ON-LINE SUPPLEMENT Table E1. Definition of cardiac-related events

ON-LINE SUPPLEMENT
Table E1. Definition of cardiac-related events
Cardiac-related events have been defined as any event that, when coded according to
the Medical Dictionary for Regulatory Activities v. 15.0, will belong to:
•
the system organ class “Cardiac disorders”
•
the high-level group terms “Cardiac and vascular investigations (excluding enzyme tests)”
in the system organ class “Investigations”
•
the high-level term “Skeletal and cardiac muscle analyses” in the system organ class
“Investigations”
•
the high-level term “Pulmonary oedemas” in the system organ class “Respiratory, thoracic
and mediastinal disorders”
•
the high-level term ”Cardiac infections” in the system organ class “Infections and
infestations”
•
the following high-level terms from the system organ class “Vascular disorders”:
“Circulatory collapse and shock”, “Vascular hypotensive disorders”, “Blood pressure
disorders NEC”, “Vascular hypertensive disorders NEC” and “Accelerated and malignant
hypertension”
•
the following preferred terms from the system organ class “General disorders and
administration site conditions”: “Cardiac death”, “Sudden cardiac death” and “Oedema due
to cardiac disease”
Table E-2
Details of the complete dataset
Trials reported by
Sears et al 2009 (1)
Additional trials
Complete dataset
Supplemetary dataset – all
patients
117 trials
32 trials
149 trials
Formoterol-exposed patients
54559
20467
75026
Salmeterol- exposed patients
4474
0
4474
CBP-exposed patients
0
4394
4394
Non-LABA-exposed patients
20477
1376
21853
Total (all trials combined)
78339
26123
104463*
Primary dataset
64 trials
15 trials
79 trials
Formoterol-exposed patients
49906
17474
67380
Salmeterol- exposed patients
4170
0
4170
CBP-exposed patients
0
4394
4394
Non-LABA-exposed patients
18098
642
18740
Total primary dataset
72174
22510
94684
Formoterol-exposed patients
8A, 10C, 19O
1A, 8C, 9O
9A, 18C, 28O
Salmeterol- exposed patients
0A, 1C, 2O
na
0A, 1C, 2O
CBP-exposed patients
na
0A, 3C, 0O
0A, 3C, 0O
Non-LABA-exposed patients
2A, 9C, 4O
0A,0C, 1O
2A, 9C, 5O
Formoterol-exposed patients
8A, 8C, 18O
0A, 7C, 9O
8A, 15C, 27O
Salmeterol- exposed patients
0A, 1C, 2O
na
0A, 1C, 2O
CBP-exposed patients
na
0A, 3C, 0O
0A, 3C, 0O
Non-LABA-exposed patients
2A, 9C, 3O
0A,0C, 1O
2A, 9C, 4O
Supplemetary dataset - deaths
Primary dataset - deaths
A: Asthma-related death; C: Cardiac-related death; O: Other death
*Unique patients. Patients in cross-over trials have only been counted once in this total. Note that the sum of the
number of patients in the 4 treatment groups = 105747.
Table E-3
Studycode
Details of budesonide/formoterol Turbuhaler and budesonide/formoterol pMDI trials - 20072011 update
Included
in the
primary
analysis
?
Reason
for
omission
from
primary
analysis
Duration
Comparator(s)
Age range
Number of
patients
evaluable
for safety
Blinded or
open-label
Design
Maintenance or
as-needed use
or adjustable
dosing
Study
name
1 year
BUD/FORM + BUD
+ TERB prn
18-65
127
DB
P
M + AN
EOS
1 year
None
18-80
138
O
O
M
Budesonide/formoterol Turbuhaler
trials
D5890C00003
Yes
D5890C00009
No
Not
controlled
Duration
D5890C00010
No
8 weeks
BUD + THEOP
17-89
346
D
P
M
D5890L00001
Yes
1 year
BUD/FORM; BUD +
FORM
12-95
1776
O
P
M + AN
SHARE
D5890L00004
Yes
6 months
CBP
12-94
1538
O
P
M + AN
SOLO
D5890L00005
Yes
6 months
CBP
12-89
1004
O
P
M + AN
SYMPHON
IE
D5890L00007
No
1 week
FORM; PLA
25-56
28
DB
C
M
SMILDA
D5890L00008
Yes
6 months
CBP
12-87
1835
O
P
M + AN
MONO
D5890L00009
Yes
6 months
CBP
12-87
912
O
P
M + AN
SALTO
D5890L00010
Yes
6 months
CBP
17-89
652
O
P
M + AN
SPAIN
Design
D5890L00011
Yes
6 months
CBP
18-81
1461
O
P
M + AN
DESOLO
D5890L00012
No
Design
26 weeks
no
18-89
571
O
O
M + AN
RELEASE
D5890L00012
No
Design
2 months
BUD
18-45
39
DB
C
M
D5890L00014
Yes
6 months
CBP
12-84
986
O
P
M + AN
D5890L00015
No
8 weeks
BUD
7 to 16
31
D
C
M
D5890L00016
Yes
26 weeks
CBP
17-77
430
O
P
M + AN
Design
STYLE
PASSION
Table E-3
Details of budesonide/formoterol Turbuhaler and budesonide/formoterol pMDI trials - 20072011 update
Studycode
Included
in the
primary
analysis
?
D5890L00017
No
D5890L00018
No
Duration
Comparator(s)
Age range
Number of
patients
evaluable
for safety
Blinded or
open-label
Design
Maintenance or
as-needed use
or adjustable
dosing
Duration
8 weeks
BUD+SABA
18-88
41
DB
P
M + AN
Design
6 months
no
18-51
160
O
P
M
Reason
for
omission
from
primary
analysis
Study
name
TEACH
D5890L00019
No
PLD na
1 year
BUD+SABA
12-80
26
O
P
M + AN
D5890L00021
No
Design
3 months
no
na
189
O
O
AMD
REALITY
D5890L00022
Yes
26 weeks
BUD/FORM +
BUD/FORM prn
18-96
8399
O
P
M + AN
EUROSMA
RT
D5890L00032
No
Duration
6 weeks
BUD/TERB; TERB
12-68
66
D
P
AN
EIB
D5890L00035
No
Not
controlled
12 weeks
None
18-81
862
O
O
M + AN
SMARTASI
A
1 year
BUD/FORM + TERB
prn
16-85
DB
P
M + AN
SAKURA
1 day
BUD/FORM + TERB
prn
20-62
48
DB
C
M + AN
HIGH
DOSE
JAPAN
Yes
D589LC00001
D589LC00003
No
Design
2091
Budesonide/formoterol pMDI trials
D5896C00021
Yes
12 weeks
BUD
12-83
250
DB
P
M
HISPANIC
D5896C00022
Yes
1 year
BUD
12-82
741
DB
P
M
AFRICAN
AMERICA
N
D5896C00023
No
Duration
2 weeks
BUD
18-76
123
DB
P
M
OEQ 1
D5896C00025
No
Duration
2 weeks
BUD
18-79
134
DB
P
M
OEQ 2
D5897C00003
No
Duration
6 weeks
BUD; BUD/FORM
12-78
742
D
P
M
ESTHER
D5897C00004
No
Duration
4 weeks
None
6 to 11
107
O
P
M
SPACER
Table E-3
Details of budesonide/formoterol Turbuhaler and budesonide/formoterol pMDI trials - 20072011 update
Studycode
Included
in the
primary
analysis
?
D589BL00003
Yes
Reason
for
omission
from
primary
analysis
Duration
Comparator(s)
Age range
Number of
patients
evaluable
for safety
Blinded or
open-label
Design
Maintenance or
as-needed use
or adjustable
dosing
Study
name
12 weeks
BUD
12-79
308
DB
P
M
TITAN
Table E-4 STUDY TITLE AND PUBLICATION STATUS FOR CLINICAL TRIALS INCLUDED IN THE MAIN AND THE
SUPPLEMENTARY ANALYSIS – 2007-2011update
Study code
Included
in the
main
analysis?
Study title
Publication status
Formoterol/budesonide Turbuhaler trials, double-blind, parallel-group with twice-daily treatment
D5890C00010
No
AN 8-WEEK, RANDOMISED, DOUBLE-BLIND, PARALLEL-GROUP,
MULTI-CENTRE, PHASE III STUDY COMPARING THE EFFICACY
AND SAFETY OF SYMBICORT TURBUHALER 160/4.5 UG TWICE
DAILY AND PULMICORT TURBUHALER 200 UG TWICE DAILY +
THEOLONG TABLET 200 MG .......
Ohta K et al. Efficacy and safety of budesonide/formoterol comparing
with budesonide and theophylline in Japanese adult patients with
asthma. Eur Respir J 2008;32(Suppl. 52):634s [P3626].
Ohta K et al. Efficacy and safety of budesonide/formoterol comparing with
budesonide and theophylline in Japanese adult patients with asthma [in
Japanese]. Allergol Immunol 2010;17: 624-38.
Formoterol/budesonide Turbuhaler trials, open-label, parallel-group with twice-daily treatment
D5890C00009
No
AN OPEN, PHASE III, MULTICENTRE, 52-WEEK STUDY,
EVALUATING THE SAFETY AND EFFICACY OF SYMBICORT
TURBUHALER (1, 2, AND 4 X 160/4.5 UG TWICE DAILY) IN
JAPANESE PATIENTS WITH ASTHMA
Adachi M et al. Long-term safety and efficacy of budesonide/formoterol
in Japanese patients with asthma. Eur Respir J 2008;32(Suppl. 52):813s
[E4646].
Adachi M et al. Long-term safety and efficacy of budesonide/formoterol in
Japanese patients with asthma [in Japanese]. Allergol Immunol 2010;17:266-82.
Formoterol/budesonide Turbuhaler trials, double-blind, parallel-group with maintenance plus as-needed treatment
D5890C00003
Yes
A COMPARISON OF THE INFLAMMATORY CONTROL OF ASTHMA
PROVIDED BY ONE INHALATION OF SYMBICORT® TURBUHALER®
160/4.5 ΜG/INHALATION BID PLUS AS-NEEDED VERSUS ONE
INHALATION OF SYMBICORT® TURBUHALER® 320/9
ΜG/INHALATION BID + ONE INHALATION OF PULMICORT®
TURBUHALER® 400 ΜG/DOSE BID PLUS TERBUTALINE
TURBUHALER® 0.4 MG/INHALATION AS-NEEDED. A 12-MONTH,
RANDOMISED, DOUBLE-BLIND, PARALLEL-GROUP, ACTIVECONTROLLED, MULTINATIONAL, PHASE IIIB STUDY IN ADULT
PATIENTS WITH ASTHMA
Pavord I et al. Airway inflammation in patients with asthma with high-fixed
or low-fixed plus as-needed budesonide/formoterol. J Allergy Clin
Immunol 2009;123:1083-9.
Table E-4 STUDY TITLE AND PUBLICATION STATUS FOR CLINICAL TRIALS INCLUDED IN THE MAIN AND THE
SUPPLEMENTARY ANALYSIS – 2007-2011update
Study code
D589LC00001
Included
in the
main
analysis?
Yes
Study title
A COMPARISON OF SYMBICORT® MAINTENANCE AND RELIEVER
THERAPY (SYMBICORT TURBUHALER® 160/4.5 ΜG, ONE
INHALATION BID PLUS AS NEEDED) AND SYMBICORT
TURBUHALER 160/4.5 ΜG, ONE INHALATION BID PLUS
TERBUTALINE TURBUHALER 0.4 MG/INHALATION AS NEEDED,
FOR TREATMENT OF ASTHMA – A 12-MONTH, RANDOMIZED,
DOUBLE-BLIND, PARALLEL GROUP, ACTIVE-CONTROLLED,
MULTINATIONAL PHASE III STUDY IN ASTHMATIC PATIENTS AGED
16 YEARS AND ABOVE
Publication status
Atienza T et al. Budesonide/formoterol maintenance and reliever therapy via
Turbuhaler® vs. fixed-dose budesonide/formoterol plus terbutaline in patients
with asthma: Phase III study results. Respirology 2013;18:354-63.
Formoterol/budesonide Turbuhaler trials, open-label parallel-group with maintenance plus as-needed treatment, performed by local marketing companies
D5890L00001
Yes
SYMBICORT AND HEALTH ECONOMICS IN A REAL LIFE
EVALUATION – SHARE – A RANDOMISED, OPEN-LABEL,
PARALLEL-GROUP, MULTICENTRE STUDY TO ASSESS THE
ASTHMA RELATED HEALTH CARE COSTS, IN ORDINARY CLINICAL
PRACTICE DURING 12 MONTHS
Ställberg B et al. A real-life cost-effectiveness evaluation of
budesonide/formoterol maintenance and reliever therapy in asthma. Respir Med
2008;102:1360-70.
D5890L00004
Yes
A COMPARISON OF SYMBICORT SINGLE INHALER THERAPY
(SYMBICORT 200 TURBUHALER 1 INHALATION B.I.D. PLUS AS
NEEDED) AND CONVENTIONAL BEST PRACTICE FOR THE
TREATMENT OF PERSISTENT ASTHMA IN ADOLESCENTS AND
ADULTS - A 26-WEEK, RANDOMISED, OPEN ...
Sears MR et al. Budesonide/formoterol maintenance and reliever therapy:
impact on airway inflammation in asthma. Eur Respir J 2008;31:982-9.
D5890L00005
Yes
A COMPARISON OF SYMBICORT SINGLE INHALER THERAPY
(SYMBICORT® TURBUHALER® 200/6 µG, 1 INHALATION B.I.D. PLUS
AS NEEDED) AND CONVENTIONAL BEST PRACTICE FOR THE
TREATMENT OF PERSISTENT ASTHMA IN ADOLESCENTS AND
ADULTS - A 26-WEEK, RANDOMISED..
Demoly P et al. Budesonide/formoterol maintenance and reliever therapy
versus conventional best practice. Respir Med 2009;103:1623-32.
D5890L00008
Yes
A COMPARISON OF THE EFFICACY OF SYMBICORT SINGLE
INHALER THERAPY (SYMBICORT TURBUHALER 160/4.5 µG, 1 INH
BID PLUS AS NEEDED) AND CONVENTIONAL BEST STANDARD
TREATMENT FOR THE TREATMENT OF PERSISTENT ASTHMA IN
ADOLESCENTS ADULTS ETC
Søes-Petersen U et al. Budesonide/formoterol maintenance and reliever
therapy versus conventional best standard treatment in asthma in an
attempted ‘real life’ setting. Clin Respir J 2011;5:173-82.
Table E-4 STUDY TITLE AND PUBLICATION STATUS FOR CLINICAL TRIALS INCLUDED IN THE MAIN AND THE
SUPPLEMENTARY ANALYSIS – 2007-2011update
Study code
Included
in the
main
analysis?
Study title
Publication status
D5890L00009
Yes
A COMPARISON OF SYMBICORT SINGLE INHALER THERAPY
(SYMBICORT TURBUHALER 160/4.5 µG, 1 INH BID PLUS AS
NEEDED) AND CONVENTIONAL BEST PRACTICE FOR THE
TREATMENT OF PERSISTENT ASTHMA IN ADOLESCENTS AND
ADULTS- A 26-WEEK,RANDOMISED, OPEN ETC
Louis R et al. A comparison of budesonide/formoterol maintenance and
reliever therapy vs conventional best practice in asthma management. Int
J Clin Pract 2009;63:1479-88.
D5890L00010
Yes
A COMPARISON OF SYMBICORT SINGLE INHALER THERAPY
(SYMBICORT TURBUHALER 160/4.5 µG, 1 INHALATION BID AS
MAINTENANCE DOSE, AND AS NEEDED FOR SYMPTOM RELIEF,
SMART) AND THE CONVENTIONAL BEST PRACTICE FOR THE
TREATMENT OF PERSISTENT ASTHMA ....
Quirce S et al. A comparison of budesonide/formoterol maintenance and
reliever therapy versus conventional best practice in asthma management
in Spain. J Asthma 2011;48:839-47.
D5890L00011
Yes
A COMPARISON OF SYMBICORT SINGLE INHALER THERAPY
(SYMBICORT TURBUHALER 160/4.5 µG, 1 INH BID PLUS AS
NEEDED) AND CONVENTIONAL BEST PRACTICE FOR THE
TREATMENT OF PERSISTENT ASTHMA IN ADULTS- A 26-WEEK,
RANDOMISED, OPEN, PARALLEL GROUP ETC
Data on file (ClinicalTrials.gov identifier NCT00252863)
D5890L00014
Yes
A COMPARISON OF SYMBICORT SINGLE INHALER THERAPY
(SYMBICORT TURBUHALER 160/4.5 µG, 1 INHALATION BID PLUS
AS NEEDED) AND CONVENTIONAL BEST PRACTICE FOR THE
TREATMENT OF PERSISTENT ASTHMA IN ADOLESCENTS AND
ADULTS- A 26-WEEK, RANDOMISED, ...
Data on file (ClinicalTrials.gov identifier NCT00252824)
D5890L00016
Yes
A COMPARISON OF SYMBICORT SINGLE INHALER THERAPY
(SYMBICORT TURBUHALER 160/4.5 µG, 1 INHALATION B.I.D. PLUS
AS NEEDED) AND CONVENTIONAL BEST PRACTICE FOR THE
TREATMENT OF PERSISTENT ASTHMA IN ADULTS - A 26-WEEK,
RANDOMISED, OPEN-LABEL, ...
Data on file (ClinicalTrials.gov identifier NCT00628758)
Table E-4 STUDY TITLE AND PUBLICATION STATUS FOR CLINICAL TRIALS INCLUDED IN THE MAIN AND THE
SUPPLEMENTARY ANALYSIS – 2007-2011update
Study code
Included
in the
main
analysis?
Study title
Publication status
D5890L00017
No
A COMPARISON OF BUDESONIDE/FORMOTEROL TURBUHALER®
160/4.5 ΜG 2 INHALATIONS BID PLUS AS NEEDED (SYMBICORT
MAINTENANCE AND RELIEVER THERAPY) TO BUDESONIDE
TURBUHALER® 320 ΜG 2 INHALATIONS BID PLUS TERBUTALINE
TURBUHALER® 0.4 MG AS NEEDED FOR THE PREVENTION OF
ASTHMA RELAPSE FOLLOWING EMERGENCY DEPARTMENT
DISCHARGE DUE TO AN ASTHMA EXACERBATION. AN 8 WEEK,
RANDOMIZED, DOUBLE BLIND, PARALLEL GROUP, ACTIVE
CONTROLLED, MULTICENTRE PHASE IIIB EFFICACY STUDY IN
ADULT ASTHMATIC PATIENTS.
Data on file (ClinicalTrials.gov identifier NCT00326053)
D5890L00022
Yes
A PAN-EUROPEAN, OPEN LABEL, RANDOMISED STUDY
COMPARING THE EFFICACY AND COST-EFFECTIVENESS OF
SYMBICORT® MAINTENANCE AND RELIEVER THERAPY
(SYMBICORT® SMART®) USING A MAINTENANCE DOSE OF
SYMBICORT® 160/4.5ΜG OF 1 OR 2 INHALATIONS TWICE DAILY IN
THE TREATMENT OF PERSISTENT ASTHMA. EUROSMART
Aubier M et al. Comparison of two twice-daily doses of
budesonide/formoterol maintenance and reliever therapy. Eur Respir J
2010;36:524-30.
Formoterol/budesonide Turbuhaler trials, performed by local marketing companies, other
D5890L00018
No
DOES TAILORED EDUCATION IN ASTHMA CARE HELP IMPROVE
PATIENT SATISFACTION, ADHERENCE, AND QOL (TEACH) TRIAL
Data on file (ClinicalTrials.gov identifier NCT00687310)
D5890L00019
No
A RANDOMIZED, COMPARATIVE, PARALLEL, OPEN-LABELED
STUDY TO COMPARE THE EFFICACY AND SAFETY BETWEEN
SINGLE-INHALER AND TRADITIONAL FINAL DOSING IN PATIENTS
WITH PERSISTENT ASTHMA
Data on file
D5890L00021
No
PHYSICIAN AND PATIENT PERCEPTION OF ADJUSTABLE
MAINTENANCE DOSING OF SYMBICORT TURBUHALER (REALITY)
Data on file (ClinicalTrials.gov NCT00812682)
Table E-4 STUDY TITLE AND PUBLICATION STATUS FOR CLINICAL TRIALS INCLUDED IN THE MAIN AND THE
SUPPLEMENTARY ANALYSIS – 2007-2011update
Study code
Included
in the
main
analysis?
Study title
Publication status
D5890L00032
No
A RANDOMIZED, DOUBLE BLIND, PARALLEL-GROUP STUDY WITH
USE OF BUDESONIDE/FORMOTEROL “AS NEEDED”, OR
TERBUTALINE “AS NEEDED” OR REGULAR USE OF BUDESONIDE +
TERBUTALINE “AS NEEDED”, IN PATIENTS MILD INTERMITTENT
ASTHMA AND EXERCISE INDUCED BRONCHOCONSTRICTION.
Data on file (ClinicalTrials.gov identifier NCT00989833)
D5890L00035
No
REAL LIFE EFFECTIVENESS OF SYMBICORT® MAINTENANCE AND
RELIEVER THERAPY (SYMBICORT SMART®) IN ASTHMA PATIENTS
ACROSS ASIA: SMARTASIA
Data on file (ClinicalTrials.gov identifier NCT00939341)
Formoterol/budesonide Turbuhaler trials, other
D589LC00003
No
A COMPARISON OF TOLERABILITY OF 10 INHALATIONS OF
SYMBICORT® TURBUHALER® 160/4.5 µG AND 10 INHALATIONS OF
TERBUTALINE TURBUHALER 0.4 MG ON TOP OF SYMBICORT
TURBUHALER 160/4.5 µG 1 INHALATION BID, RANDOMIZED,
DOUBLE-BLIND, CROSS OVER, .....
Saito T et al. Safety and tolerability of high-dose budesonide/formoterol
via Turbuhaler in Japanese patients with asthma: a randomized, doubleblind, crossover, active comparator-controlled, phase III study. Clin Drug
Investig 2012;32:51-61.
D5890L00007
No
A COMPARATIVE, PLACEBO-CONTROLLED, DOUBLE-BLIND,
DOUBLE-DUMMY, CROSSOVER, SINGLE CENTRE, PHASE IIIB
STUDY BETWEEN FORMOTEROL ALONE (OXIS® TURBUHALER®
4.5 ΜG) AND THE FIXED COMBINATION OF FORMOTEROL AND
BUDESONIDE (SYMBICORT® TURBUHALER®160/4.5 ΜG) ON
AIRWAY RESPONSIVENESS AND AIRWAY INFLAMMATION
INDUCED BY REPEATED LOW-DOSE ALLERGEN CHALLENGE IN
ALLERGIC PATIENTS WITH MILD ASTHMA – SMILDA.
Dahlén S et al. Effect of formoterol with or without budesonide in
repeated low-dose allergen challenge. Eur Respir J 2009;33:747-53.
D5890L00012
No
REAL LIFE EFFECTIVENESS IN ASTHMA OF SYMBICORT® SINGLE
INHALER THERAPY (RELEASE)
Small I et al. Real life effectiveness in asthma of Symbicort maintenance
and reliever therapy - results of the RELEASE study. Thorax
2007;62(Suppl. III):A97.
D5890L00013
No
COMPARATIVE EFFECTS OF BUDESONIDE AND BUDESONIDE/
FORMOTEROL ON ASTHMA CONTROL IN SMOKING ASTHMATIC
SUBJECTS
Boulet LP et al. Protocol: influence of budesonide and
budesonide/formoterol on asthma control in smoking asthmatic adults.
Open Respir Med J 2010;4:51-7.
Table E-4 STUDY TITLE AND PUBLICATION STATUS FOR CLINICAL TRIALS INCLUDED IN THE MAIN AND THE
SUPPLEMENTARY ANALYSIS – 2007-2011update
Study code
D5890L00015
Included
in the
main
analysis?
No
Study title
EINFLUSS EINER KOMBINATIONSTHERAPIE VERSUS
STEROIDMONOTHERAPIE AUF DEN FRAKTIONIERT EXHALIERTEN
NO-WERT BEI KINDERN MIT ASTHMA BRONCHIALE
Publication status
Vogelberg C et al. Influence of a combination therapy versus steroid
monotherapy on FeNO. Eur Respir J 2009;34(Suppl. 53):AB1231.
Formoterol/budesonide pMDI trials, double-blind, parallel-group with maintenance treatment
D5896C00021
Yes
A 12-WEEK, RANDOMIZED, DOUBLE-BLIND, ACTIVE-CONTROLLED,
MULTI-CENTER, PHASE IIIB STUDY COMPARING THE EFFICACY
AND EVALUATING THE SAFETY OF SYMBICORT® PMDI 160/4.5 ΜG
X 2 ACTUATIONS TWICE DAILY VERSUS BUDESONIDE HFA PMDI
160 ΜG X 2 ACTUATIONS TWICE DAILY, IN ADULT AND
ADOLESCENT (≥12 YEARS) HISPANIC SUBJECTS WITH ASTHMA
Zangrilli J et al. Efficacy of budesonide/formoterol pressurized metereddose inhaler versus budesonide pressurized metered-dose inhaler alone
in Hispanic adults and adolescents with asthma: A randomized,
controlled trial. Ann Allergy Asthma Immunol 2011;107:258-65.
D5896C00022
Yes
A 52-WEEK, RANDOMIZED, DOUBLE-BLIND, PARALLEL-GROUP,
MULTI-CENTER, PHASE IIIB STUDY COMPARING THE LONG TERM
SAFETY OF SYMBICORT®PMDI 160/4.5 ΜG X 2 ACTUATIONS
TWICE DAILY TO BUDESONIDE HFA PMDI 160 ΜG X 2 ACTUATIONS
TWICE DAILY IN ADULT AND ADOLESCENT (≥12 YEARS) AFRICANAMERICAN PATIENTS WITH ASTHMA
Brown R et al. Long-term safety and asthma control measures with a
budesonide/formoterol pressurized metered-dose inhaler in African
American asthmatic patients: A randomized controlled trial. J Allergy Clin
Immunol 2012;130:362-7.
D5896C00023
No
A TWO-WEEK, RANDOMIZED, DOUBLE-BLIND STUDY ASSESSING
THE ONSET OF EFFECT QUESTIONNAIRE (OEQ) ADMINISTERED
DAILY VERSUS WEEKLY IN ADULT SUBJECTS (≥18 YEARS OF AGE)
WITH MILD TO MODERATE ASTHMA, RECEIVING SYMBICORT®
PMDI 80/4.5 ΜG X 2 ACTUATIONS TWICE DAILY OR BUDESONIDE
HFA PMDI 80 ΜG X 2 ACTUATIONS TWICE DAILY
Published combined with D5896C00025.
A TWO-WEEK, RANDOMIZED, DOUBLE-BLIND STUDY ASSESSING
THE ONSET OF EFFECT QUESTIONNAIRE (OEQ) ADMINISTERED
PRE-DOSE VERSUS POST-DOSE IN ADULT SUBJECTS (≥18 YEARS
OF AGE) WITH MILD TO MODERATE ASTHMA, RECEIVING
SYMBICORT® PMDI 80/4.5 ΜG X 2 ACTUATIONS TWICE DAILY OR
BUDESONIDE HFA PMDI 80 ΜG X 2 ACTUATIONS TWICE DAILY
Published combined with D5896C00023.
D5896C00025
No
Leidy NK et al. Can patients with asthma feel inhaler therapy working
right away? Two randomized clinical trials testing the influence of timing
of assessment on patient perception. J Asthma 2009;46:1006-12.
Leidy NK et al. Can patients with asthma feel inhaler therapy working
right away? Two randomized clinical trials testing the influence of timing
of assessment on patient perception. J Asthma 2009;46:1006-12.
Table E-4 STUDY TITLE AND PUBLICATION STATUS FOR CLINICAL TRIALS INCLUDED IN THE MAIN AND THE
SUPPLEMENTARY ANALYSIS – 2007-2011update
Study code
Included
in the
main
analysis?
Study title
Publication status
D589BL00003
Yes
A 12-WEEK, RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY,
MULTI-CENTER, PHASE IV STUDY COMPARING THE EFFICACY
AND SAFETY OF SYMBICORT® PMDI160/4.5 ΜG × 2 ACTUATIONS
TWICE DAILY VERSUS BUDESONIDE INHALATION POWDER DPI
180 ΜG × 2 INHALATIONS TWICE DAILY, IN ADULT AND
ADOLESCENT (≥12 YEARS) AFRICAN AMERICAN SUBJECTS WITH
ASTHMA
Spector SL et al. Budesonide/formoterol pressurized metered-dose
inhaler versus budesonide: a randomized controlled trial in black patients
with asthma. J Asthma 2012;49:70-7.
D5897C00003
No
A 6-WEEK, PHASE III, DOUBLE-BLIND, RANDOMIZED, MULTICENTRE, PARALLEL-GROUP STUDY EVALUATING THE EFFICACY
AND SAFETY OF 2 ACTUATIONS SYMBICORT®
(BUDESONIDE/FORMOTEROL) PMDI 40/2.25 µG TWICE DAILY
COMPARED WITH 1 INHALATION SYMBICORT.......
Data on file (ClinicalTrials.gov identifier NCT00536731)
Formoterol/budesonide pMDI trials, open-label, parallel-group with maintenance treatment
D5897C00004
No
A 4-WEEK, OPEN-LABEL, RANDOMIZED, MULTI-CENTRE,
PARALLEL-GROUP STUDY EVALUATING THE SAFETY AND
EFFICACY OF 4 ACTUATIONS SYMBICORT®
(BUDESONIDE/FORMOTEROL) HFA PMDI 40/2.25 µG TWICE DAILY,
WITH AND WITHOUT SPACER, IN CHILDREN (6-11 YEARS).
Data on file (ClinicalTrials.gov identifier NCT00536913)
Table E-5 ALL-CAUSE MORTALITY, ASTHMA-RELATED AND CARDIAC-RELATED EVENTS IN TRIALS INCLUDED
IN THE MAIN AND THE SUPPLEMENTARY ANALYSIS – 2007-2011 update
Study code
Included
in the
main
analysis?
Number of
patients
evaluable
for safety
Formoterol-exposed patients
Number
of
patients
No. of
asthma/
cardiac/other
deaths
Non-LABA-exposed patients
No. of
asthma/
cardiac
SAEs
Number
of
patients
No. of
asthma/
cardiac/other
deaths
CBP-exposed patients
No. of
asthma/
cardiac
SAEs
Number
of
patients
No. of
asthma/
cardiac/other
deaths
No. of
asthma/
cardiac
SAEs
Formoterol/budesonide Turbuhaler trials
D5890C00003
Yes
127
127
0
0
0
2
0
0
0
D5890C00009
No
138
138
0
0
0
1
1
0
0
D5890C00010
No
346
176
0
0
0
0
0
170
D5890L00001
Yes
1776
1776
0
3
1
5
9
0
0
0
D5890L00004
Yes
1538
772
0
0
1
0
3
0
766
0
2
0
1
3
D5890L00005
Yes
1004
515
0
0
1
5
0
0
489
0
0
0
5
1
D5890L00007
No
18
16
0
0
0
0
0
16
0
0
0
0
0
0
0
0
1
0
0
D5890L00008
Yes
1835
921
0
0
0
5
0
0
914
0
0
0
6
0
D5890L00009
Yes
912
452
0
1
1
2
1
0
460
0
0
0
1
1
D5890L00010
Yes
652
326
0
0
0
0
0
0
326
0
0
0
0
0
D5890L00011
Yes
1461
736
0
0
0
2
1
0
725
0
0
0
1
0
D5890L00012
No
571
571
0
0
0
0
0
0
0
0
1
0
3
1
0
0
0
8
0
D5890L00013
No
39
39
0
0
0
0
0
39
D5890L00014
Yes
986
493
0
0
0
0
1
0
D5890L00015
No
27
27
0
0
0
0
0
27
D5890L00016
Yes
430
209
0
1
0
7
0
0
D5890L00017
No
41
21
0
0
0
0
0
20
D5890L00018
No
160
160
0
0
0
0
0
0
0
0
0
0
0
493
0
0
0
0
0
0
221
0
0
0
0
0
0
0
Table E-5 ALL-CAUSE MORTALITY, ASTHMA-RELATED AND CARDIAC-RELATED EVENTS IN TRIALS INCLUDED
IN THE MAIN AND THE SUPPLEMENTARY ANALYSIS – 2007-2011 update
Study code
Included
in the
main
analysis?
Number of
patients
evaluable
for safety
D5890L00019
No
26
11
0
0
0
0
0
15
D5890L00021
No
189
189
0
0
0
1
0
0
0
D5890L00022
Yes
8399
8399
0
1
3
23
9
0
0
D5890L00032
No
66
23
0
0
0
0
0
43
D5890L00035
No
862
862
1
1
0
1
1
0
Formoterol-exposed patients
Number
of
patients
No. of
asthma/
cardiac/other
deaths
Non-LABA-exposed patients
No. of
asthma/
cardiac
SAEs
Number
of
patients
No. of
asthma/
cardiac/other
deaths
0
0
0
0
0
0
CBP-exposed patients
No. of
asthma/
cardiac
SAEs
0
0
0
0
Number
of
patients
No. of
asthma/
cardiac/other
deaths
No. of
asthma/
cardiac
SAEs
0
0
0
D589LC00001
Yes
2091
2091
0
1
1
36
4
0
D589LC00003
No
25
25
0
0
0
0
0
23
0
0
0
0
0
0
0
Formoterol/budesonide pMDI trials
D5896C00021
Yes
250
127
0
0
0
2
0
123
0
0
0
0
0
0
D5896C00022
Yes
741
377
0
0
1
2
0
364
0
0
1
4
0
0
D5896C00023
No
123
62
0
0
0
0
0
61
0
0
0
0
0
0
D5896C00025
No
134
67
0
0
0
0
0
67
0
0
0
0
0
0
D5897C00003
No
742
499
0
0
0
1
0
253
0
0
0
1
0
0
D5897C00004
No
107
107
0
0
0
0
0
0
D589BL00003
Yes
308
153
0
0
0
0
0
155
0
0
0
1
0
0
26124
20467
1
8
9
95
30
1376
0
0
1
6
1
4394
0
3
0
25
6
22510
17474
0
7
9
91
28
642
0
0
1
5
0
4394
0
3
0
25
6
SUM
32 trials
0
Subtotals
Main dataset
only
15 trials
Table E-5 ALL-CAUSE MORTALITY, ASTHMA-RELATED AND CARDIAC-RELATED EVENTS IN TRIALS INCLUDED
IN THE MAIN AND THE SUPPLEMENTARY ANALYSIS – 2007-2011 update
Study code
Not in main
dataset
Included
in the
main
analysis?
Number of
patients
evaluable
for safety
Formoterol-exposed patients
Number
of
patients
No. of
asthma/
cardiac/other
deaths
Non-LABA-exposed patients
No. of
asthma/
cardiac
SAEs
Number
of
patients
No. of
asthma/
cardiac/other
deaths
CBP-exposed patients
No. of
asthma/
cardiac
SAEs
Number
of
patients
17 trials
3614
2993
1
1
0
4
2
734
0
0
0
1
1
0
No. of
asthma/
cardiac/other
deaths
No. of
asthma/
cardiac
SAEs
Table E-6
Cardiac-related deaths from clinical trials - 2007-2011 update – primary dataset
Cas
e#
Exposure
Study ref
Daily dose of
randomized
treatment*
Age/
Sex/
Race†
Duration
of study
(days)‡
Days in
study§
Baseline LABA
and/or ICS other
than randomized
treatment║
ICSexposed?
Cause of death
1
Formoterol
D5890L00001/843/2
202
9/320 µg FORM/BUD
plus FORM/ BUD prn
85/F/
1 year
388
-
-
Yes
Myocardial infarction
2
Formoterol
D5890L00001/919/2
042
9/320 µg FORM/BUD
plus FORM/ BUD prn
62/M/
1 year
68
-
-
Yes
Acute myocardial infarction
3
Formoterol
D5890L00009/373/1
157
9/320 µg FORM/BUD
plus FORM/ BUD prn
62/M/C
6 months
63
-
-
Yes
Myocardial infarction
4
Formoterol
D5890L00016/7/710
9/320 µg FORM/BUD
plus FORM/ BUD prn
77/M/C
6 months
3
-
-
Yes
Cardiac arrest
5
Formoterol
D5890L00022/7401
9/7067
9/320 µg FORM/BUD
plus FORM/ BUD prn
61/M/
6 months
41
-
-
Yes
Colon cancer and acute
myocardial infarction
6
Formoterol
D589LC00001/6301
/20599
9/320 µg FORM/BUD
plus TERB prn
58/F/O
1 year
80
-
-
Yes
Acute myocardial infacrtion
7
Formoterol
D5890L00001/401/3
655
BUD plus FORM ind
dose plus TERB prn
57/M/
1 year
28
-
-
Yes
Myocardial infarction
8
CBP
D5890L00004/100/1
130
NA
51/M/C
6 months
163
-
-
Yes
Heart attack
9
CBP
D5890L00004/124/2
314
NA
66/M/C
6 months
157
-
-
Yes
Myopericarditis
10
CBP
D5890L00014/1201/
390
NA
67/F/C
6 months
63
-
-
Yes
Sudden coronary death
a
†
‡
§
Randomized treatment: FORM = formoterol; BUD = budesonide
Sex: M = male; F = female. Race: C = Caucasian; O = Oriental; B = Black; X = Other (other than Caucasian, Oriental, or Black).
Duration from clinical study protocol.
Days from first dose of randomized treatment to day of death.
Table E-7
Other deaths (than cardiac- or asthma-related) from clinical trials - 2007-2011 update – primary
dataset
Cas
e#
Exposure
Study ref
Daily dose of
randomized
treatment*
Age/
Sex/
Race†
Duration
of study
(days)‡
Days
in
stud
y§
Baseline LABA and/or
ICS other than
randomized
treatment║
ICSexposed?
1
Formoterol
D5890L00004/148/1
997
9/320 µg FORM/BUD
plus FORM/ BUD prn
51/M/C
6 months
77
-
-
Yes
Injuries due to
farming accident
2
Formoterol
D5890L00005/126/1
12606
9/320 µg FORM/BUD
plus FORM/ BUD prn
78/M/
6 months
135
-
-
Yes
Sudden death
3
Formoterol
D5890L00009/410/6
36
9/320 µg FORM/BUD
plus FORM/ BUD prn
43/M/C
6 months
6
-
-
Yes
Suicide with weapon
4
Formoterol
D5890L00022/4406
5/1350
9/320 µg FORM/BUD
plus FORM/ BUD prn
40/M/
6 months
169
-
-
Yes
Metastases to liver
5
Formoterol
D5890L00022/4408
7/2228
9/320 µg FORM/BUD
plus FORM/ BUD prn
67/F/
6 months
98
-
-
Yes
Intracranial bleed
6
Formoterol
D5890L00022/4900
4/7294
9/320 µg FORM/BUD
plus FORM/ BUD prn
43/M/
6 months
91
-
Yes
Death
7
Formoterol
D589LC00001/5503
/21687
9/320 µg FORM/BUD
plus FORM/ BUD prn
62/M/C
1 year
284
-
-
Yes
Septic shock
8
Formoterol
D5896C00022/11/1
409
18/640 FORM/BUD
50/M/B
1 year
85
-
-
Yes
Cerebral vascular accident
9
Formoterol
D5890L00001/844/2
008
BUD plus FORM ind
dose plus TERB prn
73/M/
1 year
189
-
-
Yes
Death
10
Non-LABA
D5896C00022/55/1
660
640 BUD
51/F/B
1 year
279
-
-
Yes
Gunshot wound to the head
a
†
‡
§
Randomized treatment: FORM = formoterol; BUD = budesonide
Sex: M = male; F = female. Race: C = Caucasian; O = Oriental; B = Black; X = Other (other than Caucasian, Oriental, or Black).
Duration from clinical study protocol.
Days from first dose of randomized treatment to day of death.
Cause of death
Table E-8
Cas
e#
1
a
b
c
d
e
f
Exposure
Formoterol
Asthma-related deaths from clinical trials - 2007-2011 update - supplementary dataset
Study ref
D5890L00035/
0001/E000101
5
(SMARTASIA)
Daily
dosea
9/320 µg
FORM/BU
D plus
FORM/
BUD prn
Age/
Sex/
Raceb
57/F/O
Duration
of studyc
3 months
Days
in
studyd
38
Other maintenance
asthma medications
β 2agoni
st
ICS
Othe
r
-
-
-
Randomized treatment: FORM = formoterol; BUD = budesonide
Race: O = oriental
Duration from study protocol
Days from first dose of randomized treatment to day of death
The patient died from the event of exacerbation of bronchial asthma and due to inhaling a lot of fume
Herbal Chinese asthma medication
Cause of
death
FEV1
(%
predicte
d)
Reve
rsibil
ity
Years
since
diagn.
Pre
study
med
Seve
rity
Asthmae
1.27
(71%)
na
5
Chau
n Li
kangf
Mode
rate
Table E-9
Cardiac-related deaths from clinical trials - 2007-2011 update - supplementary dataset
Cas
e#
Exposure
Study ref
Daily
dosea
Age/
Sex/
Raceb
Duration
of studyc
Days
in
studyd
Other maintenance
asthma medications
Cause of
death
1
Formoterol
D5890L00035/
0005/E000501
7
(SMARTASIA)
9/320 µg
FORM/BU
D plus
FORM/
BUD prn
53/M/O
3 months
72
-
Myocardial
infarction
a
b
c
d
Randomized treatment: FORM = formoterol; BUD = budesonide
Race: O = oriental
Duration from study protocol
Days from first dose of randomized treatment to day of death
-
-
Table E-10
Formoterolrandomised
patients
Non-LABArandomised
patients
MH RR
95% CI
p-value
Number of trials
utilized
Summary of results from the Mantel-Haenszel dataset – number (%) of patients reporting
Patients
(N)
Exposure
(TTY)
Number of
(%) allcause
deaths
Number
(%) of
asthmarelated
deaths
Number
(%) of
cardiacrelated
deaths
Number
(%) of
other
deaths
Number
(%) of allcause
SAEs
Number
(%) of
asthmarelated
SAEs
Number
(%) of
cardiacrelated
SAEs
Number
(%) of
all-cause
DAEs
Number
(%) of
asthmarelated
DAEs
Number
(%) of
cardiacrelated
DAEs
22154
11,1
23 (0.10%)
6 (0.03%)
7 (0.03%)
10 (0.05%)
673 (3.0%)
187 (0.8%)
42 (0.2%)
665 (3.0%)
278 (1.3%)
78 (0.4%)
18740
9,6
15 (0.08%)
2 (0.01%)
9 (0.05%)
4 (0.02%)
565 (3.0%)
204 (1.1%)
45 (0.2%)
523 (2.8%)
291 (1.6%)
37 (0.2%)
1.38
2.75
0.74
2.07
1.02
0.83
0.83
1.03
0.81
1.55
0.71, 2.68
0.52, 14.4
0.27, 2.04
0.65, 6.60
0.90, 1.14
0.68, 1.02
0.54, 1.28
0.91, 1.16
0.68, 0.96
1.02, 2.34
0.35
0.23
0.57
0.22
0.81
0.076
0.40
0.64
0.013
0.040
10
4
3
7
39
32
13
39
38
24