Ped journal 20191122

1. Journal Reading
Presenter: FM R2 盧敬文
Supervisor: VS 王壯銘
2019.11.22

3. Global Initiative for Asthma
(GINA) Teaching slide set
2017 update

4. GINA, 2019, Whats-new-in-GINA-2019 V3

5. GINA, 2019, Whats-new-in-GINA-2019 V3

6. GINA, 2019, Whats-new-in-GINA-2019 V3

7. GINA, 2019, Whats-new-in-GINA-2019 V3

8. GINA, 2019, Whats-new-in-GINA-2019 V3

9. GINA, 2019, Whats-new-in-GINA-2019 V3

10. SYGMA 1 trial
(Symbicort Given as Needed in Mild Asthma)
≥12y/o , mild asthma
52週、雙盲隨機試驗
1. terbutaline group：
twice-daily placebo plus terbutaline used as needed
2. Budesonide–formoterol group：
twice-daily placebo plus budesonide–formoterol used as
needed
3. budesonide maintenance group：
twice-daily budesonide plus terbutaline used as needed
• As-needed Budesonide-formoterol
在症狀控制上，較as-needed terbutaline來得好，
卻較maintain budesonide差
• As-needed Budesonide-formoterol和
maintain budesonide的
嚴重發作率相近，
且都較as-needed terbutaline低

11. SYGMA 2 trial
≥12y/o , mild asthma
52週、雙盲隨機試驗
1. Budesonide–formoterol group：
twice-daily placebo plus budesonide–formoterol
used as needed
2. budesonide maintenance group：
twice-daily budesonide plus terbutaline used as
needed
• As-needed Budesonide-formoterol
在降低年度嚴重發作率上，
不比maintain budesonide差
但在症狀控制上，
較maintain budesonide差

12. Novel START trial

13. • An alternative strategy:
use of an inhaler containing a combination of an inhaled
glucocorticoid and a fast-onset β2-agonist on an as-needed basis as
reliever therapy.
• takes advantage of patients’ natural behavior
to take reliever therapy when symptomatic.

14. • whether the findings（of SYGMA 1,2 trial） translate to clinical practice
outside the setting of a rigidly controlled trial is unclear.
• not consistent with clinical practice
• Both trials use an inhaler twice a day for 12 months,
but this requirement removed the advantage of a single inhaler for symptom
relief
• both trials required that current therapy be withdrawn during a running
phase to allow for asthma control to worsen

15. • Hypothesis:
as-needed budesonide–formoterol
would be superior to
as-needed SABA
and to
inhaled glucocorticoid maintenance +
as-needed SABA
• open-label clinical trial
(Novel Symbicort Turbuhaler Asthma Reliever Therapy [Novel START])
• as-needed
• adults with mild asthma

16. Trial Design and Oversight
• 52-week, randomized, open-label, parallel group, controlled trial
conducted at 16 trial centers
• AstraZeneca funded the trial
• The protocol was approved by all the relevant ethics committees.
• Written informed consent was obtained from all the patients
• The global sponsor of the trial:
the Medical Research Institute of New Zealand

17. Patients
• 18 to 75 y/o
• diagnosis of asthma
• Inclusion:
• 過去三個月，
Use of a SABA as the sole asthma
therapy
• 但過去一個月內，
每日使用SABA少於兩次
• Exclusion:
• Hospitalization for asthma in the previous
12 months
• smoking history of more than 20 pack-years
• onset of respiratory symptoms after the age
of 40 years with a smoking history of at least
10 pack-years

18. • patients were randomly assigned, in a 1:1:1 ratio, to one of three treatment groups
• Electronic inhaler usage monitors (Adherium) were incorporated
Albuterol 100 μg,
with 2 inhalations from a
pressurized metered-dose
inhaler as needed
budesonide 200 μg,
one inhalation twice daily
+ albuterol 100 μg,
2 inhalations as needed
200 μg of budesonide +
6 μg of formoterol,
1 inhalation as needed

19. Procedures
• Seven trial visits
• Patients were withdrawn:
1. treatment failure if they had 1 severe exacerbation
2. 3 exacerbations separated by at least 7 days
3. unstable asthma that resulted in a change in the treatment assigned to
them

20. Primary Outcome Measure
• primary outcome: annualized rate of asthma exacerbations
• Exacerbation
worsening asthma that resulted in 1 or more of the following:
1. an urgent medical care consultation
e.g., a primary care visit, an emergency department [ED] visit, or hospital admission
2. a prescription of systemic glucocorticoids for any duration
3. or an episode of high β2-agonist use
more than 16 actuations of albuterol or
more than 8 actuations of budesonide–formoterol over the course of 24 hours

21. Secondary Outcome Measures
• number of exacerbations
• time to the first exacerbation
• number of severe exacerbations:
1. Prescription of systemic glucocorticoid for at least 3 days
2. or hospitalization or an ED visit + systemic glucocorticoid
• Score of ACQ-5; FEV1; FENO…etc.

22. Statistical Analysis
• intention-to-treat superiority analysis
• We estimated that with a sample of 225 patients in each treatment
group, the trial would have 80% power to detect a difference of 0.3
exacerbations per patient per year

23. Results
• Patients

24. Primary Outcome

25. Secondary
Exacerbation
Outcomes
• time-to-first-event
analysis
23%
12.5%
11.9%

26. • number of severe exacerbations
B-F
B A

27. • number of patients withdrawn (because of treatment failure)
in the budesonide–formoterol group
 lower than the number in the albuterol group
NOT differ significantly from the budesonide maintenance group

28. Other
Secondary
Outcomes
ACQ-5:
A > B-F > B
FEV1:
A ≒ B-F ≒ B
FENO:
A > B-F > B

30. Adverse effect
• 1 death
(motor vehicle accident)
in the budesonide–
formoterol group
• 1 death
(suicide)
in the budesonide
maintenance group

31. Discussion
• reducing the risk of severe exacerbations:
• budesonide maintenance superior for asthma symptom control
• asthma symptoms most bothersome  maintenance has value
• extends the findings of the double-blind, double-dummy SYGMA trials
to an open-label treatment regimen that reflects real-world practice.
Superior
to
and

32. • Extends the evidence for the efficacy of
as-needed use of budesonide–formoterol
• 為什麼本trial能做出SYGMA 1和2沒看到的，as-needed
budesonide–formoterol和budesonide maintenance兩組
，在降低嚴重發作風險上的差別？
1. avoidance of a double-dummy design
2. use of a single inhaler
3. No requirement for regular inhaler use twice daily
 real-world advantages of the regimen

33. • Unexpected observation ?
budesonide maintenance therapy plus as-needed albuterol did NOT appear to
result in a lower number of severe exacerbations than as-needed albuterol.
In the albuterol group, withdrawal because of a change in the
assigned treatment owing to unstable asthma
 healthy survivor effect
because of a reduced pool of patients in unstable condition
who could otherwise have gone on to have a severe exacerbation.

34. • The findings of our trial are consistent with evidence regarding the
treatment of moderate and severe asthma
 reduction in the median FENO from baseline to month 12
in budesonide maintenance therapy
and as-needed budesonide–formoterol
• airway inflammation as measured by FENO is highly
responsive to inhaled glucocorticoid therapy

35. Limitations
• more frequent scheduled clinic visits than would be expected
• patient awareness of the electronic monitoring of inhaler use
Strengths
• use of validated electronic inhaler monitors
identify otherwise unreported exacerbations that were not severe
• exacerbation rate: 包含episodes of high β2-agonist use
including exacerbations that did not lead the patient to seek urgent care

36. Thank you for
your attention.