Long-acting -agonists: A review of formoterol safety data from
asthma clinical trials
Malcolm R. Sears1*, Anders Ottosson2, Finn Radner2 and Samy Suissa3
Affiliations:
1Firestone
Institute for Respiratory Health, St Joseph’s Healthcare and McMaster
University, Hamilton, ON, Canada
2AstraZeneca
3Dept
*
R&D, Lund, Sweden
of Epidemiology and Biostatistics, McGill University, Montreal, QC, Canada
Corresponding author:
Malcolm R. Sears
Firestone Institute for Respiratory Health
St Joseph’s Healthcare and McMaster University
Hamilton, Ontario, Canada
Email address: searsm@mcmaster.ca
Tel: +1-905-522-1155 ext 33286
Fax: + 1-905-521-6132
Short title:
Safety of formoterol in asthma trials
Word count:
5369 (excl. abstract, refs, fig/tables and legends)
ONLINE SUPPLEMENT
2
TABLE E-1. DETAILS OF CLINICAL TRIALS INCLUDED IN THE MAIN AND THE SUPPLEMENTARY ANALYSIS
Study code
Included
in the
main
analysis?
Reason for
omission
from
primary
analysis
Duration
Comparators
1 month
PLAC
Baseline ICS
use, %
Age
range,
years
Number
of
patients
evaluable
for safety
Blinded
or open
label
Design
Maintenance or
as-needed use
or adjustable
dosing
88
18–81
221
DB
P
M
Comments
Formoterol Turbuhaler trials
37-3002
N
Duration
37-3006
Y
3 months
PLAC; TERB
89
18–82
343
DB
P
M
37-3026
Y
3 months
PLAC; TERB
86
18–79
396
DB
P
M
SD-037-0003
Y
3 months
PLAC
83
6–17
248
DB
P
M
DC-037-0002
Y
3 months
PLAC
100
6–11
301
DB
P
M
37-3008
Y
6 months
PLAC
100
18–75
239
DB
P
M
37-3018
Y
12 months
BUD
Na
17–70
853
DB
P
M
37-3041
Y
12 months
BUD
Na
19–69
60
DB
P
M
SD-037-0345
Y
12 months
PLAC; BUD
Na
11–82
1,970
DB
P
M
37-3010
N
Duration
>24 months
None
94
21–82
187
O
P
M
18 g vs. 36 g
37-3015
N
Duration
>24 months
None
100
18–71
13
O
O
M
No ref treatment
SD-037-0175
Y
3 months
TERB
100
18–75
357
DB
P
M and AN
SD-037-0123
Y
3 months
TERB
100
18–75
362
DB
P
AN
SD-037-0695
Y
6 months
TERB
93
5–17
552
DB
P
AN
SD-037-0714
Y
12 months
TERB
95
6–75
455
DB
P
AN
SD-037-0716
Y
12 months
TERB
0
6–87
674
DB
P
AN
SD-037-0699
Y
6 months
SALB
67
4–91
17,862
O
P
AN
SD-037-0739
Y
6 months
FORM
100
12–78
320
O
P
AN vs. M + AN
BU-543-0681
part A
N
Duration
1 month
BUD
100
12–83
663
DB
P
M
BU-543-0681
part B
N
Follow-up
5 months
BUD
100
12–83
Follow-up
DB
P
M
3
TABLE E-1. DETAILS OF CLINICAL TRIALS INCLUDED IN THE MAIN AND THE SUPPLEMENTARY ANALYSIS
Study code
Included
in the
main
analysis?
Reason for
omission
from
primary
analysis
Duration
Comparators
MA-037-0001
N
Not suitable
3 months
BUD
BU-037-0004
Y
3 months
DC-037-0001
Y*
BU-543-0677
N
37-3005
Baseline ICS
use, %
Age
range,
years
Number
of
patients
evaluable
for safety
Blinded
or open
label
Design
Maintenance or
as-needed use
or adjustable
dosing
Comments
100
18–66
225
DB/O
P
M
SALM
100
6–17
156
O
P
M
3 months
SALM; SALB
100
18–81
372
O
P
M
Duration
1 month
BUD + FORM
100
19–76
236
O
P
M and AN
N
Design
1 day
FORM; PLAC
Na
26–65
31
DB
C
na
37-3007
N
Design
14 days
FORM
Na
18–73
66
DB
C
na
37-3011
N
Design
14 days
FORM
Na
15–76
66
DB
C
na
37-3019
N
Design
1 day
SALB; PLAC
Na
20–56
13
DB
C
na
37-3025
N
Design
1 day
FORM; PLAC
Na
23–61
28
DB
C
na
37-3027
N
Duration
7 days
FORM; PLAC
Na
18–59
165
DB
P
na
37-3028
N
Design
1 day
SALM; PLAC
Na
20–69
28
DB
C
na
37-3040
N
Design
21 days
SALM
Na
21–66
39
DB
C
na
SD-037-0002
N
Design
1 day
SALM; PLAC
Na
7–17
65
DB
O
na
SD-037-0010
N
Duration
1 day
TERB
Na
20–64
48
DB
P
na
SD-037-0011
N
Duration
14 days
TERB; PLAC
Na
18–65
72
DB
P
na
SD-037-0012
N
Design
1 day
TERB; PLAC
Na
19–53
33
DB
C
na
SD-037-0013
N
Design
3 days
TERB
Na
38–73
28
DB
C
na
High-dose
tolerability
SD-037-0068
N
Design
1 day
SALB; PLAC
Na
20–64
29
DB
C
na
High-dose
tolerability
SD-037-0149
N
Design
1 day
TERB; PLAC
Na
8–17
27
DB
C
na
SD-037-0287
N
Design
1 day
FORM; PLAC
Na
20–70
60
DB
C
na
SD-037-0361
N
Design
1 day
SALB; PLAC
Na
18–64
36
DB
C
na
Acute
bronchoconstriction
4
TABLE E-1. DETAILS OF CLINICAL TRIALS INCLUDED IN THE MAIN AND THE SUPPLEMENTARY ANALYSIS
Study code
Included
in the
main
analysis?
Reason for
omission
from
primary
analysis
Duration
Comparators
Baseline ICS
use, %
Age
range,
years
Number
of
patients
evaluable
for safety
Blinded
or open
label
Design
Maintenance or
as-needed use
or adjustable
dosing
Comments
SD-037-0657
N
Design
1 day
FORM; PLAC
Na
18–67
23
DB
C
na
SD-037-0684
N
Design
1 day
FORM; PLAC
Na
20–81
46
DB
C
na
SD-037-0718
N
Duration
1 day
SALB
Na
18–67
88
DB
P
na
Acute
bronchoconstriction
SD-037-0724
N
Duration
1 day
SALB
Na
18–69
78
DB
P
na
Acute
bronchoconstriction
SD-037-0738
N
Design
1 day
TERB; PLAC
Na
6–11
20
DB
C
na
High-dose
tolerability
SD-037-0744
N
Design
1 day
SALB; PLAC
Na
21–66
26
DB
C
na
SD-037-0745
N
Duration
1 month
PLAC
100
20–84
282
DB
P
M
SD-004-0216
N
Duration
2 months
BUD; Zafirlukast
Na
12–72
352
DB
P
na
Formoterol pMDI trials
SD-037-0288
N
Incomplete
1 year
FORM
Na
435
DB
P
M
Abbreviated CSR
SD-037-0344
N
Incomplete
3 months
FORM; PLAC
Na
639
DB
P
M
Abbreviated CSR
SD-037-0737
N
Design
1 day
SALB; PLAC
Na
18–69
30
DB
C
na
D5126C00017
N
Design
1 day
SALB
Na
1–6
34
SB
P
na
Formoterol/budesonide Turbuhaler trials
SD-039-0348
Y
3 months
BUD
Na
18–78
467
DB
P
M
SD-039-0349
Y
3 months
BUD; BUD +
FORM
Na
18–78
362
DB
P
M
SD-039-0353
Y
3 months
BUD
Na
4–17
286
DB
P
M
SD-039-0618
Y
3 months
FLUT
Na
17–75
344
DB
P
M
SD-039-0665
Y
3 months
BUD
Na
18–80
616
DB
P
M
SD-039-0666
Y
3 months
BUD
Na
18–78
523
DB
P
M
5
TABLE E-1. DETAILS OF CLINICAL TRIALS INCLUDED IN THE MAIN AND THE SUPPLEMENTARY ANALYSIS
Study code
Included
in the
main
analysis?
Reason for
omission
from
primary
analysis
Duration
Comparators
Baseline ICS
use, %
Age
range,
years
Number
of
patients
evaluable
for safety
Blinded
or open
label
Design
Maintenance or
as-needed use
or adjustable
dosing
3 months
BUD; BUD +
FORM
Na
4–11
630
DB
P
M
2 weeks
FLUT
Na
17–75
438
DB
P
M
SD-039-0688
Y
SD-039-0671
N
SD-039-0714
Y
3 months
BUD
Na
11–17
270
DB
P
M
SD-039-0689
Y
3/6 months
BUD; BUD +
FORM
Na
12–79
456
DB
P
M
SD-039-0664
Y
6/12 months
BUD + FORM
Na
18–81
585/289
O
P
M
SD-039-0667
Y
6 months
BUD + TERB prn
Na
11–79
696
DB
P
M + AN
SD-039-0668
Y
12 months
BUD + TERB prn
Na
11–80
1,890
DB
P
M + AN
SD-039-0673
Y
12 months
BUD/FORM +
TERB prn; BUD +
TERB prn
Na
4–79
2,753
DB
P
M + AN
SD-039-0734
Y
12 months
BUD/FORM +
FORM prn;
BUD/FORM +
TERB prn
Na
12–89
3,382
DB
P
M + AN
SD-039-0735
Y*
6 months
BUD/FORM +
TERB prn;
SALM/FLUT +
TERB prn
Na
11–83
3,321
DB
P
M + AN
SD-039-0691
Y*
12 months
SALM/FLUT +
SALB prn
Na
12–84
2,135
O
P
M + AN
SD-039-0686
Y*
6 months
BUD/FORM
(fixed
maintenance
dose);
SALM/FLUT
Na
12–85
658
DB/O
P
M; AMD
Duration
Comments
3 months for BUD
treatment
6
TABLE E-1. DETAILS OF CLINICAL TRIALS INCLUDED IN THE MAIN AND THE SUPPLEMENTARY ANALYSIS
Study code
Included
in the
main
analysis?
Reason for
omission
from
primary
analysis
Duration
Comparators
Baseline ICS
use, %
Age
range,
years
Number
of
patients
evaluable
for safety
Blinded
or open
label
Design
Maintenance or
as-needed use
or adjustable
dosing
6 months
SALM/FLUT +
SALB prn
Na
12–80
2,304
DB
P
M + AN
1 month
BUD + FORM
Na
18–75
237
DB
P
M
D5890C00002
Y*
DC-039-0002
N
CN-039-0001
Y
3 months
BUD + FORM
Na
14–79
320
O
P
M
BA-039-0001
Y
4 months
BUD
Na
19–81
133
DB
P
AMD
BE-039-0001
Y
4 months
BUD/FORM bid
Na
12–81
980
O
P
AMD
DC-039-0001
Y
5 months
BUD/FORM bid
Na
12–96
995
O
P
AMD
AD-039-0001
Y
6 months
BUD/FORM bid
Na
18–80
796
O
P
AMD
MA-SYM-0001
Y
3 months
BUD/FORM bid
Na
11–82
537
O
P
AMD
IE-SYM-0001
Y
3 months
BUD/FORM bid
Na
17–82
203
O
P
AMD
CI-SYM-0001
Y
3 months
BUD/FORM bid
Na
6–87
2,358
O
P
AMD
BU-039-0004
Y
3 months
BUD/FORM bid
Na
18–87
1,553
O
P
AMD
CF-039-0001
Y
3 months
BUD/FORM bid
Na
12–100
873
O
P
AMD
CF-039-0002
Y
3 months
BUD/FORM bid
Na
12–93
2,068
O
P
AMD
BG-SYM-0003
Y
3 months
BUD/FORM bid
Na
16–87
3,297
O
P
AMD
PL-039-0001
Y
3 months
BUD/FORM bid
Na
10–53
1,606
O
P
AMD
LD-039-0001
Y
6 months
BUD/FORM bid
Na
12–83
1,034
O
P
AMD
BS-039-0002
Y
3 months
BUD/FORM bid
Na
12–78
142
O
P
AMD
LD-039-0003
Y
6 months
BUD/FORM bid +
FORM prn
Na
6–82
491
O
P
M + AN
AF-039-0001
Y
6 months
FORM prn
Na
15–63
92
DB
P
AN
39-3002
N
Design
28 days
FORM; BUD
Na
22–57
20
DB
C
na
D5890C00007
N
Design
1 day
SALB; PLAC
Na
18–50
32
DB
C
na
Duration
Comments
7
TABLE E-1. DETAILS OF CLINICAL TRIALS INCLUDED IN THE MAIN AND THE SUPPLEMENTARY ANALYSIS
Study code
Included
in the
main
analysis?
Reason for
omission
from
primary
analysis
Duration
Comparators
Baseline ICS
use, %
Age
range,
years
Number
of
patients
evaluable
for safety
Blinded
or open
label
Design
Maintenance or
as-needed use
or adjustable
dosing
Comments
SD-039-0367
N
Design
1 day
FORM; PLAC
Na
21–59
15
DB
C
na
High-dose
tolerability
SD-039-0617
N
Design
1 day
FLUT/SALM;
PLAC
Na
28–73
30
DB
C
na
SD-039-0678
N
Design
1 day
FLUT/SALM;
PLAC
Na
22–48
27
DB
C
na
SD-039-0685
N
Design
3 days
FLUT/SALM;
PLAC
Na
18–65
43
DB
C
na
SD-039-0693
N
Duration
1 day
FORM
Na
12–78
115
DB
P
na
Acute
bronchoconstriction
SD-039-0702
N
Duration
1 day
SALB
Na
13–80
103
DB
P
na
Acute
bronchoconstriction
Formoterol/budesonide pMDI trials
D5896C00001
Y
3 months
BUD
Na
12–79
618
DB
P
M
SD-039-0681
Y
3 months
BUD;
BUD/FORM
Na
11–79
679
DB
P
M
SD-039-0682
Y
3 months
BUD;
BUD/FORM
Na
6–11
622
DB
P
M
SD-039-0716
Y
3 months
BUD; PLAC;
FORM
Na
6–78
511
DB
P
M
ICS-free patients
SD-039-0717
Y
3 months
BUD; PLAC;
FORM; BUD +
FORM
Na
12–87
596
DB
P
M
ICS-free patients
SD-039-0718
Y
3 months
BUD; FORM
Na
6–15
411
DB
P
M
ICS-free patients
SD-039-0725
Y
3 months
BUD
Na
6–15
521
DB
P
M
SD-039-0726
Y
3 months
BUD; PLAC
Na
16–79
751
DB
P
M
8
TABLE E-1. DETAILS OF CLINICAL TRIALS INCLUDED IN THE MAIN AND THE SUPPLEMENTARY ANALYSIS
Study code
Included
in the
main
analysis?
Reason for
omission
from
primary
analysis
Duration
Comparators
Baseline ICS
use, %
Age
range,
years
Number
of
patients
evaluable
for safety
Blinded
or open
label
Design
Maintenance or
as-needed use
or adjustable
dosing
SD-039-0728
Y
12 months
BUD
Na
12–81
708
DB
P
M
SD-039-0715
Y
12 months
BUD/FORM
Na
12–85
673
O
P
M
SD-039-0719
Y
6 months
BUD
Na
6–11
186
O
P
M
D5896C00005
Y*
7 months
FLUT/SALM
Na
12-87
1,221
O
P
M
D5896C00010
N
Design
1 day
FORM; BUD
Na
22–63
29
O
C
na
D5896C00011
N
Design
7 days
BUD + FORM
Na
21–64
26
O
P
na
D5896C00013
N
Design
1 day
BUD + FORM
Na
6–11
24
O
C
na
SD-039-0729
N
Design
1 day
BUD; FORM
Na
18–80
201
O
C
na
SD-039-0732
N
Design
1 day
SALB;
FLUT/SALM;
PLAC
Na
18–69
55
SB
C
na
SD-039-0733
N
Design
1 day
SALB;
FLUT/SALM;
PLAC
Na
18–68
54
SB
C
na
SD-039-0738
N
Design
1 day
BUD + FORM
Na
43–67
30
O
C
na
SD-039-0743
N
Duration
6 weeks
BUD + FORM
Na
6–84
283
O
M
na
SUM
117 trials
Comments
High-dose
tolerability
78,338
* In this trial, patients exposed to salmeterol were removed from the main analysis but included in the supplementary analysis.
AMD = adjustable maintenance dosing; AN = as-needed use; bid = twice daily; BUD = budesonide; C = cross-over; CSR = clinical study report; DB = double blind; FLUT =
fluticasone; FORM = formoterol; ICS = inhaled corticosteroid; M = maintenance treatment; N = not included; na = not applicable; O = open label; P = parallel; PLAC = placebo;
pMDI = pressurized metered-dose inhaler; prn = as needed; SALB = salbutamol; SALM = salmeterol; SB = single blind; TERB = terbutaline; Y = included.
9
TABLE E-2. STUDY TITLE AND PUBLICATION STATUS FOR CLINICAL TRIALS INCLUDED IN THE MAIN AND THE
SUPPLEMENTARY ANALYSIS
Study code
Included
in the
main
analysis?
Study title
Publication status
Formoterol Turbuhaler trials, double-blind, parallel-group with twice-daily treatment
37-3002
N
A COMPARISON OF THE EFFICACY OF THREE DIFFERENT DOSES
OF A LONG ACTING B-AGONIST, D2522, AND PLACEBO INHALED
VIA TURBUHALER IN ASTHMATIC PATIENTS
Schreurs AJ, Sinninghe Damste HE, de Graaff CS, Greefhorst AP. A
dose–response study with formoterol Turbuhaler as maintenance therapy
in asthmatic patients. Eur Respir J 1996; 9: 1678-1683.
37-3006
Y
A COMPARISON OF THE EFFICACY OF INHALED D 2522 VERSUS
TERBUTALINE AND PLACEBO ADMINISTERED VIA TURBUHALER IN
PATIENTS WITH ASTHMA
Ekström T, Ringdal N, Tukiainen P, Runnerström E, Soliman S. A 3month comparison of formoterol with terbutaline via Turbuhaler. A
placebo-controlled study. Ann Allergy Asthma Immunol 1998; 81: 225230.
37-3026
Y
FORMOTEROL 6 µG B.I.D VIA TURBUHALER FOR 3 MONTHS
COMPARED WITH TERBUTALINE AND PLACEBO IN PATIENTS WITH
ASTHMA
Ekström T, Ringdal N, Sobradillo V, Runnerström E, Soliman S. Low-dose
formoterol Turbuhaler (Oxis) bid, a 3-month placebo-controlled
comparison with terbutaline (q.i.d.). Respir Med 1998b; 92: 1040-1045.
SD-037-0003
Y
A 3-MONTH, PLACEBO-CONTROLLED EFFICACY STUDY OF
FORMOTEROL TURBUHALER 4.5 µG AND 9 µG B.I.D.
(CORRESPONDING TO THE METERED DOSES 6 µG AND 12 µG,
RESPECTIVELY) IN ASTHMATIC CHILDREN AGED 6 TO 17 YEARS
von Berg A, Papageorgiou Saxoni F, Wille S, Carrillo T, Kattamis C,
Helms PJ. Efficacy and tolerability of formoterol Turbuhaler® in children.
Int J Clin Pract 2003; 57: 852-856.
DC-037-0002
Y
A RANDOMISED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY
OF THE EFFICACY, TOLERABILITY, AND COST-EFFECTIVENESS OF
FORMOTEROL TURBUHALER 6 µG AND 12 µG B.I.D. IN SIX TO
ELEVEN YEAR OLD CHILDREN WITH SYMPTOMATIC ASTHMA
Zimmerman B, D’Urzo A, Bérubé D. Efficacy and safety of formoterol
Turbuhaler when added to inhaled corticosteroid treatment in children with
asthma. Pediatr Pulmonol 2004; 37: 122-127.
37-3008
Y
THE EFFICACY OF INHALED D2522, 24 µG BID, VIA TURBUHALER. A
PLACEBO-CONTROLLED, RANDOMIZED, PARALLEL GROUP, LONGTERM STUDY IN PATIENTS WITH ASTHMA USING TERBUTALINE
0.25 MG AS RESCUE MEDICATION
van der Molen T, Postma DS, Turner MO, Meyboom-de Jong B, Malo JL,
Chapman K, Grossman R, de Graaff CS, Riemersma RA, Sears MR.
Effects of the long acting beta agonist formoterol on asthma control in
asthmatic patients using inhaled corticosteroids. Thorax 1997; 52: 535539.
37-3018
Y
FORMOTEROL AND CORTICOSTEROIDS (BUDESONIDE)
ESTABLISHING THERAPY. A LONG TERM PLACEBO CONTROLLED
STUDY OF INHALED FORMOTEROL WITH LOW OR HIGH DOSE
BUDESONIDE IN ASTHMA THERAPY
Pauwels RA, Löfdahl CG, Postma DS, Tattersfield AE, O’Byrne P, Barnes
PJ, Ullman A. Effect of inhaled formoterol and budesonide on
exacerbations of asthma. N Engl J Med 1997; 337: 1405-1411.
37-3041
Y
A LONG TERM STUDY OF THE ANTI-INFLAMMATORY EFFECTS OF
LOW DOSE BUDESONIDE PLUS FORMOTEROL VS. HIGH DOSE
BUDESONIDE IN ASTHMA THERAPY
Kips JC, O’Connor BJ, Inman MD, Svensson K, Pauwels RA, O’Byrne
PM. A long-term study of the antiinflammatory effect of low-dose
budesonide plus formoterol versus high-dose budesonide in asthma Am J
Respir Crit Care Med 2000; 161: 996-1001.
10
TABLE E-2. STUDY TITLE AND PUBLICATION STATUS FOR CLINICAL TRIALS INCLUDED IN THE MAIN AND THE
SUPPLEMENTARY ANALYSIS
Study code
SD-037-0345
Included
in the
main
analysis?
Y
Study title
OXIS AND PULMICORT TURBUHALER IN THE MANAGEMENT OF
ASTHMA
Publication status
O’Byrne PM, Barnes PJ, Rodriguez-Roisin R, Runnerstrom E, Sandstrom
T, Svensson K, Tattersfield A. Low dose inhaled budesonide and
formoterol in mild persistent asthma: the OPTIMA randomized trial. Am J
Respir Crit Care Med 2001; 164: 1392-1397.
Formoterol Turbuhaler trials, open-label, uncontrolled with twice-daily treatment
37-3010
N
A LONG-TERM OPEN SAFETY STUDY OF INHALED D2522 VIA
TURBUHALER IN PATIENTS WITH ASTHMA
Data on file
37-3015
N
A LONG-TERM OPEN SAFETY STUDY OF INHALED D2522 VIA
Data on file
TURBUHALER IN PATIENTS WITH ASTHMA, PREVIOUSLY INCLUDED
IN STUDY 37-3011
Formoterol Turbuhaler trials, double-blind, parallel-group with twice-daily plus as-needed treatment
SD-037-0175
Y
A 12-WEEK COMPARISON OF OXIS TURBUHALER (FORMOTEROL)
B.I.D. AND OXIS TURBUHALER P.R.N. VERSUS OXIS TURBUHALER
B.I.D. AND BRICANYL TURBUHALER (TERBUTALINE) P.R.N. IN
PATIENTS WITH ASTHMA ON THERAPY WITH INHALED
CORTICOSTEROIDS
Ind PW, Villasante C, Shiner RJ, Pietinalho A, Boszormenyi NG, Soliman
S, Selroos O. Safety of formoterol by Turbuhaler® as reliever medication
compared with terbutaline in moderate asthma. Eur Respir J 2002; 20:
859-866.
Formoterol Turbuhaler trials, double-blind, parallel-group with as-needed treatment
SD-037-0123
Y
A 12-WEEK COMPARISON OF 4.5 µG OXIS TURBUHALER
(FORMOTEROL) P.R.N. VERSUS 0.5 MG BRICANYL TURBUHALER
(TERBUTALINE) P.R.N. IN ASTHMATICS ON THERAPY WITH
INHALED STEROIDS
Tattersfield AE, Löfdahl C-G, Postma DS, Eivindson A, Schreurs AGM,
Rasidakis A, Ekström T. Comparison of formoterol and terbutaline for asneeded treatment of asthma: a randomised trial. Lancet 2001; 357: 257261.
SD-037-0695
Y
A 6 MONTHS COMPARISON OF THE SAFETY AND EFFICACY
Villa J, Kuna P, Egner J, Brander R. Safety of formoterol reliever therapy
PROFILES OF OXIS (FORMOTEROL) TURBUHALER AS NEEDED AND compared with terbutaline in asthmatic children taking anti-inflammatory
BRICANYL (TERBUTALINE) TURBUHALER AS NEEDED IN CHILDREN therapy [abstract]. Eur Respir J 2002; 20 (Suppl 38): 431.
WITH ASTHMA ON ANTI-INFLAMMATORY TREATMENT
SD-037-0714
Y
A 12-MONTH COMPARISON OF FORMOTEROL TURBUHALER AND
TERBUTALINE TURBUHALER BOTH USED AS NEEDED IN PATIENTS
WITH ASTHMA ON ANTI-INFLAMMATORY TREATMENT
Chuchalin A, Kasl M, Bengtsson T, Nihlen U, Rosenborg J. Formoterol
used as needed in patients with intermittent or mild persistent asthma.
Respir Med 2005; 99: 461-470.
SD-037-0716
Y
A 12-MONTH COMPARISON OF FORMOTEROL TURBUHALER AND
TERBUTALINE TURBUHALER BOTH USED AS NEEDED IN PATIENTS
WITH ASTHMA NOT USING ANTI-INFLAMMATORY TREATMENT
Chuchalin A, Kasl M, Bengtsson T, Nihlen U, Rosenborg J. Formoterol
used as needed in patients with intermittent or mild persistent asthma.
Respir Med 2005; 99: 461-470.
11
TABLE E-2. STUDY TITLE AND PUBLICATION STATUS FOR CLINICAL TRIALS INCLUDED IN THE MAIN AND THE
SUPPLEMENTARY ANALYSIS
Study code
Included
in the
main
analysis?
Study title
Publication status
Formoterol Turbuhaler trials, open-label, parallel-group with as-needed treatment
SD-037-0699
Y
REAL LIFE EFFECTIVENESS OF OXIS TURBUHALER AS NEEDED IN
ASTHMATIC PATIENTS DURING SIX MONTHS (RELIEF)
Pauwels RA, Sears MR, Campbell M, Villasante C, Huang S, Lindh A,
Petermann W, Aubier M, Schwabe G, Bengtsson T. Formoterol as relief
medication in asthma: a worldwide safety and effectiveness trial. Eur
Respir J 2003; 22: 787-794.
SD-037-0739
Y
A 6 MONTHS, RANDOMISED, OPEN, PARALLEL GROUP,
MULTICETNRE STUDY TO EXAMINE EFFICACY AND SAFETY OF AS
NEEDED VERSUS MAINTENANCE USE OF OXIS 9 MCG IN
SUBJECTS WELL CONTROLLED ON MAINTENANCE TREATMENT
WITH INHALED GCS AND LONG ACTING B2-AGONISTS
Data on file
Formoterol Turbuhaler trials, performed by local marketing companies
BU-543-0681
part A & B
N
EFORMOTEROL IN THE MANAGEMENT OF MILD ASTHMA EFORMOTEROL TURBUHALER WITH BUDESONIDE TURBUHALER:
FLOW
Price D, Dutchman D, Mawson A, Bodalia B, Duggan S, Todd P. Early
asthma control and maintenance with eformoterol following reduction of
inhaled corticosteroid dose. Thorax 2002; 57: 791-798.
MA-037-0001
N
THE EFFICACY OF PULMICORT® TURBUHALER WITH AND WITHOUT
OXIS® TURBUHALER COMPARED TO CURRENT NON-STEROID
THERAPY IN PATIENTS WITH MILD TO MODERATE ASTHMA IN
RUSSIA (EPOCH)
Chuchalin AG, Ovcharenko SI, Goriachkina LA, Sidorenko IV, Tsoi AN.
The safety and efficacy of formoterol (Oxis®) Turbuhaler® plus budesonide
(Pulmicort®) Turbuhaler in mild to moderate asthma: a comparison with
budesonide Turbuhaler alone and current non-corticosteroid therapy in
Russia. Int J Clin Pract 2002; 56: 15-20.
BU-037-0004
Y
EFORMOTEROL VS. SALMETEROL: REDUCTION IN SHORT-ACTING
BRONCHODILATOR USAGE IN ASTHMATIC CHILDREN TREATED
WITH INHALED STEROIDS: FACT
Everden P, Campbell M, Harnden C, McGoldrick H, Bodalia B, Manion V,
Reynia S. Eformoterol Turbohaler® compared with salmeterol by dry
powder inhaler in asthmatic children not controlled on inhaled
corticosteroids. Pediatr Allergy Immunol 2004; 15: 40-47.
DC-037-0001
Y*
A CLINICAL AND ECONOMIC COMPARISON OF FORMOTEROL
TURBUHALER® VERSUS SALMETEROL AND SALBUTAMOL PMDI IN
ASTHMATIC PATIENTS NOT WELL-CONTROLLED ON INHALED
STEROID THERAPY
Mintz S, Orcheson L, Wang E. Clinical and economic evaluation of
formoterol Turbuhaler (FORM) compared with salmeterol (SALM) and
salbutamol (SALB) in moderate to severe asthma. J Allergy Clin Immunol
1999; 103: S74-75.
BU-543-0677
N
DOES EFORMOTEROL TURBOHALER ALLOW A REDUCTION IN THE O’Connor BJ, McSorley LC, Turbitt ML. Does treatment with eformoterol
NUMBER OF DRUGS USED IN ASTHMA MANAGEMENT? A STUDY
Turbohaler prn allow a reduction in the number of inhalers used to treat
COMPARING BUDESONIDE AND EFORMOTEROL TURBUHALER BID moderate to severe asthma? Am J Respir Crit Care Med 2000; 161: A191.
WITH TERBUTALINE TURBUHALER PRN VERSUS BUDESONIDE AND
EFORMOTEROL TURBUHALER BID WITH EFORMOTEROL
TURBUHALER PRN
12
TABLE E-2. STUDY TITLE AND PUBLICATION STATUS FOR CLINICAL TRIALS INCLUDED IN THE MAIN AND THE
SUPPLEMENTARY ANALYSIS
Study code
Included
in the
main
analysis?
Study title
Publication status
Formoterol Turbuhaler trials, other
37-3005
N
AN EVALUATION OF EFFICACY, TOLERABILITY AND DURATION OF
ACTION OF INHALED D2522 AFTER SINGLE DOSE
ADMINISTRATIONS TO ASTHMATICS
Data on file
37-3007
N
A COMPARISON OF THE EFFICACY OF INHALED D2522, 24 µG
B.I.D.,VIA TURBUHALER, AND FORMOTEROL, 24 µG B.I.D., CFC
INHALER IN PATIENTS WITH ASTHMA
Data on file
37-3011
N
A COMPARISON OF EFFICACY OF INHALED D-2522, 12 µG B.I.D., VIA Data on file
TURBUHALER AND FORMOTEROL, 12 µG B.I.D., CFC INHALER IN
PATIENTS WITH ASTHMA
37-3019
N
TOLERABILITY OF HIGH DOSE FORMOTEROL TURBUHALER VS.
HIGH DOSE SALBUTAMOL PMDI IN ASTHMATIC PATIENTS DURING
REGULAR TWICE DAILY TREATMENT WITH FORMOTEROL
TURBUHALER 12 µG
Data on file
37-3025
N
AN EVALUATION OF THE EFFICACY AND DURATION OF ACTION OF
D 2522 TURBUHALER (3, 6, 12 AND 24 µG) AND FORMOTEROL
PRESSURIZED METERED DOSE INHALER (12 µG) AFTER SINGLE
DOSE ADMINISTRATIONS TO ASTHMATICS
Data on file
37-3027
N
A DOUBLE-BLIND, RANDOMIZED, PARALLEL GROUP, PLACEBOCONTROLLED, DOSE-RESPONSE STUDY OF FORMOTEROL
TURBUHALER, 6, 12 AND 24 µG, ADMINISTRATED TWICE DAILY IN
PATIENTS WITH ASTHMA
Data on file
37-3028
N
AN EVALUATION OF THE EFFICACY AND DURATION OF ACTION OF
FORMOTEROL TURBUHALER (6,12 AND 24 µG) AS COMPARED
WITH SALMETEROL (SERVENT) DISKHALER (50 µG) AFTER SINGLE
DOSE ADMINISTRATIONS TO ASTHMATICS
Data on file
37-3040
N
PROTECTIVE EFFECT OF SALBUTAMOL AGAINST METHACHOLINE
BROMIDE IN ASTHMATIC PATIENTS PRE-TREATED WITH
FORMOTEROL TURBUHALER OR SALMETEROL DISKHALER
Data on file
SD-037-0002
N
EFFICACY AND TOLERABILITY OF SINGLE DOSES OF
FORMOTEROL TURBUHALER 6, 12, 24, 48 µG COMPARED TO
SALMETEROL DISKHALER 50 µG AND PLACEBO IN CHILDREN WITH
BRONCHIAL ASTHMA
Pohunek P, Matulka M, Rybnícek O, Kopriva F, Honomichlová H,
Svobodová T. Dose-related efficacy and safety of formoterol (Oxis®)
Turbuhaler® compared with salmeterol Diskhaler® in children with asthma.
Pediatr Allergy Immunol 2004; 15: 32-39.
13
TABLE E-2. STUDY TITLE AND PUBLICATION STATUS FOR CLINICAL TRIALS INCLUDED IN THE MAIN AND THE
SUPPLEMENTARY ANALYSIS
Study code
Included
in the
main
analysis?
Study title
Publication status
SD-037-0010
N
SAFETY AND EFFICACY OF FORMOTEROL TURBUHALER
ADMINISTERED TO ASTHMA/COPD PATIENTS WITH ACUTE
BRONCHIAL OBSTRUCTION. A COMPARISON WITH TERBUTALINE
(BRICANYL) TURBUHALER TREATMENT
Malolepszy J, Böszörményi Nagy G, Selroos O, Larsson P, Brander R.
Safety of formoterol Turbuhaler® at cumulative dose of 90 mcg in patients
with acute bronchial obstruction. Eur Respir J 2001; 18: 928-934.
SD-037-0011
N
PROTECTION AGAINST METHACHOLINE-INDUCED
BRONCHOCONSTRICTION AFTER FIRST DOSE AND AFTER 14
DAYS' TREATMENT: A COMPARISON OF FORMOTEROL
TURBUHALER 12 µG O.D., 6 µG B.I.D., 24 µG B.I.D., BRICANYL
TURBUHALER 0.5 MG Q.I.D. AND PLACEBO IN PATIENTS WITH
ASTHMA
Lipworth J, Tan S, Devlin M, Aiken T, Baker R, Hendrick D. Effects of
treatment with formoterol on bronchoprotection against methacholine. Am
J Med 1998; 104: 431-438.
SD-037-0012
N
DURATION OF PROTECTION OF FORMOTEROL 12 µG AGAINST
EXERCISE-INDUCED BRONCHOCONSTRICTION, COMPARED WITH
TERBUTALINE 0.5 MG AND PLACEBO, DURING REGULAR
TREATMENT WITH FORMOTEROL TURBUHALER 12 µG B.I.D. IN
ADULT ASTHMATICS
Vilsvik J, Ankerst J, Palmqvist M, Persson G, Schaanning J, Schwabe G,
Johansson Å. Protection against cold air and exercise-induced
bronchoconstriction while on regular treatment with Oxis. Respir Med
2001; 95(6): 484-490.
SD-037-0013
N
TOLERABITITY OF HIGH DOSES OF FORMOTEROL TURBUHALER
DURING THREE DAYS COMPARED WITH 6 AND 10 MG
TERBUTALINE TURBUHALER. A DOUBLE-BLIND, CROSS-OVER,
RANDOMIZED STUDY IN PATIENTS WITH ASTHMA
Tötterman KJ, Huhti L, Sutinen E, Backman R, Pientinalho A, Falck M,
Larsson P, Selroos O. Tolerability to high doses of formoterol and
terbutaline via Turbuhaler for 3 days in stable asthmatic patients. Eur
Respir J 1998; 12(3): 573-579.
SD-037-0068
N
ON THE RELATIVE THERAPEUTIC INDEX BETWEEN FORMOTEROL
TURBUHALER AND SALBUTAMOL PMDI IN ASTHMATIC PATIENTS
Rosenborg J, Larsson P, Rott Z, Böcskei C, Poczi M, Juhász G. Relative
therapeutic index between inhaled formoterol and salbutamol in asthma
patients. Respir Med 2002; 96(6): 412-417.
SD-037-0149
N
PROTECTIVE EFFECT OF SINGLE DOSES OF FORMOTEROL
TURBUHALER 4.5µG AND 9 µG (CORRESPONDING TO THE
METERED DOSES 6 µG AND 12 µG, RESPECTIVELY) COMPARED
WITH BRICANYL TURBUHALER 0.5 MG AND PLACEBO IN CHILDREN
WITH EXERCISE INDUCED BRONCHOCONSTRICTION
Grönneröd TA, von Berg A, Schwabe G, Soliman S. Formoterol via
Turbuhaler® gave better protection than terbutaline against repeated
exercise challenge for up to 12 hours in children and adolescents. Respir
Med 2000; 94(7): 661-667.
SD-037-0287
N
A DOUBLE BLIND, RANDOMIZED, PLACEBO CONTROLLED CROSSOVER STUDY TO COMPARE THE BRONCHODILATORY EFFECT OF
FORMOTEROL INHALED VIA TWO DIFFERENT TURBUHALER
DEVICES
Data on file
SD-037-0361
N
THE BRONCHODILATING EFFECT DURING 30 MINUTES OF TWO
DOSES OF FORMOTEROL TURBUHALER COMPARED TO TWO
DOSES OF SALBUTAMOL PMDI AND PLACEBO
Seberova E, Andersson A. Oxis (formoterol given by Turbuhaler) showed
as rapid an onset of action as salbutamol given by a pMDI. Respir Med
2000; 94(6): 607-611.
14
TABLE E-2. STUDY TITLE AND PUBLICATION STATUS FOR CLINICAL TRIALS INCLUDED IN THE MAIN AND THE
SUPPLEMENTARY ANALYSIS
Study code
Included
in the
main
analysis?
Study title
Publication status
SD-037-0657
N
A PLACEBO CONTROLLED SINGLE-DOSE COMPARISON BETWEEN
TWO DOSES OF INHALED FORMOTEROL VIA TURBUHALER (OXIS)
AND ORAL FORMOTEROL (ATOCK TABLETS)
Data on file
SD-037-0684
N
ON THE BRONCHODILATING EFFECT OF INHALED (R;R)- AND (S;S)FORMOTEROL COMPARED WITH THE BRONCHODILATING EFFECT
OF INHALED RAC-FORMOTEROL IN ASTHMATIC PATIENTS
Lötvall J, Palmqvist M, Ankerst J, Persson G, Rosenborg J, Bengtsson T,
Rott Z, Poczi M, Devai A, Waldeck B. The effect of formoterol over 24 h in
patients with asthma: The role of enantiomers. Pul Pharmacol Ther 2005;
18(2): 109-113.
SD-037-0718
N
A COMPARISON OF EFFICACY BETWEEN FORMOTEROL
TURBUHALER AND SALBUTAMOL PRESSURISED METERED DOSE
INHALER AND SPACER, IN SUBJECTS WITH ACUTE SEVERE
BRONCHIAL OBSTRUCTION
Boonsawat W, Charoenratanakul S, Pothirat C, Sawanyawisuth K,
Seearamroongruang T, Bengtsson T, Brander R, Selroos O. Formoterol
(OXIS®) Turbuhaler® as a rescue therapy compared with salbutamol pMDI
plus spacer in patients with acute severe asthma. Respir Med 2003;
97(9): 1067-1074.
SD-037-0724
N
COMPARISON OF FORMOTEROL (OXIS) VIA TURBUHALER WITH
SALBUTAMOL VIA PRESSURIZED METERED DOSE INHALER AND
SPACER IN PATIENTS WITH ACUTE SEVERE
BRONCHOCONSTRICTION
Rubinfeld AR, Scicchitano R, Hunt A, Thompson PJ, Van Nooten A,
Selroos O. Formoterol Turbuhaler® as reliever medication in patients with
acute asthma. Eur Respir J 2006; 27(4): 735-741.
SD-037-0738
N
TOLERABILITY OF HIGH DOSE FORMOTEROL VS. HIGH DOSE
TERBUTALINE IN ASTHMATIC CHILDREN AFTER INHALATION VIA
TURBUHALER
Kaae R, Agertoft L, Pedersen S, Nordvall SL, Pedroletti C, Bengtsson T,
Johannes-Hellberg I, Rosenborg J. Cumulative high doses of inhaled
formoterol have less systemic effects in asthmatic children 6-11 years-old
than cumulative high doses of inhaled terbutaline. Br J Clin Pharmacol
2004; 58(4): 411-418.
SD-037-0744
N
DURATION OF EFFECTS OF INHALED FORMOTEROL VERSUS
SALBUTAMOL
Data on file
SD-037-0745
N
A DOUBLE-BLIND, RANDOMISED, PLACEBO-CONTROLLED,
PARALLEL-GROUP, MULTICENTRE, PHASE II STUDY TO
DETERMINE THE EFFICACY AND SAFETY DOSE-RESPONSE OF OT
(FORMOTEROL TURBUHALER) IN ADULT JAPANESE ASTHMATIC
PATIENTS RECEIVING TREATMENT FOR 4 WEEKS
Data on file
SD-004-0216
N
OXIS TURBUHALER (FORMOTEROL), ACCOLATE (ZAFIRLUKAST)
OR PLACEBO AS AN ADD ON TREATMENT TO PULMICORT
TURBUHALER (BUDESONIDE) IN ASTHMATIC PATIENTS ON
INHALED STEROIDS
Data on file
15
TABLE E-2. STUDY TITLE AND PUBLICATION STATUS FOR CLINICAL TRIALS INCLUDED IN THE MAIN AND THE
SUPPLEMENTARY ANALYSIS
Study code
Included
in the
main
analysis?
Study title
Publication status
Formoterol pMDI trials
SD-037-0288
N
A 52-WEEK, MULTICENTRE, OPEN-LABEL, RANDOMISED, PARALLEL Data on file
GROUP, PHASE III STUDY TO COMPARE THE SAFETY OF
FORMOTEROL HFA PMDI (N=57,160) WITH OXIS TURBUHALER (N=
55,163) IN ASTHMATIC SUBJECTS 6 YEARS OF AGE AND OVER
SD-037-0344
N
A THREE-MONTH, MULTICENTRE, DOUBLE-BLIND, DOUBLEDUMMY, RANDOMISED PARALLEL GROUP, PHASE III STUDY TO
INVESTIGATE THE EFFICACY AND SAFETY OF FORMOTEROL HFA
PMDI (N=216) COMPARED WITH PLACEBO (N=210) AND OXIS
TURBUHALER (N=213) IN SUBJECTS WITH ASTHMA
Data on file
SD-037-0737
N
A COMPARISON OF THE ONSET OF ACTION OF FORMOTEROL HFA
PMDI AND SALBUTAMOL HFA PMDI AFTER SINGLE DOSE
ADMINISTRATIONS TO ASTHMATIC PATIENTS
Data on file
D5126C00017
N
A COMPARISON OF FORMOTEROL HFA PMDI VIA NEBUNETTE
SPACER AND NEBULIZED SALBUTAMOL IN THE TREATMENT OF
ACUTE BRONCHOCONSTRICTION IN CHILDREN 1-6 YEARS OF AGE
AT EMERGENCY ROOM
Data on file
Formoterol/budesonide Turbuhaler trials, double-blind, parallel-group with twice-daily treatment
SD-039-0348
Y
EFFICACY AND SAFETY OF BUDESONIDE/FORMOTEROL
TURBUHALER IN STEROID-USING ASTHMATIC ADULTS - 'COMET'
Lalloo UG, Malolepszy J, Kozma D, Krofta K, Ankerst J, Johansen B,
Thomson NC. Budesonide and formoterol in a single inhaler improves
asthma control compared with increasing the dose of corticosteroid in
adults with mild-to-moderate asthma. Chest 2003; 123: 1480-1487.
SD-039-0349
Y
EFFICACY AND SAFETY OF A FIXED COMBINATION OF
BUDESONIDE/FORMOTEROL TURBUHALER IN INHALED STEROIDUSING ASTHMATIC ADULTS
Zetterström O, Buhl R, Mellem H, Hedman J, O’Neill S, Ekström T.
Improved asthma control with budesonide/formoterol in a single inhaler,
compared with budesonide alone. Eur Respir J 2001; 18: 262-268.
SD-039-0353
Y
EFFICACY AND SAFETY OF BUDESONIDE/FORMOTEROL
TURBUHALER IN A FIXED COMBINATION IN STEROID-USING
ASTHMATIC CHILDREN - COMIC
Tal A, Simon G, Vermeulen JH, Petru V, Cobos N, Everard ML, de Boeck
K. Budesonide/formoterol in a single inhaler versus inhaled corticosteroids
alone in the treatment of asthma. Pediatr Pulmonol 2002; 34: 342-350.
SD-039-0618
Y
EFFICACY OF SYMBICORT TURBUHALER COMPARED WITH
FLUTICASONE DISKUS IN ASTHMATIC PATIENTS
Bateman ED, Bantje TA, Gomes MJ, Toumbis MG, Huber RM, Naya I,
Eliraz A. Combination therapy with single inhaler budesonide/formoterol
compared with high dose of fluticasone propionate alone in patients with
moderate persistent asthma. Am J Respir Med 2003; 2: 275-281.
16
TABLE E-2. STUDY TITLE AND PUBLICATION STATUS FOR CLINICAL TRIALS INCLUDED IN THE MAIN AND THE
SUPPLEMENTARY ANALYSIS
Study code
Included
in the
main
analysis?
Study title
Publication status
SD-039-0665
Y
SYMBICORT LOW DOSE ONCE DAILY IN MILD TO MODERATE
ASTHMATIC PATIENTS
Kuna P, Creemers JP, Vondra V, Black PN, Lindqvist A, Nihlen U,
Vogelmeier C. Once-daily dosing with budesonide/formoterol compared
with twice-daily dosing with budesonide/formoterol and once-daily
budesonide in adults with mild to moderate asthma. Respir Med 2006;
100: 2151-2159.
SD-039-0666
Y
SYMBICORT HIGH DOSE ONCE DAILY IN MILD TO MODERATE
ASTHMATIC PATIENTS
Buhl R, Creemers JPHM, Vondra V, Martelli NA, Naya IP. Once-daily
budesonide/formoterol in a single inhaler in adults with moderate
persistent asthma. Respir Med 2003; 97: 323-330.
SD-039-0688
Y
EFFICACY AND SAFETY OF SYMBICORT COMPARED TO
PULMICORT AND PULMICORT+OXIS IN STEROID USING
ASTHMATIC CHILDREN
Pohunek P, Kuna P, De Boeck K. Budesonide/formoterol improves lung
function compared with budesonide alone in children with asthma. Pediatr
Allergy Immunol 2006; 17: 458-465.
SD-039-0671
N
EFFICACY OF SYMBICORT TURBUHALER COMPARED WITH
FLUTICASONE DISKUS IN ASTHMATIC PATIENTS NOT USING
STEROIDS
Eliraz A, Fritscher CC, Perez CMR, Boonsawat W, Nang AN, Bardin P,
Kao H-P. Symbicort® (budesonide/formoterol) achieves more rapid control
of asthma than fluticasone in patients with mild asthma. Am J Respir Crit
Care Med 2002; 165(Suppl 8): A567.
SD-039-0714
Y
EFFICACY AND SAFETY OF BUDESONIDE/FORMOTEROL
TURBUHALER (160/4.5 µG B.I.D. DELIVERED DOSE) COMPARED TO
BUDESONIDE TURBUHALER (200 µG B.I.D. METERED DOSE) IN
STEROID-USING ASTHMATIC ADOLESCENT PATIENTS. A DOUBLEBLIND, DOUBLE-DUMMY, RANDOMISED, PARALLEL GROUP, PHASE
III, MULTICENTRE STUDY (ATTAIN STUDY)
AstraZeneca Study SD-039-0714. AstraZeneca Clinical Trials website.
Available from: www.astrazenecaclinicaltrials.com/Article/512766.aspx.
SD-039-0689
Y
EFFICACY AND SAFETY OF SYMBICORT1280/36 MCG DAILY
DELIVERED DOSE COMPARED TO PULMICORT 1600 MCG
METERED DOSE AND PULMICORT 1600 MCG METERED DOSE PLUS
OXIS 36 MCG DELIVERED DOSE VIA TURBUHALER IN STEROID
USING ASTHMATIC ADOLESCENTS AND ADULTS
Jenkins C, Kolarikova R, Kuna P, Caillaud D, Sanchis J, Popp W,
Pettersson E. The efficacy and safety of high-dose budesonide/formoterol
(Symbicort®) compared with budesonide administered either
concomitantly with formoterol or alone in patients with persistent
symptomatic asthma. Respirology 2006; 11: 276-286.
Formoterol/budesonide Turbuhaler trials, open-label, parallel-group with twice-daily treatment
17
TABLE E-2. STUDY TITLE AND PUBLICATION STATUS FOR CLINICAL TRIALS INCLUDED IN THE MAIN AND THE
SUPPLEMENTARY ANALYSIS
Study code
SD-039-0664
Included
in the
main
analysis?
Y
Study title
SAFETY OF A COMBINATION OF BUDESONIDE/FORMOTEROL IN A
SINGLE INHALER (SYMBICORT TURBUHALER) IN STEROID-USING
ASTHMATIC ADULTS - "COMSAFE"
Publication status
Rosenhall L, Heinig JH, Lindqvist A, Leegaard J, Stahl E, Bergqvist PB.
Budesonide/formoterol (Symbicort) is well tolerated and effective in
patients with moderate persistent asthma. Int J Clin Pract 2002; 56: 427433.
Rosenhall L, Elvstrand A, Tilling B, Vinge I, Jemsby P, Ståhl E, Jerre F,
Bergqvist PBF. One-year safety and efficacy of budesonide/formoterol in
a single inhaler (Symbicort® Turbuhaler®) for the treatment of asthma.
Respir Med 2003; 97: 702-708.
Formoterol/budesonide Turbuhaler trials, double-blind, parallel-group with maintenance plus as-needed treatment
SD-039-0667
Y
EFFICACY AND SAFETY OF SYMBICORT TURBUHALER AS SINGLE
THERAPY IN PATIENTS WITH MILD TO MODERATE ASTHMA.
(STEAM STUDY)
Rabe KF, Pizzichini E, Stallberg B, Romero S, Balanzat AM, Atienza T,
Lier PA, Jorup C. Budesonide/formoterol in a single inhaler for
maintenance and relief in mild-to-moderate asthma: a randomized,
double-blind trial. Chest 2006; 129: 246-256.
SD-039-0668
Y
EFFICACY AND SAFETY OF SYMBICORT TBH AS SINGLE THERAPY
IN PATIENTS WITH MODERATE-SEVERE ASTHMA. COMPARISON
WITH CONVENTIONAL ASTHMA THERAPY, PULMICORT TBH AS
MAINTENANCE TREATMENT COMPLEMENTED WITH BRICANYL TBH
(STEP STUDY)
Scicchitano R, Aalbers R, Ukena D, Manjra A, Fouquert L, Centanni S,
Boulet L-P, Naya IP, Hultquist C. Efficacy and safety of
budesonide/formoterol single inhaler therapy versus a higher dose of
budesonide in moderate to severe asthma. Curr Med Res Opin 2004; 20:
1403-1418.
SD-039-0673
Y
EFFICACY AND SAFETY OF BUDESONIDE/FORMOTEROL
(SYMBICORT) TURBUHALER AS SINGLE THERAPY IN PATIENTS
WITH MILD-MODERATE ASTHMA. COMPARISON WITH SYMBICORT
TURBUHALER AND PULMICORT TURBUHALER AS MAINTENANCE
THERAPY, BOTH COMPLEMENTED WITH BRICANYL TBH
O’Byrne PM, Bisgaard H, Godard PP, Pistolesi M, Palmqvist M, Zhu Y,
Ekstrom T, Bateman ED. Budesonide/formoterol combination therapy as
both maintenance and reliever medication in asthma. Am J Respir Crit
Care Med 2005; 171: 129-136.
EFFICACY OF SYMBICORT TURBUHALER 160/4.5 µG AS NEEDED
VERSUS OXIS 4.5 µG AS NEEDED AND BRICANYL 0.4 MG AS
NEEDED IN ADULTS AND ADOLESCENTS WITH ASTHMA RECEIVING
SYMBICORT TURBUHALER 160/4.5 µG TWICE DAILY AS
MAINTENANCE TREATMENT
Rabe K, Atienza T, Magyar P, Larsson P, Jorup C, Laloo U. Reduction in
asthma exacerbations with budesonide in combination with formoterol for
reliever therapy: a randomised, controlled, double-blind study. Lancet
2006; 368: 744-753.
SD-039-0734
Y
Bisgaard H, Le Roux P, Bjåmer D, Dymek A, Vermeulen JH, Hultquist C.
Budesonide/formoterol maintenance plus reliever therapy a new strategy
in pediatric asthma. Chest. 2006; 130: 1733-1743.
18
TABLE E-2. STUDY TITLE AND PUBLICATION STATUS FOR CLINICAL TRIALS INCLUDED IN THE MAIN AND THE
SUPPLEMENTARY ANALYSIS
Study code
Included
in the
main
analysis?
Study title
Publication status
SD-039-0735
Y*
COMPARISION OF THE EFFICACY AND SAFETY OF ONE
Kuna P, Peters MJ, Manjra AI, Jorup C, Naya IP, Martinez-Jimenez NE,
INHALATION OF SYMBICORT TURBUHALER 160/4.5 µG BID PLUS AS Buhl R. Effect of budesonide/formoterol maintenance and reliever
NEEDED WITH TWO INHALATIONS OF SERETIDE EVOHALER 25/125 therapy on asthma exacerbations. Int J Clin Practice 2007; 61: 725-736.
µG BID PLUS TERBUTALINE TURBUHALER 0.4 MG AS-NEEDED, AND
ONE INHALATION OF SYMBICORT® TURBUHALER® 320/9 µG BID
PLUS TERBUTALINE TURBUHALER® 0.4 MG AS-NEEDED. A 6MONTH, RANDOMISED, DOUBLE-BLIND, DOUBLE-DUMMY,
PARALLEL-GROUP, ACTIVE-CONTROLLED, MULTICENTRE, PHASE
IIIB STUDY IN ADULT AND ADOLESCENT ASTHMATIC PATIENTS
D5890C00002
Y*
EFFICACY AND SAFETY OF SYMBICORT® TURBUHALER® 160/4.5
µG/INHALATION,TWO INHALATIONS TWICE DAILY PLUS ASNEEDED, COMPARED WITH SERETIDE™ DISKUS™ 50/500
µG/INHALATION, ONE INHALATION TWICE DAILY PLUS
TERBUTALINE TURBUHALER 0.4 MG/INHALATION AS-NEEDED - A 6MONTH, RANDOMISED, DOUBLE-BLIND, PARALLEL-GROUP,
ACTIVE-CONTROLLED, MULTI-NATIONAL PHASE IIIB STUDY IN
ADULT AND ADOLESCENT PATIENTS WITH PERSISTENT ASTHMA
(AHEAD STUDY)
Bousquet J, Boulet L-P, Peters MJ, Magnussen H, Quiralte J, MartinezAguilar NE, Carlsheimer A. Budesonide/formoterol for maintenance and
relief in uncontrolled asthma vs. high-dose salmeterol/fluticasone. Resp
Med 2007; 101: 2437-2446.
Formoterol/budesonide Turbuhaler trials, open-label parallel-group with maintenance plus as-needed treatment
SD-039-0691
Y*
A COMPARISON OF THE EFFECTIVENESS OF TREATMENT WITH
SYMBICORT TURBUHALER (BUDESONIDE/FORMOTEROL; 160/4.5
µG) SINGLE INHALER THERAPY AND SERETIDE DISKUS
(SALMETEROL/FLUTICASONE; 50/100, 50/250 OR 50/500 µG) PLUS
VENTOLIN (SALBUTAMOL) AS NEEDED IN STEROID-TREATED
ADULT AND ADOLESCENT ASTHMATIC SUBJECTS. A
RANDOMISED, OPEN, PARALLEL-GROUP, PHASE IIIB,
MULTICENTRE, 12-MONTH STUDY
Vogelmeier C, D’Urzo A, Pauwels R, Merino JM, Jaspal M, Boutet S,
Naya I, Price D. Budesonide/formoterol maintenance and reliever therapy:
an effective asthma treatment option? Eur Respir J 2005; 26: 819-828.
SD-039-0686
Y*
A PHASE-III 7-MONTH STUDY TO ASSESS THE EFFICACY AND
SAFETY OF SYMBICORT(160/4.5 MCG) GIVEN EITHER AS
STANDARD THERAPY OR WITH AN ADJUSTABLE DOSING
REGIMEN VERSUS SERETIDE (50/250 MCG) GIVEN AS STANDARD
THERAPY
Aalbers R, Backer V, Kava TTK, Omenaas ER, Sandström T, Jorup C,
Welte T. Adjustable maintenance dosing with budesonide/formoterol
compared with fixed-dose salmeterol/fluticasone in moderate to severe
asthma. Curr Med Res Opin 2004; 20: 225-240.
Formoterol/budesonide Turbuhaler trials, performed by local marketing companies
19
TABLE E-2. STUDY TITLE AND PUBLICATION STATUS FOR CLINICAL TRIALS INCLUDED IN THE MAIN AND THE
SUPPLEMENTARY ANALYSIS
Study code
Included
in the
main
analysis?
Study title
Publication status
DC-039-0002
N
COMPARISON OF THE EFFICACY OF SYMBICORT®
(BUDESONIDE/FORMOTEROL) TURBUHALER® LOW DOSE
THERAPY, WITH PULMICORT® (BUDESONIDE) TURBUHALER®
PLUS OXEZE® (FORMOTEROL) TURBUHALER® MONO-PRODUCT
THERAPY, IN MILD TO MODERATE ASTHMATICS - SOLID.
Data on file
CN-039-0001
Y
AN OPEN, RANDOMISED, ACTIVE-CONTROLLED, MULTICENTRE
STUDY WITH A PARALLEL DESIGN TO ASSESS THE EFFICACY
AND SAFETY OF SYMBICORT (BUDESONIDE/FORMOTEROL)
TURBUHALER® IN INHALED STEROID-USING ASTHMATIC
PATIENTS
Data on file
BA-039-0001
Y
THE EFFECTIVENESS AND SAFETY OF AN ADJUSTABLE DOSE
SYMBICORT TURBUHALER TREATMENT REGIME VERSUS HIGHDOSE PULMICORT TURBUHALER GIVEN AS STANDARD THERAPY
Pohl WR, Vetter N, Zwick H, Hrubos W. Adjustable maintenance dosing
with budesonide/formoterol or budesonide: double-blind study. Respir
Med 2006; 100: 551-560
BE-039-0001
Y
THE REAL-LIFE EFFECTIVENESS AND SAFETY OF AN
INDIVIDUALISED SYMBICORT TURBUHALER MAINTENANCE
DOSING REGIMEN (SYMBICORT ASTHMA CONTROL PLAN)
VERSUS SYMBICORT TURBUHALER GIVEN AS STANDARD
REGULAR TWICE DAILY THERAPY IN PATIENTS WITH MODERATE
TO SEVERE ASTHMA – THE SURF STUDY
Michils A, Peché RVJ, Verbraecken JA, Vandenhoven G, Wollaert L,
Duquenne V. SURF study: real-life effectiveness of
budesonide/formoterol (B/F) adjustable maintenance dosing [abst].
Allergy Clin Immunol Int 2003; 15(Suppl 1): 56, Abst P2-P39.
DC-039-0001
Y
THE EFFECTIVENESS AND SAFETY OF AN INDIVIDUALISED
SYMBICORT TURBUHALER MAINTENANCE DOSING REGIMEN
(SYMBICORT ASTHMA CONTROL PLAN) VERSUS SYMBICORT
TURBUHALER GIVEN AS STANDARD REGULAR TWICE DAILY
THERAPY – SMART
Fitzgerald JM, Sears MR, Boulet LP, Becker AB, McIvor AR, Ernst P,
Smiljanic Georgijev NM, Lee JS, for the Canadian Investigators.
Adjustable maintenance dosing with budesonide/formoterol reduces
asthma exacerbations compared with traditional fixed dosing: a fivemonth multicentre Canadian study. Can Respir J 2003; 10: 427-434.
AD-039-0001
Y
THE EFFECTIVENESS AND SAFETY OF AN INDIVIDUALISED
SYMBICORT TURBUHALER MAINTENANCE DOSING REGIMEN
(SYMBICORT ASTHMA CONTROL PLAN - SYMBIAC) VERSUS
SYMBICORT TURBUHALER GIVEN AS STANDARD REGULAR TWICE
DAILY THERAPY
Data on file
MA-SYM-0001
Y
THE EFFECTIVENESS AND SAFETY OF AN INDIVIDUALISED
SYMBICORT TURBUHALER MAINTENANCE DOSING REGIMEN
(SYMBICORT ASTHMA CONTROL PLAN) VERSUS SYMBICORT
TURBUHALER GIVEN AS STANDARD REGULAR TWICE DAILY
THERAPY. THE SYMBICORT ADJUSTABLE MAINTENANCE STUDY
(SAM)
Smorzik Y, Yankova Z. Effectiveness of adjustable maintenance dosing
and fixed dosing with budesonide/formoterol single inhaler in a multiethnic asthma population. Eur Respir J 2004; 24(Suppl 48): 311s P1987.
20
TABLE E-2. STUDY TITLE AND PUBLICATION STATUS FOR CLINICAL TRIALS INCLUDED IN THE MAIN AND THE
SUPPLEMENTARY ANALYSIS
Study code
Included
in the
main
analysis?
Study title
Publication status
IE-SYM-0001
Y
THE EFFECTIVENESS AND SAFETY OF AN INDIVIDUALISED
SYMBICORT TURBUHALER MAINTENANCE DOSING REGIMEN
(SYMBICORT ASTHMA CONTROL PLAN) VERSUS SYMBICORT
TURBUHALER GIVEN AS STANDARD REGULAR TWICE DAILY
THERAPY. THE ADJUSTABLE MAINTENANCE STUDY
Data on file
CI-SYM-0001
Y
CONTROL OF ASTHMA BY SYMBICORT TURBUHALER.
EFFECTIVENESS AND SAFETY OF A FLEXIBLE INDIVIDUALISED
DOSING REGIMEN VERSUS A STANDARD TWICE DAILY REGIMEN
Canonica GW, Castellani P, Cazzola M, Fabbri LM, Fogliani V,
Mangrella M, Moretti A, Paggiaro P, Sanguinetti CM, Vignola AM.
Adjustable maintenance dosing with budesonide/formoterol in a single
inhaler provides effective asthma symptom control at a lower dose than
fixed maintenance dosing. Pulm Pharmacol Ther 2004; 17: 239-247
BU-039-0004
Y
THE EFFECTIVENESS AND SAFETY OF AN INDIVIDUALISED
SYMBICORT TURBUHALER MAINTENANCE DOSING REGIMEN
(SYMBICORT ASTHMA CONTROL PLAN) VERSUS SYMBICORT
TURBUHALER GIVEN AS STANDARD REGULAR TWICE DAILY
THERAPY.
Ind PW, Haughney J, Price D, Rosen JP, Kennelly J. Adjustable and
fixed dosing with budesonide/formoterol via a single inhaler in asthma
patients: the ASSURE study. Respir Med 2004; 98: 464-475.
CF-039-0001
Y
COMPARAISON DE SYMBICORT® TURBUHALER® 200/6 µG À
DOSES FIXES VERSUS SYMBICORT® TURBUHALER® 200/6 µG À
DOSES ADAPTÉES AU CONTRÔLE DE L’ASTHME SUR 16
SEMAINES DE TRAITEMENT
Data on file
CF-039-0002
Y
COMPARAISON DE SYMBICORT® TURBUHALER® 200/6 µG À
DOSES FIXES VERSUS SYMBICORT® TURBUHALER® 200/6 µG À
DOSES ADAPTÉES AU CONTRÔLE DE L’ASTHME SUR 16
SEMAINES DE TRAITEMENT EN CONSULTATION DE MÉDECINE
GÉNÉRALE
Data on file
BG-SYM-0003
Y
FORMOTEROL/BUDESONIDE IN MILD TO MODERATE ASTHMATIC
PATIENTS – THE EFFECT OF AN ASTHMA CONTROL PLAN ON
QUALITY OF LIFE AND COSTS
Buhl R, Kardos P, Richter K, Meyer Sabellek W, Brüggenjürgen B,
Willich SN, Vogelmeier C. The effect of adjustable dosing with
budesonide/formoterol on health-related quality of life and asthma control
compared with fixed dosing. Curr Med Res Opin 2004; 20: 1209-1220.
PL-039-0001
Y
SYMBICORT® TURBUHALER® (FORMOTEROL/BUDESONIDE 4.5/160
µG) IN MILD TO MODERATE ASTHMATIC PATIENTS –
COMPARISON OF THE EFFICACY OF VERSATILE DOSING
REGIMEN WITH CONVENTIONAL CONSTANT DOSING REGIMEN
DURING 12 WEEKS TREATMENT PERIOD
Data on file
21
TABLE E-2. STUDY TITLE AND PUBLICATION STATUS FOR CLINICAL TRIALS INCLUDED IN THE MAIN AND THE
SUPPLEMENTARY ANALYSIS
Study code
Included
in the
main
analysis?
Study title
Publication status
LD-039-0001
Y
THE EFFECTIVENESS AND SAFETY OF AN INDIVIDUALISED
SYMBICORT TURBUHALER MAINTENANCE DOSING REGIMEN
(SYMBICORT ASTHMA CONTROL PLAN) VERSUS SYMBICORT
TURBUHALER GIVEN AS STANDARD REGULAR TWICE DAILY
THERAPY
Ställberg B, Olsson P, Jörgensen LA, Lindarck N, Ekström T.
Budesonide/formoterol adjustable maintenance dosing reduces asthma
exacerbations versus fixed dosing. Int J Clin Pract 2003; 57: 656-666.
BS-039-0002
Y
THE EFFECTIVENESS AND SAFETY OF AN INDIVIDUALISED
SYMBICORT TURBUHALER MAINTENANCE DOSING REGIMEN
(SYMBICORT ASTHMA CONTROL PLAN) VERSUS SYMBICORT
TURBUHALER GIVEN AS STANDARD REGULAR TWICE DAILY
THERAPY
Leuppi JD, Salzberg M, Meyer L, Bucher SE, Nief M, Brutsche MH,
Tamm M. An individualized, adjustable maintenance regimen of
budesonide/formoterol provides effective asthma symptom control at a
lower overall dose than fixed dosing. Swiss Med Wkly 2003; 133: 302309.
LD-039-0003
Y
AN OPEN, RANDOMIZED, PARALLEL-GROUP, MULTICENTRE,
PHASE IIIB STUDY TO EVALUATE THE EFFICACY OF SYMBICORT®
TURBUHALER® SINGLE INHALER THERAPY (SIT), GIVEN AS A LOW
MAINTENANCE DOSE ONCE OR TWICE DAILY PLUS AS NEEDED,
COMPARED TO A HIGHER MAINTENANCE DOSE OF SYMBICORT
TURBUHALER GIVEN TWICE DAILY PLUS OXIS® TURBUHALER® AS
NEEDED DURING 24 WEEKS IN ASTHMATIC PATIENTS
Lundborg M, Wille S, Bjermer L, Tilling B, Lundgren M, Telg G, Ekström
T, Selroos O. Maintenance plus reliever budesonide/formoterol
compared with a higher maintenance dose of budesonide/formoterol plus
formoterol as reliever in asthma: An efficacy and cost-effectiveness
study. Curr Med Res Opin 2006; 22(5): 809-821.
AF-039-0001
Y
A RANDOMISED, DOUBLE-BLIND, PARALLEL-GROUP,
MULTICENTRE, PHASE-III STUDY TO EVALUATE THE EFFICACY OF
SYMBICORT® TURBUHALER® (BUDESONIDE /FORMOTEROL;
160/4.5 µG) GIVEN AS NEEDED COMPARED TO OXIS
TURBUHALER® (FORMOTEROL, 4.5 µG) GIVEN AS NEEDED
DURING 6 MONTHS IN ADULTS WITH MILD INTERMITTENT
ASTHMA - SOMA
Haahtela T, Tamminen K, Malmberg P, Zetterström O, Karjalainen J,
Ylä-Outinen H, Svahn T, Ekström T, Selroos O. Formoterol as needed
with or without budesonide in patients with intermittent asthma and
raised NO levels in exhaled air: a SOMA study. Eur Respir J 2006; 28:
748-755.
Formoterol/budesonide Turbuhaler trials, other
39-3002
N
EFFECT OF BUDESONIDE AND D2522 ON BRONCHIAL
HYPERREACTIVITY OF ASTHMATICS - A PILOT STUDY
Data on file
D5890C00007
N
ONSET OF RELIEF OF DYSPNOEA AFTER METHACHOLINE
PROVOCATION WITH SINGLE DOSES OF ONE INHALATION OF
SYMBICORT TURBUHALER 160/4.5 µG/INHALATION, TWO
INHALATIONS OF VENTOLIN VIA PMDI 100 µG/ACTUATION, OR
PLACEBO IN ADULTS WITH ASTHMA
Jonkers RE, Bantje TA, Aalbers R. Onset of relief of dyspnoea with
budesonide/formoterol or salbutamol following methacholine-induced
severe bronchoconstriction in adults with asthma: a double-blind,
placebo-controlled study. Respir Res 2006; 7: 141.
22
TABLE E-2. STUDY TITLE AND PUBLICATION STATUS FOR CLINICAL TRIALS INCLUDED IN THE MAIN AND THE
SUPPLEMENTARY ANALYSIS
Study code
Included
in the
main
analysis?
Study title
Publication status
SD-039-0367
N
TOLERABILITY OF A HIGH, CUMULATIVE DOSE OF THE FIXED
BUDESONIDE/FORMOTEROL COMBINATION INHALED VIA
TURBUHALER IN ASTHMATIC PATIENTS ON MAINTENANCE
TREATMENT WITH THE FIXED COMBINATION
Ankerst J, Persson G, Weibull E. Tolerability of a high dose of
budesonide/formoterol in a single inhaler in patients with asthma. Pulm
Pharmacol Ther 2003; 16(3): 147-151.
SD-039-0617
N
ONSET OF ACTION OF SYMBICORT TURBUHALER COMPARED
WITH SERETIDE DISKUS IN ASTHMATIC PATIENTS
AstraZeneca Study SD-039-0617. AstraZeneca Clinical Trials website.
Available from: www.astrazenecaclinicaltrials.com/Article/512581.aspx.
SD-039-0678
N
THE ONSET OF EFFECT OF A SINGLE DOSE OF A
GLUCOCORTICOSTEROID AND BETA2-AGONIST INHALED BY A
SINGLE INHALER AFTER METHACHOLINE PROVOCATION IN
ASTHMA. A STUDY COMPARING SYMBICORT® TURBUHALER® AND
SERETIDETM DISKUSTM
van der Woude HJ, Boorsma M, Bergqvist PBF, Winter TH, Aalbers R.
Budesonide/formoterol in a single inhaler rapidly relieves methacholineinduced moderate-to-severe bronchoconstriction. Pulm Pharmacol Ther
2004; 17(2): 89-95.
SD-039-0685
N
A RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY, PLACEBOCONTROLLED, 3-WAY CROSSOVER, PHASE IIIB, MULTICENTRE
STUDY TO ASSESS THE ONSET OF EFFECT OF SYMBICORT®
TURBUHALER® (BUDESONIDE/FORMOTEROL; 320/9 µG, MORNING
AND EVENING) AND SERETIDE DISKUS
Data on file
SD-039-0693
N
A RANDOMISED, DOUBLE-BLIND, DOUBLE-DUMMY, PARALLELGROUP, MULTICENTRE, PHASE-III STUDY TO INVESTIGATE THE
EFFECT OF SYMBICORT® TURBUHALER®
(BUDESONIDE/FORMOTEROL) 1280/36 µG TOTAL DELIVERED
DOSE IN THE TREATMENT OF ACUTE ASTHMA COMPARED WITH
OXIS® TURBUHALER® (FORMOTEROL) 36 µG TOTAL DELIVERED
DOSE IN ADOLESCENT AND ADULT PATIENTS NOT RESPONDING
ADEQUATELY TO Β 2-AGONISTS
Bateman ED, Fairall L, Lombardi DM, English R. Budesonide/formoterol
and formoterol provide similar rapid relief in patients with acute asthma
showing refractoriness to salbutamol. Respir Res 2006; 7(1): 13.
SD-039-0702
N
EFFICACY OF SYMBICORT® TURBUHALER®
(BUDESONIDE/FORMOTEROL) 1280/36 µG TOTAL DELIVERED
DOSE COMPARED TO SALBUTAMOL PMDI WITH SPACER 1600 µG
TOTAL METERED DOSE IN THE MANAGEMENT OF ACUTE ASTHMA
IN ADOLESCENTS AND ADULTS. A DOUBLE-BLIND, DOUBLEDUMMY, RANDOMISED, PARALLEL-GROUP, PHASE-III,
MULTICENTRE STUDY
Balanag VM, Yunus F, Yang P-C, Jorup C. Efficacy and safety of
budesonide/formoterol compared with salbutamol in the treatment of
acute asthma. Pulm Pharmacol Ther 2006; 19(2): 139-147.
23
TABLE E-2. STUDY TITLE AND PUBLICATION STATUS FOR CLINICAL TRIALS INCLUDED IN THE MAIN AND THE
SUPPLEMENTARY ANALYSIS
Study code
Included
in the
main
analysis?
Study title
Publication status
Formoterol/budesonide pMDI trials, double-blind, parallel-group with maintenance treatment
D5896C00001
Y
A RANDOMIZED, DOUBLE-BLIND, ACTIVE-CONTROLED, PARALLELGROUP, SINGLE-DUMMY, MULTICENTER, 12 WEEK STUDY TO
ASSESS THE EFFICACY AND SAFETY OF SYMBICORT PMDI 160/4.5
µG X 2 ACTUATIONS ONCE-DAILY (QD) COMPARED TO
SYMBICORT PMDI 80/4.5µG X 2 ACTUATIONS QD, SYMBICORT
PMDI 80/4.5µG X 2 ACTUATIONS TWICE-DAILY (BID) AND TO
BUDESONIDE PMDI 160 µG X 2 ACTUATIONS QD IN ASTHMATIC
SUBJECTS 12 YEARS OF AGE AND OLDER
AstraZeneca Study D5896C00001. AstraZeneca Clinical Trials website.
Available from: www.astrazenecaclinicaltrials.com/Article/528065.aspx.
SD-039-0681
Y
A RANDOMIZED, DOUBLE-BLIND, PARALLEL-GROUP,
MULTICENTRE, PHASE III STUDY TO COMPARE THE EFFICACY
AND SAFETY OF SYMBICORT PMDI160/4.5 2 ACT BID WITH THAT
OF PULMICORT PMDI 200 2 ACT BID AND SYMBICORT TH 160/4.5 2
INH BID IN ADOLESCENTS AND ADULTS WITH ASTHMA
Morice AH, Osmanliev D, Arheden L, Beckman O. Therapeutic
equivalence of a novel budesonide/formoterol pMDI versus
budesonide/formoterol Turbuhaler® in adolescents and adults with
asthma. J Allergy Clin Immunol 2005a; 115(Suppl 2): S2, Abst 8.
SD-039-0682
Y
A 12-WEEK, RANDOMIZED, DOUBLE-BLIND, PARALLEL-GROUP,
MULTICENTRE, PHASE III STUDY TO COMPARE THE EFFICACY
AND SAFETY OF SYMBICORT PMDI WITH THAT OF PULMICORT
PMDI AND SYMBICORT TURBUHALER IN CHILDREN WITH ASTHMA
Morice AH, Kukova Z, Arheden L, Beckman O. The novel
budesonide/formoterol pMDI is therapeutically equivalent to
budesonide/formoterol Turbuhaler® in children with asthma. J Allergy Clin
Immunol 2005b; 115(Suppl 2): S209, Abst 833.
SD-039-0716
Y
A TWELVE-WEEK, RANDOMIZED, DOUBLE-BLIND, DOUBLEDUMMY, PLACEBO-CONTROLLED TRIAL OF SYMBICORT (80/4.5
µG) VERSUS ITS MONO-PRODUCTS (BUDESONIDE AND
FORMOTEROL) IN CHILDREN (>= 6 YEARS OF AGE) AND ADULTS
WITH ASTHMA - SPRUCE 80/4.5
Corren J, Korenblat PE, Miller JC, O’Brien CD, Mezzanotte WS.
Comparative assessment of asthma control with budesonide and
formoterol in one pressurized metered-dose inhaler (pMDI) versus
budesonide and formoterol in individual inhalers and placebo. J Allergy
Clin Immunol 2007; 119(1 Suppl 1): S248, Abst 972.
SD-039-0717
Y
A TWELVE-WEEK, RANDOMIZED, DOUBLE-BLIND, DOUBLEDUMMY, PLACEBO-CONTROLLED TRIAL OF SYMBICORT
(160/4.5µG) VERSUS ITS MONO-PRODUCTS (BUDESONIDE AND
FORMOTEROL) IN ADOLESCENTS (>= 12 YEARS OF AGE) AND
ADULTS WITH ASTHMA - SPRUCE 160/4.5
Noonan MJ, Rosenwasser LJ, Martin P, O'Brien CD, O'Dowd L. Effect of
budesonide and formoterol administered via one pressurized metereddose inhaler on lung function in adults and adolescents with moderate to
severe persistent asthma. J Allergy Clin Immunol 2007; 119(1 Suppl 1):
S2, Abst 7.
SD-039-0718
Y
A TWELVE-WEEK, RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY
TRIAL OF SYMBICORT (40/4.5 µG) VERSUS ITS MONO-PRODUCTS
(BUDESONIDE AND FORMOTEROL) IN ASTHMATIC CHILDREN
AGED SIX TO ELEVEN YEARS - SEEDLING 40/4.5
AstraZeneca Study SD-039-0718. AstraZeneca Clinical Trials website.
Available from: www.astrazenecaclinicaltrials.com/Article/528063.aspx.
24
TABLE E-2. STUDY TITLE AND PUBLICATION STATUS FOR CLINICAL TRIALS INCLUDED IN THE MAIN AND THE
SUPPLEMENTARY ANALYSIS
Study code
Included
in the
main
analysis?
Study title
Publication status
SD-039-0725
Y
A TWELVE-WEEK, RANDOMIZED, DOUBLE-BLIND, DOUBLEDUMMY, ACTIVE-CONTROLLED STUDY OF SYMBICORT PMDI
ADMINISTERED ONCE DAILY IN CHILDREN AND ADOLESCENTS 6
TO 15 YEARS OF AGE WITH ASTHMA - SPROUT
AstraZeneca Study SD-039-0725. AstraZeneca Clinical Trials website.
Available from: www.astrazenecaclinicaltrials.com/Article/528061.aspx.
SD-039-0726
Y
A TWELWE-WEEK, RANDOMIZED, DOUBLE-BLIND, DOUBLEDUMMY, PLACEBO- AND ACTIVE-CONTROLLED STUDY OF
SYMBICORT PMDI ADMINISTERED ONCE DAILY IN ADULTS AND
ADOLESCENTS WITH ASTHMA - STEM
Bleecker ER, Berger WE, O'Dowd L, Miller CJ, Mezzanotte WS. Safety
of once-daily budesonide (BUD) and formoterol (FM) administered via
one pressurized metered-dose inhaler (pMDI) in patients with asthma.
Proc Am Thorac Soc 2007; (Abstracts issue): Abst A190.
SD-039-0728
Y
A 52 WEEK, RANDOMIZED, DOUBLE-BLIND, SINGLE-DUMMY,
PARALLEL-GROUP, MULTICENTER STUDY COMPARING THE
LONG-TERM SAFETY OF SYMBICORT PMDI 160/4.5 µG X4 INH BID
TO SYMBICORT PMDI 160/4.5 µG X2 INH BID AND BUDESONIDE
PMDI160 µG X4 INH BID IN ADULT AND ADOLESCENT SUBJECTS
WITH ASTHMA
O'Brien CD, Peters SP, Prenner BM, Martin P. Long-term safety of
budesonide/formoterol pressurized metered-dose inhaler (BUD/FM
pMDI) in asthma patients: adverse events and asthma exacerbations.
Proc Am Thorac Soc 2007; (Abstracts issue): Abst A188.
Formoterol/budesonide pMDI trials, open-label, parallel-group with maintenance treatment
SD-039-0715
Y
AN OPEN, PARALLEL GROUP RANDOMIZED, MULTIPLE CENTRE
PHASE III STUDY TO COMPARE THE LONG TERM (52 WEEKS)
SAFETY OF SYMBICORT PMDI 160/4.5 µG 2 ACTUATIONS B.I.D.
WITH THAT OF SYMBICORT TBH 160/4.5 µG INH S B.I.D. IN ADULTS
AND ADOLESCENTS WITH ASTHMA
Morice AH, Hochmuth L, Puterman A, Arheden L, Beckman O.
Comparable safety of a novel budesonide/formoterol pMDI versus
budesonide/formoterol Turbuhaler® in adolescents and adults with
asthma. J Allergy Clin Immunol 2005c; 115(Suppl 2): S3, Abst 9.
Morice AH, Hochmuth L, Ekelund J, Thorén A, Puterman AS.
Comparable long-term safety and efficacy of a novel
budesonide/formoterol pressurized metered-dose inhaler versus
budesonide/formoterol Turbuhaler® in adolescents and adults with
asthma. Pulm Pharmacol Ther 2007; Epub ahead of print.
SD-039-0719
Y
A SIX-MONTH, RANDOMIZED, OPEN-LABEL SAFETY STUDY OF
SYMBICORT (160/4.5µG) COMPARED TO PULMICORT
TURBUHALER IN ASTHMATIC CHILDREN AGED SIX TO ELEVEN
YEARS
AstraZeneca Study SD-039-0719. AstraZeneca Clinical Trials website.
Available from: www.astrazenecaclinicaltrials.com/Article/528062.aspx.
D5896C00005
Y*
A TWO-STAGE RANDOMIZED, OPEN-LABEL, PARALLEL GROUP,
PHASE III, MULTICENTER, 7-MONTH STUDY TO ASSESS THE
EFFICACY AND SAFETY OF SYMBICORT PMDI ADMINISTERED
EITHER AS FIXED OR AS AN ADJUSTABLE REGIMEN VERSUS A
FIXED REGIMEN OF ADVAIR IN SUBJECTS 12 YEARS OF AGE AND
OLDER WITH ASTHMA
J Allergy Clin Immunol (submitted September 2007)
25
TABLE E-2. STUDY TITLE AND PUBLICATION STATUS FOR CLINICAL TRIALS INCLUDED IN THE MAIN AND THE
SUPPLEMENTARY ANALYSIS
Study code
Included
in the
main
analysis?
Study title
Publication status
Formoterol/budesonide pMDI trials, other
D5896C00010
N
A STUDY TO ASSESS THE PHARMACOKINETICS OF BUDESONIDE
AND FORMOTEROL ADMINISTERED AS SINGLE DOSES VIA
SYMBICORT PMDI (160/4.5 µG), BUDESONIDE PMDI, PULMICORT
TURBUHALER AND OXIS TURBUHALER IN PATIENTS WITH
ASTHMA
Data on file
D5896C00011
N
AN OPEN-LABEL, PARALLEL-GROUP STUDY TO ASSESS THE
STEADY STATE PHARMACOKINETICS OF BUDESONIDE AND
FORMOTEROL ADMINISTERED VIA SYMBICORT PMDI (160/4.5 µG)
FOR 6 AND A HALF DAYS IN ASTHMA PATIENTS COMPARED WITH
HEALTY SUBJECTS
Ankerst J, Lotvall J, Tronde A, Gillen M, Borgstrom L. Systemic
bioavailability of budesonide (BUD) and formoterol (FM) administered via
one pressurized metered-dose inhaler (pMDI) in asthma patients and
healthy subjects. Proc Am Thorac Soc 2007: A192, Abst K9.
D5896C00013
N
AN OPEN, RANDOMIZED, TWO-WAY, CROSSOVER STUDY
EVALUATING THE PHARMACOKINETICS OF BUDESONIDE AND
FORMOTEROL FROM SYMBICORT PMDI VERSUS PULMICORT
TURBUHALER PLUS OXIS TURBUHALER WHEN GIVEN TO
CHILDREN WITH ASTHMA AGED 6 TO 11 YEARS
Data on file
SD-039-0729
N
A RANDOMIZED, MULTICENTER, OPEN-LABEL, ACTIVECONTROLLED, SINGLE-DOSE, 5-PERIOD, INCOMPLETE BLOCK,
CROSS-OVER STUDY TO EVALUATE THE RELATIVE
BRONCHODILATING EFFECTS OF FORMOTEROL WHEN
ADMINISTERED VIA SYMBICORT PMDI OR OXIS TURBUHALER TO
ADULTS WITH STABLE ASTHMA
Mezzanotte WS, Miller CJ, Senn S. Comparative bronchodilatory effects
of formoterol dry-powder inhaler (DPI) versus the combination of
formoterol and budesonide pressurized metered-dose inhaler. J Allergy
Clin Immunol 2007; 119(1 Suppl 1): S248, Abst 971.
SD-039-0732
N
A RANDOMIZED, MULTICENTER, PLACEBO- AND ACTIVECONTROLLED, SINGLE-DOSE, 4-PERIOD, CROSSOVER STUDY TO
EVALUATE THE BRONCHODILATING EFFECT OF SYMBICORT PMDI
VERSUS ADVAIR DISKUS AND VENTOLIN HFA
Data on file
SD-039-0733
N
A RANDOMIZED, MULTICENTER, PLACEBO- AND ACTIVECONTROLLED, SINGLE-DOSE, 4-PERIOD, CROSSOVER STUDY TO
EVALUATE THE BRONCHODILATING EFFECT OF SYMBICORT PMDI
VERSUS ADVAIR DISKUS AND VENTOLIN HFA
Data on file
26
TABLE E-2. STUDY TITLE AND PUBLICATION STATUS FOR CLINICAL TRIALS INCLUDED IN THE MAIN AND THE
SUPPLEMENTARY ANALYSIS
Study code
Included
in the
main
analysis?
Study title
Publication status
SD-039-0738
N
AN OPEN LABEL, TWO-WAY CROSSOVER STUDY IN SUBJECTS
WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE OF THE
RELATIVE SYSTEMIC BIOAVAILABILITY OF BUDESONIDE AND
FORMOTEROL WHEN INHALED AS A SINGLE DOSE OF 1280/36 µG
FROM SYMBICORT PMDI COMPARED WITH BUDESONIDE PMDI
PLUS FORMOTEROL TURBUHALER (OXIS)
Data on file
SD-039-0743
N
A MULTICENTER, RANDOMIZED, OPEN-LABEL STUDY TO ASSESS
THE FUNCTIONALITY OF SYMBICORT® PMDI WITH AN ACTUATION
COUNTER DURING USE BY CHILDREN, ADOLESCENTS, AND
ADULTS WITH STABLE, INHALED CORTICOSTEROID-DEPENDENT
ASTHMA
Data on file
* In this trial, patients exposed to salmeterol were removed from the main analysis but included in the supplementary analysis.
N = not included; pMDI = pressurized metered-dose inhaler; SALM = salmeterol; Y = included
27
TABLE E-3. ALL-CAUSE MORTALITY, ASTHMA-RELATED AND CARDIAC-RELATED EVENTS IN TRIALS INCLUDED
IN THE MAIN AND THE SUPPLEMENTARY ANALYSIS
Study code
Included
in the
main
analysis?
Number of
patients
evaluable
for safety
Formoterol-exposed patients
Number
of
patients
Non-LABA-exposed patients
No. of
asthma/
cardiac/other
deaths
No. of
asthma/
cardiac
SAEs
Number
of
patients
No. of
asthma/
cardiac/other
deaths
Salmeterol-exposed patients
No. of
asthma/
cardiac
SAEs
Number
of
patients
No. of
asthma/
cardiac/other
deaths
No. of
asthma/
cardiac
SAEs
Formoterol Turbuhaler trials
37-3002
N
221
165
0
0
0
2
0
56
0
0
0
0
0
0
–
–
–
–
–
37-3006
Y
343
114
0
0
0
0
0
229
0
0
0
5
0
0
–
–
–
–
–
37-3026
Y
396
135
0
0
0
0
0
261
0
0
0
3
0
0
–
–
–
–
–
SD-037-0003
Y
248
164
1
0
0
4
0
84
0
0
0
0
0
0
–
–
–
–
–
DC-037-0002
Y
301
200
0
0
0
1
0
101
0
0
0
1
0
0
–
–
–
–
–
37-3008
Y
239
125
0
0
0
1
0
114
0
0
0
3
0
0
–
–
–
–
–
37-3018
Y
853
426
0
0
1
3
0
427
0
0
0
8
2
0
–
–
–
–
–
37-3041
Y
60
29
0
0
0
1
0
31
0
0
0
0
0
0
–
–
–
–
–
SD-037-0345
Y
1,970
869
1
0
0
7
2
1,101
0
0
0
11
4
0
–
–
–
–
–
37-3010
N
187
187
0
2
0
8
6
0
–
–
–
–
–
0
–
–
–
–
–
37-3015
N
13
13
0
0
0
1
0
0
–
–
–
–
–
0
–
–
–
–
–
SD-037-0175
Y
357
357
0
0
0
3
1
0
–
–
–
–
–
0
–
–
–
–
–
SD-037-0123
Y
362
182
0
0
0
0
0
180
0
0
0
0
1
0
–
–
–
–
–
SD-037-0695
Y
552
277
0
0
0
6
0
275
0
0
0
8
0
0
–
–
–
–
–
SD-037-0714
Y
455
228
0
0
0
3
0
227
0
0
0
3
0
0
–
–
–
–
–
SD-037-0716
Y
674
333
0
0
0
1
0
341
0
0
0
2
0
0
–
–
–
–
–
SD-037-0699
Y
17,862
8,924
3
6
4
106
20
8,938
2
7
2
120
30
0
–
–
–
–
–
SD-037-0739
Y
320
320
0
0
0
0
1
0
–
–
–
–
–
0
–
–
–
–
–
BU-543-0681
part A
N
663
333
0
0
0
0
0
330
0
0
1
1
0
0
–
–
–
–
–
28
TABLE E-3. ALL-CAUSE MORTALITY, ASTHMA-RELATED AND CARDIAC-RELATED EVENTS IN TRIALS INCLUDED
IN THE MAIN AND THE SUPPLEMENTARY ANALYSIS
Study code
Included
in the
main
analysis?
Number of
patients
evaluable
for safety
BU-543-0681
part B
N
Follow-up
MA-037-0001
N
225
BU-037-0004
Y
DC-037-0001
Formoterol-exposed patients
Number
of
patients
Non-LABA-exposed patients
No. of
asthma/
cardiac/other
deaths
No. of
asthma/
cardiac
SAEs
0
0
0
0
0
111
0
0
0
0
0
156
80
0
0
0
0
Y*
372
132
0
0
0
BU-543-0677
N
236
236
0
0
37-3005
N
31
31
0
37-3007
N
66
66
37-3011
N
66
37-3019
N
37-3025
Number
of
patients
No. of
asthma/
cardiac/other
deaths
Salmeterol-exposed patients
No. of
asthma/
cardiac
SAEs
Number
of
patients
No. of
asthma/
cardiac/other
deaths
No. of
asthma/
cardiac
SAEs
0
0
0
1
0
0
–
–
–
–
–
114
0
0
0
1
0
0
–
–
–
–
–
0
0
–
–
–
–
–
76
0
0
0
0
0
2
0
119
0
0
0
0
0
121
0
0
0
1
0
0
2
0
0
–
–
–
–
–
0
–
–
–
–
–
0
0
0
0
31
0
0
0
0
0
0
–
–
–
–
–
0
0
0
0
0
0
–
–
–
–
–
0
–
–
–
–
–
66
0
0
0
0
1
0
–
–
–
–
–
0
–
–
–
–
–
13
13
0
0
0
0
0
11
0
0
0
0
0
0
–
–
–
–
–
N
28
28
0
0
0
0
0
27
0
0
0
0
0
0
–
–
–
–
–
37-3027
N
165
123
0
0
0
0
0
42
0
0
0
0
0
0
–
–
–
–
–
37-3028
N
28
28
0
0
0
0
0
25
0
0
0
0
0
26
0
0
0
0
0
37-3040
N
39
38
0
0
0
0
0
0
–
–
–
–
–
38
0
0
0
0
0
SD-037-0002
N
65
65
0
0
0
0
0
42
0
0
0
0
0
42
0
0
0
0
0
SD-037-0010
N
48
24
0
0
0
0
0
24
0
0
0
0
1
0
–
–
–
–
–
SD-037-0011
N
72
44
0
0
0
1
0
28
0
0
0
0
0
0
–
–
–
–
–
SD-037-0012
N
33
26
0
0
0
0
0
26
0
0
0
0
0
0
–
–
–
–
–
SD-037-0013
N
28
28
0
0
0
0
1
27
0
0
0
0
0
0
–
–
–
–
–
SD-037-0068
N
29
29
0
0
0
0
0
28
0
0
0
0
0
0
–
–
–
–
–
SD-037-0149
N
27
27
0
0
0
0
0
25
0
0
0
0
0
0
–
–
–
–
–
29
TABLE E-3. ALL-CAUSE MORTALITY, ASTHMA-RELATED AND CARDIAC-RELATED EVENTS IN TRIALS INCLUDED
IN THE MAIN AND THE SUPPLEMENTARY ANALYSIS
Study code
Included
in the
main
analysis?
Number of
patients
evaluable
for safety
SD-037-0287
N
60
SD-037-0361
N
SD-037-0657
Formoterol-exposed patients
Number
of
patients
Non-LABA-exposed patients
Number
of
patients
No. of
asthma/
cardiac/other
deaths
Salmeterol-exposed patients
No. of
asthma/
cardiac/other
deaths
No. of
asthma/
cardiac
SAEs
No. of
asthma/
cardiac
SAEs
Number
of
patients
No. of
asthma/
cardiac/other
deaths
No. of
asthma/
cardiac
SAEs
60
0
0
0
0
0
59
0
0
0
0
0
0
–
–
–
–
–
36
36
0
0
0
0
0
36
0
0
0
0
0
0
–
–
–
–
–
N
23
22
0
0
0
0
0
20
0
0
0
0
0
0
–
–
–
–
–
SD-037-0684
N
46
46
0
0
0
0
0
44
0
0
0
0
0
0
–
–
–
–
–
SD-037-0718
N
88
44
0
0
0
0
0
44
0
0
0
0
0
0
–
–
–
–
–
SD-037-0724
N
78
38
0
0
0
3
0
40
0
0
0
4
0
0
–
–
–
–
–
SD-037-0738
N
20
18
0
0
0
0
1
19
0
0
0
0
0
0
–
–
–
–
–
SD-037-0744
N
26
26
0
0
0
0
0
25
0
0
0
0
0
0
–
–
–
–
–
SD-037-0745
N
282
209
0
0
0
0
0
73
0
0
0
0
0
0
–
–
–
–
–
SD-004-0216
N
352
118
0
0
0
1
0
234
0
0
0
0
0
0
–
–
–
–
–
Formoterol pMDI trials
SD-037-0288
N
435
435
0
0
1
5
1
0
–
–
–
–
–
0
–
–
–
–
–
SD-037-0344
N
639
429
0
0
1
2
0
210
0
0
0
1
0
0
–
–
–
–
–
SD-037-0737
N
30
30
0
0
0
0
0
30
0
0
0
0
0
0
–
–
–
–
–
D5126C00017
N
34
17
0
0
0
0
0
17
0
0
0
0
0
0
–
–
–
–
–
230
0
0
0
1
0
237
0
0
0
0
0
0
–
–
–
–
–
0
1
0
124
0
0
0
0
0
0
–
–
–
–
–
0
0
0
0
0
–
–
–
–
–
Formoterol/budesonide Turbuhaler trials
SD-039-0348
Y
467
SD-039-0349
Y
362
238
0
SD-039-0353
Y
286
148
0
0
0
5
0
138
0
SD-039-0618
Y
344
168
0
0
0
0
0
176
0
0
0
3
0
0
–
–
–
–
–
SD-039-0665
Y
616
409
0
0
0
1
0
207
0
0
0
2
0
0
–
–
–
–
–
0
30
TABLE E-3. ALL-CAUSE MORTALITY, ASTHMA-RELATED AND CARDIAC-RELATED EVENTS IN TRIALS INCLUDED
IN THE MAIN AND THE SUPPLEMENTARY ANALYSIS
Study code
Included
in the
main
analysis?
Number of
patients
evaluable
for safety
SD-039-0666
Y
523
SD-039-0688
Y
SD-039-0671
Formoterol-exposed patients
Number
of
patients
Non-LABA-exposed patients
Number
of
patients
No. of
asthma/
cardiac/other
deaths
Salmeterol-exposed patients
No. of
asthma/
cardiac/other
deaths
No. of
asthma/
cardiac
SAEs
No. of
asthma/
cardiac
SAEs
Number
of
patients
No. of
asthma/
cardiac/other
deaths
No. of
asthma/
cardiac
SAEs
352
0
1
0
1
0
171
0
0
0
0
1
0
–
–
–
–
–
630
417
0
0
0
0
0
213
0
0
0
0
0
0
–
–
–
–
–
N
438
218
0
0
0
0
0
220
0
0
0
1
0
0
–
–
–
–
–
SD-039-0714
Y
270
136
0
0
0
0
0
134
0
0
0
1
0
0
–
–
–
–
–
SD-039-0689
Y
456
341
0
0
1
2
0
115
0
0
0
0
1
0
–
–
–
–
–
SD-039-0664
Y
585
585
0
0
0
5
2
0
–
–
–
–
–
0
–
–
–
–
–
SD-039-0667
Y
696
354
0
0
0
0
1
342
0
0
0
1
1
0
–
–
–
–
–
SD-039-0668
Y
1,890
947
0
0
1
5
7
943
0
2
0
11
1
0
–
–
–
–
–
SD-039-0673
Y
2,753
1,828
1
0
1
23
7
925
0
0
1
12
2
0
–
–
–
–
–
SD-039-0734
Y
3,382
3,382
0
1
3
65
13
0
–
–
–
–
–
0
–
–
–
–
–
SD-039-0735
Y*
3,321
2,202
1
0
0
20
4
0
–
–
–
–
–
1,119
0
1
0
15
1
D5890C00002
Y*
2,304
1,151
0
0
0
5
5
0
–
–
–
–
–
1,153
0
0
0
5
4
SD-039-0691
Y*
2,135
1,064
0
0
0
10
7
0
–
–
–
–
–
1,071
0
0
2
15
6
SD-039-0686
Y*
658
434
0
0
0
3
1
0
–
–
–
–
–
224
0
0
0
0
0
DC-039-0002
N
237
237
0
0
0
1
0
0
–
–
–
–
–
0
–
–
–
–
–
CN-039-0001
Y
320
320
0
0
0
0
0
0
–
–
–
–
–
0
–
–
–
–
–
BA-039-0001
Y
133
65
0
0
0
0
0
68
0
0
0
0
1
0
–
–
–
–
–
BE-039-0001
Y
980
980
0
0
0
0
2
0
–
–
–
–
–
0
–
–
–
–
–
DC-039-0001
Y
995
995
0
0
0
1
0
0
–
–
–
–
–
0
–
–
–
–
–
AD-039-0001
Y
796
796
1
0
1
1
2
0
–
–
–
–
–
0
–
–
–
–
–
MA-SYM-0001
Y
537
537
0
0
0
2
0
0
–
–
–
–
–
0
–
–
–
–
–
31
TABLE E-3. ALL-CAUSE MORTALITY, ASTHMA-RELATED AND CARDIAC-RELATED EVENTS IN TRIALS INCLUDED
IN THE MAIN AND THE SUPPLEMENTARY ANALYSIS
Study code
Included
in the
main
analysis?
Number of
patients
evaluable
for safety
IE-SYM-0001
Y
203
CI-SYM-0001
Y
BU-039-0004
Formoterol-exposed patients
Number
of
patients
Non-LABA-exposed patients
No. of
asthma/
cardiac/other
deaths
No. of
asthma/
cardiac
SAEs
203
0
0
0
1
1
2,358
2,358
0
0
1
5
Y
1,553
1,553
0
0
0
CF-039-0001
Y
873
873
0
0
CF-039-0002
Y
2,068
2,068
0
BG-SYM-0003
Y
3,297
3,297
PL-039-0001
Y
1,606
LD-039-0001
Y
BS-039-0002
Number
of
patients
Salmeterol-exposed patients
No. of
asthma/
cardiac/other
deaths
No. of
asthma/
cardiac
SAEs
Number
of
patients
No. of
asthma/
cardiac/other
deaths
No. of
asthma/
cardiac
SAEs
0
–
–
–
–
–
0
–
–
–
–
–
2
0
–
–
–
–
–
0
–
–
–
–
–
44
3
0
–
–
–
–
–
0
–
–
–
–
–
0
1
0
0
–
–
–
–
–
0
–
–
–
–
–
0
2
2
1
0
–
–
–
–
–
0
–
–
–
–
–
0
0
1
5
4
0
–
–
–
–
–
0
–
–
–
–
–
1,606
0
0
0
0
0
0
–
–
–
–
–
0
–
–
–
–
–
1,034
1,034
0
0
0
0
3
0
–
–
–
–
–
0
–
–
–
–
–
Y
142
142
0
0
0
1
1
0
–
–
–
–
–
0
–
–
–
–
–
LD-039-0003
Y
491
491
0
0
0
0
2
0
–
–
–
–
–
0
–
–
–
–
–
AF-039-0001
Y
92
92
0
0
0
0
0
0
–
–
–
–
–
0
–
–
–
–
–
39-3002
N
20
20
0
0
0
0
0
18
0
0
0
0
0
0
–
–
–
–
–
D5890C00007
N
32
31
0
0
0
0
0
32
0
0
0
0
0
0
–
–
–
–
–
SD-039-0367
N
15
15
0
0
0
0
0
14
0
0
0
0
0
0
–
–
–
–
–
SD-039-0617
N
30
30
0
0
0
0
0
30
0
0
0
0
0
30
0
0
0
0
0
SD-039-0678
N
27
27
0
0
0
0
0
24
0
0
0
0
0
25
0
0
0
0
0
SD-039-0685
N
43
42
0
0
0
0
0
43
0
0
0
0
0
41
0
0
0
0
0
SD-039-0693
N
115
115
0
0
0
2
0
0
–
–
–
–
–
0
–
–
–
–
–
SD-039-0702
N
103
55
0
0
0
0
0
48
0
0
0
0
0
0
–
–
–
–
–
465
0
0
0
0
1
153
0
0
0
0
0
0
–
–
–
–
–
Formoterol/budesonide pMDI trials
D5896C00001
Y
618
32
TABLE E-3. ALL-CAUSE MORTALITY, ASTHMA-RELATED AND CARDIAC-RELATED EVENTS IN TRIALS INCLUDED
IN THE MAIN AND THE SUPPLEMENTARY ANALYSIS
Study code
Included
in the
main
analysis?
Number of
patients
evaluable
for safety
SD-039-0681
Y
679
SD-039-0682
Y
SD-039-0716
Formoterol-exposed patients
Number
of
patients
No. of
asthma/
cardiac/other
deaths
Salmeterol-exposed patients
No. of
asthma/
cardiac/other
deaths
No. of
asthma/
cardiac
SAEs
462
0
0
0
0
0
217
0
0
0
1
0
0
–
–
–
–
–
622
415
0
0
0
0
0
207
0
0
0
2
0
0
–
–
–
–
–
Y
511
253
0
0
0
0
0
258
0
0
0
0
0
0
–
–
–
–
–
SD-039-0717
Y
596
362
0
0
0
2
2
234
0
0
0
0
0
0
–
–
–
–
–
SD-039-0718
Y
411
266
0
0
0
1
0
145
0
0
0
0
0
0
–
–
–
–
–
SD-039-0725
Y
521
352
0
0
0
4
0
169
0
0
0
1
0
0
–
–
–
–
–
SD-039-0726
Y
751
453
0
0
0
0
0
298
0
0
0
0
0
0
–
–
–
–
–
SD-039-0728
Y
708
575
0
0
0
3
2
133
0
0
0
0
1
0
–
–
–
–
–
SD-039-0715
Y
673
673
0
0
0
14
4
0
–
–
–
–
–
0
–
–
–
–
–
SD-039-0719
Y
186
123
0
0
0
2
0
63
0
0
0
0
0
0
–
–
–
–
–
D5896C00005
Y*
1,222
816
0
0
0
1
2
0
–
–
–
–
–
406
0
0
0
2
1
D5896C00010
N
29
29
0
0
0
0
0
29
0
0
0
0
0
0
–
–
–
–
–
D5896C00011
N
26
26
0
0
0
0
0
0
–
–
–
–
–
0
–
–
–
–
–
D5896C00013
N
24
24
0
0
0
0
0
0
–
–
–
–
–
0
–
–
–
–
–
SD-039-0729
N
201
194
0
0
0
0
0
125
0
0
0
0
0
0
–
–
–
–
–
SD-039-0732
N
55
50
0
0
0
0
0
55
0
0
0
0
0
51
0
0
0
0
0
SD-039-0733
N
54
47
0
0
0
0
0
54
0
0
0
0
0
51
0
0
0
0
0
SD-039-0738
N
30
30
0
0
0
0
0
0
–
–
–
–
–
0
–
–
–
–
–
SD-039-0743
N
254
254
0
0
0
0
0
0
–
–
–
–
–
0
–
–
–
–
–
117 trials
78,339
54,559
8
10
19
402
113
20,477
2
9
4
207
46
4,474
0
1
2
38
12
SUM
Number
of
patients
Non-LABA-exposed patients
No. of
asthma/
cardiac
SAEs
Number
of
patients
No. of
asthma/
cardiac/other
deaths
No. of
asthma/
cardiac
SAEs
Subtotals
33
TABLE E-3. ALL-CAUSE MORTALITY, ASTHMA-RELATED AND CARDIAC-RELATED EVENTS IN TRIALS INCLUDED
IN THE MAIN AND THE SUPPLEMENTARY ANALYSIS
Study code
Included
in the
main
analysis?
Number of
patients
evaluable
for safety
Main dataset
only
64 ials
Not in main
dataset
53 rials
Formoterol-exposed patients
Number
of
patients
No. of
asthma/
cardiac/other
deaths
72,174
49,906
8
8
17
374
6,165
4,653
0
2
2
28
Non-LABA-exposed patients
No. of
asthma/
cardiac
SAEs
Salmeterol-exposed patients
Number
of
patients
No. of
asthma/
cardiac/other
deaths
No. of
asthma/
cardiac
SAEs
Number
of
patients
No. of
asthma/
cardiac/other
deaths
No. of
asthma/
cardiac
SAEs
103
18,098
2
9
3
198
45
4,170†
0
1
2
38
12
10
2,379
0
0
1
9
1
304
0
0
0
0
0
* In this trial, patients exposed to salmeterol were removed from the main analysis but included in the supplementary analysis.
† Consequently, these 4,170 salmeterol-randomized patients have not been included in the OVERALL-dataset.
LABA = long-acting 2-agonist; N = not included; SAE = serious adverse event; SALM = salmeterol; pMDI = pressurized metered-dose inhaler; Y = included
34
TABLE E-4. 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. 8.0, will belong to:
o
the system organ class “Cardiac disorders”
o
the high-level group terms “Cardiac and vascular investigations (excluding enzyme
tests)” in the system organ class “Investigations”
o
the high-level term “Skeletal and cardiac muscle analyses” in the system organ class
“Investigations”
o
the high-level term “Pulmonary oedemas” in the system organ class “Respiratory,
thoracic and mediastinal disorders”
o
the high-level term ”Cardiac infections” in the system organ class “Infections and
infestations”
o
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”
o
the following preferred terms from the system organ class “General disorders and
administration site conditions”: “Cardiac death”, “Sudden cardiac death”, “Positive
cardiac inotropic effect”, “Negative cardiac inotropic effect” and “Oedema due to
cardiac disease”
Note that when multiple serious adverse events with outcome = death have been recorded on the report of a case of death, and at least one of these events was cardiac-related,
the death has been considered to be cardiac-related.
35
TABLE E-5. DETAILS OF ALL CARDIAC-RELATED DEATHS
Case
no.
Randomized
treatment
Study ref.
Duratio
n‡
Daily dose Age/sex Number of
of
/ race†
days on
randomized
randomize
treatment*
d
treatment
Days in
study
until
onset/
death§
Baseline LABA
and/or ICS other
than randomized
treatment║
Considered
as ICSexposed
patient?
Cause of death
Deaths in patients included in the OVERALL-dataset
1
Formoterol
SD-037-0699/
12048/120429
180
FORM prn
78/M/C
132
132/132
SALM
FLUT
Yes
Cardiac failure;
myocardial infarction
2
Formoterol
SD-037-0699/
25003/250932
180
FORM prn
64/M/C
114
103/114
FORM
BUD
Yes
Cardiopulmonary
failure
3
Formoterol††
SD-037-0699/
25006/250728
180
FORM prn
70/M/C
181
183/183
–
–
No
Myocardial infarction
4
Formoterol
SD-037-0699/
26044/261119
180
FORM prn
82/F/C
26
26/26
–
FLUT
Yes
Myocardial
ischaemia
5
Formoterol║║
SD-037-0699/
26048/260574
180
FORM prn
73/F/C
98
99/109
SALM
FLUT
Yes
Myocardial infarction;
cardiac failure;
intestinal ischaemia
6
Formoterol
SD-037-0699/
27010/270740
180
FORM prn
77/F/C
121
120/121
SALM
FLUT
Yes
Myocardial infarction
7
Formoterol
SD-039-0666/
105/532
90
9/320 g
FORM /BUD
74/M/C
79
79/79
x
x
Yes
Cardiac arrest
8
Formoterol
SD-039-0734/
1920/2959
365
9/320 g
FORM/BUD
plus TERB
prn
66/F/C
251
251/251
x
x
Yes
Cardiac arrest
9
Non-LABA**
SD-037-0699/
11211/111059
180
SALB prn
77/M/C
74
74/74
–
–
No
Aortic stenosis;
tracheobronchitis
10
Non-LABA**
SD-037-0699/
45106/451169
180
SALB prn
51/F/O
38
38/38
–
–
No
Sudden cardiac
death
11
Non-LABA††
SD-037-0699/
23070/230793
180
SALB prn
61/M/C
210
211/211
FORM
BUD
Yes
Cardiac arrest
36
12
Non-LABA§§
SD-037-0699/
25131/250274
180
SALB prn
71/F/C
30
30/54
–
FLUT
Yes
Cardiac failure;
ovarian cancer
13
Non-LABA
SD-037-0699/
43007/430125
180
SALB prn
55/M//O
96
93/96
–
–
No
Myocardial infarction;
coronary artery
disease
14
Non-LABA
SD-039-0668/
153/945
365
BUD 640 g
+ TERB prn
55/M/C
91
91/91
x
x
Yes
Myocardial infarction
15
Non-LABA
SD-039-0668/
153/946
365
BUD 640 g
+ TERB prn
47/F/C
347
316/347
x
x
Yes
Hypertrophic
cardiomyopathy
16
Non-LABA
SD-037-0699/
42007/420205
180
SALB prn
65/M/O
57
48/57
SALM
FLUT
Yes
Myocardial infarction
17
Non-LABA
SD-037-0699/
82001/820011
180
SALB prn
78/M/C
44
41/44
SALM
FLUT
Yes
Myocardial infarction
Deaths in patients not included in the OVERALL-dataset
1
Formoterol
37-3010/4/415
>900
36 g FORM
62/M/C
730
533/730
x
BUD
Yes
Cardiac failure
2
Formoterol
37-3010/4/430
>900
18–36 g
FORM
58/M/C
524
79/587
x
BDP
Yes
Cardiac failure
3
Salmeterol
SD-039-0735/
1202/1111
180
100/500
SALM/FLUT
37/M/C
169
165/172
x
x
Yes
Cardiac failure
* Randomized treatment: BUD = budesonide; FLUT = fluticasone; FORM = formoterol; ; prn = as needed SALB = salbutamol; TERB = terbutaline.
†
Sex: F = female; M = male. Race: C = Caucasian; O = Oriental; X = Other (other than Caucasian, Oriental and Black).
Duration in days from clinical study protocol.
§ Days from first day of randomized treatment to day of onset of event leading to death/day of death.
║ Medications taken in addition to the study drug as maintenance therapy: BDP = beclomethasone dipropionate; BUD = budesonide; FLUT = fluticasone; LABA = long-acting β
2
agonist: SALM = salmeterol; – = none reported; x = none allowed.
** These patients were exposed to formoterol prn: one erroneously received formoterol instead of salbutamol at start of treatment, and one used salbutamol for 5 weeks then
exchanged medication with a formoterol-randomized patient and died 2 days later; the physician could not determine which drug was used before death.
†† Patient completed study. 1-2 days later the patient died of an event not reported during randomized treatment
║║ Died 10 days post-operatively from myocardial infarction, stop date for drug use uncertain, likely discontinued 10 days before death.
§§ Died 24 days post-operatively from cardiac failure, stop date for drug use uncertain, likely discontinued 24 days before death
LABA = long-acting β2 agonist; ICS = inhaled corticosteroid
‡
37
TABLE E-6. DETAILS OF ALL DEATHS OTHER THAN ASTHMA- OR CARDIAC-RELATED
Case
No.
Randomized
treatment
Study ref
Duration‡
Daily dose of
randomized treatment*
Age/sex/
race†
Number of
days on
randomized
treatment
Days in
study until
onset/
death§
Cause of death
Deaths in patients included in the OVERALL-dataset
1
Formoterol
37-3018/47/64719
365
18 g FORM + 640 g
BUD
33/M/C
334
336/336
Completed suicide
2
Formoterol
SD-0370699/12009/120062
180
FORM prn
69/F/C
170†††
139/233
Ovarian cancer
3
Formoterol
SD-0370699/25049/250515
180
FORM prn
62/F/C
153
150/153
Brain neoplasm
4
Formoterol
SD-0370699/26028/260158
180
FORM prn
65/M/C
113
112/113
Cerebrovascular accident
5
Formoterol
SD-0370699/51054/511157
180
FORM prn
13/F/C
165
165/165
Carbon monoxide poisoning
6
Formoterol
SD-039-0673/75/1527
365
9/160 g FORM /BUD
54/F/C
326
326/326
Sudden death1
7
Formoterol
SD-039-0668/286/248
365
9/320 g FORM/BUD
plus FORM/ BUD prn
74/F/C
229†††
214/330
Metastases to peritoneum
8
Formoterol
SD-0390734/1103/1728
365
9/320 g FORM/BUD
plus FORM/ BUD prn
49/F/C
21
29/29
Death2
9
Formoterol
SD-0390734/1705/3724
365
9/320 g FORM/BUD
plus TERB prn
80/F/C
35†††
35/115
Hepatic neoplasm malignant
10
Formoterol
SD-0390734/1902/2948
365
9/320 g FORM/BUD
plus FORM prn
39/M/C
194†††
194/329
Brain neoplasm
11
Formoterol
SD-0390349/401/578070
90
18/640g FORM /BUD
36/M/C
1
1/1
Completed suicide
12
Formoterol
SD-039-0689/313/255
180
36/1/280 g FORM /BUD
56/F/C
121
121/121
Pulmonary embolism
13
Formoterol
AD-0390001/9114/911403
180
18/640g FORM /BUD
51/M
201††
102/446
14
Formoterol
CF-039-0002/1839/0001
90
18/640g FORM /BUD
72/F
61
61/61
Lung neoplasm malignant
Road traffic accident
38
15
Formoterol
CF-039-0002/2786/0001
90
18/640g FORM /BUD
66/M
73
73/73
Cerebrovascular accident
39/M
19†††
20/89
Lung neoplasm malignant
16
Formoterol
CI-SYM0001/1023/160-0339
90
18/640g FORM /BUD
17
Formoterol
BG-SYM0003/0235/06208
90
FORM/BUD inh. dose
39/M
55
55/55
Death3
18
Formoterol
D5890C00002/1201/1
313
180
18/640 g FORM/BUD
plus FORM/ BUD prn
39/F/O
173
162/174
Typhoid fever
19
Non-LABA
SD-0390673/572/1742
365
40 g BUD plus TERB
prn
67/M/O
304
304/308
Death4
20
Non-LABA
SD-0370699/26042/260502
180
SALB prn
32/M/C
208††
202/221
Hepatorenal syndrome;
hepatic cirrhosis
21
Non-LABA
SD-0370699/71050/711151
180
SALB prn
67/M/C
112
112/112
Cerebrovascular accident
Deaths in patients not included in the OVERALL-dataset
1
Formoterol
SD-037-0344/130/711
90
18g FORM
66/M
55
55/55
Sudden death5
2
Formoterol
SD-037-0288/53/246
365
58/F
22
22/22
Death6
3
Salmeterol
SD-0390691/0516/2710
365
36g FORM
SALM/FLUT║
14/M/C
92
92/92
Road traffic accident
4
Salmeterol
SD-0390691/1035/3520
365
SALM/FLUT║
69/M/C
311
312/318
Cerebral haemorrhage
5
Non-LABA
BU-5430681/5604/1304
30
640 g BUD
67/F
3
3/4
Cerebral haemorrhage
* Randomized treatment: BUD = budesonide; FLUT = fluticasone; FORM = formoterol; prn = as needed; SALB = salbutamol; TERB = terbutaline.
† Sex: F = female; M = male. Race: C = Caucasian; O = Oriental; X = Other (other than Caucasian, Oriental and Black).
‡ Duration in days from clinical study protocol.
§ Days from first day of randomized treatment to day of onset of event leading to death/day of death.
║ Individually adjusted dose.
†† Onset of event during randomized treatment. Patient completed study and subsequently died from the event.
††† Cancer diagnosed during treatment. Study drug stopped. Patient subsequently died due to the cancer.
1 Cause of death unknown. Medical history included hypertension.
2 Cause of death unknown. Depressive patient who died in ICU. Death possibly related to malprotiline and diazepam.
3 Cause of death unknown. Medical history included therapy-resistant arterial hypertension and extreme obesity.
4 Cause of death unknown. Patient experienced loss of consciousness and cyanosis and died 4 days later.
5 Cause of death unknown. Medical history included hypertension.
39
6
Cause of death unknown. No known medical history.
40
TABLE E-7 DEATHS IN THE RELIEF TRIAL BY BASELINE MEDICATION
Randomized treatment
Patients,
n
Number of
asthma-related
deaths
Number of
cardiac-related
deaths
Number of
“other” deaths
All-cause
mortality
3,105
1
1
1
3
1
5
No ICS at baseline
Formoterol prn
Salbutamol prn
3,133
1
3§
Total
6,238
2
4
2
8
Formoterol prn
3,571
1
1
3
5
Salbutamol prn
3,443
1
1
1
3
Total
7,014
2
2
4
8
Formoterol prn*
2,250
1
4
0
5
prn†
2,360
0
3
0
3
4,610
1
7
0
6
Formoterol prn
8,926
3
6
4
13
Salbutamol prn
8,936
2
7
2
11
Total
17,862
5
13
6
24
ICS but no LABA at baseline
ICS and LABA at baseline
Salbutamol
Total
All patients in SD-037-0699
* Among these, 874 were on formoterol maintenance treatment and 1,376 on salmeterol maintenance treatment.
Among the patients who suffered an asthma death, none were on formoterol maintenance versus one on
salmeterol maintenance; for cardiac death, one was on formoterol maintenance compared to three on salmeterol
maintenance.
† Among these, 922 were on formoterol maintenance treatment and 1,438 on salmeterol maintenance treatment.
Among the patients who suffered a cardiac death, one was on formoterol maintenance compared to two on
salmeterol maintenance.
§ Two of these three deaths occurred in patients randomized to salbutamol who actually were exposed to
formoterol prn: one erroneously received formoterol instead of salbutamol at start of treatment, and one used
salbutamol for 5 weeks then exchanged medication with a formoterol-randomized patient and died 2 days later;
the physician could not determine which drug was used before death.
ICS = inhaled corticosteroid; LABA = long-action β2-agonist
41
TABLE E-8. NUMBER (%) OF PATIENTS WHO REPORTED SERIOUS ADVERSE
EVENTS IN THE RELIEF TRIAL BY BASELINE MEDICATION
Randomized treatment
Patients,
n
Number (%) of patients
reporting at least one asthmarelated non-fatal SAE
Number (%) of patients reporting
at least one cardiac-related nonfatal SAE
No ICS at baseline
Formoterol prn
3,105
25
0.81%
7
0.23%
Salbutamol prn
3,133
30
0.96%
7
0.22%
Total
6,238
55
0.88%
14
0.22%
Formoterol prn
3,571
45
1.26%
5
0.14%
Salbutamol prn
3,443
43
1.25%
13
0.38%
Total
7,014
88
1.25%
18
0.26%
Formoterol prn*
2,250
36
1.60%
8
0.36%
prn†
2,360
47
1.99%
10
0.42%
4,610
83
1.80%
18
0.39%
Formoterol prn
8,926
106
1.19%
20
0.22%
Salbutamol prn
8,936
120
1.34%
30
0.34%
Total
17,862
226
1.27%
20
0.28%
ICS but no LABA at baseline
ICS and LABA at baseline
Salbutamol
Total
All patients in SD-037-0699
* Among these, 874 were on formoterol maintenance treatment and 1,376 on salmeterol maintenance treatment.
Fourteen versus 22 patients (1.60% vs. 1.60%) reported asthma-related SAEs.
† Among these, 922 were on formoterol maintenance treatment and 1,438 on salmeterol maintenance treatment.
Fifteen versus 32 patients (1.63% vs. 2.23%) reported asthma-related SAEs.
ICS = inhaled corticosteroid; LABA = long-action β2-agonist; prn = as needed
42