SERETIDE COPD CLINICAL PAPERS

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Meeting the needs of patients with COPD: patients’ preference for the Diskus inhaler compared with the

Handihaler.

A.C. MOORE, S. STONE

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Seretide and The Diskus

Study design: Questionnaires were used to assess preference and ease of use of the Diskus® and Handihaler in 256

patients with COPD. Patients had used neither device before and were asked to assess each inhaler; to rank the most

important feature of an inhaler; and to elicit an overall preference between the two. Patients considered the Diskus® to

be significantly better than the Handihaler on the three most important attributes for an inhaler device (p<0.001).

More than twice the

number of patients

preferred the Diskus®

(67%) to the Handihaler

(33%) p<0.0013

Top 3 Criteria of an ideal

inhaler accdg to patients:

1. Being quick to use

2. Ease of use

3. Knowing how many

doses are left p<0.0013

3. Moore, AC. et al. Meeting the needs of patients with COPD: patients’ preference for the Diskus inhaler compared with the Handihaler. 2004, 58, 5, 444–450.

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The Prevention of Chronic Obstructive Pulmonary Disease Exacerbations by Salmeterol/Fluticasone

Propionate or Tiotropium Bromide Jadwiga A. Wedzicha1, Peter M. A. Calverley2, Terence A. Seemungal3, Gerry Hagan4, Zainab Ansari4, and Robert A. Stockley5, for the INSPIRE Investigators

INSPIRE STUDY: Seretide vs

Tiotropium

• INSPIRE: Investigating New Standards for Prophylaxis In Reduction of Exacerbations

• Duration = 2 years

• ITT = 1,323

• Scope = 179 centers, 20 countries

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INSPIRE: Study Endpoints

• Primary Objective

– To study the effect of Seretide vs Tiotropium in reducing the rate of healthcare utilisation COPD exacerbations over 104 weeks in subjects with severe COPD.

• Main Secondary Endpoints

– Rate of symptom-defined exacerbations

– Time to withdrawal

– Post-dose FEV1

• Main Other Endpoints Health Outcomes Safety

total exacerbation rate SGRQ Adverse events

DRC data AEs of special interest

TDI All-cause Mortality

Other lung function parameters

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SFC significantly improves quality of life vs tiotropium (INSPIRE)

0.038 (-4.02, -0.12) -2.07 (0.994) Visit 12 (wk 104)

0.030 (-3.88, -0.20) -2.04 (0.936) Visit 10 (wk 80)

0.019 (-3.81, -0.34) -2.07 (0.883) Visit 8 (wk 56)

0.021 (-3.55, -0.29) -1.92 (0.832) Visit 6 (wk 32)

p-value 95% CI Difference (SE) SFC vs Tio

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

55

-2

50

45

40

0 0 10 22 34 46 58 70 82 94 106

Time (weeks)

SGR

Q t

ota

l sco

res

(un

its)

Tiotropium 18 mg

SFC 50/500 mg

1. Wedzicha JA, et al. AJRCCM 2008; 177: 19-26

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SFC resulted in 52% reduction in

risk of dying vs. Tiotropium

On-treatment Comparison from Cox’s Proportional Hazards Model

Number at Risk

0 13 26 39 52 65 78 91 104

0

1

2

3

4

5

6

7

Pro

bab

ility

of

Eve

nt

(%)

Time to Event (Weeks)

656 560 531 510 494 477 456 445 160 SFC 664 548 502 475 451 435 416 398 141 TIO

52% reduction

P=0.012

Tiotropium

SFC

Wedzicha et al AJRCCM 2008; 177: 19

8

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Overall study conclusions

• First head to head study of two main pharmacological agents used for COPD.

• Novel methodology using two different measures of exacerbations.

• No differences demonstrated for exacerbation rate and lung function.

• Seretide significantly improves Health Status after optimisation and compared to Tio.

• Seretide significantly improves survival compared to tio.

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Salmeterol and Fluticasone Propionate and Survival in Chronic Obstructive Pulmonary Disease

Peter M.A. Calverley, M.D., Julie A. Anderson, M.A., Bartolome Celli, M.D., Gary T. Ferguson, M.D., Christine Jenkins, M.D.,Paul W. Jones, M.D., Julie C. Yates, B.S., and Jorgen Vestbo,

M.D., for the TORCH investigators*

The TORCH Survival Study

Affecting Mortality in COPD: Is the Dream Becoming a Reality?

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TORCH Study • TORCH is the first study to specifically investigate

the effect of pharmacotherapy on survival as an endpoint

• The most ambitious study in COPD ever completed

a first of its kind

large patient population

reliable and robust endpoints

potential to change disease management

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Reliable and robust endpoints

Primary

• To study the effect of salmeterol/fluticasone propionate (SFC) combination vs placebo on all-cause mortality over 3 years in patients with moderate to severe COPD

Secondary

• To study the effect of SFC on:

– moderate and severe exacerbation frequency

– Health Status (SGRQ)

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Objectives of TORCH Others

• Compare effect on all-cause mortality:

– Combination vs components

– Components vs placebo

• Compare effect on COPD related mortality:

– Between treatments

• Compare effect on COPD morbidity:

– Lung function

– Other exacerbation parameters

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6112 participants

TORCH in 42 countries

Worldwide participation

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2 week run-in*

TORCH: Study Design

SFC 500/50 bd

FP 500 bd

Salmeterol 50 bd

Placebo

Duration = 3 years

1,533

1,534

1,524

1,521

6112 patients

*All ICS and inhaled LABA discontinued before run-in.

ITT population FOR GSK INTERNAL TRAINING PURPOSES ONLY- NOT FOR EXTERNAL DISTRIBUTION

Study population - inclusion

• Established history of COPD (ERS definition)

• Aged 40-80 yrs inclusive

• Smoking history ≥ 10 pack years

• Reversibility < 10% in predicted FEV1

• Pre-bronchodilator FEV1 < 60% predicted

• Pre-bronchodilator FEV1/FVC ratio ≤ 70%

• Able to use Diskus/Accuhaler

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Study population - exclusion

• Current diagnosis of asthma or respiratory disorders

other than COPD (lung cancer, sarcoidosis, TB, lung

fibrosis)

• X-ray - indicating diagnosis other than COPD

• Had a LVRS or lung transplant

• Requirement for LTOT (> 12 hrs/day) at start of study

• Receiving long term oral corticosteroid therapy

• Other disease likely to cause death within 3 yrs

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RIP †

Outcomes of patients during TORCH

1 yr 2 yr 3 yr

Primary Endpoint of all cause death measured at end of 3 years Secondary Endpoints measured when on treatment (yellow only)

A

RIP B

Withdrew

Withdrew

C

D

Post withdrawal, patients allowed to take any medication.

As more patients in placebo withdrew, it became BIASED

against Seretide †

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Premature study drug discontinuation

Vertical bars represent standard errors

More placebo patients withdrawing = more potential

bias against Seretide: sicker patients tend to discontinue

and replace placebo with better medication, and the healthier patients tend to

remain

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Summary • Seretide significantly improved:

– FEV1 compared with components and placebo

– Health status compared with components and placebo

• Seretide significantly reduced:

– FEV1 decline

– Exacerbations compared with components or placebo

– Hospitalizations compared with placebo

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Mortality conclusions In the TORCH study:

• SFC reduced the risk of dying at any time during 3 years by 17.5% vs placebo

• The absolute risk reduction was 2.6%

• FP and SAL mortality was not different to placebo, but SFC was significantly better than FP

• Differences in mortality between SFC and placebo were driven by cardiovascular, pulmonary and ‘other’ causes of death

• COPD-related deaths and deaths-on-treatment showed a similar trend to the all-cause mortality for SFC vs placebo

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Safety conclusions • SFC was generally well tolerated over three years

• The anticipated local side effects of ICS were observed

• There was an increase in reporting of pneumonia in the FP containing arms. However, there was no increase in pneumonia mortality between SFC and placebo

• There was no significant difference in the probability of total or non-traumatic fractures between groups

• In the safety sub-study (n = 658), there were no differences in BMD or the number of patients developing cataracts between groups

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Mortality and Safety Summary

• SFC 50/500 improves survival vs placebo and FP

• SFC 50/500 is generally well tolerated over three years

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TORCH: Results Summary

• SFC 50/500, in COPD patients with FEV < 60%

– Improves survival vs placebo

– Significantly improves and maintains health status vs placebo and components

– Significantly reduces the rate of exacerbations vs placebo and components

– Significantly improves lung function vs placebo and components

– Has a safety profile generally consistent with previous studies

– Led to increased reporting of pneumonia, which did not compromise the overall benefits of SFC treatment

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Seretide on Exacerbations

TORCH (vs. Placebo and individual

components over 3 years)

INSPIRE (vs. Tiotropium over 2

years)

25%

43%

Reduction in the rate of moderate/severe

exacerbations over 3 years vs control (p<0.001)1

Reduction in the rate of exacerbations requiring

oral steroids over 3 years vs control (p<0.001)1

1. Calverley PM et al. N Engl J Med. 2007; 356: 775-89. 2. Wedzicha J et al. The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or

tiotropium bromide. American Journal of Respiratory Critical Care Medicine 2008; 177: 19-26

There was no significant difference in the annual

rate of exacerbations with Seretide® vs tiotropium (1.32 vs 1.28, p=0.656)2

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Seretide on Quality of Life and Mortality

TORCH (vs. Placebo and individual

components over 3 years)

INSPIRE (vs. Tiotropium over 2

years)

3.1

17.5%

3.1 unit improvement in the SGRQ (QoL) score for

patients. Seretide provided sustained improvements in

QoL score over 3 years 1

1. Calverley PM et al. N Engl J Med. 2007; 356: 775-89. 2. Wedzicha J et al. The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or

tiotropium bromide. American Journal of Respiratory Critical Care Medicine 2008; 177: 19-26

Seretide was significantly more effective at

improving health status of the patients (2.1 unit difference, p = 0.038) vs.

Tiotropium.2

2.1

Seretide reduced the risk of mortality at any time during 3 years by

17.5%1

52% Seretide provided a 52% relative risk reduction on

all-cause mortality to patients compared to

Tiotropium.2

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