to 52 weeks
Poorly Controlled Asthma Weeks
Time frame: Weekly for up to 52 weeks
Number of Participants Experiencing at Least One Occasion With Additional Steroids for Asthma
Time frame: Day 1 up to 52 weeks
Average Change From Baseline in Asthma Control Questionnaire (ACQ-5)
Time frame: Study weeks 0,4,16,28,40,52
Average Change From Baseline in Asthma Quality of Life Questionnaire; Standard Version (AQLQ(S))
Time frame: Study weeks 0,16,28,40,52
Percentage of Controller Use Days
Time frame: up to 52 weeks
Annual Severe Asthma Exacerbation Rate
Time frame: up to 52 weeks
Annual Moderate or Severe Asthma Exacerbation Rate
Time frame: up to 52 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Nov 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 33548020FitzGerald JM, O'Byrne PM, Bateman ED, Barnes PJ, Zheng J, Ivanov S, Lamarca R, Larsdotter U, Emerath U, Jansen G, Puu M, Alagappan VKT, Surmont F, Reddel HK. Safety of As-Needed Budesonide-Formoterol in Mild Asthma: Data from the Two Phase III SYGMA Studies. Drug Saf. 2021 Apr;44(4):467-478. doi: 10.1007/s40264-020-01041-z. Epub 2021 Feb 6.
- Derived from this study: PubMed 33010810O'Byrne PM, FitzGerald JM, Bateman ED, Barnes PJ, Zheng J, Gustafson P, Lamarca R, Puu M, Keen C, Alagappan VKT, Reddel HK. Effect of a single day of increased as-needed budesonide-formoterol use on short-term risk of severe exacerbations in patients with mild asthma: a post-hoc analysis of the SYGMA 1 study. Lancet Respir Med. 2021 Feb;9(2):149-158. doi: 10.1016/S2213-2600(20)30416-1. Epub 2020 Oct 1.
- Derived from this study: PubMed 29768149O'Byrne PM, FitzGerald JM, Bateman ED, Barnes PJ, Zhong N, Keen C, Jorup C, Lamarca R, Ivanov S, Reddel HK. Inhaled Combined Budesonide-Formoterol as Needed in Mild Asthma. N Engl J Med. 2018 May 17;378(20):1865-1876. doi: 10.1056/NEJMoa1715274.
- Derived from this study: PubMed 28069068O'Byrne PM, FitzGerald JM, Zhong N, Bateman E, Barnes PJ, Keen C, Almqvist G, Pemberton K, Jorup C, Ivanov S, Reddel HK. The SYGMA programme of phase 3 trials to evaluate the efficacy and safety of budesonide/formoterol given 'as needed' in mild asthma: study protocols for two randomised controlled trials. Trials. 2017 Jan 10;18(1):12. doi: 10.1186/s13063-016-1731-4.
- Derived from this study: PubMed 27912982Reddel HK, Busse WW, Pedersen S, Tan WC, Chen YZ, Jorup C, Lythgoe D, O'Byrne PM. Should recommendations about starting inhaled corticosteroid treatment for mild asthma be based on symptom frequency: a post-hoc efficacy analysis of the START study. Lancet. 2017 Jan 14;389(10065):157-166. doi: 10.1016/S0140-6736(16)31399-X. Epub 2016 Nov 30.
- D589SC00001-statistical-analysis-plan-edition-4\_29Sep2017\_pdfaLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Paul M O'Byrne, MB, FRCP(C), FRSC principal investigator
McMaster University, Hamilton, Canada
255 sites in 18 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing budesonide bid + terbutaline 'as needed' in people with Asthma, run by AstraZeneca at 255 sites in 18 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 15 Nov 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 255 sites in Russia, Canada, Poland, China, Ukraine and 13 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 13 Sep 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
'Well-controlled Asthma Week' - a Derived Binary Variable (Yes/No) (time frame: Weekly, up to 52 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02149199, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Nov 2019.