Sfc Data in Copd (Torch & Inspire Study)

THE BENEFIT OF FLUTICASONE PROPIONATE /SALMETEROL XINAFOATE

IN COPD

SFC DATA IN COPD Short-term benefits

SFC reduces breathlessness in COPD from 1 day onwards

0

0.5

1.0

1.5

2.0

2.5

P lacebo (n=181)

Sa lmeterol 50μg bd (n=160)

SFC 50/250μg bd (n=165)

Impr

ovem

ent i

n br

eath

less

ness

sco

re

1.7 1.2

*

* p<0.001 vs placebo and salmeterol. Differences vs placebo and salmeterol exceed the clinically relevant difference threshold of 1 unit for this index. Patients were allowed as-needed salbutamol and stable regimens of theophylline could be continued Mahler Am J Respir Crit Care Med 2002

Presenter

Presentation Notes

.

SFC improves FEV1 in COPD from 1 week onwards

Mahler Am J Respir Crit Care Med 2002

p<0.001 SFC, salmeterol and FP vs placebo p=0.012 SFC vs salmeterol p=0.038 SFC vs FP

0

Salmeterol

SFC

Placebo

FP

0 2 4 6 8 12 16 20 24

Time (weeks)

200

150

100

50

–50 Mea

n ch

ange

in p

redo

se F

EV1 (

ml)

SFC DATA IN COPD Long-term benefits

Anti-inflammatory effects of SFC in COPD: reduction in CD8+ T-lymphocytes

Placebo (n=69) SFC (n=55)

0 40 80

120 160 200 240 280 320

Med

ian

cells

/mm

2

Bas e line Week 12 Bas e line Week 12

p=0.015

In a placebo-controlled 3-month biopsy study SFC 50/500μg bd was shown to have a broad range of anti-inflammatory effects that may help explain its clinical effects

Barnes Am J Respir Crit Care Med 2006

TORCH: study design

SFC 50/500μg bd n=1533

Sa lmeterol 50μg n=1521

P lacebo n=1524

FP 500μg bd n=1534

2-week run-in

All doses taken in the morning and evening for 3 years Calverley N Eng J Med 2007

Primary endpoint: The effect of SFC 50/500 mg vs placebo on all-cause mortality over 3 years in patients with moderate-to-severe COPD Secondary endpoints: The effect of SFC 50/500 mg on the rate of moderate and severe exacerbations; The effect of SFC 50/500 mg on health status (SGRQ)

Vertical bars are standard errors

18 16 14 12 10

8 6 4 2 0

Time to death (weeks)

Probability of death (%)

1524 1533 1521 1534

1464 1487 1481 1487

1399 1426 1417 1409

1293 1339 1316 1288

Placebo Salmeterol FP SFC

Number alive

0 12 24 36 48 60 72 84 96 108 120 132 144 156

HR, 0.825 (95% CI, 0.681–1.002)

p=0.052 (log-rank test)

Trend towards reduction in all-cause mortality at 3 years

Calverley N Eng J Med 2007

1350

1300

1250

1200

1150

1100

SFC slows the rate of decline of lung function over 3 years

FEV 1

(ml)

0 24 48 72 96 120 156 Weeks

–39 ml/yr

– 42 ml/yr

– 55 ml/yr

– 42 ml/yr

Placebo Salmeterol FP SFC

SFC versus placebo: 16 ml/yr, p<0.001 Salmeterol versus placebo: 13 ml/yr, p=0.003 FP versus placebo: 13 ml/yr, p=0.003

Celli BR. Am J Respir Crit Care Med 2008

0.02 9% SFC vs FP 0.002 12% SFC vs salmeterol

<0.001 25% SFC vs p lacebo

SFC significantly reduces exacerbations over 3 years

p-va lue Trea tment e ffec t

0

0.2

0.4

0.6

0.8

1.0

1.2

P lacebo

Ann

ualis

ed e

xace

rbat

ion

rate

S a lmeterol FP SFC

25% (p<0.001)

1.13

0.97 0.93 0.85


SFC significantly improves in quality of life

Vertical bars represent standard errors

p-value

SFC vs FP

SFC vs placebo

– 1.2 units – 2.2 units –3.1 units

Treatment diff

0.02 <0.001 <0.001

SFC vs salmeterol

Placebo

Salmeterol

FP

SFC


4 3 2 1 0

– 1 – 2 – 3 – 4 – 5 – 6

Adju

sted

mea

n ch

ange

SG

RQ

tota

l sco

re

0 24 48 72 96 120 156 Time (weeks)

impr

ovem

ent

Stratification by GOLD stage

N (%) patients in group GOLD stage Placebo

(n= 1524) Salmeterol (n=1521)

FP (n=1534)

SFC (n=1533)

Total (n=6112)

IV – Very severe FEV1 <30% 214 (14) 260 (17) 220 (14) 243 (16) 937 (15)

III - Severe FEV1 30% to <50%

775 (51) 739 (49) 777 (51) 728 (47) 3019 (49)

II/I – Moderate/ mild FEV1 ≥ 50%

535 (35) 522 (34) 537 (35) 562 (37) 2156 (35)

Jenkins et al. Respir Res 2009

All-cause mortality by baseline % predicted post-bronchodilator FEV1

Patien t (N) 214 260 220 243 775 739 777 728 535 522 537 562 Death (N) 52 64 53 43 118 93 140 106 61 48 53 44

Brackets s how hazard ra tio (95% CI) for ris k of dea th for SFC vs p lacebo Jenkins et al. Respir Res 2009

Prob

abili

ty o

f mor

talit

y (%

)

% FEV1 at baseline <30% 30% to <50% ≥50%

HR 0.70 (0.47, 1.05)

HR 0.67 (0.45, 0.98)

HR 0.95 (0.73, 1.24)

0

5

10

15

20

25

30

Exacerbation rate by baseline % predicted post-bronchodilator FEV1

14% (-4, 29)

Brackets show % reduction (95% CI) of exacerbations rate for SFC vs placebo Jenkins et al. Respir Res 2009

Rat

e of

mod

erat

e/se

vere

exa

cerb

atio

ns

<30% % FEV1 at baseline

30% to <50% ≥50%

31% (19, 40)

26% (17, 34)

0.8

1.2

1.4

1.6

1.8

2.0

0

0.2

0.4

0.6

Improvement (reduction) in SGRQ vs placebo by baseline % predicted post-bronchodilator FEV1

Adju

sted

mea

n ch

ange

in S

GR

Q

tota

l sco

re

<30% 30% to <50% ≥50% % FEV1 at baseline

Bas e line SGRQ s core 57.5 54.6 55.3 56.4 49.8 49.5 50.8 48.8 43.9 47.2 45.1 45.2

-5.0 (-8.7, -3.0)

-2.3 (-4.0, 0.7) -3.3 (-4.7, -1.9)

Brackets s how adjus ted mean (95% CI) d iffe rence of SFC vs p lacebo Jenkins et al. Respir Res 2009

Rate of decline in FEV1 by baseline % predicted post-bronchodilator FEV1

Adju

sted

rate

of d

eclin

e in

FE

V 1 (m

l/yea

r)

<30% 30% to <50% ≥50%

% FEV1 at baseline

Bas e line FEV1 (ml) 717 709 713 707 1108 1137 1101 1113 1634 1587 1635 1625

11 (-8, 30)

16 (5, 28) 16 (0, 32)

Brackets s how adjus ted mean (95% CI) d iffe rence of SFC vs p lacebo Jenkins et al. Respir Res 2009

INSPIRE: study design

The INSPIRE study is the first head-to-head trial to compare SFC 50/500μg Accuhaler/Diskus™ with tiotropium bromide

The study aimed to assess the effect of SFC vs tiotropium in reducing the rate of healthcare utilisation, COPD exacerbations and related outcomes over 104 weeks in patients with severe COPD

Prednisolone 30 mg/day Salmeterol 50μg bd Tiotropium 18μg qd (n=665)

SFC 50/500μg Accuhaler/Diskus bd (n=658)

1499 patients were screened and 1323 were randomised

2-week run-in

Wedzicha et al. Am J Crit Care Med 2008

SFC healthcare utilisation exacerbation rates


Tiotropium 18μg

1.28 1.32

0.69 0.85 0.97

0.82

p=0.039

0

0.5

1

1.5

2

2.5

3

3.5

Exac

erba

tion

rate

m

ean/

year

Healthcare utilisation exacerbations

Healthcare utilisation exacerbations

requiring antibiotics

Healthcare utilisation exacerbations requiring

oral corticosteroids

p=0.656 p=0.028

SFC 50/500μg

SFC: significant and sustained improvements in quality of life

–2.1-unit difference in total SGRQ score (p=0.038) at wk 104

55

–2

50

45

40

0 10 22 34 46 58 70 82 94 106

Time (weeks )

SG

RQ

tota

l sco

res

(uni

ts)

Tiotropium 18μg SFC 50/500μg


SFC improved survival over 2 years vs tiotropium

Pro

babi

lity

of d

eath

(%)

0

1

2

3

4

5

6

7

8

Time to dea th (weeks ) 0 13 26 39 52 65 78 91 104

52% relative risk reduction with SFC vs tiotropium (p=0.012)

INSPIRE showed a significant reduction in all-cause mortality with SFC vs tiotropium over 2 years (p=0.012)



Time to withdrawal: more subjects withdraw from the tiotropium arm

Probability of withdrawal prior to wk 104 SFC 34.5% Tio 41.7%

658 560 531 510 494 476 456 445 160 SFC 50/500 665 547 501 474 450 434 415 397 140 Tio 18

0 13 26 39 52 65 78 91 104

Number a t ris k

0

4

8

12

16

20

24

28

32

36

40

44

Pro

babi

lity

of e

vent

(%)

Time to event (weeks )



SFC DATA IN COPD Safety

Most common reported AEs (started during treatment)

SFC (n=1546)

COPD exacerbations

FP (n=1552)

Sa lmete ro l (n=1542)

Placebo (n=1544)

0.92 0.76 0.78 0.67

Upper respiratory tract infection 0.10 0.08 0.09 0.11 Nasopharyngitis 0.09 0.09 0.10 0.10

Pneumonia 0.04 0.04 0.07 0.07

Bronchitis 0.05 0.05 0.05 0.05

Headache 0.08 0.06 0.06 0.05

Back pain 0.04 0.04 0.04 0.04

Sinusitis 0.03 0.03 0.04 0.04

Cough 0.03 0.03 0.04 0.03

Hypertension 0.03 0.03 0.03 0.02

Rate per treatment year


Placebo (n=1544)

Sa lmetero l (n=1542)

FP (n=1552)

SFC (n=1546)

Patients with pneumonia (n) 139 162 224 248

Probability* of pneumonia by 3 years (%) 12.3 13.3 18.3 19.6

Probability of having Pneumonia

*Kaplan-Meier estimate of probability

HR 95% CI p-va lue

SFC vs placebo 1.64 (1.33, 2.02) <0.001

FP vs placebo 1.53 (1.24, 1.89) <0.001

Salmeterol vs placebo 1.09 (0.87, 1.37) 0.465

Crim et al. Eur Respir J 2009

Limitations of pneumonia data

Pneumonias were captured solely by AE reporting

There was no standardised procedure for the diagnosis or treatment of pneumonia

Chest x-rays, white blood cell count and cultures were not required for diagnosing pneumonia

When culture results were available for review, there was no evidence of opportunistic infections and the infectious agents identified were compatible with those expected in a COPD population

Crim et al. Eur Respir J 2009

Mortality from pneumonia

0.0032 0.0042 0.0031 0.0031 Fatal serious AE rate*

SFC (N = 1546)

FP (N = 1552)

SAL (N = 1542)

Placebo (N = 1544)

* Rate per treatment year

8 13 9 7 On-treatment deaths adjudicated by Clinical Endpoint Committee

1. Calverley PMA et al. NEJM 2007

Presenter

Presentation Notes

Despite an increase in pneumonia reporting in the SFC group, there was no corresponding increase in mortality with SFC due to pneumonia, although numbers are small.1 This can be seen both in the fatal SAEs2 (deaths on treatment where pneumonia was noted on the CRF) and in the CEC adjudicated deaths (deaths for the on-treatment safety population in which the Clinical Endpoint Committee adjudicated that the death was die to pnuemonia).1 CEC adjudicated deaths in the safety population for patients on treatment up to 3 years were 7 on placebo, 9 on SAL, 13 on FP and 8 on SFC. 1 References Calverley PMA, Anderson JA, Celli B. for the TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. NEJM 2007; 356(8): 775-789 GSK Data on File 2006, Clinical Study Report.

Pneumonia summary Both SFC and FP were associated with an increased reporting of

pneumonia compared with salmeterol and placebo1

The increase in reports of pneumonia as an AE in the ICS-containing treatment arms occurred despite a decrease in overall COPD exacerbations, of which pneumonia was a subset1

– The increase in reported pneumonias with SFC did not result in an increase in pneumonia-related deaths

Risk factors for pneumonia in all treatment groups were1

– older age – lower % predicted FEV1

– any COPD exacerbation in the year prior to the study – worse MRC dyspnoea score – lower BMI

Healthcare professionals should remain vigilant for the possible development of pneumonia and implement early and appropriate therapy

– signs and symptoms of COPD exacerbations and pneumonia often overlap2

1. Crim e t a l. Eur Res pir J 2009. 2. Lieberman e t a l. Ches t 2002

COPD: conclusions

Seretide offers significant benefits from day 1 onwards:1–5

– Improvement in lung function at 24 hours2,3

– Improvements in breathlessness at 2 days3

– Reduced rate of exacerbations over 3 years1

– Reduced rate of lung function decline over 3 years4

– Improvement in quality of life over 3 years1,5

1. Seretide UK SPC. 2. Dalal Chest 2009. 3. Vestbo Thorax 2005. 4. Celli Am J Respir Care Med 2008. 5. Calverley N Engl J Med 2007

TERIMA KASIH ATAS

PERHATIANNYA

Result of recent and existing data TOwards a Revolution in COPD Health

Investigating New Standards for Prophylaxis In Reduction of Exacerbations

The Understanding Potential Long-term Impacts on Function with Tiotropium

Study design : 3 yr, R, DB, C, 444 centers from 42 countries, 6112 pts

Study Design : 4 yr, R, DB, C, 487 centers from 37 countries, 5993 pts

SFC vs PBO

Tio vs PBO

Study Design : 2 yr, R, DB, DD, C, 179 centers from 20 countries, 1323 pts

SFC vs Tio

Background: Effects on FEV1 decline ICS/LABA1 & LAMA2 therapy

1. Celli B, et al. AJRCCM 2008;178:332-338 2. Tashkin D, et al. N Eng J Med 2008;359:1543-54

Salmeterol/Fluticasone propionate (50/500mcg) reduced rate of decline by 16 mL/year vs. placebo (p<0.001) Tiotropium (18mcg) reduced rate of decline by 2mL/year vs. placebo (p=0.21)

Permission applied for to reproduce figures

* * *

* *

* *

* *

* * * * *

* * * *

1.50

1.40

1.30

1.20

1.10

1.00

0 6 12 18 24 30 48 1 36 42 FE

V 1 (L

iters

) Month Day

30

After bronchodilation

Before bronchodilation

Tiotropium (N=2516)

Placebo (N=2374)

Tiotropium (N=2494)

Placebo (N=2363)

1350

1300

1250

1200

1150

1100

0 24 48 72 96 120 156

FEV 1

(mL)

Time (weeks)

-39 mL/yr

-42 mL/yr -42 mL/yr

-55 mL/yr

SFC

FP

PBO

SAL

www.ECLIPSE-copd.com

Impr

ovem

ent

SGR

Q T

otal

Sco

re (u

nits

) Placebo(n=2337)

Tiotropium(n=2478)

0

35

40

45

50

p=0.78

0 6 12 18 24 30 36 42 48

MonthIm

prov

emen

t

SGR

Q T

otal

Sco

re (u

nits

) Placebo(n=2337)

Tiotropium(n=2478)

0

35

40

45

50

p=0.78

0 6 12 18 24 30 36 42 48

Month

Tashkin DP et al. N Engl J Med 2008; 359: 1543–54.

CRM: Concomitant respiratory medication

Vertical bars represent standard errorsPlacebo Sal 50 FP 500 SFC

43210

-1-2-3-4-5-6

Adj

uste

d m

ean

chan

ge

SGR

Q to

tal s

core

0 24 48 72 96 120 156Time (weeks)

impr

ovem

ent

p-value

SFC vs FP

SFC vs placebo

-1.2 units-2.2 units-3.1 units

Treatment diff

0.02<0.001<0.001

SFC vs sal

Placebo

Sal 50

FP 500

SFC

Vertical bars represent standard errorsPlacebo Sal 50 FP 500 SFCPlacebo Sal 50 FP 500 SFC

43210

-1-2-3-4-5-6

43210

-1-2-3-4-5-6

Adj

uste

d m

ean

chan

ge

SGR

Q to

tal s

core

0 24 48 72 96 120 156Time (weeks)

impr

ovem

ent

p-value

SFC vs FP

SFC vs placebo

-1.2 units-2.2 units-3.1 units

Treatment diff

0.02<0.001<0.001

SFC vs sal

Placebo

Sal 50

FP 500

SFC

Calverley PMA et al. N Eng J Med 2007; 356: 775-789.

Improvement in QoL based on SGRQ

Salm/FP (50/500mcg) significantly improved QoL with the overall difference is 3.1 (vs placebo, over 3 years)

Tio (18mcg) not significantly improved QoL with the overall difference is 2.7( vs. Placebo, over 4 years)

Presenter

Presentation Notes

Notes UPLIFT showed that tiotropium, as add-on to baseline therapy, significantly improves health-related quality of life compared with placebo, as measured by changes in SGRQ. Overall mean between group difference in the SGRQ total score at any time was 2.7, 95% CI 2.0-3.3. ([p1550/Table2] Results for the pre-specified secondary endpoint, annual rate of decline in SGRQ in the tiotropium + concomitant respiratory medication (CRM) group compared with baseline, were non-significant (0.04±0.13 (−0.2 to 0.3) 0.78; p=0.78). [p1550/Table2] The annual rate in change in the tiotropium/CRM group was 1.25 ± 0.09 units/year compared with 1.21±0.09 units/year for placebo/CRM (p<0.001). [p1549/fig2D] Reference Tashkin DP et al. N Engl J Med 2008; 359: 1543–54.

0.029%SFC vs FP0.00212%SFC vs sal

<0.00125%SFC vs placebo

p-valueTreatment effect

0

0.2

0.4

0.6

0.8

1

1.2

Placebo

Ann

ualis

ed e

xace

rbat

ion

rate

Sal FP SFC

25% (p<0.001)

1.13

0.97 0.930.85

0.029%SFC vs FP0.00212%SFC vs sal

<0.00125%SFC vs placebo

p-valueTreatment effect

0

0.2

0.4

0.6

0.8

1

1.2

Placebo

Ann

ualis

ed e

xace

rbat

ion

rate

Sal FP SFC

25% (p<0.001)

1.13

0.97 0.930.85

Tashkin DP et al. N Engl J Med 2008; 359: 1543–54.

CRM: Concomitant respiratory medication Calverley PMA et al. N Eng J Med 2007; 356: 775-789.

Exacerbation and Related hospitalization

80

60

40

20

0

Prob

abili

ty o

f exa

cerb

atio

n (%

)

0 6 12 18 24 30 36 42 48

Month

Hazard ratio, 0.86(95% Cl, 0.81–0.91)p<0.001)

TiotropiumPlacebo

80

60

40

20

0

Prob

abili

ty o

f exa

cerb

atio

n (%

)

0 6 12 18 24 30 36 42 48

Month

Hazard ratio, 0.86(95% Cl, 0.81–0.91)p<0.001)

TiotropiumPlacebo

Salm/FP (50/500mcg) significantly reduced exacerbation over 3 years & reduced the rate of severe exacerbations requiring hospitalisation

Tio (18mcg) significantly reduced exacerbation over 4 years, however Tio did not significantly reduce the rate exacerbation requiring hospitalization

Presenter

Presentation Notes

Notes Reference Tashkin DP et al. N Engl J Med 2008; 359: 1543–54.

Tashkin DP et al. N Engl J Med 2008; 359: 1543–54. Calverley PMA et al. N Eng J Med 2007; 356: 775-789.

All cause mortality

FP


1816141210

86420


Mor

talit

y (%

)

1524153315211534

1464148714811487

1399142614171409

1293133913161288

Placebo SFC

Numberalive

0 12 24 36 48 60 72 84 96 108 120 132 144 156

SAL

17.5% risk reduction with SFC vs placebo (p=0.052)

FP


1816141210

86420


Mor

talit

y (%

)

1524153315211534

1464148714811487

1399142614171409

1293133913161288

Placebo SFC

Numberalive

0 12 24 36 48 60 72 84 96 108 120 132 144 156

SAL

17.5% risk reduction with SFC vs placebo (p=0.052)

20

15

10

5

0

Prob

abili

ty o

f dea

th fr

om

any

caus

e (%

)

0 1 2 3 4

Hazard ratio, 0.89(95% Cl, 0.79-1.02)

Tiotropium

Placebop<0.09

20

15

10

5

0

Prob

abili

ty o

f dea

th fr

om

any

caus

e (%

)

0 1 2 3 4

Hazard ratio, 0.89(95% Cl, 0.79-1.02)

Tiotropium

Placebop<0.09

Years

Mortality at 1470 days: Predefined secondary analysis

Salm/FP (50/500mcg) reduced the risk of all cause mortality by 17.5% over 3 years Tio (18mcg) reduced the risk of all cause mortality by 11% over 4 years

Presenter

Presentation Notes

Notes UPLIFT showed that tiotropium, as add-on to baseline therapy, significantly improves health-related quality of life compared with placebo, as measured by changes in SGRQ. Overall mean between group difference in the SGRQ total score at any time was 2.7, 95% CI 2.0-3.3. ([p1550/Table2] Results for the pre-specified secondary endpoint, annual rate of decline in SGRQ in the tiotropium + concomitant respiratory medication (CRM) group compared with baseline, were non-significant (0.04±0.13 (−0.2 to 0.3) 0.78; p=0.78). [p1550/Table2] The annual rate in change in the tiotropium/CRM group was 1.25 ± 0.09 units/year compared with 1.21±0.09 units/year for placebo/CRM (p<0.001). [p1549/fig2D] Reference Tashkin DP et al. N Engl J Med 2008; 359: 1543–54.

FEV1 Decline: ECLIPSE Decline by GOLD Category

GOLD 2 vs. GOLD 3, p=0.17; GOLD 2 vs. GOLD 4, p<0.001; GOLD 3 vs. GOLD 4, p=0.009

Rate of decline reduced with increasing disease severity Significantly less decline in GOLD 4 vs. GOLD 2 or 3

N Engl J Med. 2011 Sep 29;365(13):1184-92

Mortality from pneumonia

0.0032 0.0042 0.0031 0.0031 Fatal serious AE rate*

SFC (N = 1546)

FP (N = 1552)

SAL (N = 1542)

Placebo (N = 1544)

* Rate per treatment year

8 13 9 7 On-treatment deaths adjudicated by Clinical Endpoint Committee

1. Calverley PMA et al. NEJM 2007

Presenter

Presentation Notes

Despite an increase in pneumonia reporting in the SFC group, there was no corresponding increase in mortality with SFC due to pneumonia, although numbers are small.1 This can be seen both in the fatal SAEs2 (deaths on treatment where pneumonia was noted on the CRF) and in the CEC adjudicated deaths (deaths for the on-treatment safety population in which the Clinical Endpoint Committee adjudicated that the death was die to pnuemonia).1 CEC adjudicated deaths in the safety population for patients on treatment up to 3 years were 7 on placebo, 9 on SAL, 13 on FP and 8 on SFC. 1 References Calverley PMA, Anderson JA, Celli B. for the TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. NEJM 2007; 356(8): 775-789 GSK Data on File 2006, Clinical Study Report.

Sfc Data in Copd (Torch & Inspire Study)

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