# Presentation: 508794

## Efficacy and Safety Datafrom the Advair Diskus 500/50Clinical Program

**Katharine Knobil, MD**
**Vice President**
**Respiratory Clinical Development**

## Study Designs for 3 Pivotal Studiesfor Advair 500/50 in COPD

**Study Designs for 3 Pivotal Studies****for Advair 500/50 in COPD**

**	****SFCA3006****a****	****TRISTAN****b*********	****TORCH****c†**
**	****	****(SFCB3024)****	****(SCO30003)**
**	****N=674****	****N=1465****	****N=6112**
**Duration****	****6 months****	****1 year****	****3 years**
**	****Advair 500/50****	****Advair 500/50****	****Advair 500/50**
**Design****	****FP 500****	****FP 500****	****FP 500**
**	****SAL 50****	****SAL 50****	****SAL 50**
**	****Placebo****	****Placebo****	****Placebo**
** **
**Primary**
**Endpoint****	****FEV****1****	****FEV****1****	****All-Cause Mortality**

- *TRial of Inhaled STeroids ANd Long Acting ß2 Agonists
- †TOwards a Revolution in COPD Health
-  FP = Fluticasone Propionate
-  SAL = Salmeterol

- a Mahler et al. Am J Respir Crit Care Med 2002; 166:1084-1091.
- b Calverley et al. Lancet 2003; 361: 449-456.
- c Calverley et al. N Engl J Med 2007; 356: 775-789.

## Order of the Presentation

**Efficacy **
**Forced Expiratory Volume in 1 second (FEV****1****)**
**Health Related Quality of Life**
**Exacerbations**
**Mortality**
**Safety **
**Adverse Events of Special Interest**
**TORCH Safety Sub-study**
**Cardiovascular and HPA-axis assessments from pivotal studies**
**Benefit : Risk **

## Demographics and Baseline Characteristics from Pivotal Studies

- 	**SFCA3006****	****TRISTAN****	****TORCH**
**	****N=674****	****N=1465****	****N=6112**
**Age (y)**	64	63	65
**Males (%)**	66	72	76
**White (%)**	93	99	82
**Current smokers (%)**	48	51	43
**% predicted FEV****1**** (mean)**	40	45	40
**% predicted reversibility (mean)**	8	4	4

- Data on file. GlaxoSmithKline (SFCA3006, SFCB3024, SCO30003).

## Key Endpoints in the Advair 500/50 COPD Clinical Program

|  | SFCA3006
6 months | TRISTAN
1 year | TORCH
3 years |
| --- | --- | --- | --- |
| FEV1 |  |  |  |
| Health Related QoL |  |  |  |
| Exacerbation Rate |  |  |  |
| Mortality |  |  |  |

## Key Endpoints in the Advair 500/50 COPD Clinical Program

|  | SFCA3006
6 months | TRISTAN
1 year | TORCH
3 years |
| --- | --- | --- | --- |
| FEV1 |  |  |  |
| Health Related QoL |  |  |  |
| Exacerbation Rate |  |  |  |
| Mortality |  |  |  |

## Relevance of Measuring FEV1 in Patients with COPD

**In COPD, FEV****1 ****declines over time**
**Lower lung function is associated with poor outcomes, including mortality**
**FEV****1**** as an endpoint in COPD**
**Accepted, important, reproducible**
**Forms the basis of the indication of all drugs approved for COPD**

## Improvements in Trough FEV1* Seen with Advair 500/50 Over 6 Months– SFCA3006

**1**

**2**

**3**

**4**

**6**

**8**

**12**

**16**

**20**

**24**

**Endpoint**

**Improvements in Trough FEV****1********* Seen with Advair 500/50 Over 6 Months– SFCA3006**

**200**

**150**

**100**

**50**

**0**

**-50**

**Mean change in FEV****1**** (mL)**

*p*< 0.001 Advair vs Placebo at Endpoint

*p*< 0.04 Advair vs SAL and FP at Endpoint

- Adapted from Mahler et al. Am J Respir Crit Care Med 2002;166:1084-1091.

- *Primary Endpoint

- Note: Error bars are standard errors

## Improvements in Trough FEV1* Maintained with Advair 500/50 over 1 Year– TRISTAN

**Mean change in FEV****1**** (mL)**

**Improvements in Trough FEV****1********* Maintained with Advair 500/50 over 1 Year– TRISTAN**

*p*< 0.001 Advair vs Placebo over 52 weeks

**Advair 500/50**

**SAL**

**Placebo**

**FP**

**Time (weeks)**

*p*< 0.001 Advair vs SAL and FP over 52 weeks

- Adapted from Calverley, et al. Lancet 2003; 361: 449-456.

- *Primary Endpoint

- Note: Error bars are standard errors

## Improvements in Post Bronchodilator FEV1 with Advair 500/50 over 3 Years- TORCH

**Improvements in Post Bronchodilator FEV****1**** with Advair 500/50 over 3 Years- TORCH**

**Adjusted Mean Change FEV****1 ****(mL)**

- 0

- 24

- 48

- 72

- 96

- 120

- 156

**Time (Weeks)**

*p*< 0.001 Advair vs SAL and FP over 3 years

**Advair 500/50**

**SAL**

**Placebo**

**FP**

*p*< 0.001 Advair vs Placebo over 3 years

- Adapted from Calverley, et al. N Engl J Med 2007; 356: 775-789.

- Data on file, GlaxoSmithKline (SCO30003)

## Advair 500/50Improves Lung Function

**Consistent improvements in FEV****1**** seen in all 3 pivotal studies for Advair 500/50**
**Advair 500/50 significantly improved FEV****1**** compared with SAL, FP and placebo in all three studies**
**First time Advair 500/50 has shown an effect on rate of decline of FEV****1**

## Key Endpoints in the Advair 500/50 COPD Clinical Program

|  | SFCA3006
6 months | TRISTAN
1 year | TORCH
3 years |
| --- | --- | --- | --- |
| FEV1 |  |  |  |
| Health Related QoL |  |  |  |
| Exacerbation Rate |  |  |  |
| Mortality |  |  |  |

## Importance of Measuring Health Related QOL in Patients with COPD

**Important to measure impact of the disease and the effect of treatment**
**Health-related quality of life declines over time**
**Associated with poor outcomes **
**Exacerbation frequency and mortality**

## Advair 500/50 Improves Health Related QOL (SGRQ) Over 3 Years - TORCH

**Advair 500/50 Improves Health Related QOL (SGRQ) Over 3 Years - TORCH**

**-5**

**-4**

**-3**

**-2**

**-1**

**0**

**1**

**2**

**3**

**0**

**24**

**48**

**72**

**96**

**120**

**156**

**Improvement**

**Week**

**Adjusted Mean Change in**** SGRQ Total Score**

*p*< 0.001 Advair vs SAL over 3 years

*p*< 0.001 Advair vs Placebo over 3 years

*p* = 0.017 Advair vs FP over 3 years

- Vertical bars represent standard errors

- Calverley, et al. N Engl J Med 2007; 356: 775-789.

## Advair 500/50Improves Health Related QoL

**Consistent improvements seen in all 3 pivotal studies for Advair 500/50**
**Advair 500/50 significantly improved HRQoL compared with SAL, FP and placebo in all three studies**
**HRQoL maintained for 3 years**

## Key Endpoints in the Advair 500/50 COPD Clinical Program

|  | SFCA3006
6 months | TRISTAN
1 year | TORCH
3 years |
| --- | --- | --- | --- |
| FEV1 |  |  |  |
| Health Related QoL |  |  |  |
| Exacerbation
Rate |  |  |  |
| Mortality |  |  |  |

## Importance of Reducing Exacerbations

**COPD exacerbations are closely associated with symptomatic and physiological deterioration and impaired health status****1,2**
**Following a COPD exacerbation, the likelihood of further exacerbations increases****3**
**High rate of COPD exacerbations is associated with a rapid decline in lung function, increased risk of hospitalization****4,5****  and death****6**

- 1. Osman et al. Thorax 1997	2. Seemungal et al. Am J Respir Crit Care Med 1998
- 3. Seemungal et al. Am J Respir Crit Care Med 2000 	4. Donaldson et al. Thorax 2002
- 5. Garcia-Aymerich et al. Am J Respir Crit Care Med 	6. Soler-Cataluna et al. Thorax 2005
-     2001

## Definition of COPD Exacerbations in Pivotal Studies

**A worsening of symptoms serious enough to require change in management**
**Exacerbations were defined by treatment**
**Moderate: Requiring treatment with antibiotics and/or systemic corticosteroids**
**Severe: Requiring hospitalization**

## COPD Exacerbations in TRISTAN and TORCH

**Number of Moderate/Severe Exacerbations**
**1453 in TRISTAN (N = 1465, 1 year study)****	**
**13,389 in TORCH (N = 6112, 3 year study)****	**
**Rate was primary analysis of COPD exacerbations**
**Accounts for patients having multiple exacerbations**
**Accounts for varying time on treatment**

- Data on file. GlaxoSmithKline (SCO30003).

## Advair 500/50 Reduces the Rate of Moderate/Severe Exacerbations Over 1 Year- TRISTAN

- Data on file. GlaxoSmithKline (SFCB3024).
- Negative Binomial Model

**Advair****vs.****Placebo**

**Advair****vs.****FP**

**Advair****vs.****SAL**

**Placebo****	****1.47**
**SAL****	****1.09**
**FP****	****1.08**
**Advair****	****1.00**

**Annual Rate**

**Exacerbations (% reduction)**

*p*< 0.001 Advair vs Placebo*p* = NS for Advair vs components

**-35**

**-30**

**-25**

**-20**

**-15**

**-10**

**-5**

**0**

**7%**

**8%**

**32%**

## Advair 500/50 Reduces the Rate of Moderate/Severe Exacerbations Over 3 Years - TORCH

**Advair 500/50 Reduces the Rate of Moderate/Severe Exacerbations Over 3 Years - TORCH**

**Placebo****	****1.13**
**SAL****	****0.97**
**FP****	****0.93**
**Advair****	****0.85**

**Annual Rate**

**Advair****vs.****Placebo**

**Advair****vs.****FP**

**Advair****vs.****SAL**

**Exacerbations (% reduction)**

*p* = 0.002 Advair vs SAL

*p*< 0.001 Advair vs Placebo

*p* = 0.024 Advair vs FP

- Adapted from Calverley et al. N Engl J Med 2007; 356: 775-789.
- Negative Binomial Model

**-35**

**-30**

**-25**

**-20**

**-15**

**-10**

**-5**

**0**

**25%**

**9%**

**12%**

## Advair 500/50 Reduces the Rate of Exacerbations Requiring Systemic Corticosteroids - TORCH

**Advair 500/50 Reduces the Rate of E****xacerbations Requiring Systemic ****Corticosteroids - TORCH**

**Exacerbations (% reduction)**

**Placebo****	****0.80**
**SAL****	****0.64**
**FP****	****0.52**
**Advair****	****0.46**

**Annual Rate**

**Advair****vs.****Placebo**

**Advair****vs.****FP**

**Advair****vs.****SAL**

*p* < 0.001 Advair vs SAL

*p *< 0.001 Advair vs Placebo

*p* = 0.017 Advair vs FP

- Adapted from Calverley et al. N Engl J Med 2007; 356: 775-789.Negative Binomial Model

**-45**

**-40**

**-35**

**-30**

**-25**

**-20**

**-15**

**-10**

**-5**

**0**

**43%**

**13%**

**29%**

## Advair 500/50Reduced Rate of COPD Exacerbations

**Consistently reduced the rate of moderate and/or severe exacerbations**
**Significant vs SAL and FP in TORCH**
**Consistently reduced rate of exacerbations requiring systemic corticosteroids**
**Significant vs SAL and FP in TORCH**
**Advair 500/50 always provided the greatest benefit**

## Key Endpoints in the Advair 500/50 COPD Clinical Program

|  | SFCA3006
6 months | TRISTAN
1 year | TORCH
3 years |
| --- | --- | --- | --- |
| FEV1 |  |  |  |
| Health Related QoL |  |  |  |
| Exacerbation Rate |  |  |  |
| Mortality |  |  |  |

## External Committees Involved in Conduct of TORCH

**Steering Committee (SC)**
**Worked with sponsor to design, implement and manage the study**
**Clinical Endpoint Committee (CEC)**
**Independently reviewed all deaths, blinded to treatment **
**Assigned a primary cause of death and provided assessment of whether death was COPD-related**
**Safety and Efficacy Data Monitoring Committee**
**Conducted 2 planned interim analyses and**
**	****6-monthly safety reviews**

## TORCH: Study Design

**Ambitious study design**
**Over 400 centers, 42 countries, 6112 patients**
**All-cause mortality was the primary endpoint**
**COPD-related mortality assessed**
**3 years of follow up**
**Allowed COPD medications except long-acting bronchodilators, ICS, long-term systemic corticosteroids**

## Robust Assessment of Mortality 

**Conservative analysis of mortality**
**All patients were included in the primary analysis regardless of time spent on study treatment**
**Patients withdrawn early could take any treatment for COPD; analyzed by original treatment arm**
**Rigorous follow-up for 3 years, even if withdrawn from study medication**
**Only 1 patient of 6112 had unknown survival status at 3 years **

## More Patients Withdrew on Placebo Compared with Advair 500/50 

**More Patients Withdrew on Placebo Compared with Advair 500/50**** **

- Vertical bars represent standard errors

**44%**

**38%**

**36%**

**34%**

**Advair 500/50**

**SAL**

**Placebo**

**FP**

**Time to withdrawal (weeks)**

- Adapted from Calverley et al. N Engl J Med 2007;356: 775-789.

- **p*<0.001 vs. placebo
- †*p*=0.048 vs. SAL
- ‡*p*=0.010 vs. FP

- *†‡

- *

- *

## Advair 500/50 Reduced All-cause Mortality* Compared with Placebo

**Advair 500/50 Reduced All-cause Mortality* Compared with Placebo**

- 0

- 12

- 24

- 36

- 48

- 60

- 72

- 84

- 96

- 108

- 120

- 132

- 144

- 156

**Time to Death (Weeks)**

**Probability of Death (%)**

**15.2%**

- Adapted from Calverley et al. N Engl J Med 2007; 356: 775-789.

## Advair 500/50 Reduced All-cause Mortality* Compared with Placebo

**Advair 500/50 Reduced All-cause Mortality* Compared with Placebo**

- 0

- 12

- 24

- 36

- 48

- 60

- 72

- 84

- 96

- 108

- 120

- 132

- 144

- 156

**Time to Death (Weeks)**

**Probability of Death (%)**

**15.2%**

**12.6%**

**2.6%**

**17.5% risk reduction**

- Adapted from Calverley et al. N Engl J Med 2007; 356: 775-789.

## Pre-Specified Supporting Analyses for All-cause Mortality

**Placebo**

**0.811**

**(0.670, 0.982)**

**18.9%**

**0.031**

***p*****-value**

**Risk**
**Reduction**

**95% CI**

**Hazard****Ratio**

**Pre-Specified Supporting Analyses for All-cause Mortality**

**1**Cox’s Proportional Hazards Model adjusted for smoking status, age, sex, region,
- baseline FEV1 and BMI
**2** Log Rank analysis stratified by smoking status, country and participation in safety sub-study.

**Log**
**Rank****2**

**0.815**

**(0.673, 0.987)**

**18.5%**

**0.036**

**Cox’s**
**Proportional****1**

- Adapted from Calverley et al. N Engl J Med 2007; 356: 775-789.

## All-cause Mortality Over 3 years

**15.2%**

**12.6%**

**Probability of Death (%)**

**Advair 500/50**

**SAL**

**Placebo**

**FP**

- Vertical bars represent standard errors

- Adapted from Calverley et al. N Engl J Med 2007; 356: 775-789.

## All-cause Mortality Over 3 years

**All-cause Mortality Over 3 years**

**15.2%**

**12.6%**

**Probability of Death (%)**

**Advair 500/50**

**SAL**

**Placebo**

**FP**

**16.0%**

**13.5%**

- Vertical bars represent standard errors

- Adapted from Calverley et al. N Engl J Med 2007; 356: 775-789.

## All-cause Mortality at 3 Years

**All-cause Mortality at 3 Years**

- Hazard Ratio	  95% CI	*p*-value

- SAL vs Placebo	0.879	(0.73, 1.06)	0.180
- FP vs Placebo	1.060	(0.89, 1.27)	0.525
- Advair vs SAL	0.932	(0.77, 1.13)	0.481
- Advair vs FP	0.774	(0.64, 0.93)	0.007

- Adapted from Calverley et al. N Engl J Med 2007; 356: 775-789.

## All-cause Mortality:Interactions with Treatment

**No statistically significant interactions of treatment with**
**Age**
**Smoking status**
**Region**
**Baseline %predicted FEV****1**** (Gold stages)**
**Sex**
**Ethnic Origin**
**BMI**
**i.e. no evidence of difference in treatment effect**

- Calverley et al. N Engl J Med 2007; 356: 775-789. Data on file. GlaxoSmithKline (SCO30003).

## All-cause Mortality by Age –ITT Population

**Probability of death in 156 weeks (%)**

**n=701**

- Data on file GlaxoSmithKline (SCO30003)

**n=1972**

**n=2670**

**n=769**

**Age in Years**

## Hazard Ratio by Excluded Country

**Hazard Ratio by Excluded Country**

- Hazard Ratio

- Excluded Country

- 0.7

- 0.75

- 0.8

- 0.85

- 0.9

- 0.95

- 1

- Argentina
- Australia
- Austria
- Belgium
- Brazil
- Bulgaria
- Canada
- Chile
- China
- Croatia
- Czech Republic
- Denmark
- Estonia
- Finland
- France
- Germany
- Greece
- Hong Kong
- Hungary
- Iceland
- Italy
- Latvia
- Lithuania
- Malaysia
- Mexico
- Netherlands
- New Zealand
- No Excluded Country
- Norway
- Philippines
- Poland
- Romania
- Russia
- Singapore
- Slovakia
- South Africa
- Spain
- Sweden
- Taiwan
- Thailand
- USA
- Ukraine
- United Kingdom

## Role of Clinical Endpoint Committee

**Adjudication of primary cause of death**
**Determination of whether COPD related**
**COPD primary cause of death **_***or***_
**Terminal event was hypercapnic respiratory failure or failure to be liberated from a ventilator **_***or***_
**Patient would probably have survived terminal event if COPD not present**

- McGarvey et al. Thorax 2007; 62:411-415.

## Primary Cause of DeathAdjudicated by CEC

**Primary Cause of Death****Adjudicated by CEC**

**	****Placebo****	****SAL****	****FP****	****Advair**
**N=****	****1524****	****1521****	****1534****	****1533**
**All deaths****	****231****	****205****	****246****	****193**
- Cardiovascular	71	45	61	60
- Pulmonary	74	80	91	61
- Cancer	45	44	51	44
- Other	23 	22	30	11
- Unknown	18	14	13 	17

- Adapted from Calverley et al. N Engl J Med 2007; 356: 775-789.

## Primary Cause of Death: Pulmonary Adjudicated by CEC

**	****Placebo****	****SAL****	****FP****	****Advair**
**N=****	****1524****	****1521****	****1534****	****1533**
**Pulmonary****	****74****	****80****	****91****	****61**
-    COPD	60	64	67	43
-    Pneumonia	13	15	21	15
-    Pulmonary embolism	0	0	0	2
-    Other	1	1	3	1

- Data on file. GlaxoSmithKline (SCO30003).

## COPD-Related Mortality by 3 Years

**COPD-Related Mortality by 3 Years**

**6.0%**

**4.7%**

**Probability of Death (%)**

- Vertical bars represent standard errors

**22.4% risk reduction**

- Adapted from Calverley et al. N Engl J Med 2007; 356: 775-789.

## COPD-Related Mortality by 3 Years

**COPD-Related Mortality by 3 Years**

**6.0%**

**4.7%**

**6.9%**

**6.1%**

**Probability of Death (%)**

- Vertical bars represent standard errors

- Adapted from Calverley et al. N Engl J Med 2007; 356: 775-789.

## Advair 500/50Mortality Summary

**Advair demonstrated 17.5% reduction in risk of dying over 3 years versus placebo (*****p*****=0.052)**
**Two additional analyses of all-cause mortality supported the magnitude of the treatment effect (18.9% and 18.5%)**
**COPD-related mortality showed a similar trend to all-cause mortality**
**Conservative estimate of treatment effect**

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

## Consistent Benefits ofAdvair 500/50 Clinical Program

|  | SFCA3006
6 months | TRISTAN
1 year | TORCH
3 years |
| --- | --- | --- | --- |
| Improved FEV1 |  |  |  |
| Improved Health Related QoL |  |  |  |
| Reduced Exacerbation Rate |  |  |  |
| Reduced Mortality |  |  |  |

****

## Safety Profile of Advair 500/50 in Patients with COPD

## Safety Assessments

**Adverse Event Reporting **
**AEs of Special Interest (for FP-containing arms)**
**Cardiovascular Adverse Events****(for SAL-containing arms)**
**Prospective Safety Assessments**
**TORCH US Safety Sub-study**
**Cardiovascular and HPA-axis assessments from pivotal studies**

## Time on Study Medication - TORCH 

- 	**Placebo****	****SAL****	****FP****	****Advair 500/50**
**N =****	****1544****	****1542****	****1552****	****1546**
**Total Treatment**
- Time on treatment (years)	3278	3531	3555	3700
- Increased time on Treatment		8%	8%	13%
- (Compared with Placebo)

- Calverley et al. N Engl J Med 2007; 356: 775-789.Data on file. GlaxoSmithKline (SCO30003).

## Adverse Events of Special Interest During Treatment

**	****Placebo****	****SAL****	****FP****	****Advair 500/50**
**N =**** ****	****1544****	****1542****	****1552****	****1546**
**LRTIs**
**   ****Number of patients (%)****	****304 (20)****	****322 (21)****	****380 (24)****	****446 (29)**
**Bone disorders**
**   ****Number of patients (%)****	****77 (5)****	****85 (6)****	****90 (6)****	****105 (7)**
**Eye disorders**
**   ****Number of patients (%)****	****38 (2)****	****50 (3)****	****48 (3)****	****63 (4)**
**HPA axis disorders****	**
**   ****Number of patients (%)****	****2 (<1)****	****0 ****	****2 (<1)****	****0**

**Adverse Events of Special Interest During Treatment**

- Data on file. GlaxoSmithKline (SCO30003).

## Adverse Events of Pneumonia

**Adverse Events of Pneumonia**

**	****Placebo****	****SAL****	****FP****	****Advair 500/50**
**N=****	****1544****	****1542****	****1552****	****1546**
**Pneumonia terms**
**Patients with AEs (%)****	****139 (9)****	****162 (11)****	****224 (14)****	****248 (16)**
**Events / 1000 treatment years****	****52 ****	****52 ****	****84****	****88 **
**	**
**Patients with SAEs (%)****	****86 (6)****	****99 (6)****	****150 (10)****	****157 (10)**
**Events / 1000 treatment years****	****30****	****30****	****52****	****55**

- Note: Adverse events occurring on treatment

- Data on file. GlaxoSmithKline (SCO30003).

## Time to First Pneumonia Event

**Time to First Pneumonia Event**

**12.3**

**13.3**

**18.3**

**19.6**

**Probability of Pneumonia (%)**

**Advair 500/50**

**SAL**

**Placebo**

**FP**

**Time to Pneumonia (weeks)**

- Data on file. GlaxoSmithKline (SCO30003). Vertical bars represent standard errors

## Fatal Adverse Events of Pneumonia

**Fatal Adverse Events of Pneumonia**

- 	**Placebo****	****SAL****	****FP****	****Advair 500/50**
**N=****	****1544****	****1542****	****1552****	****1546**
**Pneumonia terms**
**Patients with fatal SAEs****	****10 ****	****11****	****15****	****12**
**Rate/1000 treatment years****	****3.1****	****3.1****	****4.2****	****3.2**
**CEC 1° cause of death**** **
**On treatment****	****7****	****9****	****13****	****8**

- Note: Adverse events occurring on treatment

- Data on file. GlaxoSmithKline (SCO30003).

## Evaluation of the IncreasedRisk of Pneumonia

**Patients at greatest risk in all treatment arms**
**FEV****1**** <30 percent predicted **
**Male **
**Older (>65 years)**
**Lower BMI (<25 kg/m****2****) **
**Risk factors are the same regardless of treatment group**
**No other specific predisposing factors determined for those in ICS treatment groups**
**Ongoing observational studies**
**Three studies evaluating natural history of pneumonia**
**Two studies to measure risk associated with use of Advair (including effect of dose and duration)**

## Pneumonia Summary

**Increased risk in patients receiving Advair**
**Seen in setting of reduced exacerbation rates, reduced hospitalizations and improved survival**
**No increase in pneumonia-related mortality with Advair versus placebo**
**Pneumonias were a subset of exacerbations**
**Labeling**
**Included in current labeling**
**Expanded in proposed labeling**
**Included in proposed medication guide**

## Adverse Events of Bone Fracture

**	****	****Placebo****	****SAL****	****FP****	****Advair 500/50**
**	****N=****	****1544****	****1542****	****1552****	****1546**
**Patients with fracture ****	****4%****	****4%****	****4%****	****5%**
**Fracture Event Rate **
**per 1000 treatment years**** ****	****19****	****20****	****20****	****22**
**	**

- Note: Patients can have multiple bone fractures.

- Data on file. GlaxoSmithKline (SCO30003).

## Adverse Events of Eye Disorder

**	****	****Placebo****	****SAL****	****FP****	****Advair 500/50**
**	****N=****	****1544****	****1542****	****1552****	****1546**
**Patients with Eye Disorder ****	****2%****	****3%****	****3%****	****4%**
**Eye Disorder Event Rate **
**per 1000 treatment years**** ****	****14****	****18****	****16****	****19**
**	**

- Data on file. GlaxoSmithKline (SCO30003).

## Prospective Evaluation of Long-term Safety of FP – TORCH Sub-study

**88 sites in the US; 658 patients**
**Annual Assessments**
**Bone mineral density **
**Ophthalmic exams**
**All patients required to perform assessments **

## High Prevalence of Osteoporosis/Osteopenia at Baseline – Total Hip 

**High Prevalence of Osteoporosis/Osteopenia ****at Baseline – Total Hip **

**161**

**162**

**158**

**162**

**N =**

**M**

**F**

**F**

**F**

**F**

**M**

**M**

**M**

**F = female     M = male**

- Data on file. GlaxoSmithKline (SCO30003).

**Patients (percent)**

## Percent Change in Total Hip BMD

**Percent Change in Total Hip BMD**

- Vertical bars represent standard errors

**Adjusted Mean Change (percent)**

- 0

- 48

- 108

- 158

**-5**

**-4**

**-3**

**-2**

**-1**

**1**

**0**

**Time (weeks)**

**Number**
**of**
**Patients**

**161****	****87****	****72****	****52****	****Placebo**
**162****	****105****	****82****	****78****	****SAL**
**158****	****112****	****80****	****65****	****FP**
**162****	****118****	****95****	****82****	****Advair**

- Data on file. GlaxoSmithKline (SCO30003).

## High Prevalence of Cataracts at Baseline

**High Prevalence of Cataracts at Baseline**

**N =****	****164****	****166****	****163****	****165**

**Patients (percent)**

- Data on file. GlaxoSmithKline (SCO30003).

## Ocular Assessments - Cataracts

**Ocular Assessments - Cataracts**

**	****	****Placebo****	****SAL****	****FP****	****Advair**
**	****	****	****	****	****500/50**
**N =****	****164****	****166****	****163****	****165**
**Patients with cataracts** 	**105 (64)****	****118 (71)****	****105 (64)****	****101 (61)     ****at baseline (percent)**
- 		**n=47****	****n=41****	****n=47****	****n=53 **
**Developed cataracts (percent)****	****10 (21)****	****6 (15)****	****8 (17)****	****14 (26)**
**Events/1000 treatment years****	****108****	****65****	****72****	****94**

- Data on file. GlaxoSmithKline (SCO30003).

## Ocular Assessments -  Glaucoma

**Ocular Assessments -  Glaucoma**

**	****	****Placebo****	****SAL****	****FP****	****Advair**
**	****	****	****	****	****500/50**
**N =****	****164****	****166****	****163****	****165**
**Patients with glaucoma** 	**9 (5)****	****9 (5)****	****8 (5)****	****14 (8)****	****     ****at baseline (percent)**
- 		**n=125****	****n=139****	****n=130****	****n=131 **
**Developed glaucoma (percent)****	****2 (2)****	****0****	****6 (5)****	****3 (2)**
**Events/1000 treatment years****	****7****	****0****	****20****	****9**

- Data on file. GlaxoSmithKline (SCO30003).

## HPA Axis Monitoring

**TORCH - 12-hour serial serum cortisol****1**
**~ 20% reduction compared with placebo **
**TRISTAN - 24-hour urine cortisol****1**
**~ 20% reduction compared with placebo **
**SFCA3006 - Short ACTH stimulation test****2**
**Incidence of abnormal short ACTH stimulation tests was similar across all treatment groups**

- 1Data on file. GlaxoSmithKline (SFCB3024, SCO30003).
- 2Mahler et al. Am J Respir Crit Care Med 2002; 166:1084-1091.

## Cardiac Safety 

**No increase of QTc prolongation or arrhythmias in SAL-containing treatment groups**
**No difference**** in incidence of ventricular ectopic events and changes in ECG rates across treatment groups**
**No increase in cardiac adverse event reporting**

- Data on file. GlaxoSmithKline (SFCA3006, SFCB3024, SCO30003).

## Benefit/Risk Profile ofAdvair 500/50 in Patients with COPD

## Benefit/Risk Profile forAdvair 500/50 in COPD

**Potential Risks**
**HPA - axis**
**No clinically significant suppression**
**No increase in events in the clinical program**
**Cardiac Effects **
**No increase in events in the clinical program**
**Bone and Eye Effects**
**No clinically relevant differences **
**Pneumonia**
**Increased reporting of pneumonia**
**No increased mortality from pneumonia**
**Labeling has detailed info for patients & physicians**

- Data on file. GlaxoSmithKline (SFCA3006, SFCB3024, SCO30003).

## Benefit/Risk Profile forAdvair 500/50 in COPD

**Benefits**
**Lung Function **
**Improvement vs Placebo, FP and SAL**
**Health-Related Quality of Life**
**Improvement vs Placebo, FP and SAL**
**Exacerbation Rate**
**Reduction vs Placebo, FP and SAL**
**Survival**
**17.5% reduction in all-cause mortality vs Placebo**

- Data on file. GlaxoSmithKline (SFCA3006, SFCB3024, SCO30003).

## Proposed Indication

***“******ADVAIR DISKUS 500/50 is indicated for the twice-daily maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), which includes chronic bronchitis and emphysema, and to increase survival and reduce exacerbations in patients with forced expiratory volume in 1 second (FEV******1******) <60% of predicted.”***