Transcript CLINICAL TRIAL ISSUES IN ASTHMA

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CRITICAL REVIEW OF NEW
TREATMENT STRATEGIES FOR
ASTHMA
1st March 2011
Modena,Italy
Professor Neil Barnes
Consultant Respiratory Physician
London Chest Hospital
Bart`s and the London
Trust and Medical School
[email protected]
What is good asthma control?
no (or minimal) daytime symptoms
no nocturnal symptoms or awakenings
no (or minimal) need for “rescue” treatment
no limitations on activities
(near) normal lung function
no exacerbations
GINA 2007
Adults
6
GOAL: Study design
Phase I
8- week control assessment
Phase II
4- week control assessment
SFC 50/500
or FP 500
SFC 50/250
or FP 250
SFC 50/100
or FP 100
Step 3
Step 2
Step 1
Visit
Week
1
2
3
4
5
6
7
8
9
–4
0
4
12
24
36
48
52
56
SFC = Salmeterol/fluticasone propionate
GOAL Study, Bateman E, et al. ARJCCM
COMPOSITE MEASURE OF ASTHMA CONTROL:
WELL-CONTROLLED ASTHMA OVER 8 WEEK
PERIODS (GOAL)
80
78%*
FP Phase II
SFC Phase II
FP Phase I
SFC Phase I
75%**
70%
62%**
60%
% Patients
7
60
47%
40
20
0
Steroid-naive (S1)
* P = 0.003
** P < 0.001
Low-dose ICS (S2)
Moderate-dose ICS (S3)
SFC = Salmeterol/fluticasone propionate
GOAL Study, Bateman E, et al. ARJCCM
8
WELL CONTROLLED ASTHMA
Patients controlled each
week (%)
Salm/FP
FP
100
80
60
40
20
0
–4
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Week
All patients
GOAL Study
9
SEVERE EXACERBATIONS
Mean exacerbation
rate
per patient per year
FP
Salm/FP
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.03
*
0.02
0.02
0.02
0.04
*
0.03
0
Steroid-naive (S1)
Low-dose ICS (S2)
Moderate-dose ICS (S3)
*Requiring hospitalisation/emergency visit
*P  0.014
GOAL Study
10
FP/SALM VS BUD/FORM
Exacerbations
Cochrane Review
11
FP/SALM VS BUD/FORM
am PEF
Cochrane Review
23
TRADITIONAL APPROACH AND SYMBICORT
MAINTENANCE AND RELIEVER THERAPY
(SMART)
Days with symptoms
(maintenance and relief)
Daily medication use
illustrative
As needed
β2
As needed
Symbicort
Most days patients
use no reliever
Maintenance
Maintenance
Traditional Approach
Fixed Symbicort
+ prn SABA
Symbicort
SMART
Time
26
:
METHODOLOGY CHECKLIST RCT
SECTION 1: INTERNAL VALIDITY
Evaluation criterion
How well is this criterion addressed?
1.1
Does the study address an appropriate and clearly focused question?
1.2
Was the assignment of subjects to treatment groups randomised?
1.3
Was an adequate concealment method used?
1.4
Were subjects and investigators kept ‘blind’ about treatment allocation?
1.5
Were the treatment and control groups similar at the start of the trial?
1.6
Apart from the treatment under investigation, were the groups treated equally?
1.7
Are all relevant outcomes measured in a standard, valid and reliable way?
1.8
What percentage of the individuals or clusters recruited into the study are included in the
analysis?
1.9
Were all the subjects analysed in the groups to which they were randomly allocated?
1.10
Are the results homogeneous between sites?
27
METHODOLOGY CHECKLIST
RCT
SECTION 2: OVERALL ASSESSMENT OF THE STUDY
2.1
How well was the study done to minimise bias?
Code ++, +, or 2.2
If coded as +, or - what is the likely direction in which bias might
affect the study results?
2.3
Taking into account clinical considerations, your evaluation of
the methodology used, and the statistical power of the study, are
you certain that the overall effect is due to the study
intervention?
2.4
Are the results of this study directly applicable to the patient
group targeted by this guideline?
28
METHODOLOGY CHECKLIST RCT
SECTION 3: DESCRIPTION OF THE STUDY
3.1
What interventions are evaluated in this study?
3.2
What outcome measures are used?
i.e. benefits and harms
3.3
How many patients participated in the study?
Overall number, and in each arm of the study.
3.4
What was the scale and direction of the measured effect?
3.5
Is any statistical measure of uncertainty given?
e.g. confidence intervals; p values
3.4
What are the characteristics of the study population?
e.g. age, sex, disease characteristics of the population, disease prevalence.
3.5
What are the characteristics of the study setting?
e.g. rural, urban, hospital inpatient or outpatient, general practice, community.
3.6
How many groups/sites are there in the study?
If the study is carried out on more than one group of patients, or at more than one site,
indicate how many are involved.
3.7
Are there any specific issues raised by this study?
Make any general comments on the study results and their implications
SMILE: Study design
12-month double-blind study: All patients received Bud/form 200/6 µg bid
both during run-in and following randomisation
Bud/form 200/6 + Terb 0.4 mg as reliever
n=1141
Run-in
Bud/form
200/6+Terb
R
Bud/form 200/6 + Form 6 µg as reliever
n=1140
as reliever
Budesonide
Bud/form 200/6 as maintenance & reliever
400mcg/day
Enrolled: n=3829
Randomised: n=3394
Visit:
1
Month: -0.5
2
0
3
1
4
4
5
8
n=1113
6
12
Rabe KF, et al. Lancet 2006
TIME TO FIRST SEVERE EXACERBATION
Maintenance
Bud/form + as
needed:
Patients with severe
exacerbations (%)
Terb
Form
Bud/form
25
P<0.01
20
P<0.001
P<0.005
15
10
‘SMART’ decreased risk by:
 45% vs Bud/form+ SABA
5
0
0
60
120
180
240
300
360
Days since randomisation
Rabe KF, et al. Lancet 2006
PATIENT CHARACTERISTICS
Bud/form bid + as needed:
Terb
(n=1141)
Form
(n=1140)
Bud/form
(n=1113)
450(39)
458 (40)
437 (39)
43 (12–83)
42 (12–81)
42 (12–89)
Mean FEV1, % predicted #
72
72
72
Mean reversibility in FEV1, %
24
24
24
Mean ICS at entry, mg/day
751
758
757
Long-acting b2-agonists, %
58
58
59
Mean SABA use, inh./day
during run-in
1.9
1.9
1.8
Mean % nights with awakenings
during run-in
30
28
31
Characteristic
Males, n (%)
Mean age, years (range)
# pre-bronchodilator
Rabe KF, et al. Lancet 2006
PATIENT CHARACTERISTICS
Bud/form bid + as needed:
Terb
(n=1141)
Form
(n=1140)
Bud/form
(n=1113)
450(39)
458 (40)
437 (39)
43 (12–83)
42 (12–81)
42 (12–89)
Mean FEV1, % predicted #
72
72
72
Mean reversibility in FEV1, %
24
24
24
Mean ICS at entry, mg/day
751
758
757
Long-acting b2-agonists, %
58
58
59
Mean SABA use, inh./day
during run-in
1.9
1.9
1.8
Mean % nights with awakenings
during run-in
30
28
31
Characteristic
Males, n (%)
Mean age, years (range)
# pre-bronchodilator
Rabe KF, et al. Lancet 2006
SECONDARY ENDPOINTS: MEASUREMENTS
OF ASTHMA CONTROL
Reliever Use, number of
inhalations per 24 h
2
1.8
1.5
1.02
1
0.5
0
Asthma-control days, %
50%
40%
30%
20%
10%
0%
40.4%
Nights with Awakenings, %
40%
31.1%
30%
20%
9.2%
15.1%
10%
0%
Baseline
budesonide / formoterol + as needed budesonide / formoterol
Rabe K et al Lancet 2006
BASELINE CHARACTERISTICS
Mean FEV1
% pred
% Symptom-free
days
Rescue use
(inh/day)
% Rescuefree days
% Nights with
awakenings and/or
symptoms
Exacerbation
History* (% pts with ≥1
in past year)
76%
15
1.9
26
35
31%
82%
5
1.3
32
27
14-17%
78-79%
7-8
2.3
25-26
69*
41-42%
Jarjour NN
81%
42
0.9
59
N/A
N/A
Busse WW
81%
44
0.8
65
N/A
N/A
STAY
73%
23-24
2.4-2.5
8
20-22
100%
70%
10
1.9
29
23
100%
72%
12
1.8-1.9
14-15
30-31
100%
75%
30
1.6
24
13
N/A
72-73%
9
2.3
9
32-34
100%
70-71%
11
2.2-2.3
9-10
32
100%
Study
GOAL
Bateman ED
CONCEPT
Fitzgerald JM
EXCEL
Dahl R
O’Byrne PM
STEP
Scicchitano R
SMILE
Rabe KF
STEAM
Rabe KF
COMPASS
Bateman ED
AHEAD
Bousquet J
Age= 35-46 years; ACQ=1.8-2.1 * Nights with symptoms
SMART CONTROL OUTCOMES:
COMPARED TO GINA GUIDELINE
TARGETS
SMART CONTROL OUTCOMES:
COMPARED TO GINA GUIDELINE
TARGETS
SMART CONTROL OUTCOMES:
COMPARED TO GINA GUIDELINE
TARGETS
SMART CONTROL OUTCOMES:
COMPARED TO GINA GUIDELINE
TARGETS
SMART CONTROL OUTCOMES:
COMPARED TO GINA GUIDELINE
TARGETS
COMBINATION INHALERS
In adult patients at step 3 who are poorly
controlled, the use of budesonide/formoterol in a
single inhaler as rescue medication instead of a
short acting beta2 agonist, in addition to its
regular use as a controller treatment, has been
shown to be an effective treatment option. This
management technique has not been
investigated with other combination inhalers.
Before initiating this management careful patient
education is required.
UK Asthma Guidelines
42Figure 1. Methodological quality summary: review authors' judgements about each
methodological quality item for each included study.
Cates & Lasserson 2009
43
SMART vs
HIGHER DOSE OF ICS
Rate of exacerbation
Cates & Lasserson 2009
44
SMART vs
BEST CLINICAL PRACTICE
Rate of exacerbation
Cates & Lasserson 2009
45
SMART vs
BEST CLINICAL PRACTICE
Rate of hospitalisation
Cates & Lasserson 2009
46
SMART vs
BEST CLINICAL PRACTICE
Time to exacerbation
Cates & Lasserson 2009
47
SMART vs
BEST CLINICAL PRACTICE
Discontinuations due to adverse
events
Cates & Lasserson 2009
48
OTHER RESULTS
Morning PEF 1.00% ns
Rescue medication 0.16 puffs/day NS
ACQ score not evaluable
49
DISCUSSION
The run in for the trials.... was designed
to select patients who became
symptomatic when their maintenance
treatment was reduced....
50
DISCUSSION
This implies the current evidence can
only be applied to patients whose
maintenance therapy is reduced
51
Implications for practice Single inhaler
therapy can reduce the risk of asthma
exacerbations needing oral corticosteroids in
comparison with fixed dose maintenance inhaled
corticosteroids. Guidelines and common best
practice suggest the addition of regular longacting beta2-agonist to inhaled corticosteroids for
uncontrolled asthma, and single inhaler therapy
has not been demonstrated to significantly
reduce exacerbations in comparison with current
best practice........
52
CONTROL OUTCOMES IN SMARTTREATED PATIENTS
Studies analyzed:
Rabe et al. Lancet 2006.
17%
O’Byrne et al. AJRCCM 2005.
44%
Scicchitano Curr Med Res
Opin 2004.
38%
Kuna Int J Clin Pract 2007
Bousquet Respir Med 2007.
n = 5,246
Controlled
Partly Controlled
Uncontrolled
Bateman et al. JACI 2010
THE EOS STUDY
A double blind placebo controlled study of
the effect of SMART vs conventional
treatment on airway inflammation and
remodelling in asthma
Pavord et al JACI 2009
THE EOS STUDY
One year long study
Moderately severe asthma
Bronchoscopy and biopsy at baseline
and one year
Induced sputum at baseline and on 4
further occasions
Exhaled NO at baseline and during the
trial
Pavord et al JACI 2009
Primary outcome variables
• Change in percent of eosinophils in induced sputum
from visit 1 to the mean of visit 4-7
and
• Change in number of eosinophils per area subepithelial
tissue in bronchial biopsies from visit 2 to 8
Pavord et al JACI 2009
Patient flow
Enrolment
223 enrolled
96 excluded
Run-in
2 weeks
64 allocated to SMART
Symbicort Turbuhaler
200/6 µg/inhalation b.i.d. + as-needed
Analysis
- up
Follow
Allocation
127 randomised
4 discontinuations
60 completed
BID = twice daily
Pavord et al JACI 2009
63 allocated to Fixed dose
Symbicort Turbuhaler 400/12 µg/inhalation b.i.d. +
Pulmicort Turbuhaler 400 µg/inhalation b.i.d +
Terbutaline Turbuhaler 0.4 mg/inhalation as-needed
5 discontinuations
58 completed
Treatment period
12-months
Eosinophils in sputum (%)
p=0.0038
Pavord et al JACI 2009
Eosinophils in biopsies (n/mm2)
p<0.001
Pavord et al JACI 2009
Mast cells in biopsies
p=0.0012
Pavord et al JACI 2009
Eosinophils in sputum (%) (individual curves)
Controlled
range
Pavord et al JACI 2009
IGCS drug load by treatment
Fixed dose
1600 mg/d
1600
Budesonide ( mg/day)
1200
867 mg/d
800
Symbicort SMART
Mean 604 mg/d
741 mg/d
As-needed budesonide
400
Maintenance budesonide
0
25
50
75
Cumulative period with IGCS dose (% days)
Pavord et al JACI 2009
100
63
REGULAR DOSING VS. VARIABLE DOSING:
BIOPSY INFLAMMATORY CELLS
+
% change
from baseline
**
+
n = 127
p < 0.001
** p = 0.0012
Pavord et al JACI 2009
64
CONCLUSIONS
The SMART strategy is associated with
poorer control of inflammation
This is due to too low a maintenance
dose of ICS
65
COMBINATION INHALERS
In adult patients at step 3 who are poorly
controlled, the use of budesonide/formoterol in a
single inhaler as rescue medication instead of a
short acting beta2 agonist, in addition to its
regular use as a controller treatment, has been
shown to be an effective treatment option. This
management technique has not been
investigated with other combination inhalers.
Before initiating this management careful patient
education is required.
UK Asthma Guidelines
Adults
TREATMENT STRATEGIES FOR ASTHMA:
CONCLUSION
Bud/form as rescue and maintenance
treatment is a possible option but there is a
lack of data that it meets the GINA criteria of
asthma control
Regular controller treatment can achieve and
maintain GINA guideline-defined control
including prevention of exacerbations
68
ASTHMA IN FINLAND 1981 2003
450
400
Share of asthmatics
Drug cost per patient
Deaths
Number of hospital days
Value of the index
350
300
250
200
150
100
50
0
Finnish Asthma Programme 2005
Haahtela et al. Thorax 2006
ASTHMA IN FINLAND 1981 2003
450
400
Share of asthmatics
Drug cost per patient
Deaths
Number of hospital days
Value of the index
350
300
250
200
150
100
50
0
Finnish Asthma Programme 2005
Haahtela et al. Thorax 2006